2020

January

Date: 10 January 2020

Time: 09:30 am

Place: Gonda 2nd Floor Conference Room

Speaker: Cory Inman

Title: “Modulation of Emotion and Memory via Direct Brain Stimulation in Humans: From the Laboratory into the Wild”

Abstract: The experience of emotion shapes how our memories are formed. A key structure involved in both the experience of emotion and the prioritization of emotional experiences into memory is the amygdala. In this talk, I’ll describe recent work that demonstrates the effects of direct electrical stimulation to the human amygdala on emotional experience and long‐term declarative memory. We tested whether brief electrical stimulation to the amygdala could enhance declarative memory for specific images of neutral objects without eliciting a subjective emotional response. Epilepsy patients undergoing monitoring of seizures via intracranial depth electrodes viewed a series of neutral object images, many of which were paired with brief, low amplitude electrical stimulation to the amygdala. Amygdala stimulation elicited no subjective emotional response yet led to reliably improved memory. Neuronal oscillations in the amygdala, hippocampus, and perirhinal cortex during this next‐day memory test indicated that a neural correlate of the memory enhancement was increased theta and gamma oscillatory interactions between these regions. These results show that the amygdala can initiate endogenous memory prioritization processes in the absence of emotional input, addressing a fundamental question and opening a path to future therapies.

Relevant Paper(s): https://www.pnas.org/content/pnas/115/1/98.full.pdf https://www.sciencedirect.com/science/article/pii/S002839321830112X

2019

Abstract: Memories get consolidated into long term storage through a dialogue between the hippocampus and the neocortex; most of this dialogue happens during sleep. It is thought that ripple events, where ensembles of hippocampal neurons that were active during experience synchronously fire in subsequent sleep, play a crucial role in propagating memories to the cortex during slow wave sleep. Slow wave sleep consists of alternating epochs of loosely termed "up" states, characterized by neural activity, and "down" states, characterized by relative inactivity. Hippocampal- cortical dialogue is thought to occur during the active "up" states, while "down" states are believed to represent intermittent periods of rest, where the network can recover from synaptic fatigue. A new paper by Todorova and Zugaro in Science challenges this view and demonstrates that a small number of spikes are fired during the "down" states, and that these spikes, termed "delta spikes" by the authors, play a crucial role in memory consolidation. Specifically, the authors show that cortical cells involved in learning a spatial task subsequently form cell assemblies during the "down" states in response to hippocampal ripples. They conclude that the "down" states represent isolated cortical computations that are tightly related to ongoing information processing, and play a crucial role in memory consolidation. I will review this paper and related papers, and will present some results from our lab involving computational modeling of cortical circuits during slow wave sleep that could give insight into the origin of these "delta" spikes and how it relates to hippocampal-cortical dialogue.

Relevant Paper(s): https://science.sciencemag.org/content/366/6463/377.abstract

October

Date: 25 October 2019

Time: 09:30 am

Place: Gonda 2nd Floor Conference Room

Speaker: Gary Sean Escola

Title: “Practice makes (too) perfect: Hebbian learning and the persistence of overly trained behaviors in subcortical circuits?”

Abstract: Over a century of work in experimental psychology and neuroscience has shown that the recall of memories and the performance of learned behaviors are determined by two principal variables: recency and practice. In this work, we develop a bottom-up and mechanistic understanding of the interplay between these variables in sequentially learned memories and behaviors. To do this, we begin by modeling sequential learning in a single neuron performing classification of random input patterns, and derive a mathematical expression for the neuron's forgetting curve, which quantifies the loss of old information as new information is learned. Because this simple model is unable to address the effects of practice during learning, however, we augment it with a second input pathway consisting of synaptic weights that are modified with associative Hebbian learning, leading to a generalized forgetting curve that additionally depends on the number of times that each pattern is repeated during training. In this model, patterns that are repeated multiple times during training become far more resistant to being overwritten, with near perfect recall long after patterns that are presented only once have been forgotten. We show that this is also true in a more elaborate neural network trained with reinforcement learning to perform a sequentially learned navigation task. Furthermore, due to the slow Hebbian learning in the second pathway, the signals from the two pathways gradually become aligned with one another through repeated practice, driving downstream units in similar ways. By this mechanism, control of the downstream population is gradually passed from a fast, flexible pathway with reward-based learning to a slow, robust pathway with associative learning. We suggest a neurobiological interpretation of this model, identifying the fast input with cortex, the slow input with thalamus, and the downstream population with striatum, the major locus of reinforcement learning in the brain. This interpretation provides a quantitative framework for understanding the formation of habits and the transfer of control from cortical to subcortical circuits as behaviors become automatized through extended practice.

Date: 11 October 2019

Time: 09:30 am

Place: Gonda 2nd Floor Conference Room

Speaker: Dean Buonomano

Title: “What does it mean to "understand" how a neural circuit computes?”

Abstract: The brain has the ability to flexibly perform many tasks, but the underlying mechanism cannot be elucidated in traditional experimental and modeling studies designed for one task at a time. Here, we trained single network models to perform 20 cognitive tasks that depend on working memory, decision making, categorization, and inhibitory control. We found that after training, recurrent units can develop into clusters that are functionally specialized for different cognitive processes, and we introduce a simple yet effective measure to quantify relationships between single-unit neural representations of tasks. Learning often gives rise to compositionality of task representations, a critical feature for cognitive flexibility, whereby one task can be performed by recombining instructions for other tasks. Finally, networks developed mixed task selectivity similar to recorded prefrontal neurons after learning multiple tasks sequentially with a continual-learning technique. This work provides a computational platform to investigate neural representations of many cognitive tasks.

Relevant Paper(s): https://www.nature.com/articles/s41593-018-0310-2

Date: 4 October 2019

Time: 09:30 am

Place: Gonda 2nd Floor Conference Room

Speaker: Giselle Fernandes

Title: “REM sleep–active MCH neurons are involved in forgetting hippocampus-dependent memories”

Abstract: The neural mechanisms underlying memory regulation during sleep are not yet fully understood. We found that melanin concentrating hormone–producing neurons (MCH neurons) in the hypothalamus actively contribute to forgetting in rapid eye movement (REM) sleep. Hypothalamic MCH neurons densely innervated the dorsal hippocampus. Activation or inhibition of MCH neurons impaired or improved hippocampus-dependent memory, respectively. Activation of MCH nerve terminals in vitro reduced firing of hippocampal pyramidal neurons by increasing inhibitory inputs. Wake- and REM sleep– active MCH neurons were distinct populations that were randomly distributed in the hypothalamus. REM sleep state–dependent inhibition of MCH neurons impaired hippocampus-dependent memory without affecting sleep architecture or quality. REM sleep–active MCH neurons in the hypothalamus are thus involved in active forgetting in the hippocampus.

Relevant Paper(s): https://science.sciencemag.org/content/365/6459/1308

September

Date: 27 September 2019

Time: 09:30 am

Place: Gonda 2nd Floor Conference Room

Speaker: Maria Geffen

Title: “Cortical circuits for dynamic auditory perception”

Abstract: Auditory perception is shaped by the interaction of sensory inputs with our experiences, emotions, and cognitive states. Decades of research have characterized how neuronal response properties to basic sounds, such as tones or whistles, are transformed in the auditory pathway of passively listening subjects. Much less well-understood is how the brain creates a perceptual representation of a complex auditory scene, i.e., one that is composed of a myriad of sounds, and how this representation is shaped by learning and experience. Over the last six years, our laboratory has made transformative progress in the quantitative understanding of neuronal circuits supporting dynamic auditory perception, through a combination of behavioral, electrophysiological, optogenetic and computational approaches.

June

Date: 14 June 2019

Time: 09:30 am

Place: Gonda 2nd Floor Conference Room

Speaker: Caitlin Aamodt

Title: “Pharmacological or genetic reduction of miR-128 enhances learned vocal communication”

Abstract: Learned vocal communication requires experience-dependent changes to a cortio-striato-thalamic circuit during a developmental critical period. Previously our lab generated an activity-dependent gene regulation network in the adult songbird striatopallidal song nucleus Area X to identify master regulators of singing behavior. Using this dataset we discovered that two of the genes most highly correlated to singing are the host genes for miR-128. Brain-enriched miR-128 peaks in adulthood in songbirds and humans, suggesting a role in constraining juvenile plasticity. Additionally, autism risk genes are enriched in miR-128 targets, and this microRNA is aberrantly upregulated in postmortem tissue from autism patients. Given its relevance to the disorder, miR-128 may be a viable target for therapeutic development.

In vitro studies have shown that a bioactive glycoside found in the cognitive enhancer ginseng, ginsenoside Rh2 (GRh2), modulates miR-128 levels. We hypothesized that GRh2 would rescue communication deficits in songbirds. First we isolated zebra finches during the critical period for vocal learning to generate adults with impaired song. Well after the normal critical period closure, isolated birds were returned to their parental home cage and treated daily with oral GRh2 (10mg/kg) or vehicle for four weeks. Birds that received GRh2 organized their syllables into stable sequences, whereas vehicle alone failed to enhance syllable sequencing. We next used a siRNA sponge designed to decrease miR-128 levels in Area X during the critical period for song learning. Bilateral injection of the targeting siRNA construct into Area X was sufficient to enhance learned vocal sequencing in young songbirds relative to scramble controls. During the final phase of this project we will knock down miR-128 in Area X of adult social isolates to determine whether decreased miR-128 is sufficient to recapitulate the therapeutic effects of GRh2 on birds with vocal communication deficits. These results suggest that the molecular mechanisms underlying speech and language can be pharmacologically and genetically targeted to accelerate the development of novel therapeutics for disorders like autism and intellectual disability.

Relevant Paper(s):

https://www.sciencedirect.com/science/article/pii/S0896627312000463

https://elifesciences.org/articles/30649

Date: 7 June 2019

Time: 09:30 am

Place: Gonda 2nd Floor Conference Room

Speaker: Yang Shen

Title: “Distinct hippocampal engrams control extinction and relapse of fear memory”

Abstract: Learned fear often relapses after extinction, suggesting that extinction training generates a new memory that coexists with the original fear memory; however, the mechanisms governing the expression of competing fear and extinction memories remain unclear. We used activity-dependent neural tagging to investigate representations of fear and extinction memories in the dentate gyrus. We demonstrate that extinction training suppresses reactivation of contextual fear engram cells while activating a second ensemble, a putative extinction engram. Optogenetic inhibition of neurons that were active during extinction training increased fear after extinction training, whereas silencing neurons that were active during fear training reduced spontaneous recovery of fear. Optogenetic stimulation of fear acquisition neurons increased fear, while stimulation of extinction neurons suppressed fear and prevented spontaneous recovery. Our results indicate that the hippocampus generates a fear extinction representation and that interactions between hippocampal fear and extinction representations govern the suppression and relapse of fear after extinction.

Abstract: Memory is coded by patterns of neural activity in distinct circuits. Therefore, it should be possible to reverse engineer a memory by artificially creating these patterns of activity in the absence of sensory experience. In olfactory conditioning, an odor conditioned stimulus (CS) is paired with an unconditioned stimulus (US; for example, a footshock), and the resulting CS-US association guides future behavior. Here we replaced the odor CS with optogenetic stimulation of a specific olfactory glomerulus and the US with optogenetic stimulation of distinct inputs into the ventral tegmental area that mediates either aversion or reward. In doing so, we created a fully artificial memory in mice. Similarly to a natural memory, this artificial memory depended on CS-US contingency during training, and the conditioned response was specific to the CS and reflected the US valence. Moreover, both real and implanted memories engaged overlapping brain circuits and depended on basolateral amygdala activity for expression.

Relevant Paper(s): https://www.nature.com/articles/s41593-019-0389-0#MOESM1

which integrates methods and approaches from these previous papers:

https://www.nature.com/articles/nature11527

https://www.nature.com/articles/nn.4104

https://www.nature.com/articles/nn.3519

Date: 10 May 2019

Time: 09:30 am

Place: Gonda 2nd Floor Conference Room

Speaker: Radhika Palkar

Title: “Multi-sensory Gamma Stimulation Ameliorates Alzheimer’s-Associated Pathology and Improves Cognition”

Abstract: We previously reported that inducing gamma oscillations with a non-invasive light flicker (gamma entrainment using sensory stimulus or GENUS) impacted pathology in the visual cortex of Alzheimer’s disease mouse models. Here, we designed auditory tone stimulation that drove gamma frequency neural activity in auditory cortex (AC) and hippocampal CA1. Seven days of auditory GENUS improved spatial and recognition memory and reduced amyloid in AC and hippocampus of 5XFAD mice. Changes in activation responses were evident in microglia, astrocytes, and vasculature. Auditory GENUS also reduced phosphorylated tau in the P301S tauopathy model. Furthermore, combined auditory and visual GENUS, but not either alone, produced microglial-clustering responses, and decreased amyloid in medial prefrontal cortex. Whole brain analysis using SHIELD revealed widespread reduction of amyloid plaques throughout neocortex after multi-sensory GENUS. Thus, GENUS can be achieved through multiple sensory modalities with wide-ranging effects across multiple brain areas to improve cognitive function.

Relevant Paper(s): https://www.sciencedirect.com/science/article/pii/S0092867419301631

Date: 3 May 2019

Time: 09:30 am

Place: Gonda 2nd Floor Conference Room

Speaker: Megha Sehgal

Title: “Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation”

Abstract: The neurobiological mechanisms underlying the induction and remission of depressive episodes over time are not well understood. Through repeated longitudinal imaging of medial prefrontal microcircuits in the living brain, we found that prefrontal spinogenesis plays a critical role in sustaining specific antidepressant behavioral effects and maintaining long-term behavioral remission. Depression-related behavior was associated with targeted, branch-specific elimination of postsynaptic dendritic spines on prefrontal projection neurons. Antidepressant-dose ketamine reversed these effects by selectively rescuing eliminated spines and restoring coordinated activity in multicellular ensembles that predict motivated escape behavior. Prefrontal spinogenesis was required for the long-term maintenance of antidepressant effects on motivated escape behavior but not for their initial induction.

Relevant Paper(s): https://science.sciencemag.org/content/364/6436/eaat8078

April

Date: 26 April 2019

Time: 09:30 am

Place: Gonda 2nd Floor Conference Room

Speaker: Joung-Hun Kim

Title: “ Dopamine Receptors in Accumbal Cholinergic Interneurons for Susceptibility to Cocaine Seeking”

Abstract: We are much interested in cellular & molecular mechanisms underlying memory persistence and the ongoing modification. Out of them, we have carried out experiments to parse cellular mechanisms underlying sustained seeking behaviors that would arise after repeated usage of psychostimulants such as cocaine. We first attempted to assess and quantify the seeking behavior of mice under progressive ratio schedule of cocaine self-administration, which enabled us to divide subject animals into two groups: susceptible mice that exhibited craving behaviors to cocaine infusion and resilient ones that did not show compulsive cocaine seeking. Striatal cholinergic interneurons (ChINs) play critical roles in processing of reward-related information, mainly by controlling the medium spiny neurons (MSNs) of the nucleus accumbens (NAc). We found that in vivo activity of accumbal ChINs was increased by cocaine injection in drug-naïve and resilient mice, but it was different to cocaine in susceptible mice. Cell-type-specific RNA sequencing of striatal regions from susceptible and resilient mice, produced a number of DEGs between two groups. Our transcriptome and physiological analyses indicated that ChINs in the NAc displayed higher abundance of dopamine D2 receptor (DrD2) in the susceptible mice, compared to those in the resilient animals. A series of experiments revealed substantial evidence that increased abundance of DrD2 at ChiNs is necessary and sufficient for occurrence of susceptibility traits to cocaine infusion. Collectively, our data provide novel mechanistic insights into the susceptibility to cocaine addiction and ultimately contribute to the development and refinement of therapeutic interventions to these types of disorders.

Relevant Paper(s):

https://www.sciencedirect.com/science/article/pii/S0006322311000618?via%3Dihub

http://www.jneurosci.org/content/37/45/10867.long

Date: 19 April 2019

Time: 09:30 am

Place: Gonda 2nd Floor Conference Room

Speaker: David Glanzman

Title: “Early life experience drives structural variation of neural genomes in mice”

Abstract: The brain is a genomic mosaic owing to somatic mutations that arise throughout development. Mobile genetic elements, including retrotransposons, are one source of somatic mosaicism in the brain. Retrotransposition may represent a form of plasticity in response to experience. Here, we use droplet digital polymerase chain reaction to show that natural variations in maternal care mediate the mobilization of long interspersed nuclear element-1 (LINE-1 or L1) retrotransposons in the hippocampus of the mouse brain. Increasing the amount of maternal care blocks that accumulation of L1. Maternal care also alters DNA methylation at YY1 binding sites implicated in L1 activation and affects expression of the de novo methyltransferase DNMT3a. Our observations indicate that early life experience drives somatic variation in the genome via L1 retrotransposons.

Relevant Paper(s): https://science.sciencemag.org/content/359/6382/1395.abstract

Date: 12 April 2019

Time: 09:30 am

Place: Gonda 2nd Floor Conference Room

Speaker: Victoria Corbit

Title: “Circuits-specific corticostriatal synaptic abnormalities in a mouse model of compulsive behavior”

Abstract: Obsessive-Compulsive Disorder (OCD) is defined by the presence of obsessive intrusive thoughts and compulsive behaviors linked to these thoughts. Although the exact neuronal mechanisms leading to the development and expression of these symptoms are unclear, hyperactivity in LOFC and caudate is consistently observed in OCD patients at baseline and with symptom provocation. Homologous corticostriatal circuitry has been shown to be dysregulated in the Sapap3-KO OCD mouse model. Specifically, hyperactivity in central striatum spiny projection neurons (SPNs) has been correlated with compulsive grooming in this model, but it is unclear what specific cellular and synaptic mechanisms lead to this hyperactivity.

To determine if increased intrinsic excitability plays a role in SPN hyperactivity in Sapap3-KOs, we examined intrinsic properties in SPNs in the central striatum. We found no differences in intrinsic properties, suggesting that dysfunction underlying SPN hyperactivity is not at the level of the striatum. To assess whether cortical inputs were increased onto SPNs in Sapap3-KOs, we injected channelrhodopsin2 (ChR2) into LOFC and recorded optogenetically-evoked synaptic responses. Contrary to our expectations, LOFC inputs were weaker onto SPNs. To further understand what other cortical inputs may be influencing SPN activity, we used retrograde fluorogold tracing to look for alternative sources of increased excitatory input in Sapap3-KOs . We discovered that M2 cortex, which is thought to be homologous to primate supplementary motor regions, sends projections to central striatum that overlap with those from LOFC. By conducting optogenetic slice physiology experiments, we found that M2-evoked EPSCs were increased onto SPNs in the central striatum of Sapap3-KOs relative to WTs. To understand how this increased M2 synapse strength may play a role in compulsive grooming behavior in the Sapap3-KO mice, I am currently conducting in vivo investigations of this circuit. These studies include in vivo electrophysiology, calcium imaging, and optogenetic manipulations of the M2 and central striatal circuit. Our data suggest that shifting primary cortical control of central striatum from LOFC to M2 may lead to compulsive/ abnormal repetitive behaviors through excessive selection of maladaptive behavior patterns. These results highlight the possible role of supplementary motor areas in the generation of abnormal repetitive behaviors, which may lead to a conceptual shift in both clinical and preclinical OCD research.

Date: 5 April 2019

Time: 09:30 am

Place: Gonda 2nd Floor Conference Room

Speaker: Paul Mathews

Title: “Cerebellar contributions to cognitive behavior”

Abstract: The cerebellum has a clear role in the coordination of motor movement, as diseases or insults that disrupt cerebellar function result in the loss of motor control. However, over the past 5-10 years multiple independent lines of research strongly suggests the cerebellum plays a much broader role in animal behavior, contributing to aspects of cognition, emotion, and executive function. In the first half of my talk, I will provide an overview of multiple recent rodent studies that link specific cerebellum-to-forebrain circuits to aspects of cognitive behavior, including social cognition and behavioral flexibility. In the second half, I will present recent preliminary experiments from my own laboratory using a new behavioral paradigm (at least to the cerebellar field) to examine the role of the cerebellum in behavioral flexibility.

Relevant Paper(s):

http://science.sciencemag.org/content/363/6424/eaav0581.full

Abstract: Estrogen has wide-reaching effects in the brain. In 75% of breast cancer patients, treatment with estrogen-modulating endocrine therapies are part of standard care to prevent cancer recurrence. However, the effects of these treatments on cognition are not well-studied. This talk will briefly review the evidence describing how changes in estrogen affect cognitive functioning, including naturally occurring menopause and the introduction of endocrine therapy in breast cancer patients. I will also describe the recently published results of the longest longitudinal examination of neuropsychological functioning over time in breast cancer survivors on endocrine therapy, and next steps in my interrogation of this issue.

Relevant Paper(s): https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.31858

Date: 1 March 2019

Time: 09:30 am

Place: Gonda 2nd Floor Conference Room

Speaker: James Howe

Title: “The mouse as a model for neuropsychiatric drug development”

Abstract: Much has been written about the validity of mice as a preclinical model for brain disorders. Critics cite numerous examples of apparently effective treatments in mouse models that failed in human clinical trials, raising the possibility that the two species’ neurobiological differences could explain the high translational failure rate in psychiatry and neurology (neuropsychiatry). However, every stage of translation is plagued by complex problems unrelated to neurobiological conservation. Therefore, although these case studies are intriguing, they cannot alone determine whether these differences observed account for translation failures. Our analysis of the literature indicates that most neuropsychiatric treatments used in humans are at least partially effective in mouse models, suggesting that neurobiological differences are unlikely to be the main cause of neuropsychiatric translation failures.

Abstract: Learning and memory depend on neuronal plasticity originating at the synapse and requiring nuclear gene expression to persist. However, how synapse-to-nucleus communication supports long-term plasticity and behavior has remained elusive. Among cytonuclear signaling proteins, γCaMKII stands out in its ability to rapidly shuttle Ca2+/CaM to the nucleus and thus activate CREB-dependent transcription. Here we show that elimination of γCaMKII prevents activity-dependent expression of key genes (BDNF, c-Fos, Arc), inhibits persistent synaptic strengthening, and impairs spatial memory in vivo. Deletion of γCaMKII in adult excitatory neurons exerts similar effects. A point mutation in γCaMKII, previously uncovered in a case of intellectual disability, selectively disrupts CaM sequestration and CaM shuttling. Remarkably, this mutation is sufficient to disrupt gene expression and spatial learning in vivo. Thus, this specific form of cytonuclear signaling plays a key role in learning and memory and contributes to neuropsychiatric disease.

Relevant Paper(s):

https://www.nature.com/articles/s41467-018-04705-8

Date: 1 February 2019

Time: 09:30 am

Place: Gonda 2nd Floor Conference Room

Speaker: Walter Gonzalez

Title: “Persistence of patterns of neuronal activity through time, noise, and damage in the hippocampus”

Abstract: Memories can persist for decades but how they are stably encoded in individual and groups of neurons is not known. To investigate how experiencing the same environment affects the stability of neuronal representations over time we implanted bilateral microendoscopes in transgenic mice to image the activity of pyramidal neurons in the hippocampus over weeks as mice run in a linear track. Most of the neurons (90 %) are active in the linear track every day, however, the response of neurons to specific cues in the track or home cage changes across days. Approximately 40 % of place and time cells lose fields between two days; however, on timescales longer than two days the resemblance of the neuronal pattern to the first-day decrease only 1 % for each additional day. Despite continuous changes, place/time cells can recover their fields after a 10-day period of no task or following CA1 damage. Recovery of these neuronal patterns is characterized by transient changes in firing fields which ultimately converge to the original representation. Unlike individual neurons, groups of neurons with inter and intrahemispheric synchronous activity form stable place and time fields across days for months. Neurons whose activity was synchronous with a large group of neurons were highly likely to preserve their responses to a task in the maze (place or time) across multiple days. These results support the view that although task-relevant information stored in individual neurons is relatively labile, it can persist in networks of neurons with synchronized activity spanning both hemispheres.

Relevant Paper(s):

https://www.nature.com/articles/nn.3329

https://www.sciencedirect.com/science/article/pii/S0166223613000556

January

Date: 25 January 2019

Time: 09:30 am

Place: Gonda 2nd Floor Conference Room

Speaker: Carlos Portera-Cailliau

Title: “An amygdalar neural ensemble that encodes the unpleasantness of pain”

Abstract: Pain is an unpleasant experience. How the brain’s affective neural circuits attribute this aversive quality to nociceptive information remains unknown. By means of time-lapse in vivo calcium imaging and neural activity manipulation in freely behaving mice encountering noxious stimuli, we identified a distinct neural ensemble in the basolateral amygdala that encodes the negative affective valence of pain. Silencing this nociceptive ensemble alleviated pain affective-motivational behaviors without altering the detection of noxious stimuli, withdrawal reflexes, anxiety, or reward. Following peripheral nerve injury, innocuous stimuli activated this nociceptive ensemble to drive dysfunctional perceptual changes associated with neuropathic pain, including pain aversion to light touch (allodynia). These results identify the amygdalar representations of noxious stimuli that are functionally required for the negative affective qualities of acute and chronic pain perception.

Relevant Paper(s): http://science.sciencemag.org/content/363/6424/276.full

Date: 18 January 2019

Time: 09:30 am

Place: Gonda 2nd Floor Conference Room

Speaker: Anubhuthi Goel

Title: “Dissecting Circuit Dynamics of Sensory Discrimination and Behavior”

Abstract: In order to make sense of the continuous stream of incoming sensory information the cortex must learn to discriminate between a myriad of different stimuli. This sensory discrimination relies on the spatial (e.g., the orientation of a line) and temporal (e.g., duration) features of stimuli. For example, discriminating the orientation of visual stimuli is critical for playing sports, driving or judging emotions, while estimating intervals and durations is important for anticipating the onset of a predator’s actions, the duration of traffic lights, or prosody. Sensory discrimination is thus fundamental for learning and memory, and generating complex behavior, although our understanding of the mechanistic link is limited. In particular the question of how are the temporal features of stimuli or a stimulus duration represented in the brain remains largely unanswered? Theoretical and psychophysical studies suggest that temporal intervals in sensory input are encoded in the changing pattern of active neurons or the evolving population response within a local recurrent network. Using a novel and radical ‘learning in a dish’ model, I trained networks in vitro on different temporal intervals, and showed that the temporal pattern of experience was indeed encoded in the network dynamics, as a result of time window specific modification of excitatory – inhibitory (E-I) balance. The fundamental importance of optimal sensory discrimination is evident in disorders such as autism and autism spectrum disorders (ASD), where sensory processing impairments are often observed. To test the idea that abnormal sensory discrimination contributes to higher order cognitive impairments I used Fmr1-/- mice, a mouse model of autism, and a go/no-go visual perceptual discrimination task for head-restrained mice, and discovered that, compared to wild-type (WT) mice, Fmr1-/- mice take significantly longer to discriminate between gratings drifting in two orthogonal orientations (90o task). The delayed learning was mediated by a reduction in the number of orientation selective cells in primary visual cortex (V1) and reduced parvalbumin (PV) cell functional output, potentially contributing to abnormal E-I balance. A chemogenetic strategy restored PV cell output and rescued behavior. Importantly, for the first time in the field of autism, using analogous sensory discrimination paradigms both in mice and humans, I found that human subjects with FXS exhibit similar impairments in visual discrimination, as Fmr1-/- mice. These findings highlight the contribution of balanced and task dependent E-I changes in encoding sensory input and suggest that simple therapeutic strategies that dynamically restore the E-I balance in cortical circuits may be of value in treating specific behavioral impairments.

My future goals include delineating the network dynamics underlying sensory discrimination of temporal intervals and sequences, and how this impacts learning in normal as well pathological conditions.

Relevant Paper(s): https://www.nature.com/articles/s41593-018-0231-0/

https://www.sciencedirect.com/science/article/pii/S0896627316302537

Date: 11 January 2019

Time: 09:30 am

Place: Gonda 2nd Floor Conference Room

Speaker: Michael Fanselow

Title: “Conditional Freezing, Flight and Darting?”

Abstract: The general question I will discuss is how does fear translate into specific patterns of action. Mostly I'll talk about some new data from our lab--and seek advice as to where to go from here.

Optional Paper(s): https://www.nature.com/articles/nature21047

https://cdn.elifesciences.org/articles/11352/elife-11352-v2.pdf

2018

December

Date: 14 December 2018

Time: 09:30 am

Place: Gonda 2nd Floor Conference Room

Speaker: Helen Motanis

Title: “Network activity of Fragile X circuits”

Abstract: Fragile X syndrome (FXS) is the most common inherited learning disability disorder and is characterized by developmental delays. Here we use an in vitro approach to study network level abnormalities in FX circuits, such reduced systems help bridge molecular/cellular and systems levels of analyses, and observed deficits are less likely to be a consequence of differences in nurture or compensatory mechanisms. First we found that developmental delays are indeed observed in vitro: both whole-cell recordings and 2-photon calcium imaging revealed that FX circuits exhibited a significant developmental delay of spontaneous network activity that was specific to the emergence of Up-states. In contrast to younger FX circuits, mature circuits revealed normal spontaneous activity. These findings are the first to confirm the presence of an in vitro developmental delay in FX circuits.

Mechanistically, the early decrease in spontaneous activity was not associated with a decrease in evoked EPSP strength. However, evoked EPSP strength was reduced in mature FX circuits confirming another developmental delay.

We also examined network-level homeostatic plasticity by using chronic optogenetic stimulation to emulate an increase in externally driven activity. Both WT and FX circuits exhibited normal homeostatic plasticity of evoked and spontaneous activity.

Lastly and because FX is mainly characterized as a learning disability, we established two protocols of in vitro ‘temporal learning’. These protocols were based on a combination of optical and electrical stimulations that allowed us to establish interval/temporal learning in WT circuits. Preliminary data suggest that FX circuits show deficits in this type of in vitro learning.

Our results revealed multiple waves of developmental delays in FX circuits: first a delay in spontaneous activity, followed by a delay in evoked EPSP strength. In addition, our results indicate that FX circuits are able to adapt to relatively simple forms of learning (normal homeostatic plasticity) but not to forms of learning that require the circuits to do major network reorganizations (deficits in temporal learning). These results hint to the possibility that some previously described neural phenotypes observed in FX may be compensatory.

Date: 7 December 2018

Time: 09:30 am

Place: Gonda 2nd Floor Conference Room

Speaker: Wendy Herbst

Title: “Long-Term Potentiation requires a rapid burst of Dendritic Mitochondrial Fission during Induction”

Abstract: Synaptic transmission is bioenergetically demanding, and the diverse processes underlying synaptic plasticity elevate these demands. Therefore, mitochondrial functions, including ATP synthesis and Ca2+ handling, are likely essential for plasticity. Although axonal mitochondria have been extensively analyzed, LTP is predominantly induced postsynaptically, where mitochondria are understudied. Additionally, though mitochondrial fission is essential for their function, signaling pathways that regulate fission in neurons remain poorly understood. We found that NMDAR-dependent LTP induction prompted a rapid burst of dendritic mitochondrial fission and elevations of mitochondrial matrix Ca2+. The fission burst was triggered by cytosolic Ca2+ elevation and required CaMKII, actin, and Drp1, as well as dynamin 2. Preventing fission impaired mitochondrial matrix Ca2+ elevations, structural LTP in cultured neurons, and electrophysiological LTP in hippocampal slices. These data illustrate a novel pathway whereby synaptic activity controls mitochondrial fission and show that dynamic control of fission regulates plasticity induction, perhaps by modulating mitochondrial Ca2+ handling.

Abstract: The Morris Water Maze tests hippocampus dependent spatial learning, memory and navigation. But the neural basis of this is poorly characterized, owing to the difficulty of electrophysiological recording in this task. To overcome this, we developed a virtual water maze task in which rats run >100 trials per session. Here we focus on three stimuli that modulate neural firing: head angle, episodic distance, and allocentric position. The main findings are summarized below:

1. Despite good task performance, we observed very little allocentric spatial selectivity.

2. Many cells were modulated by episodic distance, and the distribution of peak locations was biased towards short distances.

3. Many cells were modulated by head angle, and the population of these cells was biased towards the hidden reward zone.

4. Across sessions, the percentage of neurons that were tuned was positively correlated with behavioral performance.

5. Both behavioral performance and the activation of neurons increased with experience within a single session.

Thus, although there is little hippocampal allocentric spatial selectivity, other navigationally relevant parameters are encoded, and this tuning is correlated with behavior, thus linking behavioral learning with hippocampal activity and cellular mechanisms of plasticity.

Paper(s): Cushman et al., 2013: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0080465

Date: 2 November 2018

Time: 09:30 am

Place: Gonda 2nd Floor Conference Room

Speaker: Panayiota Poirazi

Title: “Challenging the point neuron dogma: FS basket cells as 2-stage nonlinear integrators”

Abstract: Fast Spiking (FS) basket cells constitute one of the main types of hippocampal and neocortical interneurons. While their importance in controlling executive functions is extensively recognized, most studies focus on their molecular and anatomical features, completely ignoring their dendritic processing. Exciting new findings reveal that the dendrites of certain interneuron types exhibit non-linear integration. These findings question the dominant hypothesis that interneurons act as linear summing units, also known as point neurons.

To address this issue, we developed detailed, biologically constrained biophysical models of FS basket cells using anatomical reconstructions of both hippocampal and cortical neurons. Synaptic stimulation within their dendrites, predicts the co-existence of two distinct integration modes: supralinear and sublinear. Morphological features such as dendritic length and/or diameter influence the integration mode and these features differ between hippocampal and cortical neurons. By generating a large number of different spatial patterns of synaptic activation we find that spatially dispersed inputs lead to higher firing rates than inputs clustered within a few dendrites in both Hippocampus and PFC models. These nonlinear dendritic features provide resource savings when it comes to learning in large neuronal networks. Moreover, a 2-layer Artificial Neural Network (ANN) with both sub- and supralinear hidden nodes can predict the firing rate of the aforementioned models much better than a linear ANN.

Our predictions challenge the current dogma, whereby interneurons are treated as linear summing devices, essentially void of dendrites. We propose that FS basket cells, like pyramidal neurons, also operate like a 2-stage processing device.

Paper(s): https://www.biorxiv.org/content/early/2018/01/22/251314

October

Date: 26 October 2018

Time: 09:30 am

Place: CHS 23-105

Speaker: Manuel Lopez Aranda

Title: “mTOR-dependent interferon signaling in microglia and social memory deficits in a mouse model of tuberous sclerosis”

Abstract: There is growing evidence that environmental factors, such as immune activation, contribute to the severity and range of cognitive phenotypes in neuropsychiatric disorders. However, the cell types and the molecular mechanism(s) responsible for these cognitive phenotypes remain unclear. We have multiple lines of evidence that in male mice with a tuberous sclerosis mutation (Tsc2+/-), immune activation during a critical phase of post-natal development, triggers an mTOR-dependent, self-perpetuating cycle of IFN production in microglia. This disrupts hippocampal plasticity and causes behavioral phenotypes, including social memory deficits as well as alterations in ultrasonic vocalization patterns (USV), under conditions that do not affect either wild type or female mice. Importantly, our human epidemiological studies show a strong correlation between the prevalence of infections during childhood, and a future diagnose of neuropsychiatric disorders, suggesting that our results in mice are mirrored by human findings. These results open new therapeutical opportunities for neuropsychiatric disorders, and demonstrate the critical importance of microglia during early post-natal development in cognitive function, including social memory.

Paper(s): https://www.nature.com/articles/mp2010115

Date: 19 October 2018

Time: 09:30 am

Place: Gonda 2nd Floor Conference Room

Speaker: Alex Chubykin

Title: “Impaired Visual Familiarity Circuit in Fmr1 KO Mice”

Abstract: The brain differentially processes information, depending on its familiarity. To differentiate between familiar and novel stimuli, the brain needs to be able to recognize familiar stimuli or their prominent physical features. However, there has been a poor understanding of how this process occurs at the mechanistic level. We have recently discovered a new mechanism encoding visual familiarity via persistent low-frequency oscillations in the mouse primary visual cortex (V1). We then determined that the familiarity-evoked oscillations are attenuated in the Fmr1 KO mice, the mouse model of Fragile X syndrome, the most common inherited form of autism and intellectual disability. To identify the neuronal circuit involved in the generation of these oscillations, we have performed channelrhodopsin-assisted circuit mapping (CRACM). We have discovered that following visual experience, there was an increase in the strength of the excitatory connections formed by the pyramidal neurons in layer 5 onto the fast-spiking interneurons in layer 4. Interestingly, this connection was weaker in the Fmr1 KO mice, which correlated with the weaker familiarity-evoked oscillations in vivo. Our findings suggest the critical role of the intracortical excitatory connections onto fast-spiking interneurons for the visual familiarity in V1.

Date: 12 October 2018

Time: 09:30 am

Place: Gonda 2nd Floor Conference Room

Speaker: Jennifer Achiro

Title: “Astrocytic Activation Generates De Novo Neuronal Potentiation and Memory Enhancement”

Abstract: Astrocytes respond to neuronal activity and were shown to be necessary for plasticity and memory. To test whether astrocytic activity is also sufficient to generate synaptic potentiation and enhance memory, we expressed the Gq-coupled receptor hM3Dq in CA1 astrocytes, allowing their activation by a designer drug. We discovered that astrocytic activation is not only necessary for synaptic plasticity, but also sufficient to induce NMDA-dependent de novo long-term potentiation in the hippocampus that persisted after astrocytic activation ceased. In vivo, astrocytic activation enhanced memory allocation; i.e., it increased neuronal activity in a task-specific way only when coupled with learning, but not in home-caged mice. Furthermore, astrocytic activation using either a chemogenetic or an optogenetic tool during acquisition resulted in memory recall enhancement on the following day. Conversely, directly increasing neuronal activity resulted in dramatic memory impairment. Our findings that astrocytes induce plasticity and enhance memory may have important clinical implications for cognitive augmentation treatments.

Paper(s): https://doi.org/10.1016/j.cell.2018.05.002

Date: 5 October 2018

Time: 09:30 am

Place: Gonda 2nd Floor Conference Room

Speaker: Juan Luis Romero Sosa

Title: “Integrating time from experience in the lateral entorhinal cortex”

Abstract: The encoding of time and its binding to events are crucial for episodic memory, but how these processes are carried out in hippocampal–entorhinal circuits is unclear. Here we show in freely foraging rats that temporal information is robustly encoded across time scales from seconds to hours within the overall population state of the lateral entorhinal cortex. Similarly pronounced encoding of time was not present in the medial entorhinal cortex or in hippocampal areas CA3–CA1. When animals’ experiences were constrained by behavioural tasks to become similar across repeated trials, the encoding of temporal flow across trials was reduced, whereas the encoding of time relative to the start of trials was improved. The findings suggest that populations of lateral entorhinal cortex neurons represent time inherently through the encoding of experience. This representation of episodic time may be integrated with spatial inputs from the medial entorhinal cortex in the hippocampus, allowing the hippocampus to store a unified representation of what, where and when.

Paper(s): https://www.nature.com/articles/s41586-018-0459-6

September

Date: 28 September 2018

Time: 09:30 am

Place: Gonda 2nd Floor Conference Room

Speaker: Dean Buonomano

Title: “Learning to play chess through Deep Reinforcement Learning: What should neuroscientists learn from machine learning?”

Abstract: The game of chess is the most widely-studied domain in the history of artificial intelligence. The strongest programs are based on a combination of sophisticated search techniques, domain-specific adaptations, and handcrafted evaluation functions that have been refined by human experts over several decades. In contrast, the AlphaGo Zero program recently achieved superhuman performance in the game of Go, by tabula rasa reinforcement learning from games of self-play. In this paper, we generalise this approach into a single AlphaZero algorithm that can achieve, tabula rasa, superhuman performance in many challenging domains. Starting from random play, and given no domain knowledge except the game rules, AlphaZero achieved within 24 hours a superhuman level of play in the games of chess and shogi (Japanese chess) as well as Go, and convincingly defeated a world-champion program in each case.

Paper(s): Mastering Chess and Shogi by Self-Play with a General Reinforcement Learning Algorithm

https://arxiv.org/abs/1712.01815

Mastering the game of Go without human knowledge

https://www.nature.com/articles/nature24270/

June

Date: 15 June 2018

Time: 09:30 am

Place: Gonda 2nd Floor Conference Room

Speaker: David Glanzman

Title: “RNA from Trained Aplysia Can Induce an Epigenetic Engram for Long-Term Sensitization in Untrained Aplysia”

Abstract: The precise nature of the engram, the physical substrate of memory, remains uncertain. Here, it is reported that RNA extracted from the central nervous system of Aplysia given long-term sensitization (LTS) training induced sensitization when injected into untrained animals; furthermore, the RNA-induced sensitization, like training-induced sensitization, required DNA methylation. In cellular experiments, treatment with RNA extracted from trained animals was found to increase excitability in sensory neurons, but not in motor neurons, dissociated from naïve animals. Thus, the behavioral, and a subset of the cellular, modifications characteristic of a form of nonassociative long-term memory (LTM) in Aplysia can be transferred by RNA. These results indicate that RNA is sufficient to generate an engram for LTS in Aplysia and are consistent with the hypothesis that RNA-induced epigenetic changes underlie memory storage in Aplysia.

Paper(s): http://www.eneuro.org/content/5/3/ENEURO.0038-18.2018

http://www.eneuro.org/content/5/3/ENEURO.0193-18.2018

Date: 8 June 2018

Time: 09:30 am

Place: Gonda 2nd Floor Conference Room

Speaker: Carlos Portera-Cailliau

Title: “Distinct learning-induced changes in stimulus selectivity and interactions of GABAergic interneuron classes in visual cortex”

Abstract: How learning enhances neural representations for behaviorally relevant stimuli via activity changes of cortical cell types remains unclear. We simultaneously imaged responses of pyramidal cells (PYR) along with parvalbumin (PV), somatostatin (SOM), and vasoactive intestinal peptide (VIP) inhibitory interneurons in primary visual cortex while mice learned to discriminate visual patterns. Learning increased selectivity for task-relevant stimuli of PYR, PV and SOM subsets but not VIP cells. Strikingly, PV neurons became as selective as PYR cells, and their functional interactions reorganized, leading to the emergence of stimulus-selective PYR–PV ensembles. Conversely, SOM activity became strongly decorrelated from the network, and PYR–SOM coupling before learning predicted selectivity increases in individual PYR cells. Thus, learning differentially shapes the activity and interactions of multiple cell classes: while SOM inhibition may gate selectivity changes, PV interneurons become recruited into stimulus-specific ensembles and provide more selective inhibition as the network becomes better at discriminating behaviorally relevant stimuli.

Paper(s): https://www.nature.com/articles/s41593-018-0143-z

Time: 09:30 am

Place: Gonda 2nd Floor Conference Room

Speaker: Frank Krasne

Title: “What is post-natal neurogeneis good for?”

Abstract: I will describe what I consider are currently the two most prominent hypotheses for the reason for post-natal neurogenesis. I will also discuss another hypothesis which has been mentioned in the literature with less emphasis but I think is likely to be most important.

Papers: The talk will feature ideas from various papers, two of which are cited below:

https://www.sciencedirect.com/science/article/pii/S0896627308010192

http://www.jneurosci.org/content/38/13/3190

Date: 4 May 2018

Time: 09:30 am

Place: Gonda 2nd Floor Conference Room

Speaker: Kate Wassum

Title: “Does dopamine only compute errors in reward prediction? New data says no.”

Abstract: For two decades the activity of midbrain dopamine neurons has been thought to report errors in reward prediction, whether something is better or worse than predicted. This is the critical teaching signal that allows predictions to be updated, aka, model-free reinforcement learning. A series of new reports have, however, challenged the notion that dopamine only reports reward predictions errors. I will review the key findings of these reports.

Papers: https://elifesciences.org/articles/13665

https://www.nature.com/articles/nn.4538

https://www.sciencedirect.com/science/article/pii/S0896627317307407?via%3Dihub

https://www.sciencedirect.com/science/article/pii/S0960982217312472?via%3Dihub

https://www.biorxiv.org/content/early/2017/12/13/232678

April

Date: 27 April 2018

Time: 09:30 am

Place: Gonda 2nd Floor Conference Room

Speaker: Walt Babiec

Title: “LTP requires postsynaptic PDZ-domain interactions with glutamate receptor/auxiliary protein complexes”

Abstract: Long-term potentiation (LTP) is the most compelling cellular and molecular model for learning and memory. Both AMPARs and KARs, two separate classes of glutamate receptor with very limited homology, express normal LTP in pyramidal neurons. However, the general underlying molecular mechanism remains a mystery. Here, with the strategy of single-cell molecular replacement we show that the PDZ-binding domains of AMPAR/TARP and KAR/Neto receptor complexes are essential for basal synaptic transmission and LTP. Our work suggests that the glutamate receptors share the same postsynaptic requirement for LTP.

Papers: http://www.pnas.org/content/115/15/3948

Date: 20 April 2018

Time: 09:30 am

Place: Gonda 2nd Floor Conference Room

Speaker: Asa Hatami

Title: “Differential inhibition of the a-secretase ADAM10 by Ab variants containing FAD mutations”

Abstract: We show amyloid-beta (Aβ) peptides containing mutations associated with FAD and those with chiral mutations adopt different sets of amyloid conformations and have different aggregation kinetics. The distinct ensembles of amyloid confirmations adopted by the Aβ variants during the aggregation time course differentially inhibited ADAM10 activity. Our findings for the first time highlight a potential novel toxic mechanism associated with specific confirmations of Aβ that warrant further investigation and could lead to identification of specific conformations that may be cleared by immunotherapy to produce benefit in Alzheimer’s Disease.

Papers: None published on the project, but background information is reported in the papers below

http://www.jbc.org/content/early/2017/01/03/jbc.M116.755264

https://www.ncbi.nlm.nih.gov/pubmed/27060954

https://www.ncbi.nlm.nih.gov/pubmed/12506200

Date: 13 April 2018

Time: 09:30 am

Place: Gonda 2nd Floor Conference Room

Speaker: Michael Fanselow

Title: “The Adult Human Neurogenesis Saga”

Two recent papers come to the exact opposite conclusions about the presence of hippocampal neurogenesis in adult humans. Seems like something we oughta know. No solution promised.

Papers: https://www.nature.com/articles/nature25975

http://www.cell.com/cell-stem-cell/fulltext/S1934-5909(18)30121-8

Date: 06 April 2018

Time: 09:30 am

Place: Gonda 2nd Floor Conference Room

Speaker: Jin Zhang

Title: “Illuminating the Biochemical Activity Architecture of the Cell”

The complexity and specificity of many forms of signal transduction are widely suspected to require spatial microcompartmentation and dynamic modulation of the activities of signaling molecules, such as protein kinases, phosphatases and second messengers. We have developed a series of fluorescent biosensors to probe the compartmentalized signaling activities. In this talk, I will focus on cAMP/PKA and PI3K/Akt/mTORC1 signaling pathways and present studies where we combined genetically encoded fluorescent biosensors, superresolution imaging, targeted biochemical perturbations and mathematical modeling to probe the biochemical activity architecture of the cell.

March

Date: 23 March 2018

Time: 09:30 am

Place: Gonda 2nd Floor Conference Room

Speaker: Jiannis Taxidis

Title: “Hippocampal Spiking Sequences encoding odors and time during working-memory activation”

Abstract: Neuronal spiking sequences are a candidate mechanism for the brain to retain information in memory for short time periods. Studies suggest that the hippocampus is involved in working-memory tasks by encoding time through such temporal sequences. But the circuit mechanisms underlying these population dynamics are not well understood. What type of information do these sequences encode? How do they adjust to increasing memory load and how stable are they across multiple days? Are they causally linked to working-memomory? I will be presenting our work which addresses these questions through in vivo two-photon calcium imaging and optogenetic manipulation of hippocampal area CA1 in head-fixed mice while they are performing an olfactory working-memory task. We have observed ‘odor-cells’ that were active during the presentation of specific odor stimuli and ‘delay- cells’ that were active during specific time points of the delay following odor stimuli. These neurons were spatially intermingled and, collectively, formed odor-specific temporal spiking sequences encoding both time and odor-identity while working-memory is activated. By tracking the same cells over days or by extending the memory load within a recording session, we found that these sequences were partly reshaped. Odor-representation remained stable whereas delay-cells remapped their activity shifting their fields backward or forward in time, revealing a dynamic time-representation. Finally, disrupting these sequences optogenetically during learning of the task, revealed the importance of entorhinal inputs that shape such dynamics. This work indicates that two different neural codes coexist in CA1. A stable stimulus-driven one and an internally-generated unstable one encoding task-relevant time. Untangling the properties and mechanisms that generate and sustain these two representations is crucial for understanding the emergence of any population encoding in the hippocampus and its role in memory formation.

Date: 9 March 2018

Time: 09:30 am

Place: Gonda 2nd Floor Conference Room

Speaker: Jeffrey Donlea

Title: “Persistent activity in a recurrent circuit underlies courtship memory in Drosophila”

Papers: https://elifesciences.org/articles/31425

Authors: Xiaoliang Zhao, Daniela Lenek, Ugur Dag, Barry J. Dickson, Krystyna Keleman

Abstract: Recurrent connections are thought to be a common feature of the neural circuits that encode memories, but how memories are laid down in such circuits is not fully understood. Here we present evidence that courtship memory in Drosophila relies on the recurrent circuit between mushroom body gamma (MBγ), M6 output, and aSP13 dopaminergic neurons. We demonstrate persistent neuronal activity of aSP13 neurons and show that it transiently potentiates synaptic transmission from MBγ>M6 neurons. M6 neurons in turn provide input to aSP13 neurons, prolonging potentiation of MBγ>M6 synapses over time periods that match short-term memory. These data support a model in which persistent aSP13 activity within a recurrent circuit lays the foundation for a short-term memory.

Date: 2 March 2018

Time: 09:30 am

Place: Gonda 2nd Floor Conference Room

Speaker: Jennifer Achiro

Title: “Anxiety Cells in a Hippocampal-Hypothalamic Circuit”

https://www.sciencedirect.com/science/article/pii/S0896627318300199

Authors: Jessica C. Jimenez, Katy Su, Alexander R. Goldberg, Victor M. Luna, Jeremy S. Biane, Gokhan Ordek, Pengcheng Zhou, Samantha K. Ong, Matthew A. Wright, Larry Zweife, Liam Paninski, René Hen, Mazen A. Kheirbek

The hippocampus is traditionally thought to transmit contextual information to limbic structures where it acquires valence. Using freely moving calcium imaging and optogenetics, we show that while the dorsal CA1 subregion of the hippocampus is enriched in place cells, ventral CA1 (vCA1) is enriched in anxiety cells that are activated by anxiogenic environments and required for avoidance behavior. Imaging cells defined by their projection target revealed that anxiety cells were enriched in the vCA1 population projecting to the lateral hypothalamic area (LHA) but not to the basal amygdala (BA). Consistent with this selectivity, optogenetic activation of vCA1 terminals in LHA but not BA increased anxiety and avoidance, while activation of terminals in BA but not LHA impaired contextual fear memory. Thus, the hippocampus encodes not only neutral but also valence related contextual information, and the vCA1-LHA pathway is a direct route by which the hippocampus can rapidly influence innate anxiety behavior.

February

Date: 23 February 2018

Time: 09:30 am

Place: Gonda 2nd Floor Conference Room

Speaker: Jason Moore

Title: “Control of Hetero-synaptic Spike-Timing-Dependent Plasticity by Inhibition”

Modeling: Hiratani & Fukai, J. Neuroscience 2017: http://www.jneurosci.org/content/37/50/12106.long Experiment: Paille et al., J. Neuroscience 2013: http://www.jneurosci.org/content/33/22/9353

From Hiratani & Fukai, 2017: Recent experimental studies reveal that relative differences in spike timings experienced among neighboring glutamatergic and GABAergic synapses on a dendritic branch significantly influences changes in the efficiency of these synapses. This heterosynaptic form of spike-timing-dependent plasticity (STDP) is potentially important for shaping the synaptic organization and computation of neurons, but its functional role remains elusive. Through computational modeling at the parameter regime where previous experimental results are well reproduced, we show that heterosynaptic plasticity serves to finely balance excitatory and inhibitory inputs on the dendrite. Our results suggest a principle of GABA-driven neural circuit formation.

Date: 16 February 2018

Time: 09:30 am

Place: Gonda 2nd Floor Conference Room

Speaker: Tom O'Dell

Title: “The C-terminal tails of endogenous GluA1 and GluA2 differentially contribute to hippocampal synaptic plasticity and learning”

https://www.nature.com/articles/s41593-017-0030-z

https://www.nature.com/articles/s41593-017-0029-5

Authors: S. Hrvatin, D. R. Hochbaum, M. A. Nagy, M. Cicconet, K. Robertson, L. Cheadle, R. Zilionis, A. Ratner, R. Borges-Monroy, A. M. Klein, B. L. Sabatini & M. E. Greenberg

Activity-dependent transcriptional responses shape cortical function. However, a comprehensive understanding of the diversity of these responses across the full range of cortical cell types, and how these changes contribute to neuronal plasticity and disease, is lacking. To investigate the breadth of transcriptional changes that occur across cell types in the mouse visual cortex after exposure to light, we applied high-throughput single-cell RNA sequencing. We identified significant and divergent transcriptional responses to stimulation in each of the 30 cell types characterized, thus revealing 611 stimulus-responsive genes. Excitatory pyramidal neurons exhibited inter- and intralaminar heterogeneity in the induction of stimulus-responsive genes. Non-neuronal cells showed clear transcriptional responses that may regulate experience-dependent changes in neurovascular coupling and myelination. Together, these results reveal the dynamic landscape of the stimulus-dependent transcriptional changes occurring across cell types in the visual cortex; these changes are probably critical for cortical function and may be sites of deregulation in developmental brain disorders.

2017

Time: 09:30 am

Place: Gonda 2nd Floor Conference Room

Speaker: Nick Hardy

Title : “High-Level Prediction Signals in a Low-Level Area of the Macaque Face-Processing Hierarchy”

Abstract: Theories like predictive coding propose that lower-order brain areas compare their inputs to predictions derived from higher-order representations and signal their deviation as a prediction error. Here, we investigate whether the macaque face-processing system, a three-level hierarchy in the ventral stream, employs such a coding strategy. We show that after statistical learning of specific face sequences, the lower-level face area ML computes the deviation of actual from predicted stimuli. But these signals do not reflect the tuning characteristic of ML. Rather, they exhibit identity specificity and view invariance, the tuning properties of higher-level face areas AL and AM. Thus, learning appears to endow lower-level areas with the capability to test predictions at a higher level of abstraction than what is afforded by the feedforward sweep. These results provide evidence for computational architectures like predictive coding and suggest a new quality of functional organization of information-processing hierarchies beyond pure feedforward schemes.

Papers: Schwiedrzik et. al., Neuron, 2017 http://www.cell.com/neuron/fulltext/S0896-6273(17)30842-5

October

Date: 27 October 2017

Time: 09:30 am

Place: Gonda 2nd Floor Conference Room

Speaker: Nicholas J. Matiasz

Title : “ResearchMaps.org for integrating evidence”

Abstract: ResearchMaps.org is a free web app that helps scientists to plan their next experiment. Users input empirical results and hypotheses from literature; the app visualizes this information in a graphical summary known as a “research map.” In this graph-based representation, each node identifies a biological phenomenon; each directed edge between nodes shows the kinds of relations that were either hypothesized by researchers or supported by empirical results. The empirical evidence for each edge is assigned a confidence score using a Bayesian technique for evidence synthesis. This score quantifies both the convergence and consistency of the evidence, helping the user to identify which next experiments may be most useful. Every empirical edge in a research map is linked to the literature that it references, so users can access additional details of the annotated literature. In ongoing work, we are working to automate two time-consuming tasks: (1) the extraction of empirical evidence from the literature, and (2) the derivation of hypotheses that may be untested yet logically consistent with what is known.

N. J. Matiasz, J. Wood, W. Wang, A. J. Silva, W. Hsu (2017). Computer-aided experiment planning toward causal discovery in neuroscience. In Frontiers in Neuroinformatics 11:12. http://mii.ucla.edu/repository/584.pdf

A. J. Silva and K. R. Müller (2015). The need for novel informatics tools for integrating and planning research in molecular and cellular cognition. In Learning & Memory 22:494–498. http://www.silvalab.com/silvapapers/SilvaMuller2015.pdf

A. Landreth and A. J. Silva (2013). The need for research maps to navigate published work and inform experiment planning. In Neuron 79:411–415. http://www.silvalab.com/silvapapers/S2Neuron2013.pdf

Date: 20 October 2017

Time: 09:30 am

Place: Gonda 2nd Floor Conference Room

Speaker: Nazim Kourdougli

Title : “The dorsal subiculum as a “detour” to retrieve episodic memory”

http://www.cell.com/cell/fulltext/S0092-8674(17)30820-6

Abstract: The memory of a new experience is stored in neuronal ensembles distributed across several microcircuits of the hippocampal formation and other brain structures. These neuronal clusters may store different aspects of the episodic memory, such as “what” is the information stored and its emotional context (e.g. “where” and “when” a particular event occurred). When these memories are retrieved, the neuronal ensemble originally activated is then recalled. In a recent study published in Cell, S. Tonegawa’s lab shows that dorsal subiculum and the circuit, CA1 to dorsal subiculum to medial entorhinal cortex layer 5, play a crucial role selectively in the retrieval of episodic memories. Conversely, the direct CA1 to medial entorhinal cortex layer 5 circuit is essential specifically for memory formation. These data suggest that the subiculum-containing detour loop is dedicated to meet the requirements associated with recall such as rapid memory updating and retrieval-driven instinctive fear responses. Overall, this report identified a two-circuit system underpinning the capacity of the hippocampus to integrate the “what”, “when” and “where” of episodic memory capacity.

Date: 13 October 2017

Time: 09:30 am

Place: Gonda 2nd Floor Conference Room

Speaker: Melissa Malvaez

Title : “Amygdala-Cortical Circuits in reward value encoding and retrieval”

Abstract: The value of an anticipated reward is a key element in the decision to engage in its pursuit. This value is encoded when the reward is experienced in a relevant motivational state. The basolateral amygdala (BLA) is required for this incentive learning process, but how it achieves this function within the broader reward-seeking circuitry is unknown. Moreover, it remains unclear whether the BLA participates in retrieving value information for guiding reward seeking. The BLA receives dense glutamatergic innervations from several cortical regions, including the orbitofrontal cortex (OFC), a region also implicated in value attribution. We first examined BLA excitatory input activity using electroenzymatic biosensors to make near-real time measurements of BLA glutamate concentration changes during value encoding (experience with a food reward in novel hungry state) and a subsequent reward-seeking test. We found that glutamate is transiently released in the BLA during reward value encoding and immediately preceding bouts of subsequent value-guided reward-seeking activity, but only if rats had previously encoded and, therefore, retrieved the value of the anticipated reward to guide actions. Using a pharmacological approach, BLA NMDA receptors were found to be necessary for encoding a positive change in reward value, and both AMPA and NMDA receptors were necessary for subsequent value-guided reward seeking. We next sought to identify the specific cortical afferent contributors to these input signals. Given the anatomical and functional distinctions within the OFC, we specifically targeted either the lateral or medial OFC using chemogenetic and optogenetic approaches to bidirectionally modulate the activity of these projections to the BLA. Activity in lateral OFC to BLA projections was found to be both necessary for and sufficient to enhance encoding of a positive change in reward value, but not for subsequent retrieval of this information for online decision making. Conversely, projections from the medial OFC were not required for incentive learning, but were found to be necessary for retrieval of reward value and sufficient to enhance value-guided reward seeking actions. These data demonstrate that the BLA participates in both the encoding and retrieval of reward value via excitatory input from the OFC and that there is a double dissociation of the contribution of lateral vs. medial OFC to BLA projections to encoding vs. retrieval, respectively. These data have important implications for the myriad diseases marked by maladaptive reward valuation and decision-making.

Date: 06 October 2017

Time: 09:30 am

Place: Gonda 2nd Floor Conference Room

Speaker: Dean Buonomano

Title : “Behavioral time scale synaptic plasticity underlies CA1 place fields”

Authors: Bittner, Milstein, Grienberger, Romani, and Magee.

http://science.sciencemag.org/content/357/6355/1033.full

Abstract: How do synaptic or other neuronal changes support learning? This subject has been dominated by Hebb's postulate of synaptic change. Although there is strong experimental support for Hebbian plasticity in a number of preparations, alternative ideas have also been developed over the years. Bittner et al. provide in vivo, in vitro, and modeling data to support the view that non-Hebbian plasticity may underlie the formation of hippocampal place fields (see the Perspective by Krupic). Instead of multiple pairings, a single strong Ca2+ plateau potential in neuronal dendrites paired with spatial inputs may be sufficient to produce place cells.Science, this issue p. 1033; see also p. 974Learning is primarily mediated by activity-dependent modifications of synaptic strength within neuronal circuits. We discovered that place fields in hippocampal area CA1 are produced by a synaptic potentiation notably different from Hebbian plasticity. Place fields could be produced in vivo in a single trial by potentiation of input that arrived seconds before and after complex spiking. The potentiated synaptic input was not initially coincident with action potentials or depolarization. This rule, named behavioral time scale synaptic plasticity, abruptly modifies inputs that were neither causal nor close in time to postsynaptic activation. In slices, five pairings of subthreshold presynaptic activity and calcium (Ca2+) plateau potentials produced a large potentiation with an asymmetric seconds-long time course. This plasticity efficiently stores entire behavioral sequences within synaptic weights to produce predictive place cell activity.

June

Date: 09 June 2017

Time: 09:30 am Place : Gonda 2nd Floor Conference Room

Speaker: Tom O'Dell

Title: Gone in 60 seconds: The role of CamKII in LTP and learning

Abstract: The calcium/calmodulin-dependent protein kinase CamKII has long been known to have a crucial role in both LTP and learning. An intriguing property of CamKII is that it undergoes auto-phosphorylation at a site (Thr286) that converts CamKII into a persistently active form. Although the ability of auto-phosphorylated CamKII to remain active even in the absence of calcium/calmodulin has long been thought to have an important role in the long-term maintenance of LTP and memory, results from experimental tests of this idea have been mixed. Recently, Ryohei Yasuda’s laboratory has re-examined the role of CamKII in LTP and learning using a FRET-based reporter of CamKII activity and a novel, photoactivatable CamKII inhibitor. Their results indicate that the temporal requirement for CamKII activity in plasticity and learning is surprisingly short (1 minute or less) and thus constitutively active, auto-phosphorylated forms of CamKII do not directly contribute to the long-term maintenance of LTP and memory.

Papers: Chang et al. (2017) CaMKII autophosphorylation is necessary for optimal integration of Ca2+ signals during LTP induction, but not maintenance. Neuron http://www.sciencedirect.com/science/article/pii/S0896627317303987

Murakoshi et al. (2017) Kinetics of endogenous CaMKII required for synaptic plasticity revealed by optogenetic kinase inhibitor. Neuron http://www.sciencedirect.com/science/article/pii/S0896627317303537

May

Date: 19 May 2017

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Cortical gamma band synchronization through somatostatin interneurons

Speaker: Anubhuthi Goel

http://www.nature.com/neuro/journal/vaop/ncurrent/full/nn.4562.html?WT.feed_name=subjects_neuroscience

Abstract: Gamma band rhythms may synchronize distributed cell assemblies to facilitate information transfer within and across brain areas, yet their underlying mechanisms remain hotly debated. Most circuit models postulate that soma-targeting parvalbumin-positive GABAergic neurons are the essential inhibitory neuron subtype necessary for gamma rhythms. Using cell-type-specific optogenetic manipulations in behaving animals, we show that dendrite-targeting somatostatin (SOM) interneurons are critical for a visually induced, context-dependent gamma rhythm in visual cortex. A computational model independently predicts that context-dependent gamma rhythms depend critically on SOM interneurons. Further in vivo experiments show that SOM neurons are required for long-distance coherence across the visual cortex. Taken together, these data establish an alternative mechanism for synchronizing distributed networks in visual cortex. By operating through dendritic and not just somatic inhibition, SOM-mediated oscillations may expand the computational power of gamma rhythms for optimizing the synthesis and storage of visual perceptions.

Date: 12 May 2017

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Delay activity of specific prefrontal interneuron subtypes modulates memory-guided behavior

Speaker: Alexandra Stolyarova

http://www.nature.com/neuro/journal/vaop/ncurrent/full/nn.4554.html#affil-auth

Abstract: Memory-guided behavior requires maintenance of task-relevant information without sensory input, but the underlying circuit mechanism remains unclear. Calcium imaging in mice performing a delayed Go or No-Go task revealed robust delay activity in dorsomedial prefrontal cortex, with different pyramidal neurons signaling Go and No-Go action plans. Inhibiting pyramidal neurons by optogenetically activating somatostatin- or parvalbumin-positive interneurons, even transiently during the delay, impaired task performance, primarily by increasing inappropriate Go responses. In contrast, activating vasoactive intestinal peptide (VIP)-positive interneurons enhanced behavioral performance and neuronal action plan representation. Furthermore, while endogenous activity of somatostatin and parvalbumin neurons was strongly biased toward Go trials, VIP neurons were similarly active in Go and No-Go trials. Somatostatin or VIP neuron activation also impaired or enhanced performance, respectively, in a delayed two-alternative forced-choice task. Thus, dorsomedial prefrontal cortex is a crucial component of the short-term memory network, and activation of its VIP neurons improves memory retention.

April

Date: 21 April 2017

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Chromatin remodeling inactivates activity genes and regulates neural coding

Speaker: Caitlin Aamodt

http://science.sciencemag.org/content/353/6296/300.long

Activity-dependent transcription influences neuronal connectivity, but the roles and mechanisms of inactivation of activity-dependent genes have remained poorly understood. Genome-wide analyses in the mouse cerebellum revealed that the nucleosome remodeling and deacetylase (NuRD) complex deposits the histone variant H2A.z at promoters of activity- dependent genes, thereby triggering their inactivation. Purification of translating messenger RNAs from synchronously developing granule neurons (Sync-TRAP) showed that conditional knockout of the core NuRD subunit Chd4 impairs inactivation of activity-dependent genes when neurons undergo dendrite pruning. Chd4 knockout or expression of NuRD-regulated activity genes impairs dendrite pruning. Imaging of behaving mice revealed hyperresponsivity of granule neurons to sensorimotor stimuli upon Chd4 knockout. Our findings define an epigenetic mechanism that inactivates activity-dependent transcription and regulates dendrite patterning and sensorimotor encoding in the brain.

Perspective: http://science.sciencemag.org/content/353/6296/218

Date: 14 April 2017

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Use of Larval Zebrafish to Unravel the Cellular and Molecular Basis of Memory

Speaker: Adam Roberts

The Glanzman laboratory investigates the cellular and molecular mechanisms of learning-related synaptic interactions in the larval zebrafish brain. Zebrafish larvae possess relatively simple neural circuits that are readily defined due to their key biological attributes and to the current availability of powerful genetic tools for analyzing those attributes. Importantly, the simple neural circuits in larval zebrafish mediate basic forms of learning and memory, including habituation, sensitization and classical conditioning. In this talk, I will describe some of the key molecular processes that underlie memory in zebrafish larvae, and describe progress toward the visualization of engrams in the zebrafish brain.

Background paper: http://www.sciencedirect.com/science/article/pii/S2211124715012498

Date: 7 April 2017

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Deletion of PAC1 Receptors From the Medial Intercalated Cells of the Amygdala Enhances Fear Generalization and Decreases Fear Extinction Whereas Deletion From the Basolateral Amygdala Decreases Fear Acquisition

Speaker: Abha Rajbhandari

Post-traumatic stress disorder (PTSD) involves inappropriate inhibitory control over fear after exposure to life-threatening traumatic experiences. Previous studies have linked the neuropeptide pituitary adenylate cyclase activating peptide (PACAP) and its G-coupled receptor PAC1 to PTSD diagnosis and symptom severity. PACAP and PAC1 are expressed in the neural circuitry of fear and regulate conditioned fear behaviors. Using mice expressing green fluorescent protein (GFP) in PACAP containing neurons we found that PACAP-containing neurons in the basolateral portion of the amygdala project into the medial intercalated cells (mICCs). mICCs are crucial for modulating fear extinction and express PAC1 receptors. Therefore, we investigated whether deletion of PAC1 receptors from the mICCs alters fear acquisition, generalization or extinction via AAV-driven Cre-recombinase infusion in PAC1 floxed mice. The results indicate that deletion of PAC1 receptors from the intercalated cells enhances fear generalization and reduces fear extinction potentially by decreasing feed-forward inhibition into the CeA. Deletion of these receptors from the BLA leads to deficit in fear acquisition. These results indicate that PACAP/PAC1 may play differential role in fear depending on the site of action in the fear circuitry. The finding that the mICCs modulate fear generalization is a novel and interesting as studies have focused on the role of ICCs in fear extinction, but not generalization.

Links to relevant papers:

https://www.ncbi.nlm.nih.gov/pubmed/24516127

https://www.ncbi.nlm.nih.gov/pubmed/21350482

March

Date: 24 March 2017

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Modeling and Experimental Analysis of Sensory and Motor Timing within Recurrent Neural Networks

Speaker: Vishwa Goudar

Relevant papers: http://www.jneurosci.org/content/37/4/854 https://arxiv.org/abs/1701.00838

Much of the brain's computations are temporal in nature. Information commonly processed by the brain's circuits, such as a spoken word or a handwritten signature, is defined as much by how it unfolds in time as by its spatial structure at any given moment in time. Similarly, anticipating an upcoming event demands the ability to accurately tell time. While the neural mechanisms underlying spatiotemporal processing are not known, "state-space" models hypothesize that neural circuits encode temporal patterns in their dynamics as continuous neural trajectories. In this talk, I will describe two studies aimed at understanding neural basis of temporal processing. First, I will discuss a modeling study showing how a single recurrent neural network model can simultaneously encode time-varying sensory and motor patterns as continuous neural trajectories - specifically the network can perform a complex sensory-motor task in which spoken digits are transcribed into written digits. Crucially, this approach addresses the long-standing problem of temporal invariance: the network identifies the same stimulus played at different speeds. Second, I will describe a collaborative study with the Masmanidis lab, where we analyzed the neural encoding of anticipatory timing. Consistent with the notion of a "population clock", the striatum and cortex have been shown to encode elapsed time in their ongoing population-level dynamics. Our findings indicate that both the striatal and cortical networks encoded time, but striatal networks outperform the orbitofrontal cortex. These results are consistent with the hypothesis that temporal information is encoded in a widely distributed manner throughout multiple brain areas, but that the striatum may have a privileged role in timing because it has a more accurate “clock” as it integrates information across multiple cortical areas.

Date:17 March 2017

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Dopamine or Not Dopamine? Perceptual decision-making in Parkinson’s Disease

Speaker: Alessandra Perugini

Relevant papers: http://www.sciencedirect.com/science/article/pii/S0960982216305346

http://www.sciencedirect.com/science/article/pii/S0960982216306091

We recently found that people with Parkinson’s disease (PD) are impaired in making decisions under conditions of sensory uncertainty, when integration of sensory and memory information is required, but they are unimpaired when sensory information is clear. This impairment results from an inability to set the appropriate decision threshold when memory is required (Perugini et al., 2016). Here, I extend my previous work and test whether the observed behavioral deficit in combining memory and sensory information is related to dopaminergic medications. I will show that people with PD are impaired at using memory to make perceptual decisions, with or without dopaminergic medications, thus opening the possibility that the impairment is part of the disease process itself. To further assess this, I also tested a group of people with dystonia who are unresponsive to dopamine medications. These people show impairments similar to those seen in PD, indicating that it is the disease and not dopamine that results in this impairment. Additional preliminary data in patients with PD show an interaction between dopamine, decision-making and motor-phenotype. Together these results implicate circuits other than the well-known dopaminergic frontostriatal circuit in cognitive impairments in PD.

Date:10 March 2017

Time: 09:30 am

Title: Using Neuroscience to Help Understand Fear and Anxiety: A Two-System Framework

Speaker: Zachary Pennington

Paper: http://ajp.psychiatryonline.org/doi/full/10.1176/appi.ajp.2016.16030353

Tremendous progress has been made in basic neuroscience in recent decades. One area that has been especially successful is research on how the brain detects and responds to threats. Such studies have demonstrated comparable patterns of brain-behavior relationships underlying threat processing across a range of mammalian species, including humans. This would seem to be an ideal body of information for advancing our understanding of disorders in which altered threat processing is a key factor, namely, fear and anxiety disorders. But research on threat processing has not led to significant improvements in clinical practice. The authors propose that in order to take advantage of this progress for clinical gain, a conceptual reframing is needed. Key to this conceptual change is recognition of a distinction between circuits underlying two classes of responses elicited by threats: 1) behavioral responses and accompanying physiological changes in the brain and body and 2) conscious feeling states reflected in self-reports of fear and anxiety. This distinction leads to a "two systems" view of fear and anxiety. The authors argue that failure to recognize and consistently emphasize this distinction has impeded progress in understanding fear and anxiety disorders and hindered attempts to develop more effective pharmaceutical and psychological treatments. The two-system view suggests a new way forward.

Date: 3 March 2017

Speaker: Carlos Portera-Cailliau

Title: A Neural Circuit for Auditory Dominance over Visual Perception

Paper: http://www.cell.com/neuron/pdf/S0896-6273(17)30007-7.pdf

When conflicts occur during integration of visual and auditory information, one modality often dominates the other, but the underlying neural circuit mechanism remains unclear. Using auditory-visual discrimination tasks for head-fixed mice, we found that audition dominates vision in a process mediated by interaction between inputs from the primary visual (VC) and auditory (AC) cortices in the posterior parietal cortex (PTLp). Co-activation of the VC and AC suppresses VC-induced PTLp responses, leaving AC-induced responses. Furthermore, parvalbumin-positive (PV+) interneurons in the PTLp mainly receive AC inputs, and muscimol inactivation of the PTLp or optogenetic inhibition of its PV+ neurons abolishes auditory dominance in the resolution of cross-modal sensory conflicts without affecting either sensory perception. Conversely, optogenetic activation of PV+ neurons in the PTLp enhances the auditory dominance. Thus, our results demonstrate that AC input-specific feedforward inhibition of VC inputs in the PTLp is responsible for the auditory dominance during cross-modal integration.

February

Date: 24 February 2017

Speaker: Mohammed Pervez Alam

Title: Humanin mimetics as potential candidates for modulation of learning and memory impairments

Humanin (HN), a 24-amino acid bioactive peptide that exerts its effects through gp130 interaction, increases cell survival after exposure to Abeta and NMDA-induced toxicity. HN and its analog have also been shown to ameliorate the learning and memory impairment induced by scopolamine and diazepam. However, HN due to its peptidic structure presents challenges in its development as a therapeutic drug. Therefore, a small molecule gp130 agonist mimetic of HN would allow for more rapid development and ease of delivery into the brain. We have designed and synthesized analogs of the gp130 agonist (identified through screening) and conducted an exploratory medicinal chemistry structure-activity relationship (SAR) to identify small-molecule humanin mimetics as lead candidate(s). Continuous flow-chemistry was used to facilitate syntheses of new analogs as it allows a green-chemistry approach for synthesis and SAR optimization. The analogs generated has enabled us to gain chemical insights into the SAR and elucidated the potential of a small molecule gp130 agonist to protect against learning and memory impairments-

Date: 10 February 2017

Speaker: Trsitan Shuman

Title: Breakdown of spatial coding and synchronization in epilepsy

Epilepsy causes dramatic cell death and reorganization of interneuron circuits in both humans and rodent models but the consequences of these changes on the hippocampal network remain unknown. Using in vivo electrophysiology in head-fixed mice running in virtual reality, I have found dramatic alterations of hippocampal processing in chronically epileptic mice. Epileptic mice had reduced local field potential amplitude and coherence, altered cross-frequency coupling, and altered phase preferences to ongoing theta oscillations. In addition, using calcium imaging with miniature microscopes, I have found that place fields in epileptic mice contained less spatial information and were highly unstable across days. Together, these findings indicate that desynchronization within the hippocampus contributes to the cognitive dysfunction observed in epilepsy.

Date: 03 February 2017

Speaker: Evan Hart

Title: Basolateral amygdala and anterior cingulate contributions to effortful choice behavior

The basolateral amygdala (BLA) and anterior cingulate cortex (ACC) are known to be involved in appetitive behavior, yet their role in cost-benefit choice of qualitatively different rewards (more/less preferred), beyond magnitude differences (larger/smaller), is poorly understood. We assessed the roles of BLA and ACC on effortful choice behavior. Rats were surgically prepared with either cannulae in BLA or NMDA lesions of ACC and trained to stable lever pressing for sucrose pellets on a progressive ratio schedule. Rats were then introduced to a choice: freely-available chow was concurrently available while they could work for the preferred sucrose pellets. BLA inactivations produced a significant decrease in lever presses for sucrose pellets compared to vehicle, and chow consumption was unaffected. Inactivation had no effect on sucrose pellet preference when both options were freely available. Critically, when lab chow was not concurrently-available, BLA inactivations had no effect on the number of lever presses for sucrose pellets, indicating that primary motivation in the absence of choice remains intact with BLA offline. After a test under specific satiety for sucrose pellets, BLA inactivation rendered animals less sensitive to devaluation relative to control. The effects of BLA inactivations in our task are not mediated by decreased appetite, an inability to perform the task, a change in food preference, or decrements in primary motivation. Similar to BLA inactivation, ACC lesions produced a significant decrease in lever presses for sucrose pellets compared to sham-operated rats (SHAM), and chow consumption was unaffected. Also like BLA inactivations, ACC lesions had no effect on sucrose pellet preference when both options were freely-available. However, in contrast to our BLA findings, when lab chow was not concurrently available ACC lesions reduced the number of lever presses for sucrose pellets. After a test under specific satiety for sucrose pellets, ACC lesions had no effect on sensitivity to devaluation relative to SHAM. The effects of ACC lesions in our task are not mediated by decreased appetite, a change in food preference, or changes in value of the preferred reward, and instead may be due to general work aversion. Taken together, BLA supports the specific value and effortful choice of a preferred option, and the ACC supports willingness to exert effort generally.

January

Date: 27 January 2017

Speaker: Shan Huang

Title: Increased Dendritic Spine Turnover and Clustering in Retrosplenial Cortex Accompany Memory Enhancement

Dendritic spines are the postsynaptic sites of excitatory synapses on pyramidal neurons. Structural plasticity mediated by addition and elimination of dendritic spines is thought to underlie the formation of long-term memory. Here, we performed two-photon in vivo imaging of dendritic spines in mouse retrosplenial cortex (RSC) before and after learning. We report that spine turnover prior to learning predicts future learning performance in contextual fear conditioning. Contextual learning leads to addition of new spines that are spatially clustered in RSC, and the amount of clustering correlates with learning performance. Accordingly, a genetic manipulation that augments contextual and spatial learning also causes enhancements in pre-learning spine turnover and learning-related clustering. Remarkably, dendritic segments with increased pre-learning spine turnover are more likely to gain clustered spines after learning, suggesting a spatial relationship between the two structural activities. One implication of these findings is that increased spine turnover allow neurons to more efficiently sample the synaptic space during learning in order to optimize information acquisition. Once acquired, spine clustering may stabilize this information, thus strengthening memory circuits.

Date: 13 January

Speaker: Paul Mathews

Title: Activation of Direct and Indirect Pathway Medium Spiny Neurons Drives Distinct Brain-wide Responses

Paper: http://www.cell.com/neuron/abstract/S0896-6273(16)30263-X

A central theory of basal ganglia function is that striatal neurons expressing the D1 and D2 dopamine receptors exert opposing brain-wide influences. However, the causal influence of each population has never been measured at the whole-brain scale. Here, we selectively stimulated D1 or D2 receptor-expressing neurons while visualizing whole-brain activity with fMRI. Excitation of either inhibitory population evoked robust positive BOLD signals within striatum, while downstream regions exhibited significantly different and generally opposing responses consistent with—though not easily predicted from—contemporary models of basal ganglia function. Importantly, positive and negative signals within the striatum, thalamus, GPi, and STN were all associated with increases and decreases in single-unit activity, respectively. These findings provide direct evidence for the opposing influence of D1 and D2 receptor-expressing striatal neurons on brain-wide circuitry and extend the interpretability of fMRI studies by defining cell-type-specific contributions to the BOLD signal.

Date: 6 January

Speaker: Nina Lichtenberg

Title: A bottom-up amygdala-cortical circuit controls cue-triggered reward-expectation

Appropriate decision making often requires integrating what can be perceived in the environment (e.g., presence of stimuli, available actions) with information that is currently unobservable (e.g., knowledge of the specific stimulus- or action-reward relationships). The orbitofrontal cortex (OFC) and basolateral amygdala (BLA) are two identified key nodes in the circuit that support this expectation-guided reward seeking. Understanding of the function of this circuit is, however, limited by the fact that we do not know whether BLA-OFC circuitry contributes to the online control of decision making, whether any contribution of this circuit is via direct monosynaptic projections, or the direction of information transfer. Therefore, we used designer receptor-mediated inactivation of top-down OFC-BLA or bottom-up BLA-OFC monosynaptic projections to evaluate their respective contributions to the ability to retrieve a stored memory of a specific predicted reward and to use this expectation to guide and motivate reward seeking and decision making. BLA-OFC, but not OFC-BLA projections were found to be necessary for a cue-triggered reward expectation to selectively invigorate the performance of actions expected to earn the same unique reward. BLA-OFC projections were not necessary for a reward itself to similarly motivate action, suggesting a more selective role for this projection in the motivating influence of currently unobservable rewarding events. Moreover, these projections were required when reward expectations were generated by reward-predictive cues, but were not necessary when expectations were based on one’s own knowledge of action-reward relationships. These data reveal a new circuit controlling in the cued recall of precise reward memories and the use of this information to motivate specific action plans.

2016

December

Date: 16 December

Speaker: Ann Hoffman

Title: Auditory sensitivity contributes to enhanced fear after traumatic brain injury

Traumatic brain injury (TBI) is a silent epidemic and is labeled the signature injury of troops in recent military operations, a population that are often exposed to stressful stimuli and emotional trauma. While TBI is typically known to impair learning and memory for neutral events, traumatic fear memories are enhanced after TBI, consistent with increased prevalence of comorbid TBI and post-traumatic stress disorder (PTSD). The amygdala receives rich sensory and limbic inputs and coordinated plasticity within these networks are required for normal fear learning and memory. While these underlying neural mechanisms of fear and defensive behavior have been extensively studied in the healthy brain, how these systems are affected and contributing factors to enhanced fear following TBI are not well understood. This talk will provide an overview of the neural circuitry underlying auditory fear conditioning in the context of vulnerability to TBI enhanced fear. I will also discuss evidence in support of the hypothesis that sensory sensitivity may contribute to the development enhanced fear learning and the development of comorbid TBI and PTSD.

Date: 09 December

Speaker: Leonardo Christov-Moore

Title: Targeted enhancement of cortical-hippocampal brain networks and associative memory

Paper discussed: http://science.sciencemag.org/content/345/6200/1054.long

The influential notion that the hippocampus supports associative memory by interacting with functionally distinct and distributed brain regions has not been directly tested in humans. The authors used targeted noninvasive electromagnetic stimulation to modulate human cortical-hippocampal networks and tested effects of this manipulation on memory. Multiple-session stimulation increased functional connectivity among distributed cortical- hippocampal network regions and concomitantly improved associative memory performance. These alterations involved localized long-term plasticity because increases were highly selective to the targeted brain regions, and enhancements of connectivity and associative memory persisted for ~24 hours after stimulation. Targeted cortical-hippocampal networks can thus be enhanced noninvasively, demonstrating their role in associative memory.

November

Date: 18 November

Speaker: Professor Wickliffe Abaraham (Professor and Co-Director of Brain Research, NZ, Department of Psychology, Brain Health Research Center University of Otago)

Title: Regulation of memory mechanisms by secreted amyloid precursor protein-α

Secreted amyloid precursor protein-α (sAPPα), generated by non-amyloidogenic cleavage of amyloid precursor protein, is neuroprotective, neurotrophic, neurogenic and facilitates LTP and memory. However the mechanisms of its action on LTP are poorly understood. Recently we have found that sAPPa facilitates trafficking of glutamate receptors to the cell surface and stimulates protein synthesis and there is a coupling between these events. These and other findings suggest that sAPPa may have therapeutic potential. Supporting this proposal, we have found using a gene therapy approach that sAPPa can rescue spatial memory and LTP deficits in a mouse model of Alzheimer’s disease.

Date: 4 November

Speaker: Kostya Bakhurin

Title: A basal ganglia circuit for evaluating action outcomes

The basal ganglia, a group of subcortical nuclei, play a crucial role in decision making by selecting actions and evaluating their outcomes. While much is known about the function of the basal ganglia circuitry in selection, how these nuclei contribute to outcome evaluation is less clear. Here we show that neurons in the habenula-projecting globus pallidus (GPh) are essential for evaluating action outcomes and are regulated by a specific set of inputs from the basal ganglia. We found in a classical conditioning task that individual mouse GPh neurons bidirectionally encode whether an outcome is better or worse than expected. Mimicking these evaluation signals with optogenetic inhibition or excitation is sufficient to reinforce or discourage actions in a decision making task. Moreover, cell-type-specific synaptic manipulations revealed that the inhibitory and excitatory inputs to the GPh are necessary for mice to appropriately evaluate positive and negative feedback, respectively. Finally, using rabies virus-assisted monosynaptic tracing, we discovered that the GPh is embedded in a basal ganglia circuit wherein it receives inhibitory input from both striosomal and matrix compartments of the striatum, and excitatory input from the “limbic” regions of the subthalamic nucleus (STN). Our results provide the first direct evidence that information about the selection and evaluation of actions is channelled through distinct sets of basal ganglia circuits, with the GPh representing a key locus where information of opposing valence is integrated to determine whether action outcomes are better or worse than expected. (Paper: Stephenson-Jones et al)

October

Date: 28 October

Speaker: Jenny Achiro

Title: Ventral CA1 neurons store social memory

The medial temporal lobe, including the hippocampus, has been implicated in social memory. However, it remains unknown which parts of these brain regions and their circuits hold social memory. Here, we show that ventral hippocampal CA1 (vCA1) neurons of a mouse and their projections to nucleus accumbens (NAc) shell play a necessary and sufficient role in social memory. Both the proportion of activated vCA1 cells and the strength and stability of the responding cells are greater in response to a familiar mouse than to a previously unencountered mouse. Optogenetic reactivation of vCA1 neurons that respond to the familiar mouse enabled memory retrieval and the association of these neurons with unconditioned stimuli. Thus, vCA1 neurons and their NAc shell projections are a component of the storage site of social memory.

Paper: Okuyama et al

Date: 14 October

Speaker: Cynthia He (Young Investigator)

Title: Impaired adaptation underlies tactile overreactivity in Fragile X mice

Fragile X Syndrome (FXS) is the most common single-gene cause of autism and mental impairment, and sensory overreactivity is a frequent symptom in both FXS and other autism spectrum disorders. In the well-established Fmr1^-/- mouse model of FXS, our lab and others have found evidence of network hyperexcitability and alterations in spontaneous activity in primary somatosensory cortex, changes which could contribute to the sensory overreactivity seen in FXS. However, it is not yet known how sensory stimulation triggers abnormal responses at the circuit level in the Fmr1^-/- mice, nor how network-level responses lead to altered sensory perception, especially during development. We used in vivo two-photon calcium imaging of Layer (L) 2/3 neurons expressing GCaMP6s to investigate abnormalities in whisker-evoked network activity in the barrel cortex of Fmr1^-/- mice at P14-16 (a developmental critical period). We tested the hypothesis that in Fmr1^-/- mice at P14-16, L2/3 neurons show abnormal whiskerevoked activity, synchrony, and/or adaptation to persistent stimulation. We have found significant differences between wild-type and Fmr1^-/- mice in whisker-evoked responses of L2/3 neurons and in neuronal adaptation to persistent stimulation. We also developed a novel assay of behavioral response to whisker stimulation and found altered motor adaptation in P14-16 Fmr1^-/- mice, as well as increased tactile defensiveness in adult mice. Our circuit-to-symptom approach has shown cortical-level sensory processing defects at a critical age, which may contribute to tactile overreactivity during both development and adulthood in the Fmr1^-/- mice.

September

Date: 30 September 2016

Speaker: Dean Buonomano

Title: Remembering to Freeze: Prefrontal neuronal assemblies temporally control fear behaviour

Precise spike timing through the coordination and synchronization of neuronal assemblies is an efficient and flexible coding mechanism for sensory and cognitive processing. In cortical and subcortical areas, the formation of cell assemblies critically depends on neuronal oscillations, which can precisely control the timing of spiking activity. Whereas this form of coding has been described for sensory processing and spatial learning, its role in encoding emotional behaviour remains unknown. Fear behaviour relies on the activation of distributed structures, among which the dorsal medial prefrontal cortex (dmPFC) is known to be critical for fear memory expression. In the dmPFC, the phasic activation of neurons to threat-predicting cues, a spike-rate coding mechanism, correlates with conditioned fear responses and supports the discrimination between aversive and neutral stimuli. However, this mechanism does not account for freezing observed outside stimuli presentations, and the contribution of a general spike-time coding mechanism for freezing in the dmPFC remains to be established. Here we use a combination of single-unit and local field potential recordings along with optogenetic manipulations to show that, in the dmPFC, expression of conditioned fear is causally related to the organization of neurons into functional assemblies. During fear behaviour, the development of 4 Hz oscillations coincides with the activation of assemblies nested in the ascending phase of the oscillation. The selective optogenetic inhibition of dmPFC neurons during the ascending or descending phases of this oscillation blocks and promotes conditioned fear responses, respectively. These results identify a novel phase-specific coding mechanism, which dynamically regulates the development of dmPFC assemblies to control the precise timing of fear responses.

June

Date: 03 June 2016

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Neural Mechanisms of Real-World Episodic Memory Retrieval: Investigations using functional neuroimaging and wearable camera technology

Speaker: Tiffany Chow

The retrieval of everyday occurrences is a fundamental facet of memory. However, the neural correlates of episodic memory retrieval have typically been assessed with laboratory-based approaches that are not necessarily representative of how these processes occur for real-world events. These types of laboratory-based experimental paradigms may even elicit neural activation that differs from studies using more naturalistic approaches. To address this, wearable camera technology was used to document participants' lives and the resultant photographs were utilized as memory probes during fMRI scan sessions. Multivariate and univariate analyses revealed striking dissociations in the neural activation corresponding to the photographic source, pre-exposure, and temporal order of events. Multi-voxel pattern analyses were applied within networks associated with episodic memory retrieval and demonstrated the ability to robustly decode characteristics of photographic source and pre-exposure. Analyses also revealed an interaction between the networks' decoding capabilities. Moreover, brain activity in the hippocampus was interrogated for changes along the longitudinal axis, which demonstrated a gradation of differential activation for the memory processes examined in the experiment. These findings contribute to current understanding of episodic memory retrieval processes for events and experiences that occurred in the real world.

May

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Robust neuronal dynamics in premotor cortex during motor planning

Speaker: Vishwa Goudar

Neural activity maintains representations that bridge past and future events, often over many seconds. Network models can produce persistent and ramping activity, but the positive feedback that is critical for these slow dynamics can cause sensitivity to perturbations. Here we use electrophysiology and optogenetic perturbations in the mouse premotor cortex to probe the robustness of persistent neural representations during motor planning. We show that preparatory activity is remarkably robust to large-scale unilateral silencing: detailed neural dynamics that drive specific future movements were quickly and selectively restored by the network. Selectivity did not recover after bilateral silencing of the premotor cortex. Perturbations to one hemisphere are thus corrected by information from the other hemisphere. Corpus callosum bisections demonstrated that premotor cortex hemispheres can maintain preparatory activity independently. Redundancy across selectively coupled modules, as we observed in the premotor cortex, is a hallmark of robust control systems. Network models incorporating these principles show robustness that is consistent with data.

Paper: Li, Svoboda and Druckmann_Nature 2016

Date: 13 May 2016

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: A role for basolateral amygdala in updating expected outcome value in uncertain environments

Speaker: Alexandra Stolyarova

Many everyday decisions from foraging for food to choosing between investment options rely on representations of expected outcome values that are based on previous experience. In naturalistic settings, outcomes of choices are not singular events of constant value but are instead embedded in dynamic reward distributions that fluctuate from one experience to the next. Basolateral amygdala (BLA) and orbitofrontal cortex (OFC) participate in outcome valuation in such volatile environments but their specific roles in this process are frequently difficult to dissociate. To systematically study the neural mechanisms of value updating in uncertain reward conditions, we developed a novel choice task in rodents in which outcome values are determined by normally-distributed delays to reward receipt. At baseline, rats are required to respond to one of two options on a touchscreen, each identical in mean reward rate (1 sucrose pellet/ 10s) but different in the variance of outcome distributions. Following the establishment of stable performance, rats experience reward upshifts (1/ 5s with variance kept constant) and downshifts (1/ 20s) on each option independently and in counterbalanced order, always followed by a return to baseline conditions. This approximates outcome variability encountered by animals in more naturalistic settings. I will summarize results from molecular, computational modeling, and lesion experiments in our lab utilizing this behavioral paradigm, demonstrating a specific role for BLA in guiding choice behavior under conditions of uncertainty and updating value expectations in response to changes in reward conditions. Preliminary evidence suggests OFC may anchor choice to the mean rate of reward, and that BLA instead dynamically adjusts the learning rate, or the degree to which value estimates are updated in response to new reward information, to guide flexible choice behavior in volatile environments.

For a review of previous findings implicating BLA in outcome valuation: http://www.sciencedirect.com/science/article/pii/S0149763415300373

Date: 06 May 2016

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Divergent Routing of Positive and Negative Information from the Amygdala during Memory Retrieval

Speaker: Jennifer Tribble

Paper Discussed: http://www.sciencedirect.com/science/article/pii/S0896627316001835

Although the basolateral amygdala (BLA) is known to play a critical role in the formation of memories of both positive and negative valence, the coding and routing of valence-related information is poorly understood. Here, we recorded BLA neurons during the retrieval of associative memories and used optogenetic-mediated phototagging to identify populations of neurons that synapse in the nucleus accumbens (NAc), the central amygdala (CeA), or ventral hippocampus (vHPC). We found that despite heterogeneous neural responses within each population, the proportions of BLA-NAc neurons excited by reward predictive cues and of BLA-CeA neurons excited by aversion predictive cues were higher than within the entire BLA. Although the BLA-vHPC projection is known to drive behaviors of innate negative valence, these neurons did not preferentially code for learned negative valence. Together, these findings suggest that valence encoding in the BLA is at least partially mediated via divergent activity of anatomically defined neural populations.

April

Date: 29 April 2016

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Aging-Related Hyperexcitability in CA3 Pyramidal Neurons Is Mediated by Enhanced A-Type K+ Channel Function and Expression

Speaker: Ryan Guglietta

Paper Discussed: http://www.jneurosci.org/content/35/38/13206.long

Aging-related impairments in hippocampus-dependent cognition have been attributed to maladaptive changes in the functional properties of pyramidal neurons within the hippocampal subregions. Much evidence has come from work on CA1 pyramidal neurons, with CA3 pyramidal neurons receiving comparatively less attention despite its age-related hyperactivation being postulated to interfere with spatial processing in the hippocampal circuit. Here, we use whole-cell current-clamp to demonstrate that aged rat (29-32 months) CA3 pyramidal neurons fire significantly more action potentials (APs) during theta-burst frequency stimulation and that this is associated with faster AP repolarization (i.e., narrower AP half-widths and enlarged fast afterhyperpolarization). Using a combination of patch-clamp physiology, pharmacology, Western blot analyses, immunohistochemistry, and array tomography, we demonstrate that these faster AP kinetics are mediated by enhanced function and expression of Kv4.2/Kv4.3 A-type K(+) channels, particularly within the perisomatic compartment, of CA3 pyramidal neurons. Thus, our study indicates that inhibition of these A-type K(+) channels can restore the intrinsic excitability properties of aged CA3 pyramidal neurons to a young-like state. Significance statement: Age-related learning deficits have been attributed, in part, to altered hippocampal pyramidal neuronal function with normal aging. Much evidence has come from work on CA1 neurons, with CA3 neurons receiving comparatively less attention despite its age-related hyperactivation being postulated to interfere with spatial processing. Hence, we conducted a series of experiments to identify the cellular mechanisms that underlie the hyperexcitability reported in the CA3 region. Contrary to CA1 neurons, we demonstrate that postburst afterhyperpolarization is not altered with aging and that aged CA3 pyramidal neurons are able to fire significantly more action potentials and that this is associated with faster action potential repolarization through enhanced expression of Kv4.2/Kv4.3 A-type K(+) channels, particularly within the cell bodies of CA3 pyramidal neurons.

Date: 22 April 2016

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Stimulus-Response Habit Learning in Humans

Speaker: Tara Patterson

Much of what we know about stimulus-response habit learning comes from experiments performed with non-human animals, and the precise location and nature of the habit learning system in the human brain remains unclear. For example, in the rat, subregions of the striatum that underlie goal-directed and habit behavior have been discovered using lesion techniques, but research on the extent to which this subregional specificity holds in the human brain has yielded mixed results. In this talk, I will discuss a recent meta-analysis of the human habit learning literature, and present empirical work from our lab on how stress and distraction influence habit learning in humans.

Relevant papers:

Iaria et al., 2003: http://www.jneurosci.org/content/23/13/5945.long Tricomi et al., 2009: http://onlinelibrary.wiley.com/doi/10.1111/j.1460-9568.2009.06796.x/full Schwabe & Wolf, 2012: http://www.jneurosci.org/content/32/32/11042.full Patterson et al., 2013: http://onlinelibrary.wiley.com/doi/10.1002/hipo.22174/full

Date: 15 April 2016

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Memory retrieval by activating engram cells in mouse models of early Alzheimer's disease

Speaker: David Glanzman

Paper discussed: http://www.nature.com/nature/journal/v531/n7595/full/nature17172.html

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive memory decline and subsequent loss of broader cognitive functions. Memory decline in the early stages of AD is mostly limited to episodic memory, for which the hippocampus has a crucial role. However, it has been uncertain whether the observed amnesia in the early stages of AD is due to disrupted encoding and consolidation of episodic information, or an impairment in the retrieval of stored memory information. Here we show that in transgenic mouse models of early AD, direct optogenetic activation of hippocampal memory engram cells results in memory retrieval despite the fact that these mice are amnesic in long-term memory tests when natural recall cues are used, revealing a retrieval, rather than a storage impairment. Before amyloid plaque deposition, the amnesia in these mice is age-dependent, which correlates with a progressive reduction in spine density of hippocampal dentate gyrus engram cells. We show that optogenetic induction of long-term potentiation at perforant path synapses of dentate gyrus engram cells restores both spine density and long-term memory. We also demonstrate that an ablation of dentate gyrus engram cells containing restored spine density prevents the rescue of long-term memory. Thus, selective rescue of spine density in engram cells may lead to an effective strategy for treating memory loss in the early stages of AD.

Date: 08 April 2016

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Promoter-Specific Effects of DREADD Modulation on Hippocampal Synaptic Plasticity and Memory Formation

Speaker: Walt Babiec

Paper discussed: http://www.jneurosci.org/content/36/12/3588.long

The Wood Lab provides us with a cautionary tale on the use and interpretation of chemo-/opto-genetics to manipulate brain function and behavior. Sometimes it's more complicated than adding a little more excitation. Abstract is below.

Designer receptors exclusively activated by designer drug (DREADDs) are a novel tool with the potential to bidirectionally drive cellular, circuit, and ultimately, behavioral changes. We used DREADDs to evaluate memory formation in a hippocampus-dependent task in mice and effects on synaptic physiology in the dorsal hippocampus. We expressed neuron-specific (hSyn promoter) DREADDs that were either excitatory (HM3D) or inhibitory (HM4D) in the dorsal hippocampus. As predicted, hSyn-HM3D was able to transform a subthreshold learning event into long-term memory (LTM), and hSyn-HM4D completely impaired LTM formation. Surprisingly, the opposite was observed during experiments examining the effects on hippocampal long-term potentiation (LTP). hSyn-HM3D impaired LTP and hSyn-HM4D facilitated LTP. Follow-up experiments indicated that the hSyn-HM3D-mediated depression of fEPSP appears to be driven by presynaptic activation of inhibitory currents, whereas the hSyn-HM4D-mediated increase of fEPSP is induced by a reduction in GABAAreceptor function. To determine whether these observations were promoter specific, we next examined the effects of using the CaMKIIα promoter that limits expression to forebrain excitatory neurons. CaMKIIα-HM3D in the dorsal hippocampus led to the transformation of a subthreshold learning event into LTM, whereas CaMKIIα-HM4D blocked LTM formation. Consistent with these findings, baseline synaptic transmission and LTP was increased in CaMKIIα-HM3D hippocampal slices, whereas slices from CaMKIIα-HM4D mice produced expected decreases in baseline synaptic transmission and LTP. Together, these experiments further demonstrate DREADDs as being a robust and reliable means of modulating neuronal function to manipulate long-term changes in behavior, while providing evidence for specific dissociations between LTM and LTP.

Date: 01 April 2016

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: The calcium sensor synaptotagmin 7 is required for synaptic facilitation

Speaker: Tom O'Dell

Paper discussed: http://www.nature.com/nature/journal/v529/n7584/full/nature16507.html

Activity-dependent forms of short-term plasticity (STP), such as facilitation and depression, dynamically adjust the strength of synaptic transmission in response to different patterns of presynaptic activity. Although STP is thought to have a fundamental role in the ability of synapses to process information contained in patterns of presynaptic spike action potentials, it has been difficult to test this notion experimentally, as the molecular mechanisms underlying STP are poorly understood. Recent findings from Wade Regehr’s laboratory have, however, revealed a crucial role of the synaptotagmin isoform Syt7 in facilitation. These findings not only provide key new insights into the molecular mechanisms responsible for STP but also provide the basis for future studies examining the role of short-term facilitation in neuronal computation.

March

Date: 18 March 2016

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Spatial Gene-Expression Gradients Underlie Prominent Heterogeneity of CA1 Pyramidal Neurons

Speaker: Sylvia Neumann

Paper discussed: http://www.cell.com/neuron/fulltext/S0896-6273(15)01086-7

Tissue and organ function has been conventionally understood in terms of the interactions among discrete and homogeneous cell types. This approach has proven difficult in neuroscience due to the marked diversity across different neuron classes, but it may be further hampered by prominent within-class variability. Here, we considered a well-defined canonical neuronal population—hippocampal CA1 pyramidal cells (CA1 PCs)—and systematically examined the extent and spatial rules of transcriptional heterogeneity. Using next-generation RNA sequencing, we identified striking variability in CA1 PCs, such that the differences within CA1 along the dorsal-ventral axis rivaled differences across distinct pyramidal neuron classes. This variability emerged from a spectrum of continuous gene-expression gradients, producing a transcriptional profile consistent with a multifarious continuum of cells. This work reveals an unexpected amount of variability within a canonical and narrowly defined neuronal population and suggests that continuous, within-class heterogeneity may be an important feature of neural circuits.

Date: 11 March 2016

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Therapies for hyperactive networks in Alzheimer disease

Speaker: Carlos Portera-Cailliau

Carlos will present the following paper Busche_immunoRx_NatNeurosci_2015 which used in vivo two-photon imaging in mouse models of Alzheimer disease and found that two different antibodies to Aβ used for treatment were ineffective at repairing neuronal dysfunction and caused an increase in cortical hyperactivity. This unexpected finding provides a possible cellular explanation for the lack of cognitive improvement by immunotherapy in human studies. Afterwards, he will discuss the following related articles: Busche_Science_2008

Kuchibhotla_Neuron_2008

Busche_PNAS_2012

Date: 04 March 2016

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Hippocampal Neural Activity in a Virtual Morris Water Maze

Speaker: Jason Moore

Abstract: It is commonly believed that a stable cognitive map of space is necessary for the successful execution of any navigation task. Indeed, removal or impairment of the hippocampus, which contains place cells thought to underlie the cognitive map, impairs performance in the Morris Water Maze task, demonstrating a crucial role of hippocampal activity in this task. However, it is unclear if this also means that hippocampal spatial selectivity is required for successful execution of this landmark-based spatial navigation task. Using virtual reality equipment, rats can be trained to solve a virtual Morris Water Maze task, where they must pay attention to the visual cues. This holds a number of advantages, including decreased stress on the animal, and a dry recording condition facilitating electrophysiological recording. I will present results from measuring neural responses from the dorsal hippocampus while the rats executed this virtual navigation task. Surprisingly, we found weak allocentric spatial selectivity in pyramidal neurons of CA1, traditionally described as “place cells.” Instead, these cells showed strong tuning to the distance the rat had traveled, regardless of start position. We also observed directional tuning as well as temporal modulation around the time of reward. These results demonstrate that allocentric spatial selectivity is not necessary for successful landmark-based navigation. Instead, a representation of distance travelled combined with head direction information is sufficient to solve this task and generate an expectation of reward at the appropriate time.

February

Date: 26 February 2016

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Robustness and fragility in the assembly and function of brain circuits

Speaker: Carlos Lois

abstract: Our laboratory investigates the assembly of brain circuits and the mechanisms by which the activity of neurons in these circuits give rise to behavior. In this seminar I will talk about recent studies from my lab where we investigate how interactions between genetically determined programs and neuronal activity regulate the assembly of brain circuits and behavioral output. First, I will talk about how electrical activity regulates the survival and formation of functional synapses in new neurons as they integrate into the adult brain. Second, I will present experiments in which we genetically perturb neuronal activity and observe mechanisms that ensure the constancy of behavior. Third, I will present data regarding how mutations in transgenic songbirds perturb vocal learning behavior. Finally, I will describe a new genetic method that will allow us to investigate the wiring diagram of brain circuits.

Papers discussed: Watching Synaptogenesis in the Adult Brain_Annual Review of Neuroscience

Genetically Increased Cell-Intrinsic Excitability Enhances Neuronal Integration into Adult Brain Circuits_Neuron_2010

Increased Cell-Intrinsic Excitability Induces Synaptic Changes in New Neurons in the Adult Dentate Gyrus That Require Npas4_J Neuroscience_2013

Link to Speaker's website: http://carlosloislab.blogspot.com.es/2014/09/home.html

Date: 19 February 2016

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Patients with Parkinson’s disease show impaired use of priors in conditions of sensory uncertainty

Speaker: Alessandra Perugini

Abstract: Successful interaction with the environment requires an ability to evaluate sensory stimuli and choose a course of action. Sometimes sensory information is unreliable and other information is needed. An effective strategy is to evaluate the physical properties of a stimulus and if uncertainty remains, combine that information with what was experienced previously in similar situations. The neuronal circuits that underlie our ability to link past experience to ongoing decisions are unknown. We explore here whether patients with Parkinson’s disease, a neurodegenerative disease known to involve the basal ganglia, are impaired in perceptual decision-making when sensory information is uncertain and prior information is required to guide decisions. We designed a perceptual decision-making task and manipulated the statistics of the sensory stimuli to determine the influence of past experience on decision-making in the presence of sensory uncertainty. By using a combination of psychophysics and computational modeling, we show that patients with Parkinson’s disease are impaired at combining information from past experience with current sensory information to guide perceptual decision-making compared to healthy people. We also show that the failure to combine prior information with sensory information is independent of feedback learning. We suggest a role of the Basal Ganglia in the integration of past information with ongoing sensory information to guide decision-making.

Date: 12 February 2016

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Causal Cognition in Rats

Speaker: Aaron Blaisdell

Abstract: David Hume posed a dilemma: How do we derive cause-effect relationships in the absence of direct causal perception? His answer was that knowledge of the causal texture of the world was merely an inference (or illusion) derived from observed statistical regularities. Recent challenges from Philosophy, Statistics, and Psychology argue that we can go beyond the information given (i.e., contingency) by dissecting cause-effect relationships using our own actions (i.e., interventions) on the world. I will present evidence that like humans, rats can a) build causal models (i.e., causal maps) of the world using associative processes; b) derive causal inferences from causal maps and their interventions on them; and c) rely on their own sense of agency to derive predictions from interventions.

Date: 5 February 2016

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Grid Cells among C. Elegans’ 302 Neurons? – Exploring the Origin of Space-Time Perception through Ultra-High Speed Microscopy

Speaker: Katsushi Arisaka

Abstract: Throughout the evolutionary process, organisms have developed remarkably sensitive neurosensory mechanisms in order to effectively navigate a given space-time. However, a fundamental issue lies in the fact that these sensory neurons are only able to detect temporal fluctuations of a given stimuli, without any inherent spatial information. Therefore, in order to navigate space efficiently, the temporal stimuli must be reconciled with spatial information through the integration of signals from motor neuron efferents. Unfortunately, progress in this field has been rather slow and restricted to theoretical models, flowcharts, and unintuitive block diagrams. A practical approach, through the whole-brain investigation of the simplest model organism C. elegans (with 302 neurons), would act to shed light on the process of spatial perception. Consequentially, we have developed innovative, ultra-high speed microscopes to observe the whole-brain activity of C. elegans, while it is freely navigating in 2D or 3D under well-controlled experimental conditions. More than a hundred UCLA undergraduate students have conducted this research over the last two years in form of a science club named the Elegant Mind Club. Our intriguing discoveries and our future directions will be presented.

http://www.cell.com/cell/references/S0092-8674(15)01196-4

http://home.physics.ucla.edu/~arisaka/home/

http://www.elegantmind.org/

January

Date: 29 January 2016

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Labelling and optical erasure of synaptic memory traces in the motor cortex

http://www.nature.com/nature/journal/v525/n7569/full/nature15257.html

Speaker: Megha Sehgal

Abstract: Dendritic spines are the major loci of synaptic plasticity and are considered as possible structural correlates of memory. Nonetheless, systematic manipulation of specific subsets of spines in the cortex has been unattainable, and thus, the link between spines and memory has been correlational. We developed a novel synaptic optoprobe, AS-PaRac1 (activated synapse targeting photoactivatable Rac1), that can label recently potentiated spines specifically, and induce the selective shrinkage of AS-PaRac1-containing spines. In vivo imaging of AS-PaRac1 revealed that a motor learning task induced substantial synaptic remodelling in a small subset of neurons. The acquired motor learning was disrupted by the optical shrinkage of the potentiated spines, whereas it was not affected by the identical manipulation of spines evoked by a distinct motor task in the same cortical region. Taken together, our results demonstrate that a newly acquired motor skill depends on the formation of a task-specific dense synaptic ensemble.

Date: 22 January 2016

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Prefrontal Parvalbumin Neurons in Control of Attention

Speaker: Maria Lazaro

Paper: http://www.cell.com/cell/abstract/S0092-8674(15)01557-3

Abstract: While signatures of attention have been extensively studied in sensory systems, the neural sources and computations responsible for top-down control of attention are largely unknown. Using chronic recordings in mice, we found that fast-spiking parvalbumin (FS-PV) interneurons in medial prefrontal cortex (mPFC) uniformly show increased and sustained firing during goal-driven attentional processing, correlating to the level of attention. Elevated activity of FS-PV neurons on the timescale of seconds predicted successful execution of behavior. Successful allocation of attention was characterized by strong synchronization of FS-PV neurons, increased gamma oscillations, and phase locking of pyramidal firing. Phase-locked pyramidal neurons showed gammaphase-dependent rate modulation during successful attentional processing. Optogenetic silencing of FS-PV neurons deteriorated attentional processing, while optogenetic synchronization of FS-PV neurons at gamma frequencies had pro-cognitive effects and improved goal-directed behavior. FS-PV neurons thus act as a functional unit coordinating the activity in the local mPFC circuit during goal-driven attentional processing.

Date: 15 January 2016

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Dynamic Control of Response Criterion in Premotor Cortex during Perceptual Detection under Temporal Uncertainty

Speaker: Nick Hardy

Abstract: Under uncertainty, the brain uses previous knowledge to transform sensory inputs into the percepts on which decisions are based. When the uncertainty lies in the timing of sensory evidence, however, the mechanism underlying the use of previously acquired temporal information remains unknown. We study this issue in monkeys performing a detection task with variable stimulation times. We use the neural correlates of false alarms to infer the subject’s response criterion and find that it modulates over the course of a trial. Analysis of premotor cortex activity shows that this modulation is represented by the dynamics of population responses. A trained recurrent network model reproduces the experimental findings and demonstrates a neural mechanism to benefit from temporal expectations in perceptual detection. Previous knowledge about the probability of stimulation over time can be intrinsically encoded in the neural population dynamics, allowing a flexible control of the response criterion over time.

Paper: http://www.sciencedirect.com/science/article/pii/S0896627315003645

Further reading: http://www.pnas.org/content/103/39/14266 http://www.nature.com/neuro/journal/v8/n12/full/nn1587.html

Date: 8 January 2016

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Central Ghrelin/GHS-R1a activation modulates neuronal excitability, memory and emotion

Speaker: Yu Zhou

Ghrelin is an orexigenic brain-gut hormone promoting feeding and regulating energy metabolism in human and rodents. Its receptor, the growth hormone secretagogue receptor 1a (GHS-R1a), is a highly conserved GPCR that has broad distribution in the central nervous systems. Increasing evidence has shown that GHS-R1a signaling modulates neuronal activity and changes behaviors including reward-seeking and memory performance, but the underlying mechanism is largely unknown. Our study first showed that ghrelin/GHS-R1a activation enhances firing of nigral dopaminergic neurons by inhibiting KV7/KCNQ/M-channels, leading to increased dopamine release in striatum and reduced catalepsy elicited by haloperidol. Secondly, we checked the effect of ghrelin/GHS-R1a activation on memory. Similarly, ghrelin/GHS-R1a activation increases neuronal excitability in hippocampal CA1 and lateral amygdala (LA). However, we found that micro-infusion of ghrelin into LA activates GHS-R1a but interferes with the CTA acquisition. Consistently, micro-infusion of ghrelin into the CA1 of dorsal hippocampus blocks memory performance in MWM, CFC and NPR; While GHS-R1a KO mice showed enhanced memory. PLC and PI3K activation and subsequent inwardly rectifying K+ (Kir2.x) channels disability may contribute to the suppression of ghrelin/GHS-R1a activation on memory. In addition, we found that ghrelin increased, while GHS-R1a antagonist or GHS-R1a knock-out suppressed anxiety- and depression- like behaviors induced by both repeated restraint and chronic social defeat stress model of depression. Further studies are required to uncover how hyperactivity triggered by ghrelin or GHS-R1a activation regulates memory acquisition and mood expression.

Background papers: 1. Andrews Z (2010) the extra-hypothalamic actions of ghrelin on neuronal function. Trends in Neurosciences, 2011, 34( 1): 31-40. 2. Song L, Zhu Q, Liu T, Yu M, Xiao K, Kong Q, Zhao R, Li GD, Zhou Y (2013) Ghrelin modulates lateral amygdala neuronal firing and blocks acquisition for conditioned taste aversion. PLoS One 8,e65422 3. Shi L, Bian X, Qu Z, Ma Z, Zhou Y, Wang K, Jiang H, Xie J (2013) Peptide hormone ghrelin enhances neuronal excitability by inhibition of Kv7/KCNQ channels. Nat Commun 4, e1435 4. Sanger GJ, Furness JB (2016) Ghrelin and motilin receptors as drug targets for gastrointestinal disorders. Nat Rev Gastroenterol Hepatol 13(1):38-48. 5. Ribeiro LF, Catarino T, Santos SD, Benoist M, van Leeuwen JF, Esteban JA, Carvalho AL. (2014) Ghrelin triggers the synaptic incorporation of AMPA receptors in the hippocampus. Proc Natl Acad Sci U S A. 111(1):E149-58.

2015

December

Date: 18 December 2015

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Optogenetic Control of Cell Signaling in Mammalian Cells

Speaker: Won Do Heo

Date: 11 December 2015

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Theta-gamma coupling in human hippocampal CA1 during learning of subsequently recollected items

Natalia Tchemodanov, Ali Titiz, Emily Mankin, Peter Schuette, Michelle Tran, Itzhak Fried, Nanthia Suthana

Speaker: Nanthia Suthana

Abstract: Growing evidence suggests that coupling between the phase of theta and the amplitude of gamma oscillations, known as phase-amplitude cross frequency coupling (CFC), may play a role in hippocampal-dependent memory. Since the hippocampus consists of smaller subregions CA1-4, dentate gyrus and subiculum, which show differential roles in learning and memory, we investigated whether CFC occurs within human hippocampal subregions during a learning and memory task. Local field potential (LFP) activity was recorded from microelectrodes within human hippocampal subregions in epilepsy patients implanted with intracranial depth electrodes. Subjects completed an object recognition task, where novel images (targets) were learned and later viewed with similar (lure) images to be identified as OLD or NEW. Theta-gamma CFC was significantly higher within hippocampal CA1 during learning of subsequently recollected compared to forgotten items. This effect was not present in other hippocampal subregions and therefore suggests a specific role for CFC in the human hippocampal CA1 subregion during learning that relates to whether an item will later be recollected.

Date: 04 December 2015

Time: 09:30 am

Place: CHS 13-105

Title: Regulation of fear memory after retrieval - mechanisms of transition from fear to safety

Speaker: Satoshi Kida

Memory retrieval is not a passive phenomenon. Previous studies have presented evidence that memory retrieval is a dynamic process during which memories can be made stronger, weaker, or their content can be altered. Recent studies have shown that reactivated memory becomes labile after retrieval and is re-stabilized through a gene expression-dependent process known as memory reconsolidation. Memory reconsolidation after retrieval may be used to maintain or update long-term memories, reinforcing or integrating new information into them. In classical Pavlovian fear conditioning paradigms, the reactivation of conditioned fear memory by re-exposure to the conditioned stimulus (CS) in the absence of the unconditioned stimulus (US) also initiates extinction as a form of new learning that weakens fear memory expression (i.e., a new CS-no US inhibitory memory that competes with the original CS-US memory trace). Thus, in the fear conditioning paradigms, memory retrieval also includes extinction learning. Therefore, when fear memory is retrieved, the dominance of the original (fear) or new (extinction) memory traces is thought to determine the fate of memory through their competition.　We have tried to understand mechanisms by which the fate of retrieved fear memory is determined. We identified reconsolidation and extinction neurons, and found a memory process for the transition of memory phases from reconsolidation to extinction.

November

Date: 20 November 2015

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Encoding of action by the Purkinje cells of the cerebellum

Speaker: Kostya Bakhurin

Authors: David J. Herzfeld, Yoshiko Kojima, Robijanto Soetedjo & Reza Shadmehr Execution of accurate eye movements depends critically on the cerebellum, suggesting that the major output neurons of the cerebellum, Purkinje cells, may predict motion of the eye. However, this encoding of action for rapid eye movements (saccades) has remained unclear: Purkinje cells show little consistent modulation with respect to saccade amplitude or direction, and critically, their discharge lasts longer than the duration of a saccade. Here we analysed Purkinje-cell discharge in the oculomotor vermis of behaving rhesus monkeys (Macaca mulatta) and found neurons that increased or decreased their activity during saccades. We estimated the combined effect of these two populations via their projections to the caudal fastigial nucleus, and uncovered a simple-spike population response that precisely predicted the real-time motion of the eye. When we organized the Purkinje cells according to each cell’s complex-spike directional tuning, the simple-spike population response predicted both the real-time speed and direction of saccade multiplicatively via a gain field. This suggests that the cerebellum predicts the real-time motion of the eye during saccades via the combined inputs of Purkinje cells onto individual nucleus neurons. A gain-field encoding of simple spikes emerges if the Purkinje cells that project onto a nucleus neuron are not selected at random but share a common complex-spike property.

Date: 13 November 2015

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: The role of corticostriatal circuits in negative occasion setting

Speaker: Justin Shobe

Abstract: In a complex environment individual cues alone often have poor predictive value. However, animals can learn to use multiple cues to resolve situational ambiguity, thereby allowing them to make more informed behavioral responses. For instance, the sight of food triggers an instinctual approach response, but an experienced animal will only proceed in the absence of any innate as well as learned signs of danger. In these situations, it is remarkable how even neutral cues can, through learning, gain powerful inhibitory control over behavior. This is true even when discrete cues are separated in time, clearly indicating that memory processes, such as working memory, can hold onto critical information for later use. Primarily this process has been studied at the behavioral level. Thus, it is unclear how neuronal circuits generate these kinds of inhibitory signals as well as how this information is maintained across time to modulate the recall of subsequent representations that drive specific behavioral outcomes. In order to address these questions, I will discuss our simplified Pavlovian feature negative conditioning paradigm that captures the critical hallmarks of this learning because it is the pattern of temporally separated odors (rather than an individual odor) that predicts the absence of a reward delivery. Specifically, mice learn that a reward follows a single odor presented alone (CS1àR) but if this odor is preceded by a separate cue (CS2) the trial is unrewarded (CS2-CS1àNR). Mice appear to solve this task using an ‘occasion setting’ strategy because we observe that the CS2 feature cue temporarily and specifically modulates the association between the CS1 target cue and reward. Thus, we hypothesize that CS2 initiates a working memory component that selectively gates the ability of the CS1 to trigger reward representations. Consistent with this interpretation, we simultaneously recorded activity in regions that are critical for working memory (the frontal cortex) and reward processing (the striatum) using large-scale multichannel microelectrode arrays (256 channels/region) and found significantly diminished activity during the target CS1 presentation only when it follows the feature cue (CS2). Taken together this suggests that, within cortico-striatal circuits, cue pattern can establish inhibitory gating properties that mediate behavioral responses.

Date: 7 November 2015

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Low noise encoding of touch in cortex

Speaker: Samuel Andrew Hires

http://www.ncbi.nlm.nih.gov/pubmed/26245232

October

Date: 30 October 2015

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Early postnatal immune activation plays a critical role in both the social and spatial memory deficits in an animal model of tuberous sclerosis

Speaker: Manuel López Aranda

Abstract: While autism spectrum disorder (ASD) affects approximately 1 % of the world population, 40-50% of individuals affected by tuberous sclerosis (TSC) are also diagnosed with ASD. Interactions between the TSC gene mutations and other risk factors, such as pre and post-natal immune activation, could account for the partial penetrance of ASD in TSC. In my talk, I will present unpublished findings from our laboratory that demonstrate that early postnatal immune activation induces memory deficits in Tsc2 heterozygous adult mice: our KO and pharmacological experiments suggest that strong immune activation modulated by the interferon system in Tsc2 mice leads to social memory deficits, while background levels of immune activation lead to spatial memory phenotypes in Tsc2 mice. Additionally, I will present results in Tsc2 mice that suggest that an FDA approved drug could be used to either prevent, or reverse the spatial and social memory deficits associated with TSC.

Links background papers: http://www.ncbi.nlm.nih.gov/pubmed/21079609 http://www.ncbi.nlm.nih.gov/pubmed/21115397

Date: 23 October 2015

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Memory Formation and Transcriptional Activation

Speaker: Shivan Bonanno

Korb et al., 2015 Nature Neuroscince

Precise regulation of transcription is crucial for the cellular mechanisms underlying memory formation. However, the link between neuronal stimulation and the proteins that directly interact with histone modifications to activate transcription in neurons remains unclear. Brd4 is a member of the bromodomain and extra-terminal domain (BET) protein family, which binds acetylated histones and is a critical regulator of transcription in many cell types, including transcription in response to external cues. Small molecule BET inhibitors are in clinical trials, yet almost nothing is known about Brd4 function in the brain. Here we show that Brd4 mediates the transcriptional regulation underlying learning and memory. The loss of Brd4 function affects critical synaptic proteins, which results in memory deficits in mice but also decreases seizure susceptibility. Thus Brd4 provides a critical link between neuronal activation and the transcriptional responses that occur during memory formation.

Date: 09 October 2015

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Epigenetic Mechanisms of Habit Learning

Speaker: Melissa Malveaz (Wassum lab)

Abstract: Considerable evidence suggests that instrumental behavior depends on two distinct learning processes; one cognitive, in which the relationship between actions and their consequences is encoded, and one habitual, involving the formation of stimulus-response associations. These processes rely on dissociable neural circuits, but beyond this very little is known about the mechanisms required to form these associative memories. Given the recently ascribed role for epigenetics in memory formation, we examined the role of one such mechanism, histone acetylation, in instrumental learning. Rats were trained to lever press for a food reward and were administered the non-specific histone deacetylase (HDAC) inhibitor sodium butyrate (NaB) immediately following each training session. Following training, devaluation of the food outcome was used to probe cognitive versus habitual control of instrumental behavior. Although both groups learned the task, those rats treated with NaB showed insensitivity to outcome devaluation earlier in training than vehicle-treated rats, suggesting that HDAC inhibition potentiated habit formation. Insensitivity to degradation in the action-outcome contingency was also observed and the potentiation of habit occurred regardless of training schedule (i.e., random interval v. ratio). Systemic HDAC inhibition increased histone H4 lysine 8 acetylation specifically in the dorsal striatum, a major component of the instrumental learning circuit. In follow-up experiments, selective modulation of HDAC3 activity in the dorsolateral striatum was found to be sufficient to modulate the sensitivity of instrumental action to devaluation. These data identify chromatin modification by histone acetylation as an important mechanism in the development of stimulus-response associative memories. Moreover, the results suggest that HDAC inhibition can potentiate habitual over cognitive instrumental learning processes, a finding with important implications for the therapeutic application of HDAC inhibitors.

Date: 02 October 2015

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Deep Learning: What should neuroscientists learn from machine learning?

Speaker: Dean Buonomano

Deep learning http://www.nature.com/nature/journal/v521/n7553/full/nature14539.html Human-level control through deep reinforcement learning http://www.nature.com/nature/journal/v518/n7540/full/nature14236.html

September

Date: 25 September 2015

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Motor cortex is required for learning but not for executing motor skill

Speaker: Paul Mathews

The motor cortex is often considered the main controller for movement, but a new study shows that well-trained paw movements can be performed with equal precision after lesions of the entire motor cortex; the motor cortex is, however, required for learning a new task in naïve animals.

Paper:http://www.sciencedirect.com/science/article/pii/S0896627315002202?np=y

Perspective: http://www.sciencedirect.com/science/article/pii/S0960982215004364

June

Date: 12 June 2015

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Time Cells in the Hippocampus: a new dimension for mapping memories

Speaker: Helen Motanis (Buonomano Lab)

Recent studies have revealed the existence of hippocampal neurons that fire at successive moments in temporally structured experiences. Several studies have shown that such temporal coding is not attributable to external events, specific behaviours or spatial dimensions of an experience. Instead, these cells represent the flow of time in specific memories and have therefore been dubbed 'time cells'. The firing properties of time cells parallel those of hippocampal place cells; time cells thus provide an additional dimension that is integrated with spatial mapping. The robust representation of both time and space in the hippocampus suggests a fundamental mechanism for organizing the elements of experience into coherent memories. My talk will focus on a series of papers by the Eichenbaum lab showing the involvement of the Hippocampus in the memory of sequence of events Fortin et al. 2002 NatureNeuroscience , Manns et al., 2007 Neuron and the discovery of 'Time cells' Kraus et al., 2013 Neuron , MacDonald et al., 2013 JNS , Eichenbaum 2014 NatureNsReviews.

May

Date: 29 May 2015

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Cell-type-specific sensorimotor processing in striatal projection neurons during goal-directed behavior

Speaker: Tanya Sippy

Speaker Bio: Dr. Sippy started her neuroscience career as an undergraduate at UCLA studying synaptic mechanisms underlying short term plasticity. She then completed her MD and PhD degrees at Columbia University where she became interested how different interneuronal subtypes influence local circuit processing. Afterward, Dr. Sippy completed a postdoctoral fellowship at the EPFL in Lausanne, Switzerland, where she applied the technique of in vivo patch clamp to study the role of striatal neuron subtypes during rewarded behaviors. She is currently at New York University where she is pursuing her residency in the psychiatry research track.

Abstract: A key function of the brain is to interpret incoming sensory information in the context of learned associations in order to guide adaptive behavior. However, the neuronal circuits and causal mechanisms underlying goal-directed sensorimotor transformations remain to be clearly defined for the mammalian brain. The basal ganglia, including the striatum and the dopamine reward system, are thought to be involved in action initiation and selection and their dysfunction is associated with Parkinson’s disease, as well as other brain disorders typically involving sensorimotor deficits. We investigated the role of the striatum in a simple task in which mice learn to lick for water reward in response to a single brief whisker deflection (Sachidhanandam et al., 2013). Mice were trained to detect single deflections of the C2 whisker, and report the deflection by licking a spout to obtain water. Whole-cell recordings revealed strong task-related modulation of membrane potential in the somatosensory striatum. Membrane potential depolarization was significantly larger in hit versus miss trials, correlating with perceptual report. This depolarization has two phases; an early phase corresponding to the sensory stimulation, and a late phase, which we define as the period after the early phase before the animal licks, both of which are larger during hit trials. In addition, in a minority of cells where that fire action potentials, the probability of firing action potentials is higher during hit trials. Interestingly, in response to sensory whisker stimulation, D1R-expressing direct pathway striatal projection neurons transiently depolarized more rapidly and more strongly than D2R-expressing indirect pathway neurons. Transient activity in D1R-expressing neurons could therefore contribute to driving the licking behavior. We tested this hypothesis using optogenetics, finding that transient stimulation of D1R-expressing direct pathway striatal projection neurons, but not D2R-expressing indirect pathway neurons, robustly evoked licking in trained mice. Our results are consistent with learned, goal-directed sensorimotor transformations resulting from enhanced signaling in D1R-expressing striatal projection neurons of the direct ‘go’ pathway.

Background papers: http://www.nature.com/nature/journal/v521/n7552/full/nature14225.html

Date: 15 May 2015

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: AMPA receptor Phosphorylation and Synaptic Plasticity

Speaker: Tom O'Dell

Phosphorylation-dependent changes in the activity and trafficking of AMPA-type glutamate receptors is thought to have a crucial role in both LTP and LTD. Moreover, PKA-mediated phosphorylation of AMPA receptor GluA1 subunits is responsible for the enhancement of LTP induction and learning induced by modulatory neurotransmitters such as norepinephrine. Recent findings from Yasunori Hayashi’s laboratory using a novel, quantitative biochemical technique (Phos-tag SDS-PAGE) to measure the stoichiometry of AMPA receptor phosphorylation indicate, however, that very few, if any, AMPA receptors are phosphorylation at sites implicated in synaptic plasticity. In my talk I will discuss the implications of the new findings from Hayashi’s lab and describe the results from recent experiments in our lab addressing this question.

Paper: http://www.cell.com/neuron/abstract/S0896-6273%2814%2901078-2

Date: 1 May 2015

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Artificial Association of Pre-stored Information to Generate a Qualitatively New Memory

Speaker: Sarah Hersman (Fanselow Lab)

Memory is thought to be stored in the brain as an ensemble of cells activated during learning. Although optical stimulation of a cell ensemble triggers the retrieval of the corresponding memory, it is unclear how the association of information occurs at the cell ensemble level. Using optogenetic stimulation without any sensory input in mice, we found that an artificial association between stored, non-related contextual, and fear information was generated through the synchronous activation of distinct cell ensembles corresponding to the stored information. This artificial association shared characteristics with physiologically associated memories, such as N-methyl-D-aspartate receptor activity and protein synthesis dependence. These findings suggest that the association of information is achieved through the synchronous activity of distinct cell ensembles. This mechanism may underlie memory updating by incorporating novel information into pre-existing networks to form qualitatively new memories.

Paper: http://www.cell.com/cell-reports/abstract/S2211-1247%2815%2900270-3

Background Material:

Optogenetic stimulation of memory engram leading to memory retrieval:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3331914/

Creation of artificial memories:

http://www.ncbi.nlm.nih.gov/pubmed/22442487

http://www.sciencemag.org/content/341/6144/387

http://www.ncbi.nlm.nih.gov/pubmed/25322798

April

Date: 24 April 2015

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Some Observations on Biological Noise

Speaker: Walt Babiec (O'Dell Lab)

Behavioral and anatomical studies support a functional segmentation between dorsal and ventral hippocampus. The dorsal (posterior in primates) hippocampus performs primarily cognitive functions. The ventral (anterior in primates) relates to stress, emotion, and affect. Perhaps to help in mediating these different roles, Schaffer collateral (SC) fiber synapses onto pyramidal cells (PCs) in the CA1 region of the dorsal and ventral hippocampus exhibit striking differences in both short-term and long-term plasticity. Importantly, evoked and spontaneous synaptic transmission may involve distinct molecular mechanisms, pools of presynaptic vesicles, and postsynaptic receptors. For this reason, we’ve been examining evoked and spontaneous transmission at SC-PC excitatory synapses in CA1 of dorsal and ventral hippocampus to determine whether the properties of spontaneous transmitter release also differ along the septotemporal axis of the hippocampus. Given the robust differences in short-term plasticity at excitatory synapses in the CA1 region of dorsal and ventral hippocampus, we’ve been particularly interested in examining whether the higher probability of transmitter release at ventral synapses (suggested by reduced paired-pulse facilitation compared to dorsal hippocampus) is associated with higher levels of spontaneous transmitter release. I’ll be talking about some observations we’ve found so far.

Background Material:

Fanselow & Dong: http://www.sciencedirect.com/science/article/pii/S0896627309009477

Kavalali: http://www.nature.com/nrn/journal/v16/n1/full/nrn3875.html

Kaeser & Regehr: http://www.annualreviews.org/doi/full/10.1146/annurev-physiol-021113-170338?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed&

Date: 17 April 2015

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Branch-specific dendritic Ca2+ spikes cause persistent synaptic plasticity

Speaker: Anu Goel (Portera Lab)

The brain has an extraordinary capacity for memory storage, but how it stores new information without disrupting previously acquired memories remains unknown. Here we show that different motor learning tasks induce dendritic Ca2+ spikes on different apical tuft branches of individual layer V pyramidal neurons in the mouse motor cortex. These task-related, branch-specific Ca2+ spikes cause long-lasting potentiation of postsynaptic dendritic spines active at the time of spike generation. When somatostatin-expressing interneurons are inactivated, different motor tasks frequently induce Ca2+ spikes on the same branches. On those branches, spines potentiated during one task are depotentiated when they are active seconds before Ca2+ spikes induced by another task. Concomitantly, increased neuronal activity and performance improvement after learning one task are disrupted when another task is learned. These findings indicate that dendritic-branch-specific generation of Ca2+ spikes is crucial for establishing long-lasting synaptic plasticity, thereby facilitating information storage associated with different learning experiences.

Date: 10 April 2015 (YOUNG INVESTIGATOR SEMINAR)

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Corticostriatal Plasticity in Reward History and Addiction

Speaker: Andrew Thompson (Izquierdo Lab)

The striatum is important for learning from the decisions we make and altering behavior to maximize reward acquisition rate. Through dopaminergic modulation of the direct and indirect pathways, the striatum serves as a final ‘gate’ between impulse and action. Drugs of abuse such as methamphetamine exert their rewarding effects by increasing dopamine release to the striatum, reinforcing the preceding behaviors. Corticostriatal long-term potentiation occurs when three events coincide: presynaptic activation, postsynaptic activation, and time-locked phasic dopamine signaling. Brain derived neurotrophic factor (BDNF) is released in an activity-dependent manner from cortical input neurons, triggering a phosphorylation event at the tropomyosin-related kinase B (TrkB) receptor, activating intracellular signaling pathways which strengthen the associated synapse. Therefore, periods of high and low TrkB signaling in the striatum create critical windows for reward learning. Here we show that methamphetamine and exercise alone are both able to transiently increase TrkB signaling in the rat striatum, but that pre-exposure to methamphetamine blocks the effect of exercise on this measure.

Date: 03 April 2015 (YOUNG INVESTIGATOR SEMINAR)

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Rodent Hippocampal Activity in Real and Virtual Environments

Speaker: Zahra M. Aghajan (Mehta Lab)

The hippocampus is linked to our ability to form episodic memories by providing a spatial cognitive map together with the content of experiences. In rodents, the focus has largely been on the role of hippocampus in the representation of space but despite decades-long research, the underlying mechanisms remain unknown. It has been shown that multiple sensory and motor inputs reach the hippocampus and can modulate its activity. In real world (RW) environments however, the contributions of these inputs are confounded. Thus, to dissociate these contributions and thereby elucidate the mechanisms of spatial selectivity, we used a virtual reality (VR) setup.

We found comparable levels of hippocampal spatiotemporal selectivity on linear tracks in RW and VR. In contrast, during random foraging in two-dimensions, spatial selectivity was severely diminished in VR. Nevertheless, most spikes occurred within ~2-s-long hippocampal motifs—with similar structure to that in RW—within which hippocampal temporal code was intact, demonstrating a decoupling between the spatial and the temporal codes. Further, additional experiments and analysis revealed significant directional selectivity in the hippocampus in RW and VR. Notably, contrary to the impairment of spatial selectivity in VR, the degree of directional selectivity was identical in both worlds and determined by the angular information contained in the visual cues. Taken together, these results suggest that while visual cues alone are insufficient to generate a stable localized representation in the spatial domain, they are sufficient to elicit—and play a causal role in—hippocampal directional selectivity.

Relevant papers:

http://www.sciencemag.org/content/340/6138/1342.full

http://www.nature.com/neuro/journal/v18/n1/full/nn.3884.html

http://biorxiv.org/content/early/2015/03/28/017210

March

Date: 20 March 2015

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Ensemble dynamics in the lateral amygdala encode the formation of new fear memories

Speaker: Benjamin Grewe (Golshani Lab)

Previous research has investigated molecular, synaptic and cellular substrates of fear memory in the basolateral amygdala (BLA), but neural ensemble mechanisms underlying fear learning remain unknown. Using miniaturized imaging techniques we recorded neuronal ensembles in the BLA of freely moving mice and followed ensemble coding of conditioned and unconditioned stimuli throughout a multi day fear learning paradigm. We were able to show how aversive experiences during fear learning change the ensemble code of a neutral conditioned stimulus, to incorporate elements of aversive coding.

Date: 06 March 2015

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: A temporal shift in the circuits mediating retrieval of fear memory

Speaker: Michael Einstein (Golshani Lab)

Fear memories allow animals to avoid danger, thereby increasing their chances of survival. Fear memories can be retrieved long after learning, but little is known about how retrieval circuits change with time. Here we show that the dorsal midline thalamus of rats is required for the retrieval of auditory conditioned fear at late (24 hours, 7 days, 28 days), but not early (0.5 hours, 6 hours) time points after learning. Consistent with this, the paraventricular nucleus of the thalamus (PVT), a subregion of the dorsal midline thalamus, showed increased c-Fos expression only at late time points, indicating that the PVT is gradually recruited for fear retrieval. Accordingly, the conditioned tone responses of PVT neurons increased with time after training. The prelimbic (PL) prefrontal cortex, which is necessary for fear retrieval, sends dense projections to the PVT. Retrieval at late time points activated PL neurons projecting to the PVT, and optogenetic silencing of these projections impaired retrieval at late, but not early, time points. In contrast, silencing of PL inputs to the basolateral amygdala impaired retrieval at early, but not late, time points, indicating a time-dependent shift in retrieval circuits. Retrieval at late time points also activated PVT neurons projecting to the central nucleus of the amygdala, and silencing these projections at late, but not early, time points induced a persistent attenuation of fear. Thus, the PVT may act as a crucial thalamic node recruited into cortico-amygdalar networks for retrieval and maintenance of long-term fear memories.

February

Date: 27 February 2015

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Strategies for Early Detection and Treatment of Neurodegeneration

Speaker: Gary Small

Background Papers: Small et al., 2008 Bookheimer et al., 2008 Chen et al., 2014 Small et al., 2013 Small et al., 2012 Small et al., 2006

Date: 20 February 2015 </font> YOUNG INVESTIGATOR SEMINAR

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Co-allocation of neural ensembles links different memories across time

Speaker: Denise Cai (Silva Lab) While there have been significant advances in the understanding of the mechanisms underlying the storage of single memories, real-world memories, however, involve the integration of multiple memories across time, with one memory affecting how another is processed and stored. Recent studies find that virally increasing neuronal excitability changes the probability of that neuron to participate in a memory trace (i.e. cellular allocation). This leads to the prediction that the induction of one memory will trigger a time-dependent increase in excitability that will then affect the cellular allocation of a subsequent memory, thus sharing a neural ensemble will link the two memories across time. Using in vivo calcium imaging (with miniaturized fluorescent microscopes in freely behaving mice), the TetTag transgenic system, we found that a given contextual memory can affect which CA1 neurons store a subsequent contextual memory 5 hours later (when there is increased excitability in the neurons participating in the first memory) but not 7 days later. The CA1 neuronal ensembles representing each of the two memories co-allocate significantly (>20% above chance) when they are separated by 5 hours but not by 7 days. Interestingly, we found evidence that the co-allocation between cellular ensembles also led to contextual linking as fear from a context paired with shock was generalized to a non-shocked context when the two episodes were spaced by 5 hours, but not by 7 days. We found enhanced behavioral memory for the second episode, when spaced 5 hours from the first episode but not when spaced by 7 days, presumably due to the transient increase in excitability. Finally, our studies in older mice, known to have decreased excitability in CA1, revealed a disruption of co-allocation processes that link memories across time. Altogether, these results provide important insights into how intrinsic changes in excitability can serve to temporally and contextually link multiple memories.

Background Papers: Silva et al., 2009 Rogerson et al., 2014

Date: 13 February 2015

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Activity-Induced Nr4a1 Regulates Spine Density and Distribution Pattern of Excitatory Synapses in Pyramidal Neurons

Speaker: Shivan Bonanno (Martin Lab)

Excitatory synapses occur mainly on dendritic spines, and spine density is usually correlated with the strength of excitatory synaptic transmission. We report that Nr4a1, an activity-inducible gene encoding a nuclear receptor, regulates the density and distribution of dendritic spines in CA1 pyramidal neurons. Nr4a1 overexpression resulted in elimination of the majority of spines; however, postsynaptic densities were preserved on dendritic shafts, and the strength of excitatory synaptic transmission was unaffected, showing that excitatory synapses can be dissociated from spines. mRNA expression profiling studies suggest that Nr4a1-mediated transcriptional regulation of the actin cytoskeleton contributes to this effect. Under conditions of chronically elevated activity, when Nr4a1 was induced, Nr4a1 knockdown increased the density of spines and PSDs specifically at the distal ends of dendrites. Thus, Nr4a1 is a key component of an activity-induced transcriptional program that regulates the density and distribution of spines and synapses.

Yelin Chen, Yuanyuan Wang, Ali Ertürk, Dara Kallop, Zhiyu Jiang, Robby M. Weimer, Joshua Kaminker, Morgan Sheng

Date: 06 February 2015 YOUNG INVESTIGATOR SEMINAR

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Dissociable profiles of generalization/discrimination in human hippocampus during visual associative memory retrieval

Speaker: Natalie De Shetler (Rissman Lab)

A number of recent high-resolution functional magnetic resonance imaging (hr-fMRI) studies have identified differential discrimination and generalization responses in hippocampal subfields. The combined CA3 / dentate gyrus (CA3DG) region responds similarly to novel stimuli and close lure images of previously viewed stimuli, a discrimination sometimes equated to pattern separation processes. Conversely, activity in CA1 to these same lure images tends to be comparable with that elicited by repeated stimuli. In a parallel line of research into hippocampal subfield functions, several studies have found that the CA1 region is particularly sensitive to whether events match or mismatch one’s memory-based expectations (e.g., associative novelty). However, the expression of these effects may differ according to whether subjects are explicitly oriented towards the goal of detecting mnemonic targets or whether the detection is incidental. We conducted a hr-fMRI study to determine if the previously described profile of mnemonic discrimination in CA3DG and generalization in CA1 persist in an explicit associative memory recall task. Each trial of our task required subjects to retrieve a previously learned visual associate in response to an arbitrarily paired verbal cue stimulus, hold the retrieved memory in mind for a brief interval, and then evaluate whether a visual probe stimulus was the same, similar, or dissimilar from the studied associate. In both CA3DG and CA1 we found match enhancement effects (same > novel). Consistent with prior work, CA3DG responded comparably to lures and novels (discrimination), and CA1 responded comparably to lures and repeated targets (generalization). Importantly, our results reflect dissociable profiles to task conditions. CA3DG discriminated old from new irrespective of the task relevance context, showing the same degree of match enhancement to all repeated images, regardless of whether they were correctly or incorrectly paired; in contrast, CA1 generalized only for repeated stimuli with correct item pairings, while responding to incorrectly paired repeats as if they were novel stimuli.

January

Date: 30 January 2015

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Cerebellar plasticity and motor learning deficits in a copy-number variation mouse model of autism

Speaker: Katrina Choe (Otis Lab)

A common feature of autism spectrum disorder (ASD) is the impairment of motor control and learning, occurring in a majority of children with autism, consistent with perturbation in cerebellar function. Here we report alterations in motor behaviour and cerebellar synaptic plasticity in a mouse model (patDp/+) for the human 15q11-13 duplication, one of the most frequently observed genetic aberrations in autism. These mice show ASD-resembling social behaviour deficits. We find that in patDp/+ mice delay eyeblink conditioning—a form of cerebellum-dependent motor learning—is impaired, and observe deregulation of a putative cellular mechanism for motor learning, long-term depression (LTD) at parallel fibre-Purkinje cell synapses. Moreover, developmental elimination of surplus climbing fibres—a model for activity-dependent synaptic pruning—is impaired. These findings point to deficits in synaptic plasticity and pruning as potential causes for motor problems and abnormal circuit development in autism.

Paper:

Piochon, Kloth, Grasselli, Titley, Nakayama, Hashimoto, Wan, et al.

Additional reading:

http://www.sciencedirect.com/science/article/pii/S0896627306007707

http://www.ncbi.nlm.nih.gov/pubmed/19563756

Date: 23 January 2015

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Delta-Opioid Receptors Mediate Unique Plasticity onto Parvalbumin-Expressing Interneurons in Area CA2 of the Hippocampus

Speaker: Ashley Kees (Mehta Lab)

Inhibition is critical for controlling information transfer in the brain. However, the understanding of the plasticity and particular function of different interneuron subtypes is just emerging. Using acute hippocampal slices prepared from adult mice, we report that in area CA2 of the hippocampus, a powerful inhibitory transmission is acting as a gate to prevent CA3 inputs from driving CA2 neurons. Furthermore, this inhibition is highly plastic, and undergoes a long-term depression following high-frequency, 10 Hz, or theta-burst induction protocols. We describe a novel form of long-term depression at parvalbumin-expressing (PV+) interneuron synapses that is dependent on delta-opioid receptor (DOR) activation.

Paper

Background

Date: 16 January 2015 YOUNG INVESTIGATOR SEMINAR

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Learning-Dependent Behavioral Correlates of Striatal Functional Connectivity

Speaker: Konstantin Bakhurin(Masmanidis Lab)

Because of its unique microcircuit structure, striatal activity is heavily dependent on the patterning of excitatory input the structure receives from a wide range of upstream areas. These synapses are the sites of NMDA-dependent plasticity that is thought to be important for mediating striatal-dependent forms of learning. Therefore, changes in the relationships between striatal neurons and input patterns during learning may result in a reorganization of striatal network activity. We used novel silicon-based electrophysiological probe technology to simultaneously record spiking activity from large populations of neurons in the striatum of awake, behaving mice learning a reward-guided odor-discrimination task. Using correlation-based analysis to characterize the coordinated firing of striatal neurons, we observed that during periods of rest, MSNs that preferentially encode reward-predicting odor cues were more likely to be synchronized to each other than to other, non-preferring MSNs. Furthermore, we found that the resting-state functional connectivity between reward-preferring and non-preferring MSNs was negatively correlated with animals’ performance in the task. This property was detected during early stages of learning, but was absent after extended training. These results demonstrate a learning-dependent relationship between behavioral performance and the correlated state of MSNs that fire in response to cues that predict a salient outcome.

Date: 9 January 2015 YOUNG INVESTIGATOR SEMINAR

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Pronounced impact of out of phase food intake on learning and memory

Speaker: Dawn Loh (Colwell Lab)

The circadian system is a finely tuned network of central and peripheral oscillators headed by a master pacemaker, the suprachiasmatic nucleus (SCN), which governs daily rhythms in behavior and physiology, including cognition. Disruption of the circadian system by genetic mutations or environmental manipulations has severe consequences on learning and memory. In prior work, we established the negative impact of acute jet lag on cognition, demonstrating that acute misalignment of the network of circadian oscillators has pronounced effects on long term memory.

In this study, we sought to determine the effects of chronic and stable misalignment of the circadian network by scheduling access to food at an inappropriate phase of the daily cycle, which alters the phase of many peripheral circadian oscillators without affecting the SCN. Mice were allotted a six hour window in which food was made available either during their active phase (aligned), or during their inactive phase (misaligned). Crucially, in the central nervous system, we determined that misaligned feeding alters the phase of the hippocampal circadian oscillator.

Chronic misalignment of food access resulted in reduced performance on the novel object recognition test and had a severe impact on the recall of contextual fear conditioning, indicating deficits in hippocampal-dependent learning and memory. Critically, although the temporal pattern of sleep was altered, there was no difference in the amount of sleep between the aligned and misaligned groups, thus ruling out effects of sleep deprivation on memory. At the physiological level, misaligned feeding led to deficits in hippocampal long term potentiation, suggesting circadian disruption affects synaptic plasticity.

Our findings suggest that circadian misalignment of the hippocampal oscillator has far-reaching effects on not only hippocampal physiology, but also on the functional outcome of long term memory, and highlight the importance of circadian regulation on cognition.

2014

December 2014

Date: 19 December 2014 SPECIAL SEMINAR

Time: 09:30 am

Place : Gonda 1st Floor Conference Room

Title: Fast protein-synthesis dependent memory traces require the release of stalled polysomes and are independent of translation initiation

Speaker: Wayne Sossin (McGill University)

The Integrated Center for Learning and Memory Journal Club is pleased to welcome Dr. Wayne Sossin of McGill University. All are invited.

Dr. Sossin is a world-renowned investigator of the biochemical changes that occur in the brain during learning and memory. Of particular interest to him is the identification of molecular memory traces that underlie behavioural memory. Currently, his laboratory is investigating several candidates for this molecular trace, including the activation of persistent kinases and the regulated translation of new proteins.

Date: 12 December 2014

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: A category-free neural population supports evolving demands during decision-making

Speaker: Ben Huang

The posterior parietal cortex (PPC) receives diverse inputs and is involved in a dizzying array of behaviors. These many behaviors could rely on distinct categories of neurons specialized to represent particular variables or could rely on a single population of PPC neurons that is leveraged in different ways. To distinguish these possibilities, we evaluated rat PPC neurons recorded during multisensory decisions. Newly designed tests revealed that task parameters and temporal response features were distributed randomly across neurons, without evidence of categories. This suggests that PPC neurons constitute a dynamic network that is decoded according to the animal's present needs. To test for an additional signature of a dynamic network, we compared moments when behavioral demands differed: decision and movement. Our new state-space analysis revealed that the network explored different dimensions during decision and movement. These observations suggest that a single network of neurons can support the evolving behavioral demands of decision-making.

David Raposo, Matthew Kaufman and Anne Churchland

Date: 05 December 2014

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Local impermeant anions establish the neuronal chloride concentration - Novel options for memory storage?

Speaker: Felix Schweizer

Neuronal intracellular chloride concentration [Cl(-)](i) is an important determinant of γ-aminobutyric acid type A (GABA(A)) receptor (GABA(A)R)-mediated inhibition and cytoplasmic volume regulation. Equilibrative cation-chloride cotransporters (CCCs) move Cl(-) across the membrane, but accumulating evidence suggests factors other than the bulk concentrations of transported ions determine [Cl(-)](i). Measurement of [Cl(-)](i) in murine brain slice preparations expressing the transgenic fluorophore Clomeleon demonstrated that cytoplasmic impermeant anions ([A](i)) and polyanionic extracellular matrix glycoproteins ([A](o)) constrain the local [Cl(-)]. CCC inhibition had modest effects on [Cl(-)](i) and neuronal volume, but substantial changes were produced by alterations of the balance between [A](i) and [A](o). Therefore, CCCs are important elements of Cl(-) homeostasis, but local impermeant anions determine the homeostatic set point for [Cl(-)], and hence, neuronal volume and the polarity of local GABA(A)R signaling.

Local Impermeant Anions Establish the Neuronal Chloride Concentration

November 2014

Date: 07 November 2014

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: The Living Record of Memory: Genes, Neurons and Synapses

Speaker: Kelsey Martin

(This week Kelsey Martin will be presenting her SFN Presidential Special Lecture during the ICLM journal club.)

Memory requires stimulus-induced changes in gene expression, which in turn, alters synaptic connectivity and wiring in the brain. In this way, experience combines with our genome to determine who we are as individuals. This talk describes efforts to understand how experience regulates gene expression within neurons, how stimulus-induced signals are transported from distal synapses to the nucleus to alter gene expression, and how gene expression is spatially restricted to specific subcellular compartments.

October 2014

Date: 31 October 2014

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Chronic early-life stress alters developmental and adult neurogenesis and impairs cognitive function in mice

Speaker: Viren Makhijani

Early-life stress (ES) increases vulnerability to psychopathology and impairs cognition in adulthood. These ES-induced deficits are associated with lasting changes in hippocampal plasticity. Detailed information on the neurobiological basis, the onset and progression of such changes and their sex specificity is currently lacking but is required to tailor specific intervention strategies. Here Naninck et al. use a chronic ES mouse model based on limited nesting and bedding material from postnatal day (P) 2-9 to investigate; 1) if ES leads to impairments in hippocampus-dependent cognitive function in adulthood, and 2) if these alterations are paralleled by changes in developmental and/or adult hippocampal neurogenesis. ES increased developmental neurogenesis (proliferation and differentiation) in the dentate gyrus (DG) at P9, and the number of immature (NeurD1+) cells migrating postnatally from the secondary dentate matrix, indicating prompt changes in DG structure in both sexes. ES lastingly reduced DG volume and the long-term survival of developmentally born neurons in both sexes at P150. In adult male mice only, ES reduced survival of adult-born neurons (BrdU/NeuN+ cells), while proliferation (Ki67+) and differentiation (DCX+) were unaffected. These changes correlated with impaired performance in all learning and memory tasks used here. In contrast, in female mice, despite early alterations in developmental neurogenesis, no lasting changes were present in adult neurogenesis after ES and the cognitive impairments were less prominent and only apparent in some cognitive tasks. We further show that, although neurogenesis and cognition correlate positively, only the hippocampus-dependent functions depend on changes in neurogenesis, whereas cognitive functions that are not exclusively hippocampus-dependent do not. This study indicates that chronic ES has lasting consequences on hippocampal structure and function in mice and suggests that male mice are more susceptible to ES than females. Unraveling the mechanisms that underlie the persistent ES-induced effects may have clinical implications for treatments to counteract ES-induced deficits.

Paper: Naninck et al. (2014)

Background: Oomen eta al. (2010)

Date: 24 October 2014

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Engineering a memory with LTD and LTP

Speaker: David Glanzman

It has been proposed that memories are encoded by modification of synaptic strengths through cellular mechanisms such as long-term potentiation (LTP) and long-term depression (LTD). However, the causal link between these synaptic processes and memory has been difficult to demonstrate. Nabavi et al. present data to show that fear conditioning, a type of associative memory, can be inactivated and reactivated by LTD and LTP, respectively. This is done, first, by conditioning an animal to associate a foot shock with optogenetic stimulation of auditory inputs targeting the amygdala, a brain region known to be essential for fear conditioning. Subsequent optogenetic delivery of LTD conditioning to the auditory input inactivated memory of the shock. Then subsequent optogenetic delivery of LTP conditioning to the auditory input reactivated memory of the shock. Thus, engineered inactivation and reactivation of a memory using LTD and LTP, supports a causal link between these synaptic processes and memory.

Paper: Nabavi et al. (2014)

Background: [http://www.nature.com/news/flashes-of-light-show-how-memories-are-made-1.15330 Flashes of light show how memories are made

Date: 17 October 2014

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Sensory-evoked LTP driven by dendritic plateau potentials in vivo

Speaker: Carlos Portera-Cailliau

Long-term synaptic potentiation (LTP) is thought to be a key process in cortical synaptic network plasticity and memory formation. Hebbian forms of LTP depend on strong postsynaptic depolarization, which in many models is generated by action potentials that propagate back from the soma into dendrites. However, local dendritic depolarization has been shown to mediate these forms of LTP as well As pyramidal cells in supragranular layers of the somatosensory cortex spike infrequently it is unclear which of the two mechanisms prevails for those cells in vivo. Using whole-cell recordings in the mouse somatosensory cortex in vivo, Gambino et al. demonstrate that rhythmic sensory whisker stimulation efficiently induces synaptic LTP in layer 2/3 (L2/3) pyramidal cells in the absence of somatic spikes. The induction of LTP depended on the occurrence of NMDAR (N-methyl-D-aspartate receptor)-mediated long-lasting depolarizations, which bear similarities to dendritic plateau potentials. In addition, they show that whisker stimuli recruit synaptic networks that originate from the posteromedial complex of the thalamus (POm). Photostimulation of channelrhodopsin-2 expressing POm neurons generated NMDAR-mediated plateau potentials, whereas the inhibition of POm activity during rhythmic whisker stimulation suppressed the generation of those potentials and prevented whisker-evoked LTP. Taken together, this data provide evidence for sensory-driven synaptic LTP in vivo, in the absence of somatic spiking. Instead, LTP is mediated by plateau potentials that are generated through the cooperative activity of lemniscal and paralemniscal synaptic circuitry.

Paper: Holtmaat_Nature_2014

Date: 10 October 2014

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Sleep promotes branch-specific formation of dendritic spines after learning.

Speaker: Adam Frank (Silva Lab)

How sleep helps learning and memory remains unknown. Recently the Gan lab has reported in mouse motor cortex that sleep after motor learning promotes the formation of postsynaptic dendritic spines on a subset of branches of individual layer V pyramidal neurons. New spines are formed on different sets of dendritic branches in response to different learning tasks and are protected from being eliminated when multiple tasks are learned. Neurons activated during learning of a motor task are reactivated during subsequent non–rapid eye movement sleep, and disrupting this neuronal reactivation prevents branch-specific spine formation. These findings indicate that sleep has a key role in promoting learning-dependent synapse formation and maintenance on selected dendritic branches, which contribute to memory storage.

Paper: Sleep promotes branch-specific formation of dendritic spines after learning

Background Papers: Govindarajan et al (2011) Xu et al (2009)

Date: 03 October 2014

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Volitional modulation of optically recorded calcium signals during neuroprosthetic learning

Speaker: Dean Buonomano

Brain-machine interfaces are not only promising for neurological applications, but also powerful for investigating neuronal ensemble dynamics during learning. We trained mice to operantly control an auditory cursor using spike-related calcium signals recorded with two-photon imaging in motor and somatosensory cortex. Mice rapidly learned to modulate activity in layer 2/3 neurons, evident both across and within sessions. Learning was accompanied by modifications of firing correlations in spatially localized networks at fine scales.

Paper: Volitional modulation of optically recorded calcium signals during neuroprosthetic learning

May 2014

Date: 16 May 2014

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Olfactory cortical neurons read out a relative time code in the olfactory bulb

Speaker: Anu Goel (Buonomano Lab)

Neurons are not only sensitive to the spatial features of stimuli but are also capable of extracting temporal information from stimuli. There are several reports of temporally selective neurons in invertebrates, vertebrates as well as mammals. In particular there is evidence that neurons in the auditory system respond preferentially when pairs or sequences of tones are presented in a specific order with a certain temporal interval between them. The mechanisms underlying this temporal specificity remain to be examined in detail, but one potential candidate is the state-dependent network model. Today I will discuss evidence from a study in the rodent olfactory system where the authors show that piriform cortex neurons exhibit temporal selectivity to specific spatio-temporal stimuli delivered optogenetically to the olfactory bulb.

Paper: Olfactory cortical neurons read out a relative time code in the olfactory bulb

Date: 9 May 2014

Time: 9:30 am

Place : Gonda 2nd Floor Conference Room

Title: DNA Encoding of Learned Information

Speaker: David Glanzman

The point of these papers is that learned information is encoded as changes in DNA structure. And, further, that learned information (here, olfactory fear conditioning) can be transmitted to one's offspring. I will focus my presentation on the paper by Suberbielle et al. (2013) and bring in the paper by Dias and Ressler (2014) at the end.

Date: 2 May 2014

Time: 9:30 am

Place : Gonda 2nd Floor Conference Room

Title: Temporal structure of motor variability is dynamically regulated and predicts motor learning ability

Speaker: Alex Reeves (Otis Lab)

Individual differences in motor learning ability are widely acknowledged, yet little is known about the factors that underlie them. Here the authors explore whether movement-to-movement variability in motor output, an ubiquitous if often unwanted characteristic of motor performance, predicts motor learning ability. Surprisingly, the authors found that higher levels of task-relevant motor variability predicted faster learning both across individuals and across tasks in two different paradigms, one relying on reward-based learning to shape specific arm movement trajectories and the other relying on error-based learning to adapt movements in novel physical environments. The authors then show that training can reshape the temporal structure of motor variability, aligning it with the trained task to improve learning. These results provide experimental support for the importance of action exploration, a key idea from reinforcement learning theory, showing that motor variability facilitates motor learning in humans and that our nervous systems actively regulate it to improve learning.

Article

News and Views by Reza Shadmehr

April 2014

Date: 25 April 2014

Time: 10:00 am

Place : Gonda 1st Floor Conference Room (1357)

Title: Genetic dissection of a septohypothalamic circuit that controls stress-induced persistent anxiety

Speaker: Todd Anthony (Caltech)

This is a special seminar for a job opening in Neurobiology.

Relevant Paper: Control of Stress-Induced Persistent Anxiety by an Extra-Amygdala Septohypothalamic Circuit

Date: 18 April 2014

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Dendritic inhibition in the hippocampus supports fear learning

Speaker: Sarah Hersman

Fear memories guide adaptive behavior in contexts associated with aversive events. The hippocampus forms a neural representation of the context that predicts aversive events. Representations of context incorporate multisensory features of the environment, but must somehow exclude sensory features of the aversive event itself. Lovett-Barron et al. investigated this selectivity using cell type-specific imaging and inactivation in hippocampal area CA1 of behaving mice. Aversive stimuli activated CA1 dendrite-targeting interneurons via cholinergic input, leading to inhibition of pyramidal cell distal dendrites receiving aversive sensory excitation from the entorhinal cortex. Inactivating dendrite-targeting interneurons during aversive stimuli increased CA1 pyramidal cell population responses and prevented fear learning. We propose subcortical activation of dendritic inhibition as a mechanism for exclusion of aversive stimuli from hippocampal contextual representations during fear learning.

Paper

Further Reading: A. Losonczy, B. V. Zemelman, A. Vaziri, J. C. Magee, Nat. Neurosci. 13, 967 – 972 (2010)

M. Lovett-Barron et al., Nat. Neurosci. 15, 423 – 430, S1 – S3 (2012)

S. Royer et al., Nat. Neurosci. 15, 769 – 775 (2012).

Date: 11 April 2014

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Role of CCR5 in learning and memory

Speaker: Miou Zhou

This is another in the ICLM Young Investigator Lecture Series

Through a large screening of mouse strains in order to understand mechanisms responsible for long-term and remote memories, we found C-C chemokine receptor 5 (CCR5) mutant mice were one of the candidates that show enhancement in long-term and remote memories while with no changes in short-term memory. CCR5 is a G-protein coupled receptor involved in immune responses. CCR5 is also an important co-receptor which HIV uses to enter its target cells. Although CCR5 has been widely studied in immune responses and in AIDS, the role of CCR5 in plasticity and in learning and memory is not clear. Our studies show that CCR5 mutation enhances both hippocampal and cortical plasticity and results in memory enhancement, while CCR5 overexpression in excitatory neurons causes spatial memory deficits. These results suggest that CCR5 plays an important role in memories.

Date: 04 April 2014

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Exosomes and Intercellular Signaling in the Brain

Speaker: Kelsey Martin

I'll focus on a research paper from Vivian Budnik's lab showing a role for exosomes in retrograde signaling at the fly neuromuscular junction, and provide some background from cell biological studies on the function of exosomes in transferring proteins and nucleic acids between cells. I've included a recent review from Holly Cline's lab that summarizes known functions of exosomes in neurological disease and injury, and addresses possible roles for exosomes in normal brain development and functioning.

I think this is an emerging area of cell biology that is likely to be important to the biology of learning and memory.

Budnik Paper: Regulation of Postsynaptic Retrograde Signaling by Presynaptic Exosome Release

Cline Review: Exosomes function in cell – cell communication during brain circuit development

March 2014

- - Moved to May 16th ***

Date: 28 March 2014

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Olfactory cortical neurons read out a relative time code in the olfactory bulb

Speaker: Anu Goel (Buonomano Lab)

Neurons are not only sensitive to the spatial features of stimuli but are also capable of extracting temporal information from stimuli. There are several reports of temporally selective neurons in invertebrates, vertebrates as well as mammals. In particular there is evidence that neurons in the auditory system respond preferentially when pairs or sequences of tones are presented in a specific order with a certain temporal interval between them. The mechanisms underlying this temporal specificity remain to be examined in detail, but one potential candidate is the state-dependent network model. Today I will discuss evidence from a study in the rodent olfactory system where the authors show that piriform cortex neurons exhibit temporal selectivity to specific spatio-temporal stimuli delivered optogenetically to the olfactory bulb.

Paper: Olfactory cortical neurons read out a relative time code in the olfactory bulb

Date: 21 March 2014

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Behavior-driven FoxP2 regulation is necessary for songbird vocal learning

Speaker: Jon Heston (White Lab)

This is the third of this year's ICLM Junior Scientist Lecture Series.

Mutations in the transcription factor FoxP2 give rise to a specific language impairments in humans, making FoxP2 one of the few molecular toeholds into understanding the neural mechanisms underlying learned vocalization. Work by my lab and others has demonstrated that FoxP2 plays a necessary role in songbird vocal learning. My research extends these observations by using viral mediated overexpression of FoxP2 to show that behavior-driven decreases in FoxP2 levels are necessary for normal vocal learning. Moreover, I show that FoxP2 overexpression does not affect basal levels of variability but instead interferes with the ability to dynamically regulate vocal variability. Finally, I present preliminary evidence that suggests bidirectional shifts in basal ganglia output offer a plausible mechanism for these online changes in vocal variability. These results elucidate one mechanism by which FoxP2 supports vocal learning and gives insights into the potential treatment of speech and language disorders.

Here's a review that some might find helpful:

Twitter evolution: converging mechanisms in birdsong and human speech

Date: 14 March 2014

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Variability and reproducibility in recurrent neural networks

Speaker: Rodrigo Laje (University of Quilmes, Argentina)

Rodrigo is a collaborator with Dean Buonomano.

Abstract: I'll show the experimental and theoretical work we've done during my past stay in Dean's lab, published in 2013. I'll show how our brain might use a non-ticking clock to keep time, and how this reflects in the statistics of a timing task. For this to be possible a very rich neural activity is needed, which is usually associated with lack of reproducibility. This work led us to the discovery of a new "beast": a neural network whose activity is, paradoxically, both variable and reproducible.

Date: 07 March 2014

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Mechanisms of fear sensitization caused by acute traumatic stress: from induction to expression to potential cure

Speaker: Jennifer Perusini

This is the second of this year's ICLM Junior Scientist Lecture Series.

Abstract: Inappropriate fear regulation after severe stress is a hallmark of post-traumatic stress disorder (PTSD). We developed a model called stress-enhanced fear learning (SEFL), in which an acute footshock stressor nonassociatively and permanently enhances conditional fear learning in rats. SEFL is accompanied by several additional symptoms relevant to PTSD. We demonstrate that corticosterone acting at glucocorticoid receptors in the basolateral amygdala (BLA) is necessary to induce SEFL. Moreover, we show that corticosterone drives long-term AMPA receptor (R) subunit, glutamate receptor 1 (GluA1), expression in the BLA. Infusing an AMPAR antagonist into the BLA after the stress temporarily prevented sensitized fear expression, while specifically targeting GluA1 synthesis in the BLA using antisense oligonucleotides post-stress produced a long-lasting reversal of SEFL. These results elucidate novel neurobiological mechanisms underlying sensitized behavioral responses observed in PTSD and further indicate that a single antisense treatment directed at AMPARs within the BLA surprisingly restores normal fear responding.

A background paper can be found here:

http://www.sciencedirect.com/science/article/pii/S0149763405000606

February 2014

Date: 28 February 2014

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Specific evidence of low-dimensional continuous attractor dynamics in grid cells

Speaker: Nick Hardy

I'll be presenting the paper "Specific evidence of low-dimensional continuous attractor dynamics in grid cells" by Yoon et al.

Abstract: We examined simultaneously recorded spikes from multiple rat grid cells, to explain mechanisms underlying their activity. Among grid cells with similar spatial periods, the population activity was confined to lie close to a two-dimensional (2D) manifold: grid cells differed only along two dimensions of their responses and otherwise were nearly identical. Relationships between cell pairs were conserved despite extensive deformations of single-neuron responses. Results from novel environments suggest such structure is not inherited from hippocampal or external sensory inputs. Across conditions, cell-cell relationships are better conserved than responses of single cells. Finally, the system is continually subject to perturbations that, were the 2D manifold not attractive, would drive the system to inhabit a different region of state space than observed. These findings have strong implications for theories of grid-cell activity and substantiate the general hypothesis that the brain computes using low-dimensional continuous attractors.

Relevant Materials:

The paper is found here

The paper doesn't present original experiments, but reanalyzes these data from these papers: http://www.pnas.org/content/109/43/17687

http://www.nature.com/neuro/journal/v10/n6/full/nn1905.html

http://www.sciencemag.org/content/312/5774/758

http://www.nature.com/nature/journal/v436/n7052/full/nature03721.html

The data from the last 2 papers can be publicly downloaded here:

http://www.ntnu.edu/kavli/research/grid-cell-data

Date: 21 February 2014

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Dynamic Reconfiguration of Hippocampal Interneuron Circuits during Spatial Learning

Speaker: Ashley Kees

Back from studying space-time, learning, and the brain in Santa Barbara, Ashley Kees will be sharing some of her knowledge with us.

In the hippocampus, cell assemblies forming mnemonic representations of space are thought to arise as a result of changes in functional connections of pyramidal cells. We have found that CA1 interneuron circuits are also reconfigured during goal-oriented spatial learning through modification of inputs from pyramidal cells. As learning progressed, new pyramidal assemblies expressed in theta cycles alternated with previously established ones, and eventually overtook them. The firing patterns of interneurons developed a relationship to new, learning-related assemblies: some interneurons associated their activity with new pyramidal assemblies while some others dissociated from them. These firing associations were explained by changes in the weight of monosynaptic inputs received by interneurons from new pyramidal assemblies, as these predicted the associational changes. Spatial learning thus engages circuit modifications in the hippocampus that incorporate a redistribution of inhibitory activity that might assist in the segregation of competing pyramidal cell assembly patterns in space and time.

Relevant Materials:

Paper

Date: 14 February 2014

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Basal ganglia subcircuits distinctively encode the parsing and concatenation of action sequences

Speaker: Kostya Bakhurin

This Valentine's Day, Kostya will be discussing a center of reward and desire while breaking hearts, presenting this paper from an alum of the Silva Lab.

Chunking allows the brain to efficiently organize memories and actions. Although basal ganglia circuits have been implicated in action chunking, little is known about how individual elements are concatenated into a behavioral sequence at the neural level. Using a task in which mice learned rapid action sequences, we uncovered neuronal activity encoding entire sequences as single actions in basal ganglia circuits. In addition to neurons with activity related to the start/stop activity signaling sequence parsing, we found neurons displaying inhibited or sustained activity throughout the execution of an entire sequence. This sustained activity covaried with the rate of execution of individual sequence elements, consistent with motor concatenation. Direct and indirect pathways of basal ganglia were concomitantly active during sequence initiation, but behaved differently during sequence performance, revealing a more complex functional organization of these circuits than previously postulated. These results have important implications for understanding the functional organization of basal ganglia during the learning and execution of action sequences.

Relevant Materials:

Paper

Basal Ganglia Primer

Date: 07 February 2014

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: Distance-Dependent Scaling of AMPA Receptors: Whatever Happened To That Idea?

Speaker: Walt Babiec

The Super Bowl is over and pitchers and catchers report later this month, so I'll use a baseball metaphor. I'm pinch hitting this week due to a bunch of schedule reshuffles and no one else's interest in taking this week. Magee and Cook (2000) first reported distance-dependent scaling of AMPA receptor synapses strength in hippocampal pyramidal cells, but the origins of this scaling are not well understood. We will discuss a recent paper from the Nicoll Lab that takes on the question of whether this scaling is driven cell autonomously or as a result of extrinsic hippocampal factors.

January 2014

Date: 31 January 2014

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: LTP requires a reserve pool of glutamate receptors independent of subunit type

Speaker: Tom O'Dell

Long-term potentiation (LTP) of synaptic transmission is thought to be an important cellular mechanism underlying memory formation. A widely accepted model posits that LTP requires the cytoplasmic carboxyl tail (C-tail) of the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor subunit GluA1. To find the minimum necessary requirement of the GluA1 C-tail for LTP in mouse CA1 hippocampal pyramidal neurons, Granger et al. used a single-cell molecular replacement strategy to replace all endogenous AMPA receptors with transfected subunits. In contrast to the prevailing model, they found no requirement of the GluA1 C-tail for LTP. In fact, replacement with the GluA2 subunit showed normal LTP, as did an artificially expressed kainate receptor not normally found at these synapses. The only conditions under which LTP was impaired were those with markedly decreased AMPA receptor surface expression, indicating a requirement for a reserve pool of receptors. These results suggest a fundamental change in thinking with regard to the core molecular events underlying synaptic plasticity is required.

Relevant Materials:

Paper

Welberg Commentary

Sheng, Malinow, Huganir Commentary

Date: 24 January 2014

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title: A Cholinergic Mechanism for Reward Timing within Primary Visual Cortex

Speaker: Helen Motanis (Buonomano lab)

This week I have chosen a paper entitled ‘A Cholinergic Mechanism for Reward Timing within Primary Visual Cortex’ by Chubykin et al. 2013. Neurons in rodent primary visual cortex (V1) relate operantly conditioned stimulus-reward intervals with modulated patterns of spiking output, but little is known about the locus or mechanism of this plasticity. The authors show that cholinergic basal forebrain projections to V1 are necessary for the neural acquisition, but not the expression, of reward timing in the visual cortex of awake, behaving animals. The authors also mimic reward timing in vitro by pairing white matter stimulation with muscarinic receptor activation at a fixed interval and show that this protocol results in the prolongation of electrically evoked spike train durations out to the conditioned interval. Together, these data suggest that V1 possesses the circuitry and plasticity to support reward time prediction learning and the cholinergic system serves as an important reinforcement signal, which, in vivo, conveys to the cortex the outcome of behavior.

Date: 17 January 2014

Time: 09:30 am

Place : Gonda 1st Floor Conference Room

Title: Long-term potentiation (LTP), from humble beginnings to major significance

Speaker: Terje Lømo (University of Oslo)

2013

December 2013

Date: 13 December 2013

Time: 09:30 am

Place : Gonda 2303 (2nd Floor Conference Room)

Title: Attention enhances synaptic efficacy and the signal-to-noise ratio in neural circuits.

Speaker: Michael Einstein (Golshani Lab)

Attention enhances the processing of salient visual stimuli. Despite thirty years of research on the correlates of attention in the visual cortex, the mechanism by which attention boosts the signal of a salient visual stimulus is still of great debate. One argument is that attention depolarizes visual cortical cells, which could increase neuronal gain by raising the probability for inputs to trigger spiking. Others say that attention synchronizes specific neural populations in such a way that their impact on downstream neurons is increased. Briggs et al. (2013) adds a new piece to the puzzle by testing how attention alters synaptic weights between the LGN and primary visual cortex in monkeys. This research suggests that attention primarily synchronizes specific neural populations as a means to increase the signal to noise ratio of attended stimuli. To conclude, I will reflect on the impact of this paper and suggest future directions for the field.

Reference: Briggs F, Mangun GR, Usrey WM (2013) Attention enhances synaptic efficacy and the signal-to-noise ratio in neural circuits. Nature 499: 476-80. http://www.nature.com/nature/journal/v499/n7459/full/nature12276.html

Date: 06 December 2013

Time: 09:30 am

Place : Gonda 2303 (2nd Floor Conference Room)

Title: Selection of distinct populations of dentate granule cells in response to inputs as a mechanism for pattern separation in mice.

Speaker: Denise Cai (Silva Lab)

I'd like to present this paper from the Gage/Mayford lab and discuss it in the context of the work from the Tonegawa lab (Liu et al., 2012, Ramirez et al., 2013) with their reactivation of dentate studies.

Gage/Mayford Reference: http://elife.elifesciences.org/content/2/e00312

Tonegawa References: Liu et al., 2012 Ramirez et al., 2013

November 2013

Date: 22 November 2013

Time: 09:30 am

Place : Gonda 2303 (2nd Floor Conference Room)

Title: Maturation of silent synapses in amygdala-accumbens projection contributes to incubation of cocaine craving

Speaker: Paul Mathews (Otis Lab)

This week I have chosen to present a paper entitled "Maturation of silent synapses in amygdala-accumbens projections contributes to incubation of cocaine craving," by Lee at al. Previous research has shown that after repeated cocaine exposure there is a rapid "silencing" of dendritic synapses in medium spiny neurons of the nucleus accumbens. These silenced synapses become rapidly (over days) un-silenced through the incorporation of Ca2+ permeable, rather than Ca2+ impermeable AMPA receptors, which normally predominate the synapse. The authors of this paper present experiments that suggest that these newly un-silenced synapses composed of Ca2+ permeable AMPA receptors underlie the cellular basis for incubated cocaine craving. Given the wide range of experimentation, from behavior to cellular physiology I think this paper should have plenty to interest most ICLM journal club participants.

Reference: http://www.nature.com/neuro/journal/v16/n11/full/nn.3533.html

Date: 15 November 2013

Time: 09:30 am

Place : Gonda 2303 (2nd Floor Conference Room)

Title: Spatial representations along the longitudinal hippocampal axis: Tradeoff between memory interference and generalization

Speaker: Isabel Muzzio (Dept. of Psychology, University of Pennsylvania)

The hippocampus has long been implicated in contextual gating of aversive events. Lesion and neuroanatomical studies indicate that the dorsal hippocampus specializes in spatial processing while the ventral hippocampus is more involved in emotion and anxiety. However, it is currently unclear if these regions work as independent modules processing distinct types of information or sensory and emotional inputs are integrated along the longitudinal hippocampal axis to provide a comprehensive representation of context. To investigate this question, my lab has conducted in vivo recordings from freely moving mice while animals form and retrieve contextual representations of different emotional valence in the dorsal and ventral hippocampus. We have found evidence that space is faithfully coded in both the dorsal and ventral regions in different manners. In the dorsal hippocampus, sparse finely tuned representations remap in response to the altered valence of a context forming a new stable spatial representation. Conversely, in the ventral hippocampus space is represented through population coding and emotional valence is coded through changes in firing rate. Furthermore, our data show that having a spatial representational gradient along the longitudinal axis favors a tradeoff between memory interference and generalization.

Date: 01 November 2013

Time: 09:30 am

Place : Gonda 2303 (2nd Floor Conference Room)

Title: Epigenetics in action: social regulation of microRNAs

Speaker: Stephanie White

My talk with discuss how the speech and language related gene, FoxP2, is regulated 'on line' during social interactions. Relevance to the LMP community is that this occurs within procedural learning circuitry in the basal ganglia. Perhaps not surprisingly, the model system in question is the songbird, especially given that lab rodents do not learn how to squeak.

Relevant Paper: "miR-9 and miR-140-5p Target FoxP2 and Are Regulated as a Function of the Social Context of Singing Behavior in Zebra Finches"

Shi Z, Luo G, Fu L, Fang Z, Wang X, Li X (2013) J Neurosci 33:16510-21.

http://www.jneurosci.org/content/33/42/16510.long

October 2013

Date: 25 October 2013

Time: 09:30 am

Place : Gonda 2303 (2nd Floor Conference Room)

Title: Perineuronal Nets and Plasticity

Speaker: Kelsey Martin

I will discuss a recent PNAS paper from Roger Tsien (see below) that is essentially a hypothesis paper about the function of perineuronal nets and long-term plasticity. I will also present work from other research papers on perineuronal nets during developmental and adult plasticity.

"Very long-term memories may be stored in the pattern of holes in the perineuronal net"

Tsien, RY (2013) PNAS 110:12456.

http://www.pnas.org/content/110/30/12456.full?sid=ec9e5dc0-bb51-46f5-b83c-313145c456ee

Date: 11 October 2013

Time: 09:30 am

Place : Gonda 2303 (2nd Floor Conference Room)

Title: Where in the Cell Is Long-Term Memory?

Speaker: David Glanzman

I will be presenting recent work from my lab.

There are no papers to read specifically for the presentation. But the following provide useful background information:

Cai, D., Pearce, K., Chen, S., and Glanzman, D. L. (2011). Protein kinase M maintains long-term sensitization and long-term facilitation in Aplysia. J. Neurosci. 31, 6421-6431. (http://www.jneurosci.org/content/31/17/6421.long)

Cai, D., Pearce, K., Chen, S., and Glanzman, David L. (2012). Reconsolidation of long-term memory in Aplysia. Curr. Biol. 22, 1783-1788. (http://www.sciencedirect.com/science/article/pii/S0960982212008639)

Date: 04 October 2013

Time: 09:30 am

Place : Gonda 2303 (2nd Floor Conference Room)

Title : Metabotropic NMDA Receptor Function

Speaker: Walt Babiec

Recently, two laboratories have reported data from hippocampal slice culture that the depression of AMPA receptor mediated transmission by amyloid beta is blocked by competitive NMDA receptor antagonists, e.g., APV, but not non-competitive antagonists, e.g., MK-801. One of these, the Malinow Laboratory, has proposed that NMDA receptors not only display an ionotropic function but a metabotropic function. They suggest that this metabotropic function, which requires NMDA receptor activation but not cation flux, is necessary and sufficient for generating long-term depression (LTD), which they argue mediates this amyloid beta effect. This week, we will review that data offered in support of their metabotropic NMDA hypothesis of LTD, as well as some data we have taken in the O’Dell Laboratory investigating whether such a function persists in adult animals, thus enhancing its potential for relevance to neurological disorders of aging such as Alzheimer’s Disease.

Covering This Week’s Paper: “Metabotropic NMDA receptor function is required for NMDA receptor-dependent long-term depression” PNAS (2013) 110:4027. Sadegh Nabavia, Helmut W. Kessels, Stephanie Alfonso, Jonathan Aow, Rocky Fox, and Roberto Malinow http://www.pnas.org/content/110/10/4027.long

September 2013

Date: 27 September 2013

Time: 09:30 am

Place : Gonda 2303 (2nd Floor Conference Room)

Title : The Value of Messy Neural Responses

Speaker: Dean Buonomano

Covering This Week’s Paper: “The importance of mixed selectivity in complex cognitive tasks” Nature (2013) 497:585-590. Rigotti M, Barak O, Warden MR, Wang X-J, Daw ND, Miller EK, Fusi S http://www.nature.com/nature/journal/v497/n7451/full/nature12160.html

May 2013

Date: May 10th

Time: 09:30 am

Place : Gonda 2nd Floor Conference Room

Title : Hilar Mossy Cell Degeneration Causes Transient Dentate Granule Cell Hyperexcitability and Impaired Pattern Separation

Speaker: Sarah Hersman

Although excitatory mossy cells of the hippocampal hilar region are known to project both to dentate granule cells and to interneurons, it is as yet unclear whether mossy cell activity’s net effect on granule cells is excitatory or inhibitory. To explore their influ- ence on dentate excitability and hippocampal func- tion, we generated a conditional transgenic mouse line, using the Cre/loxP system, in which diphtheria toxin receptor was selectively expressed in mossy cells. One week after injecting toxin into this line, mossy cells throughout the longitudinal axis were degenerated extensively, theta wave power of dentate local field potentials increased during exploration, and deficits occurred in contextual discrimination. By contrast, we detected no epilepti- form activity, spontaneous behavioral seizures, or mossy-fiber sprouting 5–6 weeks after mossy cell degeneration. These results indicate that the net effect of mossy cell excitation is to inhibit granule cell activity and enable dentate pattern separation.

Neuron. 2012 Dec 20;76(6):1189-200. doi: 10.1016/j.neuron.2012.10.036. Hilar mossy cell degeneration causes transient dentate granule cell hyperexcitability and impaired pattern separation. Jinde S, Zsiros V, Jiang Z, Nakao K, Pickel J, Kohno K, Belforte JE, Nakazawa K.

Front Neural Circuits. 2013;7:14. doi: 10.3389/fncir.2013.00014. Epub 2013 Feb 12. Hilar mossy cell circuitry controlling dentate granule cell excitability. Jinde S, Zsiros V, Nakazawa K.

Date: May 3rd

Time: 09:30 am

Place : Gonda ****1st Floor Conference Room****

Title : ICLM Journal Club Special Lecture

Speaker: Yiota Poirazi

The goal of this presentation is to provide a set of predictions generated by biophysical and theoretical neuron models regarding the role of dendrites in information coding across three different brain regions: the hippocampus, the prefrontal cortex and the amygdala. Towards this goal I will present modelling studies –along with supporting experimental evidence- that investigate how dendrites may be used to facilitate the coding of both spatial and temporal information at the single cell, the microcircuit and the neuronal network level. I will first discuss how the dendrites of individual CA1 pyramidal neurons may allow a single cell to discriminate between familiar versus novel memories and propagate this information to down stream cells [1]. I will then discuss how these dendritic nonlinearities may enable stimulus specificity in individual PFC pyramidal neurons during working memory [2] and underlie the emergence of sustained activity at the single cell and the microcircuit level [2,3]. Finally, I will present findings from our ongoing work in collaboration with Alcino Silva regarding the role of dendrites in shaping the formation of fear memory engrams in the amygdala.

1. Pissadaki, E.K., Sidiropoulou K., Reczko M., and Poirazi, P. “Encoding of spatio-temporal input characteristics by a single CA1 pyramidal neuron model” PLoS Comp. Biology, 2010 Dec;6(12): e1001038.

2. Sidiropoulou, K. and Poirazi, P. “Predictive features of persistent activity emergence in regular spiking and intrinsic bursting model neurons” (PLoS Comp. Biology, 2012 April; 8(4): e1002489)

3. Papoutsi, A., Sidiropoulou, K., and Poirazi, P. “PFC microcircuits as tunable and predictive modules of persistent activity.” (submitted)

April 2013

Date: April 12th

Time: 09:30 am

Place : Gonda 2303

Title : Neural mechanisms mediating inferential reasoning in rats.

Speaker: Cynthia Fast

Abstract: Many decisions are made under conditions of uncertainty. We rarely have access to all of the information in our environment that is pertinent to making an important decision. In fact, our lives are replete with ambiguous situations that nonetheless require consideration. Yet it is unclear what cognitive and neural processes enable the distinction between explicit and ambiguous situations. Moreover, it is unknown what processes mediate inferential reasoning when an ambiguous situation has been detected. We have recently discovered that rats are capable of distinguishing between the ambiguous absence of an event and its explicit absence. That is, like humans, rats appear to recognize the conditions under which they should be able to observe an event and those conditions under which the event should be hidden from observation. Interestingly, this ability depends on prior learning. In a series of experiments, we explored the necessary and sufficient features of prior learning that contribute to sensitivity to ambiguity as well as potential underlying neural mechanisms. Specifically, micro-infusions of scopolamine into the dorsal hippocampus appear to eliminate this reasoning ability, suggesting a critical role for hippocampal cholinergic modulation under normal conditions. Additionally, analysis of cfos expression in the brains of reasoning and non-reasoning rats offer further insight into possible neural circuits mediating reasoning about absent events.

Date: April 5th

Time: 09:30 am

Place : Gonda 2303

Title : "Prkcz null mice show normal learning and memory" and "PKM-ζ is not required for hippocampal synaptic plasticity, learning and memory"

Speaker: David Glanzman

Authors: Lee AM, Kanter BR, Wang D, Lim JP, Zou ME, Qiu C, McMahon T, Dadgar J, Fischbach-Weiss SC, Messing RO.

Abstract: Protein kinase M-ζ (PKM-ζ) is a constitutively active form of atypical protein kinase C that is exclusively expressed in the brain and implicated in the maintenance of long-term memory. Most studies that support a role for PKM-ζ in memory maintenance have used pharmacological PKM-ζ inhibitors such as the myristoylated zeta inhibitory peptide (ZIP) or chelerythrine. Here we use a genetic approach and target exon 9 of the Prkcz gene to generate mice that lack both protein kinase C-ζ (PKC-ζ) and PKM-ζ (Prkcz(-/-) mice). Prkcz(-/-) mice showed normal behaviour in a cage environment and in baseline tests of motor function and sensory perception, but displayed reduced anxiety-like behaviour. Notably, Prkcz(-/-) mice did not show deficits in learning or memory in tests of cued fear conditioning, novel object recognition, object location recognition, conditioned place preference for cocaine, or motor learning, when compared with wild-type littermates. ZIP injection into the nucleus accumbens reduced expression of cocaine-conditioned place preference in Prkcz(-/-) mice. In vitro, ZIP and scrambled ZIP inhibited PKM-ζ, PKC-ι and PKC-ζ with similar inhibition constant (K(i)) values. Chelerythrine was a weak inhibitor of PKM-ζ (K(i) = 76 μM). Our findings show that absence of PKM-ζ does not impair learning and memory in mice, and that ZIP can erase reward memory even when PKM-ζ is not present.

Authors: Volk LJ, Bachman JL, Johnson R, Yu Y, Huganir RL.

Abstract: Long-term potentiation (LTP), a well-characterized form of synaptic plasticity, has long been postulated as a cellular correlate of learning and memory. Although LTP can persist for long periods of time, the mechanisms underlying LTP maintenance, in the midst of ongoing protein turnover and synaptic activity, remain elusive. Sustained activation of the brain-specific protein kinase C (PKC) isoform protein kinase M-ζ (PKM-ζ) has been reported to be necessary for both LTP maintenance and long-term memory. Inhibiting PKM-ζ activity using a synthetic zeta inhibitory peptide (ZIP) based on the PKC-ζ pseudosubstrate sequence reverses established LTP in vitro and in vivo. More notably, infusion of ZIP eliminates memories for a growing list of experience-dependent behaviours, including active place avoidance, conditioned taste aversion, fear conditioning and spatial learning. However, most of the evidence supporting a role for PKM-ζ in LTP and memory relies heavily on pharmacological inhibition of PKM-ζ by ZIP. To further investigate the involvement of PKM-ζ in the maintenance of LTP and memory, we generated transgenic mice lacking PKC-ζ and PKM-ζ. We find that both conventional and conditional PKC-ζ/PKM-ζ knockout mice show normal synaptic transmission and LTP at Schaffer collateral-CA1 synapses, and have no deficits in several hippocampal-dependent learning and memory tasks. Notably, ZIP still reverses LTP in PKC-ζ/PKM-ζ knockout mice, indicating that the effects of ZIP are independent of PKM-ζ.

March 2013

Date: March 15th

Time: 09:30 am

Place : Gonda 5303 ***Note Room Change***

Title : Neural signals of extinction in the inhibitory microcircuit of the ventral midbrain

Speaker: Konstantin Bakhurin

Abstract: Midbrain dopaminergic (DA) neurons are thought to guide learning via phasic elevations of firing in response to reward predicting stimuli. The mechanism for these signals remains unclear. Using extracellular recording during associative learning, we found that inhibitory neurons in the ventral midbrain of mice responded to salient auditory stimuli with a burst of activity that occurred before the onset of the phasic response of DA neurons. This population of inhibitory neurons exhibited enhanced responses during extinction and was anticorrelated with the phasic response of simultaneously recorded DA neurons. Optogenetic stimulation revealed that this population was, in part, derived from inhibitory projection neurons of the substantia nigra that provide a robust monosynaptic inhibition of DA neurons. Thus, our results elaborate on the dynamic upstream circuits that shape the phasic activity of DA neurons and suggest that the inhibitory microcircuit of the midbrain is critical for new learning in extinction.

Date: March 8th

Time: 09:30 am

Place : Gonda 2303

Title : Long-term stabilization of place cell remapping produced by a fearful experience

Speaker: Michael Fanselow

Abstract: Fear is an emotional response to danger that is highly conserved throughout evolution because it is critical for survival. Accordingly, episodic memory for fearful locations is widely studied using contextual fear conditioning, a hippocampus-dependent task (Kim and Fanselow, 1992; Phillips and LeDoux, 1992). The hippocampus has been implicated in episodic emotional memory and is thought to integrate emotional stimuli within a spatial framework. Physiological evidence supporting the role of the hippocampus in contextual fear indicates that pyramidal cells in this region, which fire in specific locations as an animal moves through an environment, shift their preferred firing locations shortly after the presentation of an aversive stimulus (Moita et al., 2004). However, the long-term physiological mechanisms through which emotional memories are encoded by the hippocampus are unknown. Here we show that during and directly after a fearful experience, new hippocampal representations are established and persist in the long term. We recorded from the same place cells in mouse hippocampal area CA1 over several days during predator odor contextual fear conditioning and found that a subset of cells changed their preferred firing locations in response to the fearful stimulus. Furthermore, the newly formed representations of the fearful context stabilized in the long term. Our results demonstrate that place cells respond to the presence of an aversive stimulus, modify their firing patterns during emotional learning, and stabilize a long-term spatial representation in response to a fearful encounter. The persistent nature of these representations may contribute to the enduring quality of emotional memories.

Date: March 1st

Time: 09:30 am

Place : Gonda 2303

Title : Mechanisms controlling the gain of the visual cortex neurons during wakefulness

Speaker: Pierre-Olivier Polack

Abstract: Reliable acquisition and amplification of sensory input is the first essential step for learning and memory. During wakefulness the gain of sensory neurons can change with behavior. In particular, visual cortical neurons fire at higher rates to visual stimuli during locomotion than during immobility while maintaining orientation selectivity. The mechanisms underlying this change in gain are not understood. We performed whole cell recordings from layer 2/3 and layer 4 visual cortical excitatory neurons as well as from parvalbumin-positive and somatostatin-positive inhibitory neurons in mice free to rest or run on a spherical treadmill. We found that the membrane potential of all cell types became more depolarized and (with the exception of somatostatin-positive interneurons) less variable during locomotion. Cholinergic input was essential for maintaining the unimodal membrane potential distribution during immobility, while noradrenergic input was necessary for the tonic depolarization associated with locomotion. Our results provide a mechanism for how neuromodulation controls the gain and signal-to-noise ratio of visual cortical neurons during changes in the state of vigilance. We are now investigating whether the same mechanism is responsible for controlling selective attention to visual input during a perceptual learning task.

February 2013

Date: February 21st

Time: 09:30 am

Place : Gonda 2303

Title : FMRP Regulates Neurotransmitter Release and Synaptic Information Transmission by Modulating Action Potential Duration via BK Channels

Speaker: Felix Schweizer

Abstract: Loss of FMRP causes fragile X syndrome (FXS), but the physiological functions of FMRP remain highly debatable. Here we show that FMRP regulates neurotransmitter release in CA3 pyramidal neurons by modulating action potential (AP) duration. Loss of FMRP leads to excessive AP broadening during repetitive activity, enhanced presynaptic calcium influx, and elevated neurotransmitter release. The AP broadening defects caused by FMRP loss have a cell-autonomous presynaptic origin and can be acutely rescued in postnatal neurons. These presynaptic actions of FMRP are translation independent and are mediated selectively by BK channels via interaction of FMRP with BK channel’s regulatory β4 subunits. Information-theoretical analysis demonstrates that loss of these FMRP functions causes marked dysregulation of synaptic information transmission. FMRP-dependent AP broadening is not limited to the hippocampus, but also occurs in cortical pyramidal neurons. Our results thus suggest major translation-independent presynaptic functions of FMRP that may have important implications for understanding FXS neuropathology.

Date: February 1st

Time: 09:30 am

Place : Gonda 2303

Title : Experience-dependent plasticity of Network Dynamics

Speaker: Anubhuthi Goel

Abstract: Cortical computations underlying normal and abnormal brain function are not only dependent on modifications at individual synapses but on the net interaction between many forms of plasticity at the level of the entire network. Together multiple forms of plasticity govern the complex spatio-temporal patterns of activity within local networks – that is, neural dynamics. One particular learning rule that is critical in the development of functional neural dynamics in a controlled fashion is Homeostatic plasticity. We examined plasticity of network dynamics in cortical organotypic slices in response to chronic changes in activity and found that networks rely on a balance between spontaneous and evoked activity in order to drive their average activity levels towards homeostatic set points. Importantly our data highlights the fact that at the network level homeostatic mechanisms are not restricted to simple and traditional synaptic scaling phenomena wherein all the synapses are indiscriminately scaled up or down. Rather homeostatic mechanisms involve multiple forms of plasticity operating in parallel thereby allowing circuits to independently regulate spontaneous, monosynaptic, and polysynaptic activity.

Having gained some insight as to how homeostatic plasticity influences computations in general so that recurrent cortical circuits generate functional dynamic states in a stable fashion we examined one particularly interesting type of computation, namely, how does timing emerge from the plasticity of neural dynamics. Timing is fundamental to learning and behavior, and it is increasingly clear that in many cases timing is an emergent network phenomenon; but almost nothing is known about the neural mechanisms that underlie even the simplest of temporal tasks, such as discriminating a 100 and 200 ms interval. We have recently established that when cortical organotypic slices are chronically presented with specific intervals (using electrical stimulation), the network can in a sense “learn” the trained interval: after training, presentation of a single pulse results in increased neural activity around the expected time of the second pulse—as if the network “expected” the arrival of the second pulse. We view this as an example of an emergent computation in vitro because: First, the changes in the behavior of the network seem to rely on the interaction of many neurons in a circuit rather than the simple amplification of neural responses observed in traditional synaptic plasticity studies. Second, it can be said that a simple computation is taking place because the activity patterns in the trained network provide information about elapsed time. To examine the mechanisms of temporal pattern completion, we combined electrical and optical stimulation to provide “sensory spatio-temporal experience” to cortical organotypic slices. Our data suggests that the observed timing is in part due to evoked patterns of activity—neural trajectories—in which distinct points in time can be encoded by the population of active neurons. Furthermore based on our insights from homeostatic plasticity studies we believe that homeostatic mechanisms aid in the emergence and propagation of these neural trajectories in a stable manner.

January 2013

Date: January 25th

Time: 09:30 am

Place : Gonda 2303

Title : Spatial Regulation of Gene Expression in neurons During Synapse Formation and Synaptic Plasticity

Speaker: Sangmok Kim

Abstract: mRNA localization and regulated translation allow individual neurons to locally regulate the proteome of each of their myriad of subcellular compartments. To determine whether and how synaptogenic signals spatially regulate gene expression, we cultured a bifurcated Aplysia sensory neuron contacting a nontarget motor neuron, with which it did not form chemical synapses, and a target motor neuron, with which it formed glutamatergic synapses, and imaged RNA and protein localization. We find that RNAs and translational machinery are delivered throughout the neuron, but that translation is enriched at sites of synaptic contact. Investigation of the molecular mechanisms that promote local translation revealed a role for netrin-1/DCC signaling. Together, our study indicates that the spatial regulation of gene expression during synapse formation is mediated at the level of translation. This mechanism maximizes neuronal plasticity by rendering each compartment capable of locally changing its proteome in response to local cues.

2012

Abstract: The mammalian brain is composed of thousands of interacting neural cell types. Systematic approaches to establish the molecular identity of functional populations of neurons would advance our under- standing of neural mechanisms controlling behavior. Here, we show that ribosomal protein S6, a structural component of the ribosome, becomes phosphory- lated in neurons activated by a wide range of stimuli. We show that these phosphorylated ribosomes can be captured from mouse brain homogenates, thereby enriching directly for the mRNAs expressed in discrete subpopulations of activated cells. We use this approach to identify neurons in the hypo- thalamus regulated by changes in salt balance or food availability. We show that galanin neurons are activated by fasting and that prodynorphin neu- rons restrain food intake during scheduled feed- ing. These studies identify elements of the neural circuit that controls food intake and illustrate how the activity-dependent capture of cell-type-specific transcripts can elucidate the functional organization of a complex tissue.

October

Date: October 26th

Time: 09:30 am

Place : Gonda 2303

Title : “Why are there so many types of inhibitory neurons”

Speaker: Dr. Dean Buonomano

Related Material:

Division and subtraction by distinct cortical inhibitory networks in vivo

Nathan R. Wilson1*, Caroline A. Runyan1*, Forea L. Wang1 & Mriganka Sur1

Brain circuits process information through specialized neuronal subclasses interacting within a network. Revealing their interplay requires activating specific cells while monitoring others in a functioning circuit. Here we use a new platform for two-way light-based circuit interrogation in visual cortex in vivo to show the computational implications of modulating different subclasses of inhibitory neurons during sensory processing. We find that soma-targeting, parvalbumin-expressing (PV) neurons principally divide responses but preserve stimulus selectivity, whereas dendrite-targeting, somatostatin-expressing (SOM) neurons principally subtract from excitatory responses and sharpen selectivity. Visualized in vivo cell-attached recordings show that division by PV neurons alters response gain, whereas subtraction by SOM neurons shifts response levels. Finally, stimulating identified neurons while scanning many target cells reveals that single PV and SOM neurons functionally impact only specific subsets of neurons in their projection fields. These findings provide direct evidence that inhibitory neuronal subclasses have distinct and complementary roles in cortical computations.

Date: October 5th

Time: 09:30 am

Place : Gonda 2303

Title : “Dissecting spatial knowledge from spatial choice by hippocampal NMDA receptor deletion”

Speaker: Dr. Tom O'Dell

Summary:

Hippocampal NMDA receptors (NMDARs) and NMDAR-dependent synaptic plasticity are widely considered crucial substrates of long-term spatial memory, although their precise role remains uncertain. Here we show that Grin1∆DGCA1 mice, lacking GluN1 and hence NMDARs in all dentate gyrus and dorsal CA1 principal cells, acquired the spatial reference memory water maze task as well as controls, despite impairments on the spatial reference memory radial maze task. When we ran a spatial discrimination water maze task using two visually identical beacons, Grin1∆DGCA1 mice were impaired at using spatial information to inhibit selecting the decoy beacon, despite knowing the platform’s actual spatial location. This failure could suffice to impair radial maze performance despite spatial memory itself being normal. Thus, these hippocampal NMDARs are not essential for encoding or storing long-term, associative spatial memories. Instead, we demonstrate an important function of the hippocampus in using spatial knowledge to select between alternative responses that arise from competing or overlapping memories.

August

Date: August 17th

Time: 09:30 am

Place : ***53-105, CHS.***

Title : “Calpain: a key component of synaptic plasticity and learning & memory?”

Summary:

Prevailing theory suggests that long-term memories are encoded via a two-phase process requiring early involvement of the hippocampus followed by the neocortex. Contextual fear memories in rodents rely on the hippocampus immediately following training but are unaffected by hippocampal lesions or pharmacological inhibition weeks later. With fast optogenetic methods, we examine the real-time contribution of hippocampal CA1 excitatory neurons to remote memory and find that contextual fear memory recall, even weeks after training, can be reversibly abolished by temporally precise optoge- netic inhibition of CA1. When this inhibition is extended to match the typical time course of phar- macological inhibition, remote hippocampus depen- dence converts to hippocampus independence, suggesting that long-term memory retrieval normally depends on the hippocampus but can adaptively shift to alternate structures. Further revealing the plasticity of mechanisms required for memory recall, we confirm the remote-timescale importance of the anterior cingulate cortex (ACC) and implicate CA1 in ACC recruitment for remote recall.

Relevant Reading Material:

Cell. 2011 Oct 28;147(3):678-89. Epub 2011 Oct 20. Dynamics of retrieval strategies for remote memories. Goshen I, Brodsky M, Prakash R, Wallace J, Gradinaru V, Ramakrishnan C, Deisseroth K.

March

Date: Mar 9th

Time: 09:30 am

Place : 2nd Floor Conference Room, Gonda building.

Title : "Triggering and degrading associative memory formation"

Speaker: Joshua Johansen PhD

Summary:

Aversive experiences powerfully regulate memory formation by activating ‘teaching signal’ circuits in the brain which can engage neural plasticity in memory storage areas resulting in associative memories. Fear conditioning is a useful paradigm in which to examine the mechanisms by which aversive experiences trigger associative memories because a site of neural plasticity mediating the learning has been identified in the lateral nucleus of the amygdala. Aversive stimuli can either engage or degrade memory formation depending on the temporal placement of aversive stimuli in relation to sensory cues in the environment. Using a combination of optogenetic, electrophysiological and behavioral approaches I examined the neural mechanisms in the lateral amygdala by which aversive experiences trigger or degrade behavioral fear memory formation and neural plasticity. The results of these experiments suggest that combined Hebbian and neuromodulatory mechanisms trigger behavioral fear learning and neural plasticity in the lateral amygdala. In addition, activation of LA pyramidal neurons by aversive stimuli serves as a switch to either induce or degrade fear memory formation depending on the temporal placement of the aversive stimuli during learning.

Date: Mar 2nd

Time: 09:30 am

Place : 2nd Floor Conference Room, Gonda building.

Title : "Heterogeneous reallocation of presynaptic efficacy in recurrent excitatory circuits adapting to inactivity."

Speaker: Anubhuthi Goel, Ph.D.

Homeostatic plasticity is an important negative feedback regulator that maintains stability within networks of neurons. The synaptic basis and mechanisms underlying homeostatic plasticity have been extensively studied, however a large number of these investigations are restricted to understanding homeostatic modifications at feed forward pathways. This paper provides compelling evidence that the rules under which homeostatic plasticity operates are very different for recurrently connected networks and that traditional homogenous homeostatic adaptation is not enforced across all synapses.

Relevant Reading Material:

Nat Neurosci. 2011 Dec 18;15(2):250-7. doi: 10.1038/nn.3004. Heterogeneous reallocation of presynaptic efficacy in recurrent excitatory circuits adapting to inactivity. Mitra A, Mitra SS, Tsien RW.

February

Date: Feb 24th

Time: 09:30 am

Place : 2nd Floor Conference Room, Gonda building.

Title : "Inducible and Selective Erasure of Memories in the Mouse Brain via Chemical-Genetic Manipulation"

Speaker: Adam Frank.

Summary:

I will present Joe Tsien's 2008 Neuron paper about a chemical-genetic approach to study CaMKIIa function ("Inducible and Selective Erasure of Memories in the Mouse Brain via Chemical-Genetic Manipulation"). This paper is a continuation of work beginning in 2003, when his lab generated a CaMKIIa overexpressing mouse with a targeted mutation in CaMKIIa that makes it highly susceptible to inhibition by a modified kinase inhibitor (Wang, 2003, PNAS). This story of overexpression and inhibition of wildtype CaMKIIa activity is interesting and provocative and raises as many questions as it answers. I am particularly interested in these results as I have generated a BAC transgenic mouse that overexpresses the same CaMKIIa mutation as that generated in the Tsien lab. I am hopeful we can have a lively discussion about his results and the important questions they raise. Relevant Reading Material:

Neuron. 2008 Oct 23;60(2):353-66. Inducible and selective erasure of memories in the mouse brain via chemical-genetic manipulation. Cao X, Wang H, Mei B, An S, Yin L, Wang LP, Tsien JZ.

Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):4287-92. Epub 2003 Mar 19. Inducible protein knockout reveals temporal requirement of CaMKII reactivation for memory consolidation in the brain. Wang H, Shimizu E, Tang YP, Cho M, Kyin M, Zuo W, Robinson DA, Alaimo PJ, Zhang C, Morimoto H, Zhuo M, Feng R, Shokat KM, Tsien JZ.

January

Date: Jan 6th

Time: 09:30 am

Place : 2nd Floor Conference Room, Gonda building.

Title : "Practice makes perfect: defining the role of inhibition in vision and sensory learning."

Speaker: Sandra Kuhlman, Ph.D.

GABAergic inhibition is a key mediator of experience-dependent plasticity during postnatal development, and accumulating evidence identifies aberrant GABAergic function in schizophrenia and autism. However, the mechanisms by which inhibition regulates plasticity and learning in-vivo are largely unknown, and by extension it is not well understood how disturbance of cellular signaling pathways within inhibitory interneurons impacts cortical function in-vivo. Using in-vivo targeted electrophysiological recording of an identified inhibitory interneuron cell type, the parvalbumin (PV+) fast-spiking GABAergic interneuron, we found that visual experience uniquely broadens orientation tuning of PV+ interneurons at a time during development when excitatory neurons become more sharply tuned (Kuhlman et al., Nature Neuroscience 2011). Furthermore, we found that inhibitory broadening precedes binocular matching of excitatory orientation tuning, thus establishing that maturation of the recruitment of inhibition is a candidate for initiating binocular plasticity of excitatory neurons during the critical period. These results highlight the need for designing treatment strategies to rescue recruitment of PV+ interneurons in disease, thereby expanding the existing focus which is to enhance GABAergic synaptic output.

Perceptual learning is a progressive process of skill acquisition in which neural response properties are re-shaped by experience, even at the earliest stages of sensory processing. Thus, the very perception of the environment which informs motor output and behavioral action is itself modified during learning. How does recruitment of inhibition regulate sensory learning? Using techniques described above in combination with recent advances in head-fixed mouse behavior, this is now a tractable question in mice. I will outline a strategy to define the unique roles of specific inhibitory interneuron subclasses during ‘practice’, a.k.a. progressive learning.

Date: Jan 13th

Time: 09:30 am

Place : 2nd Floor Conference Room, Gonda building.

Title : "Inhibitory Plasticity"

Speaker: Dean Buonomano, Ph.D.

Releavant Reading Material:

Vogels TP, Sprekeler H, Zenke F, Clopath C, Gerstner W (2011) Science 334:1569-1573. Inhibitory Plasticity Balances Excitation and Inhibition in Sensory Pathways and Memory Networks http://www.sciencemag.org/content/334/6062/1569.abstract

Froemke RC, Merzenich MM, Schreiner CE (2007) Nature 450:425-429. A synaptic memory trace for cortical receptive field plasticity. http://www.nature.com/nature/journal/v450/n7168/full/nature06289.html

Date: Jan 20th

Time: 09:30 am

Place : 2nd Floor Conference Room, Gonda building.

Title : "A disinhibitory microcircuit for associative fear learning in the auditory cortex"

Speaker: Walter Babiec, Ph.D.

Summary: Learning causes a change in how information is processed by neuronal circuits. Whereas synaptic plasticity, an important cellular mechanism, has been studied in great detail, we know much less about how learning is implemented at the level of neuronal circuits and, in particular, how interactions between distinct types of neurons within local networks contribute to the process of learning. Here we show that acquisition of associative fear memories depends on the recruitment of a disinhibitory microcircuit in the mouse auditory cortex. Fear-conditioning-associated disinhibition in auditory cortex is driven by foot-shock-mediated cholinergic activation of layer 1 interneurons, in turn generating inhibition of layer 2/3 parvalbumin-positive interneurons. Importantly, pharmacological or optogenetic block of pyramidal neuron disinhibition abolishes fear learning. Together, these data demonstrate that stimulus convergence in the auditory cortex is necessary for associative fear learning to complex tones, define the circuit elements mediating this convergence and suggest that layer-1-mediated disinhibition is an important mechanism underlying learning and information processing in neocortical circuits.

Releavant Reading Material: Johannes J. Letzkus1*, Steffen B. E. Wolff1,2*, Elisabeth M. M. Meyer1,2, Philip Tovote1, Julien Courtin3, Cyril Herry3 & Andreas Lu ̈thi1 (2011) Nature 480:331-335. A disinhibitory microcircuit for associative fear learning in the auditory cortex http://www.nature.com/nature/journal/v480/n7377/full/nature10674.html

2011

January

February

Feb 25th

Time: 09:30 am

Place : 2nd Floor Conference Room, Gonda building.

Title :A selective role for dopamine in stimulus–reward learning

Speaker: Michael Faneslow

Summary: Flagel et al Nature 469, 53–57 (06 January 2011)

Supp

Apr 15th

Time: 09:30 am

Place : 2nd Floor Conference Room, Gonda building.

Title : Mushroom Body Output Neurons Encode Odor-Reward Associations

Speaker: David Glanzman

Summary: The paper describes neural correlates of odor representation and olfactory reward learning in honeybees using both population and single unit recording from the mushroom bodies.

Relevant Information: Paper

Apr 22nd

Time: 09:30 am

Place : 2nd Floor Conference Room, Gonda building.

Title :From Drosophila olfaction to a general circuit model for behavioral habituation.

Speaker: Mani Ramaswami

Summary:

Relevant Information:

Date: Apr 27th

Time: 09:30 am

Place : 2nd Floor Conference Room, Gonda building.

Title :The role of Thorase in the surface expression of glutamate receptors and its implications for synaptic plasticity and behavior

Speaker: Adam Roberts

Summary: Zhang et al., 2011 indicate that the AAA+ ATPase Thorase is required for the internalization of AMPARs by dissociating the GRIP1-GluR2 interaction. Genetic manipulation of Thorase expression modifies the surface expression of GluR1 and GluR2 in an ATP-dependent manner. Thorase KO mice have enhanced LTP, deficits in LTD, and larger AMPAR-dependent currents. These alterations in nervous system function result in deficits in learning and memory.

Relevant Information:

Paper

May

Date: May 13th

Time: 09:30 am

Place : 2nd Floor Conference Room, Gonda building.

Title :The role of Thorase in the surface expression of glutamate receptors and its implications for synaptic plasticity and behavior

Speaker: Adam Roberts

Summary: Zhang et al., 2011 indicate that the AAA+ ATPase Thorase is required for the internalization of AMPARs by dissociating the GRIP1-GluR2 interaction. Genetic manipulation of Thorase expression modifies the surface expression of GluR1 and GluR2 in an ATP-dependent manner. Thorase KO mice have enhanced LTP, deficits in LTD, and larger AMPAR-dependent currents. These alterations in nervous system function result in deficits in learning and memory.

Relevant Information:

Paper

Date: May 17th

Time 09:30 am

Place : 2nd Floor Conference Room, Gonda building.

Title: Action-Potential Modulation During Axonal Conduction

Speaker: Besim Ugzil"

Summary: Once initiated near the soma, an action potential (AP) is thought to propagate autoregeneratively and distribute uniformly over axonal arbors. We challenge this classic view by showing that APs are subject to waveform modulation while they travel down axons. Using fluorescent patch-clamp pipettes, we recorded APs from axon branches of hippocampal CA3 pyramidal neurons ex vivo. The waveforms of axonal APs increased in width in response to the local application of glutamate and an adenosine A1 receptor antagonist to the axon shafts, but not to other unrelated axon branches. Uncaging of calcium in periaxonal astrocytes caused AP broadening through ionotropic glutamate receptor activation. The broadened APs triggered larger calcium elevations in presynaptic boutons and facilitated synaptic transmission to postsynaptic neurons. This local AP modification may enable axonal computation through the geometry of axon wiring.

Releavant Information:

Paper

Date: May 17th

Time 09:30 am

Place : 2nd Floor Conference Room, Gonda building.

Title: Action-Potential Modulation During Axonal Conduction

Speaker: Besim Ugzil"

Summary: Once initiated near the soma, an action potential (AP) is thought to propagate autoregeneratively and distribute uniformly over axonal arbors. We challenge this classic view by showing that APs are subject to waveform modulation while they travel down axons. Using fluorescent patch-clamp pipettes, we recorded APs from axon branches of hippocampal CA3 pyramidal neurons ex vivo. The waveforms of axonal APs increased in width in response to the local application of glutamate and an adenosine A1 receptor antagonist to the axon shafts, but not to other unrelated axon branches. Uncaging of calcium in periaxonal astrocytes caused AP broadening through ionotropic glutamate receptor activation. The broadened APs triggered larger calcium elevations in presynaptic boutons and facilitated synaptic transmission to postsynaptic neurons. This local AP modification may enable axonal computation through the geometry of axon wiring.

Relevant Information:

Paper

Date: May 27th

Time 09:30 am

Place : 2nd Floor Conference Room, Gonda building.

Title: "What makes a place cell?"

Speaker: Justin Shobe"

Summary: Once initiated near the soma, an action potential (AP) is thought to propagate autoregeneratively and distribute uniformly over axonal arbors. We challenge this classic view by showing that APs are subject to waveform modulation while they travel down axons. Using fluorescent patch-clamp pipettes, we recorded APs from axon branches of hippocampal CA3 pyramidal neurons ex vivo. The waveforms of axonal APs increased in width in response to the local application of glutamate and an adenosine A1 receptor antagonist to the axon shafts, but not to other unrelated axon branches. Uncaging of calcium in periaxonal astrocytes caused AP broadening through ionotropic glutamate receptor activation. The broadened APs triggered larger calcium elevations in presynaptic boutons and facilitated synaptic transmission to postsynaptic neurons. This local AP modification may enable axonal computation through the geometry of axon wiring.

Releavant Information: Paper

June

Date: Jun 17th

Time: 09:30 am

Place : 2nd Floor Conference Room, Gonda building.

Title : "Insulin Signaling and Dietary Restriction Differentially Influence the Decline of Learning and Memory with Age"

Speaker: Kelsey Martin

Speaker: Dean Buonomano

Summary: A discussion on the following paper:

A cortical neural prosthesis for restoring and enhancing memory.

Speaker: Christine Serway

Summary: The interplay between brain anatomy, neural network organization and behavior has been well studied in Drosophila for over three decades. The first experimental evidence implicating the mushroom bodies (MBs) as centers of sensory integration and association in flies came from anatomical and behavioral work on brain structure mutants. Here we present a detailed analysis of three genes using mutant alleles initially described by Martin Heisenberg et al. more than 25 years ago. We characterized the different levels of associative conditioning and mushroom body defects seen in mushroom body miniature B (mbmB), small mushroom bodies (smu) and mushroom bodies reduced (mbr). This work has allowed us to implicate subsets of the MBs in different forms of associative conditioning. Surprisingly most of the mutants created in this screen have yet to be molecularly characterized. Extensive complementation analysis and sequencing revealed mbmB to be synonymous with the Drosophila Importin-2 (Imp-2). We present rescue experiments, western blot analysis, and have demonstrated that all Imp-2 domains are required for normal MB development. In Drosophila, imp-2 mediated nuclear transport is necessary for proper axon guidance, neuronal injury response, synaptic plasticity, cell proliferation and apoptosis, while its role in central brain development has not been investigated until now. This work provides a novel link between Importin--2 and MB development and offers insight on the cell biology of developmental and behavioral plasticity.

September

Date: Sep 02nd

Time: 09:30 am

Place : 2nd Floor Conference Room, Gonda building.

Title : ""Prior experience modulates a natural threshold for memory formation ""

Speaker: Kiriana Cowansage

Summary: Our current understanding of the molecular requirements for long–term memory come largely from studies that use experimental manipulations to alter average behavior. Few studies, on the other hand, have investigated the contribution of plasticity-related proteins, like CREB, to existing behavioral differences in memory strength that emerge naturally from genetically diverse populations. In this talk I will begin by presenting work from the labs of Joe LeDoux and Eric Klann (in collaboration with Sheena Josselyn) to identify rats from a normally distributed group that fail to form typical cued fear associations and express reduced baseline levels of phospho-CREB. Memory in this subset of rats was selectively improved by both pre-training exposure to contextual novelty and by virally mediated enhancement of amygdala CREB activity. These results provide some conceptual basis for current plans to investigate the cellular dynamics of weak versus strong associative memory traces in the lab of Mark Mayford, using a novel genetically encoded fluorescent timer expressed in mice under the control of neural activity.

Relevant Information:

Subach et al (2009) Nat. Chem Biol

Date: Sep 23rd

Time: 09:30 am

Place : 2nd Floor Conference Room, Gonda building.

Title : " 2½ Short Stories of Pavlov's Flies "

Speaker: Steven de Belle

Summary: Not provided

Date: Sep 30th

Time: 09:30 am

Place : 2nd Floor Conference Room, Gonda building.

Title : " Talk 1: Grid cells, theta oscillations, and a novel code phase code of the head direction signal Talk 2: Septotemporal variation in theta rhythm dynamics "

Speaker: Mark Brandon and Jake Hinman

Summary: Not provided

Relevant Materials:

http://www.sciencemag.org/content/332/6029/595.full

http://jn.physiology.org/content/105/6/2675.full.pdf+html

October

Date: Oct 14th

Time: 09:30 am

Place : 2nd Floor Conference Room, Gonda building.

Title : " AMPA receptor trafficking in reconsolidation of context fear memories "

Speaker: Tom O Dell

Summary: Not provided

Relevant Materials:

http://www.nature.com/neuro/journal/v14/n10/full/nn.2907.html

Date: Oct 28th

Time: 09:30 am

Place : 2nd Floor Conference Room, Gonda building.

Title : " Mental Schema and its Neural Correlates"

Speaker: Balaji

Summary: Not provided

Relevant Materials:

http://www.sciencemag.org/content/333/6044/891.full

November

Date: Nov 04th

Time: 09:00 am

Place : 1st Floor Conference Room, Gonda building.

Title : " The Cytoplasmic Fragile X Mental Retardation Protein1 CYFIP1 is a Key Player in Neurodevelopment: The Link with Autism"

Speaker: Claudia Bagni

Date: Nov 18th

Time: 09:30 am

Place : 2nd Floor Conference Room, Gonda building.

Title : " The h-currents, LTP,theta oscillations,grid cells and learning"

Speaker: Mayank Mehta

Summary: The hippocampal theta oscillations are thought to be critical for learning and memory and for the formation of entorhinal grid cells. Over the past few years the attention has been focused on the HCN1 channel: HCN1 channel knockout enhances theta rhythm and LTP, and improves spatial learning.

Two recent studies, one in the current issue of Neuron, from the Kandel lab, and another in the upcoming issue of Cell from the Moser lab, have measured the effect of HCN1 knockout on the entorhinal grid cells and hippocampal place cells, with many surprising results that compels us to rethink the cellular mechanisms governing grid cells and place cells.

Releavant Reading Material: http://www.sciencedirect.com/science?_ob=MiamiImageURL&_cid=272195&_user=4423&_pii=S0896627311007938&_check=y&_coverDate=2011-11-17&view=c&_gw=y&wchp=dGLzVlt-zSkzk&md5=9c0fb5a1be9056818c9b1daa13635cdf/1-s2.0-S0896627311007938-main.pdf

December

Date: Dec 9th

Time: 09:30 am

Place : 2nd Floor Conference Room, Gonda building.

Title : "Reevaluating the Role of LTD in Cerebellar Motor Learning"

Speaker: Paul Mathews

Summary: It is widely believed that changes in the strength of synapses underlies the cellular changes responsible for memory formation. In the Cerebellum theories regarding the location of the cellular changes necessary for motor learning have recently been of great debate. One particular hypothesis proposed by Marr, Albus and Ito is that errors in motor behavior lead to changes in the strength of parallel fiber (PF) inputs onto Purkinje neurons (PNs). These errors, which are believed to be carried by climbing fiber terminals originating from the inferior olive, are thought to drive long term depressions (LTD) of PF-PN synapses that are activated coincidentally with the error signal. This change in the cerebellar circuit is believed, at least in part to underlie the cellular mechanisms driving motor learning. Supporting this hypothesis are numerous studies in which blocking the pathways responsible for PF-PN LTD leads to a deficit in cerebellar mediated motor behaviors. However, it has been argued that since these manipulations effect targets that often play multiple cellular regulatory roles (mGlur1/PKC, PKG, and αCamKII) the changes observed in motor behavior may be due instead to alterations in processes unrelated to the abolition of LTD. In the paper for discussion this Friday the authors reevaluate the role LTD plays in cerebellar motor learning by disrupting LTD through preventing AMPA receptor endocytosis directly rather than effecting more precocious molecules. Their experiments show that while these manipulations prevent associative PF-PN LTD in vitro numerous tests fail to show any significant behavioral effect of LTD disruption. For LMP this Friday we will examine the previous data suggesting LTD in the cerebellar cortex is critical for motor learning as well as how these new negative findings potentially alter our view of LTD’s role in cerebellar mediated motor learning.

Releavant Reading Material: http://www.sciencedirect.com/science?_ob=MiamiImageURL&_cid=272195&_user=4423&_pii=S0896627311001991&_check=y&_origin=&_coverDate=14-Apr-2011&view=c&wchp=dGLbVlS-zSkzk&md5=b2315bb5e6d206c4b2b051a7e8edf789/1-s2.0-S0896627311001991-main.pdf

Date: Dec 16th

Time: 09:30 am

Place : 2nd Floor Conference Room, Gonda building.

Title : "Synaptic Potentiation in the Central Amygdala upon Fear Learning"

Speaker: Ayako M. Watabe, Ph.D.

Previous weeks

Contents

2020

January

Title: “Modulation of Emotion and Memory via Direct Brain Stimulation in Humans: From the Laboratory into the Wild”

2019

December

Title: “Control of mice orienting movement by optogenetic activation of the inhibitory nigrocollicular pathway”

Title: “Interhemispheric gamma synchrony between parvalbumin interneurons supports behavioral adaptation”

Title: “Can the artificial activation of a neuron pair recall an entire ensemble and trigger behavior?”

November

Title: “Chemogenetic modulation and single-photon calcium imaging in anterior cingulate cortex reveal a mechanism for effort-based decisions ”

Title: “Local protein synthesis is a ubiquitous feature of neuronal pre- and postsynaptic compartments”

Title: “Immediate and deferred epigenomic signatures of in vivo neuronal activation in mouse hippocampus”

Title: “Solo spikes in the sleeping brain help consolidate memories”

October

Title: “Practice makes (too) perfect: Hebbian learning and the persistence of overly trained behaviors in subcortical circuits?”

Title: “What does it mean to "understand" how a neural circuit computes?”

Title: “REM sleep–active MCH neurons are involved in forgetting hippocampus-dependent memories”

September

Title: “Cortical circuits for dynamic auditory perception”

June

Title: “Pharmacological or genetic reduction of miR-128 enhances learned vocal communication”

Title: “Distinct hippocampal engrams control extinction and relapse of fear memory”

May

Title: “Inhibitory Basal Ganglia Inputs Induce Excitatory Motor Signals in the Thalamus”

Title: “Hierarchical reasoning by neural circuits in the frontal cortex”

Title: “Memory formation in the absence of experience”

Title: “Multi-sensory Gamma Stimulation Ameliorates Alzheimer’s-Associated Pathology and Improves Cognition”

Title: “Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation”

April

Title: “ Dopamine Receptors in Accumbal Cholinergic Interneurons for Susceptibility to Cocaine Seeking”

Title: “Early life experience drives structural variation of neural genomes in mice”

Title: “Circuits-specific corticostriatal synaptic abnormalities in a mouse model of compulsive behavior”

Title: “Cerebellar contributions to cognitive behavior”

March

Title: “Molecular Plasticity and Memory Function in Cocaine Abuse”

Title: “Hypothalamic control of organized escape from multimodal threats”

Title: “The effects of endocrine therapy on cognitive function in breast cancer survivors”

Title: “The mouse as a model for neuropsychiatric drug development”

February

Title: “Learning with Mitochondria”

Title: “VIP Interneurons in the Hippocampus Support Goal Oriented Spatial Learning”

Title: “Calmodulin shuttling mediates cytonuclear signaling to trigger experience-dependent transcription and memory”

Title: “Persistence of patterns of neuronal activity through time, noise, and damage in the hippocampus”

January

Title: “An amygdalar neural ensemble that encodes the unpleasantness of pain”

Title: “Dissecting Circuit Dynamics of Sensory Discrimination and Behavior”

Title: “Conditional Freezing, Flight and Darting?”

2018

December

Title: “Network activity of Fragile X circuits”

Title: “Long-Term Potentiation requires a rapid burst of Dendritic Mitochondrial Fission during Induction”

November

Title: “Synapse-specific representation of the identity of overlapping memory engrams”

Title: “Autonomic and Central Nervous System Contributions to Sleep-Dependent Memory Consolidation”

Title: “Simultaneous encoding of head angle, episodic distance, and position by hippocampal activity in a virtual water maze”

Title: “Challenging the point neuron dogma: FS basket cells as 2-stage nonlinear integrators”

October

Title: “mTOR-dependent interferon signaling in microglia and social memory deficits in a mouse model of tuberous sclerosis”

Title: “Impaired Visual Familiarity Circuit in Fmr1 KO Mice”

Title: “Astrocytic Activation Generates De Novo Neuronal Potentiation and Memory Enhancement”

Title: “Integrating time from experience in the lateral entorhinal cortex”

September

Title: “Learning to play chess through Deep Reinforcement Learning: What should neuroscientists learn from machine learning?”

June

Title: “RNA from Trained Aplysia Can Induce an Epigenetic Engram for Long-Term Sensitization in Untrained Aplysia”

Title: “Distinct learning-induced changes in stimulus selectivity and interactions of GABAergic interneuron classes in visual cortex”

Title: “The Method of Loci in the modern age: Insights from Virtual reality and neuroimaging”

May

Title: “Different neuronal activity patterns induce different gene expression programs”

Title: “Neural network dynamics of temporal processing”

Title: “What is post-natal neurogeneis good for?”

Title: “Does dopamine only compute errors in reward prediction? New data says no.”

April

Title: “LTP requires postsynaptic PDZ-domain interactions with glutamate receptor/auxiliary protein complexes”

Title: “Differential inhibition of the a-secretase ADAM10 by Ab variants containing FAD mutations”

Title: “The Adult Human Neurogenesis Saga”

Title: “Illuminating the Biochemical Activity Architecture of the Cell”

March