ICLM Journal Club
This Week - 12 April 2019 (9:30 a.m., 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.
About Us
Introduction
The Integrative Center for Learning and Memory (ICLM) is a multidisciplinary center of UCLA labs devoted to understanding the neural basis of learning and memory and its disorders. This will require a unified approach across different levels of analysis, including;
1. Elucidating the molecular cellular and systems mechanisms that allow neurons and synapses to undergo the long-term changes that ultimately correspond to 'neural memories'.
2. Understanding how functional dynamics and computations emerge from complex circuits of neurons, and how plasticity governs these processes.
3. Describing the neural systems in which different forms of learning and memory take place, and how these systems interact to ultimately generate behavior and cognition.
History of ICLM
The Integrative Center for Learning and Memory formally LMP started in its current form in 1998, and has served as a platform for many interactions and collaborations within UCLA. A key event organized by the group is the weekly ICLM Journal Club. For more than 10 years, graduate students, postdocs, principal investigators, and invited speakers have presented on topics ranging from the molecular mechanisms of synaptic plasticity, through computational models of learning, to behavior and cognition. Dean Buonomano oversees the ICLM journal club with help of student/post doctoral organizers. For other events organized by ICLM go to http://www.iclm.ucla.edu/Events.html.
Current Organizers:
Current Faculty Advisor:
Past Organizers:
i) Anna Matynia(Aug 2004 - Jun 2008) (Silva Lab)
ii) Robert Brown (Aug 2008 - Jun 2009) (Balleine Lab)
iii) Balaji Jayaprakash (Aug 2008 - Nov 2011) (Silva Lab)
iv) Justin Shobe & Thomas Rogerson (Dec 2011 - June 2013) (Silva Lab)
v) Walt Babiec (O'Dell Lab) (2013-2014)
vi) Walt Babiec (O'Dell Lab) & Helen Motanis (Buonomano Lab) (2014-2017)
vii) Helen Motanis (Buonomano Lab) & Shonali Dhingra (Mehta Lab) (2017-2018)
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