ICLM Journal Club
This Week - 14 June 2019 (9:30 a.m., 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.
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 Faculty Advisor:
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