Modulatory mechanisms underlying aversive learning and the effects of rapidly acting anti-depressants on plasticity - Yevgenia Kozorovitskiy

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Thursday, March 28, 2019
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12:00pm to 1:00pm PDT
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Wu Tsai Neurosciences Institute
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Wu Tsai Neurosciences Institute, Yevgenia Kozorovitskiy

Yevgenia Kozorovitskiy, PhD

Assistant Professor of Neurobiology
Northwestern University

Host: Jun Ding


The genesis and turnover of excitatory neuronal connections underlie development, learning, and disease. Decades of studies have yielded insights into the processes that regulate the formation, pruning, function, and dysfunction of synapses. Still, making causal inferences about the regulation of synapse birth remains technically challenging within complex circuits. Here, we use multilaser 2-photon microscopy in order to probabilistically induce the de novo growth of dendritic spines and synapses with high spatiotemporal precision on genetically targeted pyramidal neurons of the medial prefrontal cortex (mPFC). Using this approach to causally interrogate structural plasticity in the mPFC in the context of aversive learning, we find that rapidly acting antidepressant drugs, such as ketamine, potently increase the potential for spinogenesis in mPFC pyramidal cells. Surprisingly, this effect depends on dopaminergic (DA) signaling from the ventral tegmental area (VTA). Low-dimensional optical readout of VTA DA neuron activity is sufficient to predict behavioral state during aversive learning. A single dose of ketamine normalizes these dynamics, recovering normal behavioral responses and glutamate uncaging-evoked plasticity. Ketamine actions are blocked by chemogenetic inhibition of DA signaling and mimicked by activating VTA DA neurons using optogenetic or chemogenetic approaches. Together, these data demonstrate a causal link between neuromodulatory systems regulating mPFC function, aversive learning, and plasticity enhancements driven by a therapeutically promising NMDAR antagonist.

Curriculum Vitae

Related papers

[1] Lei Xiao, Michael F. Priest, Jordan Nasenbeny, Ting Lu, Yevgenia Kozorovitskiy. Biased Oxytocinergic Modulation of Midbrain Dopamine Systems. Neuron, Volume 95, Issue 2, 19 July 2017, Pages 368-384.e5. DOI: 10.1016/j.neuron.2017.06.003

[2] Yevgenia Kozorovitskiy, Rui Peixoto, Wengang Wang, Arpiar Saunders, Bernardo L Sabatini. Neuromodulation of excitatory synaptogenesis in striatal development. eLife 2015;4:e10111 DOI: 10.7554/eLife.10111