VTA microcircuit dynamics during chronic stress

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ABSTRACT In this project, we will investigate the dynamics of inhibition in the ventral tegmental area (VTA) during chronic stress. GABAergic neurons make up 35% of neurons in the VTA, but relatively little is known about them. These cells are critical regulators of neighboring dopaminergic neurons, and are robustly activated by acute stress. VTA GABA neurons are thus poised to be a significant mediator of stress’s effects on the VTA. It remains unknown, however, how these neurons respond to chronic stress. In this proposal, we will take a multidisciplinary approach, utilizing electrophysiology, optogenetics, behavior, and fiber photometry to address the hypothesis that chronic stress leads to persistent hyperactivity of VTA GABA neurons and that this underlies the emergence of maladaptive behavioral responses. In the first aim, we will examine the dynamics of inhibition of VTA dopamine neurons by VTA GABA neurons during stress. In the second, we will investigate how activity of and strength of synaptic inputs onto VTA GABA neurons changes during stress. In the third aim, we will examine whether in vivo activity of VTA GABA neurons contributes to individual differences in the emergence of social anhedonia post-stress. These studies hold the potential to contribute significantly to our understanding of how the reward system is altered by stress and may lead to novel avenues for the development of therapeutic treatments for depression and other stress-linked disorders.