Role for Midbrain Glutamatergic and Epithalamic Circuitry in Stress Induced Behavioral Changes and Motivation

McGovern, Dillon J.

Graduate Thesis Or Dissertation

Role for Midbrain Glutamatergic and Epithalamic Circuitry in Stress Induced Behavioral Changes and Motivation Public Deposited

Analytics

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Citeable URL: https://scholar.colorado.edu/concern/graduate_thesis_or_dissertations/wh246t63z

Abstract

The Ventral Tegmental Area (VTA) is an evolutionarily conserved midbrain region that is critical for reinforcement learning and motivated behavior. The cellular heterogeneity of the VTA creates an opportunity to evaluate how genetically distinct neuronal populations and circuits inform motivation. The experiments within this thesis evaluate the role of glutamatergic neurons, VGluT2+, within the realms of both natural and drug seeking (oxycodone) behavior, aversion, and stress resilience. In-vivo viral monitoring and manipulation strategies (optogenetics, chemogenetics, and fiber photometry) were leveraged to record the unique neurochemical signaling dynamics of this population during motivated action and establish the causal behavioral contributions of this population and its epithalamic efferents.

Within Pavlovian reward and aversion unique GABAergic and glutamatergic signaling input to these neurons was recorded for conditioned behavioral predictors (cues) and their associated outcomes. Significant changes in intracellular calcium signaling, required for vesicular release, were recorded for the same behavioral epochs as well as drug associated cues and oral oxycodone administration. Global inhibition of this VGluT2+ population, using hM4Di, prevented drug reinstatement behavior in male mice. In addition to natural and drug seeking behavior VTA VGluT2+ neurons were significantly recruited by stress experience and directly regulated non-associative behavioral changes, such as reduced social engagement. VTA VGluT2+ inhibition during stress prevented the development of recorded behavioral deficits. Genetically distinct VTA VGluT2+ neurons were recruited by stress experience and these stress responsive neurons established dense outputs to the lateral habenula (LHb). Neurochemical signaling in this epithalamic nucleus was recorded during stress and VTA à LHb circuitry was inhibited to determine the causal role of this pathway. Blocking neurochemical output within this neuronal circuit facilitated resilience and prevented behavioral changes in motivation following stress. These foundational experiments establish clear roles for VTA VGluT2+ in diverse motivated behaviors, while critically monitoring how neurochemical signaling dynamics and circuits contribute to these behaviors.

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