Sexual divergence in prefrontal neural regulation and encoding of depression-associated behaviors
Date
2022
Authors
Wallace, Tyler, author
Myers, Brent, advisor
Hentges, Shane T., advisor
Amberg, Gregory, committee member
Conner, Bradley, committee member
Journal Title
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Volume Title
Abstract
Major depressive disorder (MDD) accounts for the most years lived with disability worldwide. Yet, despite its staggering prevalence, the biological mechanisms underpinning MDD onset are not understood, further complicated by considerable sex-based differences in MDD occurrence. The ventromedial prefrontal cortex (vmPFC) is heavily associated with MDD, though how vmPFC neural populations respond to and regulate behaviors associated with MDD, including affective state, social behaviors, and stress responding is unknown. Thus, I utilized viral methods to dissect how a genetically identified neural population within the vmPFC regulates and encodes MDD-associated behaviors. In chapter 2, I utilized an optogenetic technique to increase the firing rate of a subset of glutamatergic vmPFC neurons in conjunction with behavioral testing. My results demonstrated considerable sexual divergence in vmPFC glutamatergic influence. In males, stimulation conferred positive affect, increased social motivation, and constrained aspects of the acute stress response. While in females, stimulation did not alter behavior and augmented the acute stress response. In chapter 3, I utilized a similar optogenetic technique to dissect how vmPFC projections to the posterior hypothalamus (PH), contribute to behavioral and physiological regulation. Again, my results demonstrated sexual divergence in vmPFC circuit function. In males, stimulation of the vmPFC to PH glutamatergic circuit conferred positive affect, and constrained aspects of the acute stress response, though it did not alter social behavior. The circuit similarly conferred positive affect in females, but again augmented the acute stress response. Overall, my stimulation of vmPFC glutamatergic neurons identified that they regulate affect, social behavior, and stress responding but the specific effects are sex and circuit specific. While chapters 2 and 3 identified how specific vmPFC neural populations can regulate behavioral and physiological processes, how these neural populations respond to behavior and how these responses are disrupted in pathology was unknown. Thus, in chapter 4, I utilized fluorescent calcium indicators to record the activity of genetically-identified vmPFC glutamatergic neurons during behavioral testing. To determine changes to vmPFC neural activity in pathology, animals were exposed to a preclinical model of MDD, chronic variable stress. My results showed that vmPFC glutamatergic neurons are responsive to object, social, stressful, and rewarding stimuli regardless of sex. However chronic stress exposure altered vmPFC glutamatergic activity in males more so than females, with some of these differences accounted for by female ovarian status. Overall, the work presented in this dissertation determined how a vmPFC neural population regulates MDD-disrupted behaviors, detailed how a specific vmPFC circuit contributes to this regulatory role and measured how vmPFC neurons respond to behavior in real-time with and without a history of chronic stress.
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Subject
depression
prefrontal
stress
infralimbic
affect
social