Date of Award

Fall 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Interdepartmental Neuroscience Program

First Advisor

Picciotto, Marina

Abstract

Individuals are constantly subjected to various forms of stress, which shape the brain in different ways. The brain, in turn, must coordinate a response to adapt to the demands of the stressor. This response is coordinated via interactions between several neuromodulatory and neuroinflammatory signaling pathways. The limbic system, particularly the amygdala and hippocampus, has been highlighted as an important site for integration of these signals. These areas are critical for engaging neural, autonomic, and behavioral responses to acute stress and for plasticity-driven learning that can shape future responses to stress through a process called allostasis. Chronic exposure to stress can remodel these circuits, shifting the balance between signals and driving dysregulation of brain function and behavior as a result of allostatic load. Ultimately, these changes can manifest in psychopathologies such as depression, post-traumatic stress disorder, and addiction, with different etiologies and impacts across sexes. By modeling acute and chronic forms of stress in mice, we can deepen our understanding of the processes that regulate, and dysregulate, limbic circuits across different temporal domains in both sexes. This dissertation will begin by examining the neuromodulatory influences of norepinephrine and acetylcholine that converge on the amygdala to regulate behavioral coping responses to acute stress. Through fiber photometric, optogenetic, and immunohistochemical experiments, I address how these neuromodulators drive amygdala responses mediating innate defensive behaviors, and the impacts of controllability and sex on these responses. I will then explore how neuromodulation of microglia, the brain's resident immune cells, regulates inflammatory responses to drug exposure, ultimately contributing to the development and progression of addiction. I conclude by examining sex differences in the intersection between stress and alcohol consumption, and how neuroinflammatory processes drive problematic alcohol drinking after stressful experiences in women. Using a mouse model of chronic stress-induced drinking that replicates diverging patterns of alcohol use disorder in men and women, these experiments employ pharmacological and immunohistochemical techniques to evaluate the role of limbic microglia in responding to stress and alcohol exposure. Together, these findings illuminate the neuromodulatory and neuroinflammatory mechanisms guiding limbic responses to stress, deepening our understanding of how stress disorders and addiction manifest in men and women.

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