Date Approved

6-2023

Document Type

Dissertation

Degree Name

PhD in Molecular Cell Biology and Neuroscience

Department

Cell Biology and Neuroscience

College

Graduate School of Biomedical Sciences of Rowan University

First Advisor

Daniel Chandler, PhD

Committee Member 1

Francois Gould, PhD

Committee Member 2

Elizabeth West, PhD

Committee Member 3

Benjamin Rood, PhD

Committee Member 4

Pavan Bhargava, MD

Subject(s)

Locus Coeruleus; Neuroinflammatory Diseases; Stress, Physiological; Male; Anxiety; Anxiety Disorders

Disciplines

Behavior and Behavior Mechanisms | Biological Phenomena, Cell Phenomena, and Immunity | Cell Biology | Cellular and Molecular Physiology | Disease Modeling | Laboratory and Basic Science Research | Medical Cell Biology | Medicine and Health Sciences | Molecular and Cellular Neuroscience | Molecular Biology | Neuroscience and Neurobiology | Pathological Conditions, Signs and Symptoms

Abstract

The locus coeruleus (LC), the primary site of brain norepinephrine (NE), is a key anatomical brain region implicated in the stress response. Stress is a neuroendocrine physiologic response to a stressor that promotes organism survival through adaptive change and restoration of homeostasis. The central stress response, which drives behavioral and physiological change, is primarily mediated by activating the hypothalamic-pituitary-adrenal (HPA) axis. While advantageous in the short term, chronic stress exposure can lead to HPA axis and LC dysregulation, which are thought to contribute to the etiology of anxiety disorders. Previous studies demonstrate the effects of acute stress in increasing LC activity which correlates with rodent anxietylike behaviors. Recent studies have also implicated neuroinflammation mediated by microglia as a risk factor in mood and anxiety disorders. Despite their association with anxiety disorders, the combined contributions of stress and inflammation in potentially driving LC neuroadaptations, and their potential contribution to neuropsychiatric disorders have not been well explored.

This dissertation addresses the knowledge gap in the complex roles of stress and neuroinflammation in the etiology of anxiety disorders. Our results demonstrate increased rodent anxiety-like behaviors in the elevated plus maze (EPM) and increased LC spontaneous firing via ex-vivo electrophysiology in adolescent rats exposed to chronic stress. Surprisingly, despite similarities in anxiety-like behavior, chronic stress induces a sex-dependent LC neuroinflammation. A significant increase in activated microglia and expression of pro-inflammatory genes, cd74 and il-6, within the LC were noted in male but not female adolescent rats. Interestingly, modulation of the chronic stress-induced LC neuroinflammation through minocycline administration showed a trend for reversal of chronic stress effects in rodent anxiety-like behaviors and LC physiology. Our results suggest that chronic stress induces LC neuroinflammation, leading to rodent anxiety-like behaviors and alterations in LC neuronal physiology. Overall, our results establish the LC as an anatomical site of convergence for pro-stress and pro-inflammatory cues and imply a possible role for chronic stress-induced neuroinflammation in driving LC neuroadaptations leading to anxiety-like phenotypes.

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