Date Approved

4-2021

Document Type

Dissertation

Degree Name

PhD in Cell and Molecular Biology

Department

Cell Biology and Neuroscience

College

Graduate School of Biomedical Sciences

First Advisor

Daniel Chandler, PhD

Committee Member 1

Barry Waterhouse, PhD

Committee Member 2

Jessica Loweth, PhD

Committee Member 3

Debra Bangasser, PhD

Committee Member 4

Ronald Ellis, PhD

Subject(s)

Rats, Locus Coeruleus, Anxiety, Stress, Physiological, Receptors, Opioid, Adolescent

Disciplines

Behavioral Neurobiology | Cell Biology | Laboratory and Basic Science Research | Medical Cell Biology | Medical Neurobiology | Medicine and Health Sciences | Molecular and Cellular Neuroscience | Molecular Biology | Neurosciences | Pathological Conditions, Signs and Symptoms

Abstract

Stress is a physiological state characterized by behavioral arousal that occurs during exposure to harmful or threatening stimuli, and usually facilitates an adaptive behavioral response. The persistence of stress sometimes causes it to become maladaptive, potentially contributing to disease development, including physiological complications with altered neuroendocrine signaling and impaired function of organ systems, and psychological conditions including depression and anxiety. Anxiety disorders in particular are associated with a history of stress and are the most common class of mental disorders, with a lifetime prevalence of 33.7% in the general population. The locus coeruleus (LC) is a major node in the stress response, which integrates input from multiple stress responsive neural circuits and releases norepinephrine throughout the central nervous system (CNS) to promote vigilance and anxiety. Stress-induced adaptations in LC may lead to impaired noradrenergic transmission throughout the CNS and is thought to contribute to mood disorder pathogenesis. Although immediate cellular actions of stress on LC have been extensively studied, the long-term changes in LC are poorly described.

It is well-established that acute stress causes the release of corticotropin-releasing factor (CRF) in the CNS, including in LC, where it increases tonic firing to promote increased norepinephrine in target brain areas, thereby promoting anxiety-like behavior. However, LC morphology and stress responsiveness varies among males and females and changes throughout development. In addition, CRF activity on the LC is counteracted by endogenous opioid neurotransmission. The endogenous opioid peptides Leu- and Met-enkephalins act through d and m opioid receptors, which decrease cAMP and increase potassium conductance through a Gi-coupled mechanism, leading to cell hyperpolarization and decreased firing. Therefore, we hypothesized that acute stressor exposure would have variable impacts on LC physiology and anxiety-like behavior in rats of different ages in both sexes. We further postulated that dysregulation of LC following stress is associated with altered function of opioid receptors in LC. To test this, we used a combination of whole-cell patch clamp recordings of LC neurons, rodent assays of anxiety-like behavior, and analysis of gene and protein expression. Finally, by using a viral-genetic method, we assessed the impact of overexpression of δ-opioid receptors in LC on stress responsiveness.

Here we report that acute intense stressor exposure results in opposing changes in anxiety-like behavior and LC physiological properties in adolescent male and female rats. No such changes were observed in adult animals. We also found that the same stressor during adolescence in males is associated with impaired δ opioid receptor expression and function, which may contribute to a reduced capacity to terminate the stress response. These results suggest that endogenous opioid signaling in LC, particularly in adolescent males, is a key target, and regulator of, the stress response, and may have critical implications for the development and treatment of various stress-associated pathological conditions.

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