Author ORCID Identifier

https://orcid.org/0000-0001-6629-0897

Document Type

Dissertation

Date of Award

12-2021

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

Cliff H Summers

Abstract

Stress initiates behavioral disturbances, which are often seen as symptoms of psychiatric disorders, like post-traumatic stress disorder (PTSD), depression, and anxiety. While stress is involved in the formation of disordered states, only certain individuals are vulnerable to, and therefore experience, these outcomes. Further, females are more likely to be diagnosed with stress-induced psychiatric disorders. Elements within stress neurocircuitry offer insight into differential behavioral outcomes associated with stressful experiences; and the basolateral amygdala (BLA), where pro- and anti-stress signals are integrated, is likely an important mediator in phenotype development. The orexin system, too, while being strongly associated with sleep, motivation, and arousal, is critical for directing stress-induced responses. Produced in the hypothalamus, orexins (OrxA and OrxB) are released into the BLA where they target and activate two receptor subtypes: Orx1R and Orx2R. These receptors are found on different cells within BLA microcircuits, with Orx1R predominantly being localized to glutamatergic neurons and Orx2R having slightly higher expression in GABAergic cells. Pharmacological inhibition of Orx1R in the BLA rescues resilient behavior in stress vulnerable mice, while reducing fear freezing behavior, and promoting social learning. Alternatively, Orx2R inhibition in the BLA upsets fear learning in resilient populations, but enhances social avoidance. Alternatively, activation of Orx2R in BLA cells reduces fear freezing and increases social preference. Female mice exhibit unique behavioral patterns as a result of social stress compared to males, but phenotypic responses are observed when females are administered an Orx2R antagonist. While females have higher Orx2R expression in the BLA compared to males, pharmacological intervention with an Orx2R antagonist reveals even further distinctions within female behavioral phenotypes. Together, these results suggest the orexin system is important for defining behavioral outcomes after stress, and while sexual dimorphism exists in behavior and physiology, orexin receptor activity in the BLA appears to be a critical gating mechanism in both male and female stress-induced phenotype development.

Subject Categories

Biology | Neuroscience and Neurobiology

Keywords

anxiety, fear, female social stress, hypocretin, neurocircuit, post-traumatic stress disorder

Number of Pages

286

Publisher

University of South Dakota

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