Document Type
Dissertation
Date of Award
2026
Degree Name
Doctor of Philosophy (PhD)
Department
Biology
First Advisor
Cliff H Summers
Abstract
Social stress is important for evaluating threats and resource opportunities, however, chronic exposure initiates the onset of psychological disorders, such as anxiety, depression, and post-traumatic stress disorder (PTSD). Stress responsiveness varies between individuals and sexes, resulting in disproportionate diagnoses and ineffective treatment outcomes. Enhancing therapeutic efficacy requires understanding of stress responsivity, phenotype development, and neurocircuitry modifications. Key contributors to stress responsiveness, such as threat of aggression and motivational initiation, influence the development of resilient or vulnerable phenotypes through behavioral and molecular adaptations to stress-related neurocircuitry. The basolateral amygdala (BLA) is a brain region associated with fear learning and integrates stress signals that mediate molecular and behavioral responses. The anterior region of BLA (aBLA) contains genetic markers CamkIIα+ and Rspo2+, a Wnt-signaling mediator, on glutamatergic neurons that enhance the stress response (pro-stress) upon activation of orexin type I receptors (Orx1R, Hcrtr1) which can be modulated to dampen the stress response (anti-stress) by local inputs from GABAergic neurons containing genetic markers Gad1+/Cck+ and orexin type II receptors (Orx2R, Hcrtr2). Pharmacological intervention via Orx1R inhibition and Orx2R activation with a novel treatment known as a selective orexin receptor cross-over (SORCO) rescues resilient behavior in vulnerable populations, while reducing the fear response (freezing), promoting learning, and motivational behaviors. Resilient behavioral changes coincide with molecular adaptations to OrxRs and neuroplasticity-associated genes in stress circuitry of aBLA. Vulnerable individuals rendered resilient with OrxR-targeted anxiolytic treatment have an increase in Hcrtr2 mRNA and a decrease in Hcrtr1-expressing cells that also contain Rspo2 expression. Results herein support OrxR-dependent changes to neuroplasticity-associated genes, including an increase in Akt3 (but not Akt2) and Mtor in Hcrtr2-expressing cells for individuals treated with a drug that activates Orx2R to produce anxiolytic responses. Furthermore, female mice exposed to inescapable social stress have an increase in the percentage of cells expressing Rspo2/Hcrtr1/Wnt3a, and increased Hcrtr1 mRNA in all cells of aBLA. Together, these results implicate the orexin system, particularly the modulation of Orx1R and Orx2R on stress neurocircuitry in aBLA, have a role in defining behavioral outcomes associated with resilient and vulnerable phenotypes.
Subject Categories
Biology | Cell and Developmental Biology | Neuroscience and Neurobiology
Keywords
Basolateral Amygdala, Neuroplasticity, Orexin, Resilient, Social Stress, Vulnerable
Number of Pages
218
Publisher
University of South Dakota
Recommended Citation
John, Megan Marie, "OREXIN RECEPTOR MODULATION IN AMYGDALAR STRESS CIRCUITRY DIFFERENTIATES RESILIENT AND VULNERABLE PHENOTYPES" (2026). Dissertations and Theses. 408.
https://red.library.usd.edu/diss-thesis/408
Included in
Biology Commons, Cell and Developmental Biology Commons, Neuroscience and Neurobiology Commons