Date of Award

8-16-2024

Document Type

Open Access Dissertation

Department

Biomedical Science

First Advisor

Susan Wood

Abstract

Posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) are highly debilitating psychiatric disorders that notably share stress as an etiological factor. Stress is a common occurrence experienced daily by virtually everyone and, while most people are resilient, a substantial portion of the population exhibit risk factors that yield them susceptible to developing stress-related psychiatric disorders. One prominent factor that has long been known to increase this risk is the female biological sex with women presenting at least twice as often with disorders like PTSD and MDD compared to men. Interestingly, this bias exists distinctly during the reproductive years and coincides with natural fluctuations in ovarian hormones across the menstrual cycle. Clinical studies support a role for ovarian hormones, namely estrogen, in this susceptibility, although these findings are not always replicated in preclinical studies, particularly in those that do not evaluate behavior in the context of stress. Thus, aim 1 of the current studies tested the hypothesis that females previously exposed to stress exhibit greater anxiety-like behavior when in the presence of heightened estrogen. In support of this, estrogen is known to directly amplify production of the regulatory stress hormone, corticotropin releasing factor (CRF), within the central amygdala (CeA). Studies have shown that this occurs through activation of estrogen receptor beta (ERβ) which binds to an estrogen response element on the promoter region of the Crf gene. It is thought that estrogen signaling through ERβ in the CeA drives the increase in anxiety-like behavior and stress hormone production in females. However, the functionality of this mechanism on behavioral and physiological responses to stress has not been fully evaluated. Therefore, aim 2 of the current studies tested the hypothesis that blocking ERβ during stress exposure will mitigate expression of anxiety-related behavior and the preceding rise in CeA-CRF as a consequence of stress. In addition to its genomic actions on CRF, estrogen also enhances promoter activity of the inflammatory cytokine interleukin-1 beta (IL-1β). Aside from its main functions in fighting injurious and pathogenic insults, IL-1β acts within the central nervous system to increase neuronal firing through the IL-1 receptor (IL-1r). Excess levels of IL-1β that are common in many pathological conditions can cause this signaling to become dysregulated, resulting in overactive neuronal firing or sensitization. This specific action has been shown to occur in the locus coeruleus (LC) which is responsible for arousal state. Moreover, this region is highly sexually dimorphic with the female LC containing a larger population of neurons, exhibiting longer and more complex dendritic trees, and being more densely innervated by other stress-sensitive regions, especially the CeA. Thus, it is hypothesized that stress-induced increases in inflammation can induce LC sensitization that leads to hyperarousal. Therefore, aim 3 of the current studies tested the hypothesis that inhibition of IL-1r signaling will prevent stress-induced increases in anxiety-like behavior. Taken together, these experiments identify a specific role for estrogen in female stress susceptibility and elucidate IL-1r as a novel target for therapeutic endeavors.

Rights

© 2024, Samantha Jane Bouknight

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