ORCID

https://orcid.org/0000-0001-8541-0188

Date of Award

Fall 2024

Language

English

Embargo Period

10-29-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

College/School/Department

Department of Psychology

Program

Behavioral Neuroscience

First Advisor

Damian Zuloaga

Committee Members

Andrew Poulos, Christine Wagner

Keywords

stress, sex differences, mice, androgens, endocrinology

Subject Categories

Behavioral Neurobiology | Molecular and Cellular Neuroscience

Abstract

Mood disorders such as anxiety and depression are nearly twice as prevalent in women when compared to men, with potential contributing factors involving sex-dependent exposure to gonadal hormones and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. Androgen actions through androgen receptors (AR) or actions at estrogen receptors such as ERα, following the conversion of androgens to estradiol, have been shown to regulate stress-related behaviors as well as HPA axis responsiveness. Where androgen actions at AR appear to decrease the stress response and subsequent stress-related behaviors, actions at ERα seem to do the opposite and increase HPA axis reactivity. When the HPA axis is activated following exposure to a stressor, corticotropin-releasing factor (CRF) is released; a neuropeptide known to regulate the HPA axis, anxiety, and depression. This release of CRF creates a cascade of events that ultimately results in the release of glucocorticoids such as cortisol in humans or corticosterone in rodents. CRF can also bind to one of its receptors, CRF receptor 1 (CRFR1) which is a receptor involved in the initiation of the stress response and is critical for the regulation of the HPA axis and stress-related behaviors. With the known sex differences in stress-related mood disorders, gonadal hormone actions at CRF and CRFR1 could serve as a potential mechanism for how these behaviors are differentially displayed.

This dissertation aimed to determine co-expression of AR and ERα with CRF and its receptor CRFR1 as co-expression of these receptors with CRF and CRFR1 could be indicative of a mechanism through which androgens could modulate the stress response sex-specifically. This study also aimed to determine sex differences in neural activation patterns following stress because of the potential role in regulating behavioral and neuroendocrine stress responses. Furthermore, this dissertation investigated effects of gonadectomy (GDX) on CRFR1 positive neurons following restraint stress and determined whether treatment with DHT, an AR agonist, restores GDX effects on stress-induced CORT and protects against changes in CRFR1 cell number or cell activation. Androgen actions through AR can impact various stress functions, however the role of these actions under chronic stress conditions is unclear. Therefore, a subchronic variable stress (SCVS) paradigm was used to investigate AR as a mechanism for the regulation of the stress response by determining if use of DHT following GDX will alter the HPA axis and stress-related behaviors. This study also determined the effects of DHT on stress-induced neural activation patterns. Finally, this dissertation examined the effects of knocking down AR within CRFR1 neurons located within the paraventricular nucleus of the hypothalamus (PVN), a region critical for stress regulation, and evaluated impacts of this manipulation on the HPA axis and stress-related behavior as androgen binding to AR in these neurons could be a direct mechanism for the mediation of CRFR1 to ultimately modify stress responses.

License

This work is licensed under the University at Albany Standard Author Agreement.

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