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Sex-dependent function and regulation of the hypothalamic pituitary adrenal axis




Heck, Ashley L., author
Handa, Robert, advisor
Bouma, Gerrit, committee member
Hentges, Shane, committee member
Florant, Gregory, committee member

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Physiological responses to stressors are largely governed by a neuroendocrine axis, the hypothalamic pituitary adrenal (HPA) axis. Whereas HPA activation is necessary for body wide adaptation to a stressor via the production of glucocorticoids, its excessive or inappropriate activation can increase risk for a number of diseases. Importantly, many of these stress-related diseases exhibit a strong sex bias in prevalence, which may be related to sex differences in the activity of the HPA axis. Thus, the studies described in this dissertation examine sex differences in the regulation and function of the HPA axis in rodents to further unravel the sex-dependent vulnerability often characteristic of stress-related diseases in humans. In Chapters 2 and 3, sex differences in glucocorticoid negative feedback at the level of corticotropin releasing hormone (Crh) in the hypothalamic paraventricular nucleus (PVN), an important factor limiting HPA axis activation, are explored. Results of Chapter 2 indicate that male C57BL/6 mice exhibit a more rapid response of PVN Crh expression to the removal of glucocorticoid negative feedback due to androgen actions, likely via upstream regulatory neurons. Results of Chapter 3, alternatively, show more robust glucocorticoid receptor (GR) mediated negative feedback on PVN Crh in females, but only on a day of their reproductive cycle when circulating estrogen levels are low. Thus, a complex interplay among androgen/ estrogen actions and glucocorticoid regulatory mechanisms appears to drive sex-dependent PVN Crh expression to potentially influence sex-biased HPA activity and stress-related disease risk. In Chapters 4 and 5, the response of the HPA axis to chronic stress, a factor which is more etiologically relevant for human disease risk, is examined. The results of Chapter 4 demonstrate that female C57BL/6 mice exhibit time-of-day dependent changes in the basal and acute stress-induced activity of the HPA axis following chronic variable stress (CVS). Male mice, conversely, appear mostly resistant to the effects of CVS on HPA function until socially isolated (Chapter 5). These findings establish an essential foundation for the use of the C57BL/6 mouse, a strain typically more resistant to the effects of CVS, in future studies of sex-dependent HPA axis regulation following chronic stress.


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corticotropin releasing hormone (CRH)
hypothalamic pituitary adrenal (HPA) axis
chronic variable stress
sex differences


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