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THE ROLE OF THE FOREBRAIN GLUCOCORTICOID RECEPTOR IN HYPOTHALAMIC-PITUITARY-ADRENOCORTICAL REGULATION

FURAY, AMY REBECCA
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1187024564

Abstract Details

2007, PhD, University of Cincinnati, Medicine : Neuroscience/Medical Science Scholars Interdisiplinary.
Activation of the hypothalamic-pituitary-adrenocortical (HPA) axis plays a role in regulating basic biological functions in the basal state. During homeostatic perturbations, it potentiates and induces physiological adaptations that are designed to aid an organism in overcoming challenges and regain homeostatic equilibrium. However, prolonged HPA axis activation can be deleterious to long-term survival, so the HPA axis is subject to autoregulation via a negative feedback loop. The endpoint of HPA axis stimulation is corticosterone (CORT) release, which travels through the general circulation and inhibits further HPA axis activation at the levels of the pituitary, hypothalamus, and extra-hypothalamic structures such as the hippocampus. Central to HPA axis response and regulation is the glucocorticoid receptor (GR), a ligand dependent transcription factor that is richly expressed in limbic forebrain regions such as the hippocampus, medial prefrontal cortex, and amygdala. These same regions are differentially affected in several psychiatric disorders, and many of these disorders feature HPA axis dysregulation that includes changes in GR signaling. Females are differentially affected by some psychiatric disorders, such as depression, and there are well-established sex differences in HPA axis responsivity, suggesting a possible link between sex and stress regulation. Dysregulation of the HPA axis can also occur during the aging process. Previous studies using lesions and antagonists have implicated GR in feedback inhibition, but to date, the role of forebrain GR has not been directly tested. Here we present a series of studies investigating the role of forebrain GR in basal HPA axis regulation, and after acute and chronic stress, taking into account sex and aging as factors. We employ a forebrain specific GR knockout mouse model (FBGRKO), in which GR is developmentally disrupted via the loxP-Cre-Recombinase system. We show that forebrain GR is necessary for basal regulation of trough levels of glucocorticoids and feedback inhibition after acute psychogenic stressors, but not systemic stressors in adult male FBGRKO mice. Aged male FBGRKO mice have generalized deficits in negative feedback after stress as well as overall increased basal HPA axis drive. Conversely, female FBGRKO mice have intact diurnal rhythms of CORT secretion and normal negative feedback after acute stress exposure, with no age-specific effects. After chronic variable stress (CVS), male FBGRKO mice have facilitated CORT secretion in response to a novel stress exposure, but disruption of forebrain GR does not exacerbate the response. In contrast, female FBGRKO mice that have experienced CVS display increased HPA axis drive compared to littermate controls that also had CVS. Finally, we investigate basal regulation of the interaction between GR and its chaperone complex. We demonstrate dynamic circadian regulation of GR-protein interactions, which lays the foundation for future studies designed to determine changes in GR-protein interactions in disease states and aging.
Dr. James Herman (Advisor)
166 p.
Corticostrone; Glucocorticoid Receptor; ACTH; HPA Axis; Transgenic Mice; knockout; Negative feedback; Behavior; Elevated Plus Maze

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Citations

  • FURAY, A. R. (2007). THE ROLE OF THE FOREBRAIN GLUCOCORTICOID RECEPTOR IN HYPOTHALAMIC-PITUITARY-ADRENOCORTICAL REGULATION [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1187024564

    APA Style (7th edition)

  • FURAY, AMY. THE ROLE OF THE FOREBRAIN GLUCOCORTICOID RECEPTOR IN HYPOTHALAMIC-PITUITARY-ADRENOCORTICAL REGULATION. 2007. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1187024564.

    MLA Style (8th edition)

  • FURAY, AMY. "THE ROLE OF THE FOREBRAIN GLUCOCORTICOID RECEPTOR IN HYPOTHALAMIC-PITUITARY-ADRENOCORTICAL REGULATION." Doctoral dissertation, University of Cincinnati, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1187024564

    Chicago Manual of Style (17th edition)

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© 2007, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.