PhD, University of Cincinnati, 2007, 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 regulat (open full item for complete abstract)
Committee: Dr. James Herman (Advisor)
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