The involvement of the glucocorticoid receptor in regulating glucocorticoid ultradian rhythms
: the role of the FK506-binding protein 51

Student thesis: Doctoral ThesisDoctor of Philosophy (PhD)

Abstract

The hypothalamic-pituitary-adrenal (HPA) axis is a pivotal neuroendocrine system in mammals and the end product, glucocorticoids (GCs), are steroid hormones involved in several essential processes including cognitive functions, metabolic processes, and regulation of the inflammatory response. Glucocorticoids are secreted from the adrenal gland in response to stimulation by adrenocorticotropic hormone (ACTH), which in turn is secreted from the anterior pituitary gland following stimulation by corticotropin-releasing hormone (CRH).
The HPA axis is activated as part of the stress response and following circadian cues, and the overall GC secretion occurs in a circadian manner, with higher GC concentrations during the active phase (daytime in humans and nighttime in rodents). Moreover, this circadian variation is made up of high-frequency ultradian pulses, which have an important role in regulating gene expression in GC target tissues. Corticosterone (CORT) is the main GC in rodents, and studies in rats have shown approximately hourly pulses of CORT, which are preceded by pulses of ACTH.
Importantly, in humans, altered HPA axis activity is seen in various stress-related disorders including depression and anxiety.
Hypothalamic-pituitary-adrenal axis activity is regulated by a negative feedback loop that involves activation of the glucocorticoid receptor (GR). The GR, in turn, is regulated by its chaperone protein, FKBP51. Clinical studies have shown an association between FKBP51 polymorphism and the instances of depression. Thus, the general hypothesis is that increased FKBP51 expression can cause a hyperactive HPA axis and GC resistance.
To further investigate the role of FKBP51 in the regulation of HPA axis activity, two FKBP51-specific inhibitors were used to investigate their effects on the HPA axis in male and female rats. Serial automated blood sampling (ABS) procedures were performed in basal and stress-induced conditions following both acute, and sub-chronic (5-days) treatment with either a central and peripheral FKBP51-inhibitor (SAFit2), or a peripheral-only inhibitor (SAFit1). Furthermore, at what level of the HPA axis the SAFit compounds had their effects were investigated, by stimulating ACTH, and CORT secretion with CRH and ACTH, respectively, in SAFit2-, SAFit1-, or vehicle-treated rats. Moreover, the gene expression induction at 60 minutes post-noise stress in the hypothalamus and anterior pituitary gland following SAFit2, SAFit1, or vehicle administration were compared.
Acute treatment with SAFit2 in male rats resulted in lower maximum CORT, and lower stress-induced CORT compared to vehicle-treated rats. Similar results were observed following sub-chronic SAFit2 treatment, with lower mean, maximum, and basal CORT, and lower stress-induced CORT compared to vehicle-treated rats. Acute SAFit1 treatment had no effect in male rats, however shorter CORT pulses under basal conditions were observed, and a lower stress-induced CORT was observed following sub-chronic SAFit1 treatment in male rats compared to vehicle-treated rats.
In females, acute SAFit2 treatment had no effect, whilst acute SAFit1 treatment result in lower mean CORT, and lower stress-induced CORT compared to vehicle-treated rats. Sub-chronic treatment with SAFit2 in female rats caused lower mean, maximum, and basal CORT concentrations, but did not affect the stress-induced CORT.
Moreover, reduced CRH-induced ACTH secretion from the anterior pituitary gland was found in male rats treated for one day with either SAFit2 or SAFit1, suggesting a potential decrease in GR-mediated GC negative feedback.
These findings suggest a sexual dimorphism in the processes regulating GC-mediated negative feedback during basal conditions and following stress. Moreover, the sub-chronicSAFit1 treatment in male rats changes the pulsatility of ultradian pulses. This work has made important steps to further unravel the complexity of the HPA axis negative feedback and the sexual dimorphisms involved in this regulation.
Date of Award26 Nov 2020
Original languageEnglish
Awarding Institution
  • The University of Bristol
SupervisorStafford L Lightman (Supervisor) & Francesca Spiga (Supervisor)

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