Date of Award
Doctor of Philosophy (PhD)
Christopher A. Lowry
Repeated or chronic stress experience can precipitate serious psychiatric disorders like depression or anxiety. In many psychiatric disorders, both the hypothalamic-pituitary-adrenal (HPA) axis and brain serotonergic systems are dysregulated. My dissertation addresses the role that glucocorticoids (GCs) play in the control of brain serotonergic function. The overarching hypothesis is that chronically elevated GCs in otherwise healthy individuals, acting through corticotropin-releasing factor (CRF)-dependent mechanisms, are sufficient to worsen emotionality and alter serotonergic functionality. To test this hypothesis, I developed a non-invasive rodent model by treating adult, male rats chronically with corticosterone (CORT), the rodent equivalent to human cortisol, via the drinking water. Using behavioral tests and in situ hybridization histochemistry, I first found that chronic CORT exposure, without the the experience of external stressors per se, is sufficient to cause an anxiety- and depressive-like behavioral state, and to alter diurnal tph2, slc6a4 and htr1a mRNA expression in a dose-dependent manner that indicates overall elevated serotonergic function in anxiety-related subdivisions of the midbrain dorsal raphe nucleus (DR) . Tph2 encodes tryptophan hydroxylase (Tph2), the rate-limiting enzyme for neuronal 5-hydroxytryptamine (5-HT) synthesis, slc6a4 the serotonin transporter, and htr1a the auto-inhibitory 5-HT1A receptor. High pressure liquid chromatography (HPLC) with electrochemical detection then revealed that chronic CORT intake also increases acoustic startle stress (AS)-induced Tph activity selectively within the median raphe nucleus (MnR), dorsal hippocampus, and in the dorsal (DRD) and caudal DR (DRC), indicating respective effects on sleep/wake-, memory-, and anxiety-related serotonergic signaling. Lastly, pharmacological blockade of CRF receptor type 1 (CRFR1) within and around the DR immediately before AS resulted in a remarkable increase of AS-induced Tph activity, most likely due to inhibition of CRFR1-mediated stimulation of gamma-amino butyric acid (GABA)-ergic afferents, while CRF receptor type 2 (CRFR2) blockade prevented AS-induced increases in Tph activity within the anxiety-related DRD and DRC. These results elucidate how chronic GC exposure may impair serotonergic function, and identify signaling mechanisms that may serve as medication targets for high-risk individuals, e.g. Cushing's syndrome patients, people with a family history of mood or affective disorders, or servicemen that are sent into a predictably stressful environment.
Donner, Nina Caroline, "Glucocorticoid actions on brain serotonergic systems" (2012). Integrative Physiology Graduate Theses & Dissertations. 15.