Corticosterone Metabolism Locally Regulates Glucocorticoid Exposure in Brain



 DESCRIPTION (provided by applicant): Glucocorticoids (CORT) are essential mediators of physiology, behavior, and cognition. CORT receptors are expressed in the vertebrate brain and play a key role in mediating these responses; however, local control over CORT levels is necessary because over-exposure can be detrimental, leading to neuronal death and inhibition of neurogenesis (Mirescu and Gould, 2006; Sapolsky et al., 1985). One way the brain may achieve this control is through the actions of CORT-metabolizing enzymes 11β hydroxysteroid dehydrogenase types 1 (11β HSD1) and 2 (11β HSD2), which re-activate and de-activate CORT, respectively. While the adult rodent brain appears to abundantly express 11β HSD1 but not 11β HSD2 (Holmes et al., 2006), the songbird brain expresses type 2 and previous research has shown that this expression may be responsible for producing a regional difference in brain CORT and a buffering of the brain from the effects of stress (Katz et al., 2010; Rensel et al., 2014). In addition, it is unclear whether the rodent model is an accurate representation of the neuroendocrine system governing CORT exposure in humans; therefore there is a need for alternative models. The proposed research has two specific aims: first, the research will test the hypothesis that the CORT-metabolizing enzymes 11β HSD1 and 11β HSD2 act in concert to dynamically regulate CORT levels in discrete brain regions and limit fluctuations in blood from reaching the brain. Experiments will assess the regional distribution of both enzymes in the songbird brain, then utilize in vitro assays to establish enzyme activity and specificity in response to CORT. In addition, in vivo microdialysis and retrodialysis of an 11β HSD inhibitor will be employed in the hippocampus to assess the functional effects of 11β HSD type 2 as a buffer against CORT elevation coming from the periphery. Previous research found that neurogenesis in the songbird lateral ventricular zone (VZ) is reduced by CORT in males but not females, suggesting greater CORT inactivation in females that may be neuroprotective (Katz et al., 2008). The second specific aim of this research will test the hypothesis that the 11β HSDs are responsible for this sex difference. Sections of brain containing the lateral VZ will be exposed to CORT with or without an 11β HSD inhibitor and BrdU labeling will be quantified. Thus, experiments conducted at multiple levels of organization (both in vitro and in vivo) as well as measures of mRNA, enzyme activity, and direct neural measures of CORT will establish the nature of the mechanisms controlling local CORT exposure in brain. This research has the potential to uncover novel mechanisms of CORT regulation and inform development of future treatments for human disease characterized by glucocorticoid excess and dysregulation.