Effect of Corticosterone on Clock Gene Expression in the Dorsomedial Hypothalamus, in Rats

Many individuals may view stress as an emotion experienced by many; I, myself, was once one of those individuals. In actuality, stress is also a response composed of a series of complex events beginning with the hypothalamo-pituitary-adrenal (HPA) axis. It turns out that components of the HPA axis can be altered by input from hypothalamic nuclei such as the suprachiasmatic nucleus, SCN, and the dorsomedial hypothalamus, DMH, and external environmental cues (such as stress and photoperiod). Through connections between each other and the paraventricular nucleus (PVN-head of HPA axis), the DMH and the SCN can influence the release of corticosterone (CORTfinal product of the HPA axis), in rats. In addition to mediating the body’s stress response, we believe that CORT has the ability, through cues from the SCN, and possibly the DMH, to synchronize an individual’s circadian rhythm throughout the body during unstressed conditions. CORT potentially accomplishes this through interaction with core clock genes (per1 and bmal1), the molecular basis for an individual’s circadian rhythm, in certain brain regions, including the PVN and DMH. CORT levels are also associated with depressive disorder. A number of studies have shown that glucocorticoid receptors (GRs) do not function normally in depressed patients and that some antidepressants can directly enhance GR expression as a form of treatment (17). Moreover, depression is associated with features of disrupted circadian function, including dysregulation of CORT secretion, altered appetite time-course and impaired sleep patterns (2). Hyperactivity of the HPA axis with an enlarged pituitary and adrenal gland and consequently higher concentrations of CORT are all consistent findings in depressed patients (17). All these are evidence for the idea that the dorsomedial hypothalamus, the paraventricular nucleus, the suprachiasmatic nucleus, normal diurnal CORT secretion, GRs, and clock genes are important molecular targets to consider for the treatment of depressive disorders. In this study, we have manipulated CORT levels in order to determine whether circadian and/or stress effects on PVN and DMH per1 and bmal1 gene expression were dependent on CORT. Interestingly, we found that both per1 and bmal1 mRNA diurnal expression appear to be dependent on the tonic rhythmic release of CORT in both the DMH and PVN, but not the SCN. We also found that CORT seems to be necessary for acute stress to exert its effects on per1 mRNA expression in the PVN and DMH, and not SCN. Bmal1 expression is not influenced by acute-stress-induced CORT in any of the brain regions. These results suggest the importance of CORT as a hormone important in the synchronization of an individual’s circadian rhythm, as well as a mediator of stress-induced disruption of circadian rhythms. C h r i s t e n s e n | 3