Stress has been shown to induce adverse effects such as depression, heart disease, and hypertension (Roman et al., 2016, Aschbacher et al., 2016, Ojike et al., 2016). Following a stressful event there is an increase in circulating glucocorticoids, primarily cortisol in humans and corticosterone (CORT) in rodents. CORT is primarily controlled via the PVN, the major regulating structure in the hypothalamic-pituitary-adrenal axis (HPA axis, Ferguson et al., 2009). Normally, stressful stimuli causes activation of the PVN, triggering the release of CRH from the hypothalamus, subsequently causing the release of ACTH from the anterior pituitary gland, resulting in the production of CORT from the adrenal cortex that will negatively feedback to regulate its release.

When the HPA axis is dysregulated, CORT can become over secreted and result in depression-like behaviors (Goshen et al., 2008). However, the majority of research today uses superphysiological levels of CORT (10-15mg/kg CORT) to induce the depressive-like behavior in rats (Johnson et al., 2010). As a result, there are still discrepancies of whether the administration of superphysiological levels of CORT follows the same mechanism of stress exposure to induce depressive-like behaviors. To resolve this issue, we propose the superphysiological levels of CORT are only necessary when the circadian timing of the CORT administration is not adequately controlled.

This current work is a mechanistic study to determine whether we are able to activate the PVN and ultimately increase rat CORT levels though designer receptor exclusively activated by designer drugs (DREADD) technology. DREADDs have been used to control cellular activity in both a spatial and temporal manner to successfully analyze neural circuitry previously, and is used in this experiment to induce transcription of cellular receptors to mediate the cell response, allowing control over circulating CORT levels (American College of Neuropsychopharmacology, 2012). It is hypothesized that once the CNO ligand has been injected and binds with the DREADDs, the PVN will be activated and result in an increase of CORT.