EXPLORING MOLECULAR CHANGES IN THE EXTENDED AMYGDALA INDUCED BY CHRONIC CORTICOSTERONE ADMINISTRATION

Abstract Chronic stress is a significant risk factor for multiple psychiatric disorders, including depression. When exposed to social and/or environmental stressors, the hypothalamic-pituitary-adrenal (HPA) axis becomes activated, leading to the release of glucocorticoids (cortisol in humans, corticosterone in rodents) from the adrenal glands into the blood. This activation works to regulate various physiological processes such as metabolism, blood pressure, and immunity, allowing the body to cope with stress. Subsequently, negative feedback on the HPA axis lead to its deactivation and terminates the stress response. While, severe chronic stress can disrupt the normal functioning of the HPA axis and is believed to contribute to the development of psychiatric disorders. However, it is still unclear what kind of changes at molecular level occur in the brain due to dysfunction of the HPA axis, leading to various psychiatric symptoms. In the present study, we employed mice that were continuously administered corticosterone for 24 days as a model of chronic stress-induced HPA axis dysfunction. These mice exhibited depression-like symptoms, including body weight loss, decreased spontaneous activity, diminished sucrose preference (anhedonia), and increased immobility time during the forced swim test (despair). Next, we focused on the extended amygdala, a pivotal brain region of emotions and stress responses, and performed subnuclei-targeted tissue collection using microdissection punching system, followed by gene expression analysis by RNA-seq. As a result, we found that in the extended amygdala with complex subnuclear structures, different molecular changes were observed in each subnucleus due to chronic corticosterone administration. These findings represent a significant step toward elucidating the neural circuit alterations induced by chronic stress.