Grant: Project Grant

Depression is a leading cause of disabilities worldwide, causing mood, anxiety, and memory symptoms. Chronic stress plays a major role in the emergence of the disease. With the challenges that the world faced recently, stress has become part of our daily life, and the prevalence of depression is already spiking. The stress response involves control from the brain on hormonal release, found in the brain and bloodstream. Levels of the stress hormone (CORT) are high in patients with severe depression and limit the efficacy of treatments. Drugs limiting CORT release, like benzodiazepines (BZs) are used with antidepressants, but their non-specific activity at different alpha-subunit-containing GABAA receptors (a-GABAAR) causes undesirable side effects and limits their use. Moreover, the precise mechanism by which BZs regulate CORT release is unclear. Preliminary data from our group now suggests that BZ-derivatives with subunit selectivity at GABAARs exert novel antidepressant effects and reduce CORT release with reduced side effects. However, the same alpha-subunits of the GABAARs are altered in depression and chronic stress. Therefore, to design novel therapeutics with reduced side effects, it is essential to identify which subtype(s) regulate CORT release and determine how these receptors are affected in disease-like conditions. Here, we will first characterize which subunits contribute to the regulation of CORT release, using targeted genetic manipulation and pharmacological approaches. We will also investigate which brain regions and cell types contribute to such regulations, and how chronic stress affects GABAARs at the brain region and cell levels in male and female mice. This combined information will provide insight into the mechanisms by which a-GABAARs regulate CORT release in controlled and "depressed" states, at the cell type, brain region, and sex factor levels, and guide rational designs of novel therapeutics with reduced side effects.