Experimental Design: Investigating the Role of Autophagy and BDNF in Neuronal Death Under Chronic Stress

Chronic stress impairs adult hippocampal neurogenesis (AHN) by reducing the survival and proliferation of neural stem cells (NSCs) in the dentate gyrus. Central to this process is cortisol, which interacts with the glucocorticoid receptor (GR) and represses Brain-Derived Neurotrophic Factor (BDNF) transcription, leading to NSC death and disrupted AHN. Autophagy, a cellular degradation process, plays a dual role in cell survival and death under chronic stress. This study investigates the interplay between cortisol, BDNF, and autophagy in influencing NSC viability and AHN. Using human iPSC-derived NSCs, we explore whether GR activation reduces BDNF levels, leading to increased autophagy and cell death, or if other pathways are involved. The study also determines whether cortisol impacts BDNF synthesis, its signaling via the TrkB receptor, or both. Our research employs genetic manipulations, cortisol treatments, and assays to quantify autophagy and cell viability under stress. Understanding these mechanisms could provide insights into stress-related neuropsychiatric disorders and inform therapeutic strategies to enhance brain resilience and function under chronic stress.