MODULATION OF ADULT-BORN DENTATE GYRUS CELLS ALTERS DEPRESSIVE-LIKE BEHAVIOR AND PSILOCYBIN RESPONSE

Adult brain cytogenesis, the generation of new neurons and glial cells, persists in regions such as the hippocampal dentate gyrus (DG). Disruption of this process has been implicated in neuropsychiatric disorders, including Major Depressive Disorder (MDD), where reduced hippocampal neurogenesis correlates with emotional, motivational, and cognitive impairments. Despite the prevalence of MDD, its underlying mechanisms remain unclear, and current treatments often show limited and delayed efficacy. This study examined the role of adult-born DG neurons in depressive-like behaviors using the unpredictable chronic mild stress (uCMS) rat model, which recapitulates core features of depression. Using optogenetic manipulation, we selectively inhibited or activated newly generated DG neurons and evaluated their influence on behavior and response to Psilocybin, a psychedelic compound with rapid antidepressant effects recently approved for treatment-resistant depression. Optogenetic inhibition of adult-born neurons exacerbated uCMS-induced anhedonia, anxiety-like behavior, and cognitive deficits, while activation promoted recovery across these domains. Psilocybin treatment reversed stress-induced behavioral impairments; however, this effect required intact neurogenesis. When the generation or integration of new DG neurons was disrupted, Psilocybin’s antidepressant-like efficacy was significantly reduced. Proteomic analyses further revealed stress- and Psilocybin-sensitive protein networks linked to neurogenesis, synaptic function, and neurotransmitter signaling, which depended on the functional integrity of adult-born neurons. These findings underscore the critical role of hippocampal neurogenesis in regulating both depressive vulnerability and antidepressant responsiveness, providing mechanistic insight into Psilocybin’s therapeutic action and supporting neurogenesis-targeted approaches for improving MDD treatment.