MANF in the lateral septum dynamically regulates endoplasmic reticulum function in chronic stress response

Major depressive disorder (MDD) is primarily influenced by chronic stress as an environmental risk factor, yet the precise temporal mechanisms governing disease initiation and progression remain largely undefined. This study systematically characterized the dynamic molecular adaptations within the lateral septum (LS), a limbic hub crucial for stress processing, across the critical transition from acute to chronic stress exposure. Through longitudinal transcriptomic analysis, we identified a biphasic dynamic response in the LS, initial widespread gene upregulation during acute stress phases progressively shifted to predominant downregulation as stress persisted. This temporal reprogramming was characterized by persistent activation of the endoplasmic reticulum (ER) stress pathway, particularly involving the unfolded protein response. Most notably, the ER stress-related factor mesencephalic astrocyte-derived neurotrophic factor (MANF) exhibited a striking temporal pattern, showing rapid upregulation during acute stress, followed by sustained suppression throughout the chronic stress phases. Functional investigations established that LS-specific MANF knockdown directly induced ER dysfunction, impaired structural and functional synaptic plasticity, and promoted depressive-like behaviors. Conversely, MANF overexpression effectively rescued these pathological phenotypes. Our findings illuminate the crucial temporal dimension of LS transcriptomic reorganization in MDD pathogenesis and identify MANF as a pivotal regulator bridging ER stress adaptation to neural circuit dysfunction, providing a mechanistic foundation for early intervention strategies and biomarker development.