MANF in the Lateral Septum Dynamically Regulates Endoplasmic Reticulum Function via Transcriptomic Remodeling in Chronic Social Defeat Stress Response

This study characterized the dynamic molecular adaptations in the lateral septum (LS), a key limbic hub for stress processing, during the transition from acute to chronic social defeat stress (CSDS) in male C57BL/6J mice. Longitudinal bulk RNA-seq of LS tissue at CSDS days 1,4,7,10 revealed a biphasic endoplasmic reticulum (ER) stress response, with mesencephalic astrocyte-derived neurotrophic factor (MANF) as a core regulator. Functional validation confirmed that LS-specific MANF manipulation bidirectionally modulates ER stress, synaptic plasticity, and depressive-like behaviors in mice. Our findings identify MANF as a pivotal mediator bridging ER stress adaptation to neural circuit dysfunction in stress-induced depression.