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

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.