Lateral habenula hyperactivity and network dysfunction underpin stress-induced depressive-like behaviors in mice

The lateral habenula (LHb) is a critical hub for encoding aversive signals and regulating negative motivation in depression, yet the systemic alterations in functional connectivity and topological architecture of LHb-centered whole-brain networks induced by chronic stress remain unclear.

This study characterized LHb-associated network changes in chronic social defeat stress (CSDS)-induced depressive-like male mice using resting-state functional magnetic resonance imaging, including fractional amplitude of low-frequency fluctuations (fALFF), static/dynamic functional connectivity (sFC/dFC) and graph theory analysis, combined with a battery of behavioral assessments.

CSDS-susceptible mice exhibited typical depressive phenotypes (social avoidance, anhedonia, behavioral despair), accompanied by elevated spontaneous neuronal activity in the LHb, robust hyperconnectivity between the LHb and dorsal anterior cingulate cortex, and significantly reduced dFC variability between the LHb and subcortical regions (hippocampus, hypothalamus, midbrain). Graph theory analysis further revealed a disrupted small-world topology of the LHb-centered network, with decreased global/local efficiency, reduced clustering coefficient and increased characteristic path length.

Our findings reveal that chronic stress exposure is associated with LHb hyperactivity and widespread fronto-limbic and subcortical network remodeling. The functional and topological LHb signatures identified herein may serve as candidate biomarkers indicating stress susceptibility. This study offers multi-layered interpretative clues for network-level alterations linked to stress-associated depressive manifestations, and identifies the LHb connectome as a promising circuit candidate for follow-up targeted interventional research of mood disorders.