Reduced commissural connectivity of the habenula in depression: Translational evidence from human DTI and rodent ultrastructural analyses

Dysfunction of the habenula is increasingly implicated in the pathophysiology of major depressive disorder (MDD), yet the contribution of the habenular commissure (Hbc)−the fiber tract connecting the bilateral habenulae–remains largely unexplored. Here, we combined in vivo human neuroimaging and preclinical ultrastructural analyses to identify a previously unrecognized microstructural signature of MDD. Using diffusion tensor imaging (DTI), we observed robust reductions in fractional anisotropy (FA) and axial diffusivity (AD) within the Hbc of individuals with MDD compared with healthy controls. Notably, FA and AD values were inversely correlated with Hamilton Depression Rating Scale (HDRS) scores, linking Hbc integrity to clinical symptom severity. Complementary electron microscopy of a chronic social defeat stress model revealed reduced axon diameter and myelin thickness of interhabenular connectivity, providing convergent evidence for commissural atrophy. These cross-species data identify the habenular commissure as a novel locus of microstructural pathology in depression and highlight its potential as a diagnostic and pathophysiological biomarker for MDD.