Whole brain dimensional approach identifies shared and sex-specific networks of stress susceptibility in male and female mice.

BackgroundStress is a significant risk factor for depression and anxiety, two highly comorbid disorders with sex differences in symptom presentation and prevalence. The Chronic Variable Stress (CVS) mouse model is a useful method for examining sex-specific susceptibility, as stress can be titrated in a sex-specific manner to produce depressive- and anxiety-like behaviours across both sexes. However, the sex-specific mechanisms regarding how CVS reorganizes brain anatomy remain unclear. MethodsUsing structural magnetic resonance imaging (MRI), we provide the first whole-brain characterization of neuroanatomical changes induced by 6 or 28 days of exposure to CVS in female and male mice, respectively, and their association to behavior. We then examined the structural connectome underlying sex-specific latent dimensions of stress-susceptibility and potential molecular mechanisms using spatial gene expression analyses. ResultsCVS induced significant neuroanatomical changes in regions already implicated in depression in both sexes (e.g. nucleus accumbens and hippocampus) as well as female- and male-specific neuroanatomical changes. In females, these changes were associated with both depressive- and anxiety-like behavior. While in males, we identified two orthogonal dimensions of neuroanatomical changes associated with anxiety-like behavior or social preference. These latent dimensions are associated with sex-specific hub regions and, in females, were associated with genes enriched for protein localization to the cell surface. ConclusionOur findings indicate that different durations of CVS result in similar neuroanatomical changes in both sexes, however the direction of change and association to behavior is sex-specific. In females, these changes may be attributed to alterations in synaptic connectivity.