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bioRxiv · 10.1101/2025.05.10.653278

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

Herrera Portillo, L.·Gallino, D.·Yee, Y.·Muir, J.·Devenyi, G. A.·Bagot, R. C.·Chakravarty, M.
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Abstract

Stress is a major risk factor for depression and anxiety, two highly comorbid disorders with sex differences in symptom presentation and prevalence. Accumulating evidence on the chronic variable stress (CVS) mouse model has revealed that stress susceptibility is sex-specific, as females require less stress exposure (6 days) compared to males (21-28 days) to develop comparable adaptations in depressive- and anxiety-like behaviors. However, the neuroanatomical changes associated with stress susceptibility remain unclear in each sex. Given this differential susceptibility, elucidating these mechanisms requires a phenotype-matched approach in which stress duration is titrated in a sex-specific manner to induce comparable behavioral adaptations. Here, we used a multi-variate brain-behavior and connectomic analysis to examine signatures of stress susceptibility in female and male mice. Using structural magnetic resonance imaging (MRI), we investigate whole-brain neuroanatomical changes associated with behavioral susceptibility within each sex. We then examined the structural connectome underlying neuroanatomical changes associated with behavioral susceptibility within each sex, and putative molecular basis for behaviorally-relevant changes using spatial gene expression analyses. CVS induced significant neuroanatomical changes in regions commonly implicated in anxiety- and depressive-like phenotypes in both sexes (e.g. nucleus accumbens and hippocampus); however qualitative differences between sexes in the direction of change were observed. In addition to these changes, in females stress-induced neuroanatomical changes were associated with both depressive- and anxiety-like behavior, whereas in males we observed two orthogonal dimensions of neuroanatomical changes associated with anxiety-like behavior or social preference. The connectomic topology underlying these brain-behavior dimensions revealed the cortical hub regions for females and subcortical hub regions for males. In females, neuroanatomical changes were associated with genes enriched for protein localization to the cell surface, suggesting alterations in cholinergic signaling By implementing a phenotype-matched CVS protocol, our findings indicate that the neuroanatomical signature of stress susceptibility encompasses similar brain regions across both sexes, however the direction of change, association to behavior and connectomic properties may differ in each sex.

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Herrera Portillo, L., Gallino, D., Yee, Y., Muir, J., Devenyi, G. A., Bagot, R. C., Chakravarty, M.. 2025-05-11. Whole brain dimensional approach identifies shared and sex-specific networks of stress susceptibility in male and female mice.. https://doi.org/10.1101/2025.05.10.653278

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