Multimodal Behavior Scoring quantifies depression-like severity across chronic stress models and identifies stress-resilient mice

Introduction Rodent chronic-stress models are central to preclinical depression research, yet behavioral phenotypes are often assessed assay-by-assay, which can reduce cross-cohort comparability and mask heterogeneity across symptom domains (e.g., anhedonia, anxiety-like behavior, and behavioral despair). An integrative behavioral index may provide a more robust and interpretable measure of overall stress-induced severity and facilitate stratification of susceptible versus resilient individuals. Methods We developed the Multimodal Behavior Scoring (MBS) algorithm to integrate outcomes from standard assays—sucrose preference test (SPT), open field test (OFT), and forced swim test (FST)—into a unified severity score. MBS was evaluated in two independent paradigms, chronic unpredictable mild stress (CUMS) and chronic social defeat stress (CSDS), quantifying group discrimination, reproducibility (intraclass correlation coefficient, ICC), and phenotypic stratification. Results MBS robustly separated stressed from control mice (CUMS: +39.8%, p<0.0001; CSDS: +121.8%, p0.88). MBS further identified stress-resilient subpopulations and uncovered paradigm-specific behavioral signatures, with despair-dominant patterns in CUMS (FST–MBS, r=0.61) and anxiety-centric patterns in CSDS (OFT–MBS, r=-0.74). Excluding TST did not reduce discrimination performance. Conclusion MBS provides an integrative framework for quantifying depression-like behavioral severity and heterogeneity, enabling streamlined protocols and improving the translational utility of preclinical cohorts for biomarker discovery and antidepressant screening.