Major depressive disorder results from complex genetic and environmental interactions, with chronic stress as a key precipitating factor. Yet, individual variability in stress resilience remains poorly understood. We combined longitudinal behavioral profiling with pre-stress whole-blood metabolomics in male and female C57BL/6 mice exposed to unpredictable chronic mild stress.
Behavioral trajectories revealed sex-dependent dynamics: males displayed coherent, temporally stable stress responses, whereas females exhibited modular and variable behavioral patterns. Baseline metabolomic profiles may be associated to vulnerability in a sex-specific manner. In males, our data suggest that elevated 3-methyl-2-oxovaleric acid, valeric acid, valine, serine, and erythrose correlated with vulnerability; in females, succinic acid, serine, thymidine, and erythrose discriminated resilient from vulnerable subjects.
Integrating multiple metabolic variables improved correlation with behavioural classification. These findings suggest pre-existing, sex-specific metabolic states which are associated with stress susceptibility, highlighting peripheral metabolism as a potential biomarker of either resilience or vulnerability to depression. The authors would like to acknowledge the contribution of Experimental Models Research Core Facility G-STeP of Fondazione Policlinico Universitario ‘A.
The diagram depicted in Fig. 1 was created using BioRender.com. Ministero della Salute – Ricerca Corrente 2026. These authors contributed equally: Marco Rinaudo, Chiara D’Amelio.
These authors jointly supervised this work: Salvatore Fusco, Claudio Grassi. Dipartimento di Neuroscienze, Università Cattolica del Sacro Cuore, 00168, Rome, Italy Marco Rinaudo, Chiara D’Amelio, Francesca Natale, Roberto Piacentini, Salvatore Fusco & Claudio Grassi Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168, Rome, Italy Marco Rinaudo, Francesca Natale, Roberto Piacentini, Salvatore Fusco & Claudio Grassi European Institute of Metabolomics (EIM) Foundation, 84081, Salerno, Italy Dipartimento di Medicina, Chirurgia e Odontoiatria “Scuola Medica Salernitana”, Università di Salerno, 84081, Salerno, Italy Dipartimento di Scienze Biomediche, Università degli studi di Sassari, 07100, Sassari, Italy The authors declare no competing interest.
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