Female chronic social defeat stress (femCSDS) maps synaptic, bioenergetic and metabolic proteome remodeling in the nucleus accumbens (NAc).

INTRODUCTION: Depression disproportionately affects women, yet the molecular adaptations underlying stress susceptibility in the female brain remain poorly understood. The nucleus accumbens (NAc) is a key brain region regulating reward, motivation and affective behavior and is strongly implicated in stress-related disorders. This study aimed to characterize proteome-wide molecular adaptations in the female NAc following chronic social stress.

METHODS: We used a recently developed female chronic social defeat stress (femCSDS) paradigm and performed label-free quantitative proteomic profiling of the NAc. Differentially expressed proteins were analyzed using Ingenuity Pathway Analysis (IPA), STRING, Metascape, SynGO and transcription factor enrichment approaches to identify affected pathways, molecular networks and regulatory programs.

RESULTS: Proteomic profiling identified 851 significantly dysregulated proteins, comprising 481 downregulated and 370 upregulated proteins, indicating extensive molecular remodeling following chronic social stress. Downregulated proteins were strongly enriched for mitochondrial respiration, oxidative phosphorylation, ATP synthesis, mitochondrial quality-control pathways and metabolic processes. Network analyses identified ATP synthase subunits, respiratory chain components and Cullin-family proteins as central hubs within a highly interconnected mitochondrial-proteostatic circuit. In contrast, upregulated proteins preferentially clustered within synaptogenesis, glutamatergic signaling, endocytosis, vesicle trafficking and synaptic organization pathways. Key hub proteins included SYNJ1, DNM1, BIN1, AP2M1, EPN2 and EPN3. Disease enrichment analyses linked the proteomic signature to neurological, neurodevelopmental and mitochondrial disorders. Transcription factor enrichment and upstream regulator predictions highlighted regulatory programs involving ARNT2, ESRRA, NFE2L2, PIN1, CAMTA1 and MYT1L.

DISCUSSION: This study provides a comprehensive proteomic profile of the female NAc following female chronic social defeat stress (femCSDS). Our analysis indicates that femCSDS may induce widespread molecular remodeling in the female NAc characterized by mitochondrial dysfunction, reduced energetic capacity and altered metabolic regulation alongside enhanced synaptic remodeling. These results provide insight into female-specific stress adaptations and identify molecular pathways that may contribute to depression-related behavioral outcomes and represent potential targets for future investigation.