Discrete Nucleus Accumbens Proteomic Signatures Are Associated with Stress Vulnerability and Antidepressant Response in Wistar and Kyoto Rats

Background Depression shows significant clinical and biological heterogeneity, largely driven by individual differences in stress responsivity. The nucleus accumbens (NAc), a key integrator of motivational and affective processing, undergoes molecular remodeling under chronic stress, contributing to anhedonia and variable antidepressant efficacy. Defining how stress reshapes the NAc’s molecular architecture across biological backgrounds may reveal molecular networks underlying treatment outcomes. This study aimed to characterize NAc proteomic signatures associated with stress vulnerability and antidepressant response in two rat strains with distinct stress-related phenotypes. Methods Male Wistar and Kyoto rats were exposed to chronic mild stress (CMS) and subsequently received chronic venlafaxine or vehicle administration. Anhedonia-like behavior, behavioral reactivity, social behavior, and serum corticosterone levels were assessed. High-resolution data-independent acquisition mass spectrometry was used to identify NAc proteomic signatures. Results Across-strain comparisons revealed baseline increases in reward sensitivity, reduced social investigation, and heightened defensive and aggressive behaviors in Kyoto rats, associated with NAc cellular metabolic pathway enrichment, including alterations in Ogdhl and Nit2. Under CMS, Kyoto rats displayed early-onset anhedonia, social withdrawal, and blunted glucocorticoid output. Moreover, they showed increased NAc proteomic enrichment in mitochondrial protein degradation and oxidative stress pathways, and decreased enrichment in synaptic signaling pathways, including Ppp1r1b/DARPP-32, compared to Wistar rats.Venlafaxine reversed stress-induced behavioral and proteomic alterations in Wistar rats. In Kyoto rats, it failed to improve anhedonia, exacerbated aggressive behavior, and induced enrichment of the NAc pathway related to bioenergetics and transmembrane transport, as well as astrocyte activation-related proteins. Conclusion Strain-specific NAc proteomic signatures characterize distinct trajectories of stress vulnerability, antidepressant non-response, and adverse behavioral activation. Although these male-only proteomic signatures require functional validation across sexes and antidepressant classes, they identify molecular candidates for precision pharmacology in depression.