Vulnerability and resilience to stress-induced anhedonia are associated with a different proteomic profile: focus on protein quality control mechanisms

Major Depressive Disorder (MDD) is a severe condition whose onset is known to depend on both genetic susceptibility and stressful events experienced in critical periods of life. Accordingly, the impact of stress in individuals varies, with a few subjects developing MDD (Vulnerable) and the majority coping well (Resilient). Understanding the core mechanisms underlying these differential stress responses is essential for the identification of novel pharmacological targets and the development of more effective drugs. Accordingly, the aim of our study is employing an unbiased proteomic approach to characterize at molecular level vulnerability and resilience to stress-induced anhedonia. To this end, Wistar rats were exposed to 6 weeks of CMS, and the anhedonic phenotype was assessed weekly through the sucrose consumption test (SCT), which allowed to divide animals into resilient and vulnerable subgroups. After 24h from the last day of CMS, animals were euthanized, and ventral hippocampus dissected to perform Label-Free proteomics. Although gene ontology analysis in Vulnerable and Resilient subjects unveiled equal top-ranking enriched terms, possibly suggesting that the same processes partake to a general stress response, the proteins involved and the type of modulation may be different and thus contribute to the specific phenotype. Indeed, of the overall modulated proteins, 58 were reduced and 9 increased uniquely in vulnerable animals, while 9 downregulated and 15 upregulated were exclusively depicting the resilient group. Among the proteins with a different expression profile, we identified mediators of protein quality control pathways. Notably, CMS-Vulnerable group showed downregulation of Psmc1, Ubqln1, Uba-5 and Fbxl16, while CMS-Resilient showed a profile comparable to controls. Although preliminary and soon-to-be validated, these data might possibly reflect a compromised proteostasis in CMS-Vulnerable subjects potentially relating to the observed behavioral outcome.