Prefrontal cortex cytosolic and synaptosome proteome reveal molecular signatures of resilience to chronic social isolation stress in rats

Chronic social isolation stress (CSIS) is a well-established preclinical model for studying stress-induced neurobiological changes and their effects on behavior and brain function in depression. The prefrontal cortex (PFC), a brain region essential for emotional regulation, cognitive control, and social interactions, is particularly susceptible to stress. While CSIS exposure triggers molecular and behavioral changes characteristic of depression-like behavior, a subset of animals displays a resilient phenotype, maintaining normal neurobiological and behavioral function despite experiencing adverse conditions. Understanding the molecular differences between resilient and susceptible phenotypes is crucial for identifying biomarkers and developing novel therapeutic targets for depression. Mass spectrometry-based proteomics, combined with bioinformatics approaches, provides a powerful tool for exploring these complex cellular processes. This review focuses on proteomic changes in cytosolic and synaptosome-enriched fractions of the PFC in adult male rats following CSIS exposure, with particular emphasis on differences between resilient and susceptible animals. We summarize findings of differential protein expression across multiple biological systems, including energy metabolism, cytoskeletal organization, cellular stress defense mechanisms, neurotransmitter regulation, and synaptic function. Additionally, we present protein predictors of resilience to CSIS identified through machine learning-based analyses, highlighting potential pathways for preventing and mitigating depression-like outcomes following CSIS.