[Distinct prefrontal neuronal circuits determine repeated stress-induced behavioral styles in mice]

Stressful experiences can initiate or exacerbate mental health conditions, including depression. Depression is a complex and diverse syndrome characterized by varying symptom profiles, progression patterns, and responses to treatment. Despite this, the specific mechanisms by which prolonged stress leads to individual differences in behavior remain poorly understood. A major obstacle in advancing our understanding of the neurobiological and pathological consequences of psychosocial stress is the absence of subtype-based approaches in preclinical models. To address this gap, we implemented a behavioral subtyping strategy in preclinical research to explore how stress-induced behavioral variability is shaped by neural circuits, cellular processes, and molecular mechanisms. Using this approach, we classified stressed male mice into four distinct behavioral subtypes, based on their manifestations of social withdrawal and anhedonia-key features of many psychiatric disorders. Our findings revealed that three neural projection pathways originating from the prefrontal cortex play crucial roles in mediating these stress-related behaviors. In particular, the pathway connecting the medial prefrontal cortex (mPFC) to the anterior paraventricular thalamus (aPVT) was shown to influence a behavioral subtype marked by both social deficits and anhedonia. Moreover, we uncovered a molecular mechanism at the circuit level that underlies this specific phenotype: epigenetic repression of the Shisa2 gene by KDM5C within aPVT-projecting neurons in the mPFC contributes to the emergence of these behavioral impairments. Our research thus highlights distinct biological factors-spanning cellular, molecular, and epigenetic levels-that contribute to individual differences in stress-induced behavioral outcomes.