BACKGROUND Depression is a debilitating neuropsychiatric disorder with 20% lifetime prevalence in the developed world but only approximately half of afflicted individuals respond to currently available therapies. While there is growing understanding of the neurobiological underpinnings of the depressed brain, much less is known about the preexisting circuitry leading to selective vulnerability versus resilience. Elucidating these networks could lead to novel preventative approaches. METHODS We developed a model of acute social defeat stress (ASDS) that allows classification of male mice into “susceptible” (socially avoidant) versus “resilient” (expressing control-level social approach) one hour after exposure to six minutes of social stress. Using circuit tracing and high-resolution confocal imaging, we explored differences in activation and dendritic spine density and morphology in the prelimbic to basolateral amygdala (PL→BLA) circuit in resilient versus susceptible mice. To test the functional relevance of identified structure/function differences to divergent behavioral responses, we used an intersectional chemogenetic approach to inhibit the PL→BLA circuit during or prior to ASDS. RESULTS Susceptible mice had greater PL→BLA recruitment during ASDS and activated PL→BLA neurons from susceptible mice had more and larger mushroom spines compared to resilient mice. Inhibition of the PL→BLA circuit led to a population shift towards resilience. CONCLUSION Preexisting PL→BLA structure/function differences mediate divergent behavioral responses to ASDS in male mice. These results support the PL→BLA circuit as a biomarker of trait vulnerability and potential target for prevention of stress-induced psychopathology.

Prelimbic-amygdala overexcitability mediates trait vulnerability in a novel mouse model of acute social defeat stress