A Novel Localized Tracing Technique to Explore Intra-Amygdala Functional and Structural Connectivity Patterns as Mediators of Individual Variability in Stress Response

Neuropsychiatric disorders including anxiety and depression can be induced by stress, but not all individuals exposed to stress develop psychopathology. Therefore, probing the neural substrates that underlie trait vulnerability to stress may open the door for preventive approaches that use biological markers to identify at-risk populations. Here, we developed a novel tracing technique to probe local connectivity patterns as predictors of individual variability in stress responses. Specifically, we combined a retrograde transsynaptic rabies tracing system with cFos colocalization immediately after an acute stressor to elucidate local structural and stress-activated (functional) differences in connectivity within the amygdala complex in female and male mice along a spectrum of social approach/avoidance following acute social defeat stress. While we find no structural or functional connections within the amygdala complex as predictors of individual variability in our behavioral readout, our methods provide a novel approach to investigating cellular and behavioral individual variability in stress responses. Furthermore, we identify overall stress-activation as a predictor of social approach/avoidance in two subregions, medial amygdala and piriform-amygdala area, which may serve as potential biological markers of trait vulnerability, with possible clinical applicability. Significance Statement Exposure to stress is ubiquitous, but the outcomes of stress exposure vary greatly between individuals. Our work introduces a novel tracing technique to probe for structural and functional connectivity patterns across a broad spectrum of behavioral responses to social stress. Utilizing pre-clinical classification in conjunction with representative behavioral classification introduces to the field a mechanism to identify potential clinical targets for preventative screening for neuropsychiatric disorders as well as further individualized treatment. Notably, our work identifies two intra-amygdalar neural correlates of social stress, opening the door for future investigation of the role these regions play in mediating social stress.