Circuit-level regulation of social avoidance learning in chronically stressed mice

Project Summary
Anxiety- and stress-induced psychiatric disorders affect millions of Americans and often involve social
avoidance as a coping strategy for reducing the risk of confronting a stressor. Chronic social defeat stress
(CSDS), a widely used rodent model of stress, reliably leads to decreased social interaction in stress
susceptible animals, which may reflect clinically relevant fear-based behavior. Accordingly, our work in
129Sv/Ev mice indicates a role for fear learning in CSDS-induced social avoidance, implicating the
involvement of the basolateral nucleus of the amygdala (BLA). However, surprisingly little is known about the
contribution of the BLA to circuits underlying CSDS-induced social avoidance, where the primary focus has
been on reward circuitry. We propose to address this gap in the literature in three specific aims, using a
combination of behavior, functional circuit mapping, circuit manipulations, and in-vivo physiology. First, in Aim
1, we will investigate whether BLA inputs to the nucleus accumbens (NAc), a key region for mediating social
interactions, contribute to CSDS-induced social avoidance. To this end, we will use functional circuit mapping
to identify whether CSDS upregulates activity in BLA projections to the NAc during social avoidance of a CD-1
relative to a non-avoided conspecific. Further, using chemogenetics, we will test whether BLA-NAc projections
are necessary for CSDS-mediated social avoidance of the CD-1. Then, in Aim 2, we will use the same
methods to focus on how input from the prelimbic region (PL) of the medial prefrontal cortex to the BLA affects
social interaction in defeated and non-defeated mice. Given the importance of the PL-BLA circuit in fear
expression and avoidance learning, we expect that PL inputs to the BLA will be active during social avoidance
and necessary for expression of this learned response. Finally, in Aim 3, we will use multisite in-vivo
physiology to investigate the dynamics of PL-BLA-NAc communication during social interaction before and
after CSDS in both sexes. These findings will fill an important gap in our understanding of how fear learning
circuitry contributes to the well-studied reward circuitry that mediates non-selective social avoidance. Given the
high co-morbidity of anxiety- and mood- disorders, this project will provide critical new information to help
integrate our understanding of the fear and reward systems in mediating social avoidance, providing a more
holistic understanding of this behavioral response to stress.

Grant Number: 5R21MH135430-02
NIH Institute/Center: NIH
Principal Investigator: Nesha Burghardt