Early adversity promotes adolescent avoidance behavior by enhancing prefrontal-amygdala communication through CRH+ glutamatergic neurons

Abstract

Early life adversity (ELA) has lasting impacts on emotion circuit function1. Exposure to early maltreatment, neglect, or household instability is associated with enduring alterations in threat evaluation and response, hallmarks of mood and anxiety disorders2-4. These alterations often emerge during adolescence and are characterized by excessive avoidance that limits engagement in rewarding experiences5,6. However, the neurodevelopmental mechanisms linking ELA to increased threat responses remain unclear. We identified a stress-sensitive medial prefrontal cortex (mPFC)-basolateral amygdala pathway that co-expresses corticotropin-releasing hormone (CRH) and glutamate. We find that ELA strengthens this pathway and increases threat avoidance behavior during adolescence. Optogenetic inhibition and developmental CRH knockdown in this pathway both rescue ELA-induced elevations in adolescent avoidance, whereas broadly reducing mPFC CRH expression in typically reared mice mimics ELA phenotypes. The same manipulations produced no behavioral effects in adults. Together, our findings indicate that cell type-specific CRH signaling regulates developmental circuit plasticity, biasing emotional circuit function and potentially contributing to psychiatric vulnerability.