Sex and stress govern the function and innervation of a basolateral amygdala to nucleus accumbens corticotropin releasing hormone/GABA expressing projection

Motivated behaviors are executed by refined brain circuits. Early life adversity (ELA) is a risk for human affective disorders involving dysregulated reward behaviors. In mice, ELA causes anhedonia-like behaviors in males and augmented reward motivation in females, indicating sex-dependent disruption of reward circuit operations. We recently identified a long-range corticotropin-releasing hormone (CRH) expressing GABAergic projection from basolateral amygdala (BLA) to nucleus accumbens (NAc) that mediates reward-seeking deficits in adult ELA males—but not females. We verified a similar cell identity and electrophysiology of the projection across sexes. To probe the sex-specific role of this projection in reward behaviors, adult male and female CRH-Cre mice raised in control or ELA conditions received excitatory or inhibitory Cre-dependent DREADDs in BLA, and clozapine N-oxide or vehicle to NAc medial shell during reward behaviors. Using tissue clearing, light sheet fluorescence microscopy and deep learning pipelines, we mapped brain-wide BLA CRH + axonal projections to identify potential sex differences in its innervation. Chemogenetic manipulations in male mice demonstrated inhibitory effects of the CRH + BLA-NAc projection on reward behaviors, whereas neither excitation nor inhibition influenced female behaviors. Molecular and electrophysiological cell-identities of the projection did not vary by sex. By contrast, comprehensive whole-brain mapping uncovered significant differences in NAc innervation patterns that were both sex and ELA-dependent, as well as selective changes of innervation of other brain regions. The CRH + /GABA BLA-NAc projection that influences reward behaviors in males differs structurally and functionally in females, uncovering potential mechanisms for the profound sex-dependent impacts of ELA on reward behaviors. Significance Statement Early life adversity is a major public health issue linked to long-term mental health risks including depression. In adult mice with this history, reward behaviors are disrupted in a sex-specific manner. We identified a novel GABAergic and corticotropin releasing hormone-expressing projection from basolateral amygdala to nucleus accumbens that mediates poor reward motivation in early-adversity male mice, but has no effect in females. Here we studied why, and found important sex and experience-dependent change in the brain’s fine wiring. Our discoveries help explain sex-dependent consequences of early life adversity in people, and may inform targeted therapeutic strategies.