Sex and Stress Govern the Function and Innervation of a Basolateral Amygdala to Nucleus Accumbens Corticotropin-Releasing Hormone/GABA-Expressing Projection

Abstract

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)/GABA-expressing projection from the basolateral amygdala (BLA) to the nucleus accumbens (NAc) that mediates reward-seeking deficits in adult ELA males—but not females. 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 the BLA and clozapine- N -oxide or vehicle to the NAc medial shell during reward behaviors. Using tissue clearing, light sheet fluorescence microscopy, and deep learning pipelines, we mapped brain-wide CRH + /GABA BLA axonal projections to identify potential sex differences in its innervation. Chemogenetic manipulations in male mice demonstrated inhibitory effects of the CRH + /GABA 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. In 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.