HCN1 channels in GABAergic amygdalar neurons underpin male-biased aggressive behaviors

Aggressive behaviors typically vary between sexes, but the molecular mechanisms driving these disparities in neural coding remain unclear. We found that aggression selectively activates GABAergic neurons in the posterior substantia innominata (pSI), an extended amygdala region critical for aggression in both sexes, with male mice exhibiting elevated neuronal activity during attacks. Utilizing single-nucleus RNA sequencing, we characterized the diverse molecular landscape of pSI neurons, revealing significant differences in ion channels and hormone regulator genes that may underpin sex-specific aggression. Male pSI^Vgat neurons exhibited remarkable hyperexcitability driven by an elevated Ih. Strikingly, modulating HCN1 expression not only regulated this hyperexcitability but also influenced sexual dimorphism in aggression: silencing HCN1 in the pSI^Vgat neurons reduced male aggression, while its overexpression significantly heightened aggression in female mice. Furthermore, testosterone intensifies aggression by upregulating HCN1 expression and remodeling pSI circuits. These findings provide novel insights into sex-specific molecular mechanisms underlying social behaviors.