NRG1-ErbB4 signaling in the medial amygdala regulates sexual motivation in adult male mice

A successful mating relies on appropriate sexual motivation, whose deficits are frequently implicated in numerous neuropsychiatric disorders, including depression and schizophrenia. However, the underlying molecular mechanisms that control sexual motivation are not fully understood. Here we report that NRG1-ErbB4 signaling in the medial amygdala (MeA) plays a pivotal role in regulating sexual motivation. Through transcriptomic analysis combined with immunoblotting verification, we find that the NRG1 expression in the MeA negatively correlates with the sexual motivation levels in adult male mice. Importantly, local injection of NRG1 into MeA and knockdown of NRG1 decreases and increases the sexual motivation levels, respectively. In consistent, Knockdown of ErbB4, the main receptor of NRG1, and genetic inactivation of ErbB4 kinase in the MeA both elevates the sexual motivation levels, suggesting a necessary role of NRG1-ErbB4 signaling. Electrophysiological study indicates that ErbB4 deletion in the MeA causes decreased neuronal intrinsic excitability. Chemogenetic activation and inhibition of ErbB4-positive neurons decreases and increases the level of sexual motivation, respectively. Furthermore, we identify that the expression of hyperpolarization-activated cyclic nucleotide-gated 3 (HCN3) channel is specifically increased in adult male mice when ErbB4 is deleted. Knockdown of MeA HCN3 diminishes the effects of ErbB4 on neuronal excitability and sexual motivation. Together, our study reveals a critical molecular mechanism for the regulation of sexual motivation in adult male mice, which sheds light on developing new interventions for relevant diseases.