Synaptic ensembles between raphe and D₁R-containing accumbens shell neurons underlie postisolation sociability in males

Social animals expend considerable energy to maintain social bonds throughout their life. Male and female mice show sexually dimorphic behaviors, yet the underlying neural mechanisms of sociability and their dysregulation during social disconnection remain unknown. Dopaminergic neurons in dorsal raphe nucleus (DRN^TH) is known to contribute to a loneliness-like state and modulate sociability. We identified that activated subpopulations in DRN^TH and nucleus accumbens shell (NAc^sh) during 24 hours of social isolation underlie the increase in isolation-induced sociability in male but not in female mice. This effect was reversed by chemogenetically and optogenetically inhibiting the DRN^TH-NAc^sh circuit. Moreover, synaptic connectivity among the activated neuronal ensembles in this circuit was increased, primarily in D₁ receptor–expressing neurons in NAc^sh. The increase in synaptic density functionally correlated with elevated dopamine release into NAc^sh. Overall, specific synaptic ensembles in DRN^TH-NAc^sh mediate sex differences in isolation-induced sociability, indicating that sex-dependent circuit dynamics underlie the expression of sexually dimorphic behaviors.