Synaptic ensembles between raphe and D ₁ R-containing accumbens shell neurons underlie postisolation sociability in males

Abstract

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 D 1 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.

Increased social interaction in Shank2-deficient mice following acute social isolation

“…In the female mice, we performed the same behavioral tasks to figure out the sexual dimorphic phenotypes following acute social isolation. Grouped WT and isolated WT mice showed comparable sociability level, matching with our previous report [ 11 ], and the expression of social impairments in Shank2 −/− mice was detected regardless of sex (Fig. 1 E, F).…”

“…In male mice, higher sociability level in the isolated WT mice compared to grouped WT mice was observed (Fig. 1 B, C), reproducing the previous report [ 11 ]. Grouped Shank2 −/− mice showed social impairments, but after they underwent 24 h of social isolation, Shank2 −/− mice showed higher preference to the stranger mice than the object (Fig.…”

“…Acute (24 h) social isolation increases the motivation to socially interact [ 10 ]. Recently, it is reported that only the male mice exhibit the sociability increase while the female mice show an anxiety increase following acute isolation, providing gender-specific phenotypes [ 11 ].…”

“…We performed three-chamber test following 24 h of group-housing or social isolation [ 10 , 11 ] to examine the behavioral effect of acute social isolation in Shank2 −/− mice. As acute social isolation leads sexual dimorphic phenotypes [ 11 ], we further wondered whether sex-dependent observations are detected in Shank2 −/− mice (Fig. 1 A).…”

“…Given that individuals with ASD experience higher levels of loneliness than non-autistic individuals, we posited that the DRN, which has been implicated as a brain region involved in loneliness, may also play a role in loneliness in ASD. Acute social isolation gives rise to potentiating excitatory inputs onto the dorsal raphe nucleus (DRN) dopaminergic neurons [ 10 ] and strengthening outputs of DRN dopaminergic neurons co-releasing glutamate onto the nucleus accumbens [ 11 ]. Although complex interactions may exist due to SHANK2 deficiency, we speculate that neuronal input or/and output circuits related with dopaminergic populations of DRN may be related to the observed phenotypes in Shank2 −/− mice.…”