Social approach and social vigilance are differentially regulated by oxytocin receptors in the nucleus accumbens

Abstract

Oxytocin is currently being considered as a novel therapeutic for anxiety disorders due to its ability to promote affiliative behaviors. In the nucleus accumbens (NAc) activation of oxytocin receptors (OTR) promotes social approach (time spent near an unfamiliar individual). Here, we show that stressful social experiences reduce the expression of NAc OTR mRNA, coinciding with decreases in social approach. Social stressors also increase social vigilance, characterized as orienting to an unfamiliar individual without approaching. Vigilance is a key component of behavioral inhibition, a personality trait that is a risk factor for anxiety disorders. To understand whether NAc OTR can modulate both social approach and vigilance, we use pharmacological approaches to assess the impact of activation or inhibition of NAc OTR downstream pathways on these behaviors. First, we show that in unstressed male and female California mice, inhibition of OTR by an unbiased antagonist (L-368,899) reduces social approach but does not induce social vigilance. Next, we show that infusion of Atosiban, an OTR-Gq antagonist/OTR-Gi agonist, has the same effect in unstressed females. Finally, we show that Carbetocin, a biased OTR-Gq agonist, increases social approach in stressed females while simultaneously inhibiting social vigilance. Taken together these data suggest that OTR in the NAc differentially modulate social approach and social vigilance, primarily through an OTR-Gq mechanism. Importantly, pharmacological inhibition of OTR alone is insufficient to induce vigilance in unstressed mice, suggesting that mechanisms modulating social approach may be distinct from mechanisms modulating social vigilance.

Sexual differentiation of neural mechanisms of stress sensitivity during puberty

“…Interestingly, we observed an inverted U shaped dose-response curve of OTA administration with the 10mg/kg OTA injection not ablating social anxiety behaviors. We hypothesize this may be due to the systemic nature of the injection causing suppression of oxytocin pathways that promote social approach 66 at the higher dose. Together, these results suggest testosterone acting via androgen receptors during puberty play a key role in the sexual differentiation of oxytocin-dependent circuits of social anxiety.…”

Poly (I:C)-induced maternal immune activation modifies ventral hippocampal regulation of stress reactivity: prevention by environmental enrichment

“…Offspring were weaned into same-sex groups on P21 and maintained in their housing assignments until behavioral tests commenced (SD = 2-3 animals/cage; EE = 4-5 animals/cage). On P70, one male and one female from each litter was habituated to an open field arena (40 cm×40 cm×28 cm) for three-minutes (Duque-Wilckens et al, 2020;Williams et al, 2020). Behavior was recorded and videos scored via an automated behavioral monitoring software program (Cleversys TopScan, Reston, VA) for percent time spent in the center of the arena and total distance traveled (mm).…”

“…Duration of time animals spent actively investigating the novel mouse was evaluated across the 10-minute social exposure period. We also assessed time spent in the interaction zone and vigilance behavior during the first three-minutes of the social exposure (adapted from Duque-Wilckens et al, 2020; Williams et al, 2020). Briefly, social interaction was defined as the time animals spent within 8 cm (interaction zone) of the novel mouse.…”

Pathogens, odors, and disgust in rodents

“…OT receptors (OTR) are proposed to modulate the activity of the SDMN and related cortical and subcortical structures. An additional layer of complexity comes from the distinct signaling and cellular pathways that can be activated by OTRs coupling with either excitatory or inhibitory G-protein subunits in different brain areas ( Jurek and Neumann, 2018 ; Williams et al, 2020 ).…”

“…Social approach and avoidance involves different neural circuits and categories of OTRs. OT acting in the nucleus accumbens and ventral tegmental area facilitates social approach and reward, while aversive contexts which elicit social vigilance recruit the BNST (Steiman et al, 2018; Williams et al, 2020 ). This is of particular interest in that the BNST is a target for MeA integrated olfactory information.…”