Nucleus accumbens oxytocin modulates avoidance-related behaviors following social isolation in prairie voles

Chronic social isolation and loneliness are associated with several neuropsychiatric disorders including depression and anxiety. Given its ability to modulate a wide range of processes linked to social interactions, the therapeutic potential of the neuropeptide oxytocin has gathered interest. However, its effects are highly context-dependent, highlighting the need for preclinical models that better capture the breadth of human social interactions and the consequences of their loss. The socially monogamous prairie vole carries a high translational value due to its ability to form enduring social attachments. Here, we aimed at characterizing the role of the oxytocin neurotransmission in the nucleus accumbens (NAc) in the negative consequences of social isolation in prairie voles. Following six weeks of isolation, females exhibited an avoidance of the open arms of an elevated plus maze EPM), lower NAc oxytocin receptor (OXTR) expression, and reduced activation of oxytocin neurons in the paraventricular nucleus of the hypothalamus (PVN) that project to the NAc. Using a combination of site- and projection-specific pharmacological and chemogenetic approaches, we show that the activation of oxytocin neurotransmission in the NAc originating from the PVN reverses the avoidance-related behaviors in the EPM induced by isolation in an OXTR-dependent manner, whereas its blockade promotes avoidance-related behaviors in group-housed control females. Altogether, our findings delineate a model in which the promotion of avoidance-related behaviors following social isolation in female prairie voles is mediated by a dampened response of PVN-to-NAc oxytocin projections, providing additional insights into the negative consequences of social isolation associated with anxiety disorders.