Neural connectivity of oxytocin receptor-expressing neurons in the nucleus accumbens and their role in social attachment.

Oxytocin receptor (OXTR) activity in the nucleus accumbens (NAc) is critical for pair bonding in prairie voles. Oxtr knockdown or pharmacological blockade in this region prevents mating-induced partner preferences, while overexpression facilitates bonding. However, no prior work has selectively interrogated or manipulated Oxtr-expressing neurons during dynamic bonding behaviors. We have developed an Oxtr-P2A-Cre prairie vole line that enables direct access to specific Oxtr neural populations. We utilized Oxtr-P2A-Cre prairie voles to express inhibitory DREADDs selectively in OXTR-expressing NAc neurons. Inhibiting NAc OXTR cells during initial cohabitation did not affect subsequent partner preference formation; however, inhibition during partner preference testing increased partner-directed huddling behavior, revealing a complex role for these neurons in social interactions. Using a viral tracing approach, we found that NAc OXTR-expressing neurons receive prominent inputs from the medial prefrontal cortex, hippocampus, thalamus, and hypothalamus, while projecting strongly to the ventral pallidum, ventral tegmental area, and lateral hypothalamus. Our cell-type-specific manipulation reveals how oxytocin receptor signaling in the NAc may modulate emotional state and facilitate the complex social behaviors underlying monogamous pair bonding. This Cre-recombinase approach demonstrates the utility of cell-type-specific targeting for elucidating oxytocin neural circuit mechanisms regulating emotional and social behavior in prairie voles.