Oxytocin is known to play a role in myriad social behaviors in many species, but the neural circuits that mediate the effects of oxytocin are not well understood. A new study shows that a population of oxytocin-positive (OT) neurons in the paraventricular nucleus of the hypothalamus (PVH) responds preferentially to social stimuli and is necessary for social behavior. Deficits in this population of neurons may underlie social deficits in Shank3b knockout (KO) mice.

The work was supported in part by a Pilot Award to SFARI Investigator Garret Stuber. The authors performed in vivo two-photon calcium imaging in OT neurons in the PVH (PVH-OT) of awake, head-fixed male mice using GCaMP6s and gradient refractive index (GRIN) lenses. They found that about half of PVH-OT neurons increased their activity in the presence of a social stimulus (an anesthetized juvenile mouse), whereas only a third increased their activity in response to nonsocial stimuli, which decreased activity in about half of the neurons. Using DREADDs, they then showed that chemogenetic inhibition of PVH-OT neurons abolished the preference for social interaction in male wild-type mice in the three-chamber test, whereas chemogenetic activation of PVH-OT neurons elevated social preference even higher than what is seen in control mice.

Having shown that PVH-OT neurons are necessary for social preference in wild-type mice, Stuber and colleagues then turned to Shank3b KO mice, a mouse model of Phelan-McDermid syndrome that has previously been shown to have reduced social preference in the three-chamber test. Shank3b KO mice had reduced numbers of OT neurons in the medial PVH compared to wild-type mice. Acute, systemic treatment with an oxytocin receptor agonist, WAY267464, restored social preference in Shank3b KO mice.

These results demonstrate the importance of PVH-OT neurons in regulating social behavior in male mice and support the hypothesis that these neurons respond to social stimuli and promote the appropriate behavioral response. These findings also provide support for the possibility that modulating the OT system could be therapeutic in autism spectrum disorder (ASD). Previous clinical trials of oxytocin in ASD have produced mixed results (Yamasue et al., Curr. Opin. Neurol., 2019; Erdozain and Peñakaricano, Front. Psychiatry, 2020), but further understanding of the neural circuitry of this complex system may allow for more targeted therapeutics.