Differential Functions of Oxytocin Receptor-Expressing Neurons in the Ventromedial Hypothalamus in Social Stress Responses: Induction of Adaptive and Maladaptive Coping Behaviors

Abstract

Background: The flexibility to adjust actions and attitudes in response to varying social situations is a fundamental aspect of adaptive social behavior. Adaptive social behaviors influence an individual's vulnerability to social stress. While it has been proposed that oxytocin is a facilitator of active coping behaviors during social stress, the exact mechanisms remain unknown.

Methods: Using a social defeat stress paradigm in male mice, we identified the distribution of oxytocin receptor (OXTR)-expressing neurons in the ventrolateral part of the ventromedial hypothalamus (vlVMH) that are activated during stress by detection of c-Fos protein expression. We then investigated the role of vlVMH OXTR-expressing neurons in social defeat stress responses by chemogenetic methods or deletion of local OXTRs. The social defeat posture was measured for quantification of adaptive social behavior during repeated social stress.

Results: Social defeat stress activated OXTR-expressing neurons rather than estrogen receptor 1-expressing neurons in the rostral vlVMH. OXTR-expressing neurons in the vlVMH were glutamatergic. Chemogenetic activation of vlVMH OXTR-expressing neurons facilitated exhibition of the social defeat posture during exposure to social stress, while local OXTR deletion suppressed it. In contrast, overactivation of vlVMH-OXTR neurons induced generalized social avoidance after exposure to chronic social defeat stress. Neural circuits for the social defeat posture centered on OXTR-expressing neurons were identified by viral tracers and c-Fos mapping.

Conclusions: vlVMH OXTR-expressing neurons are a functionally unique population of neurons that promote active coping behavior during social stress, but their excessive and repetitive activation under chronic social stress impairs subsequent social behavior.

Keywords: Coping behavior; Estrogen receptor 1; Hypothalamic paraventricular nucleus; Oxytocin receptor; Social defeat posture; Ventromedial hypothalamic nucleus.