Sex-linked roles of the CRF1 and the CRF2 receptor in social behavior

Dysfunctional social behavior is a major clinical feature of mood, anxiety, autism spectrum, and substance-related disorders, and may dramatically contribute to the poor outcome of these diseases. Nevertheless, the mechanisms underlying social behavior deficits are still largely unknown. The corticotropin-releasing factor (CRF) system, a major coordinator of the stress response, has been hypothesized to modulate social behavior. CRF signaling is mediated by two receptor types, termed CRF1 and CRF2. Using the three-chamber task for sociability (i.e., preference for an unfamiliar conspecific vs. an object), this study demonstrates that CRF2 receptor null mutation (CRF2-/-) reduces sociability in female mice but increases it in male mice. Both female and male CRF2-/- mice display a preference for social odor cues over neutral cues, indicating that sex- and CRF2 receptor-dependent sociability is not due to altered olfaction or impaired social cues discrimination. Moreover, treatment with the CRF1 receptor-preferring antagonist, antalarmin, consistently induces sociability in non-social mice but disrupts it in social mice, independently of CRF2 receptor deficiency. Sex, CRF2 receptor deficiency, or antalarmin affect locomotor activity during the three-chamber test. However, throughout the study CRF1 and CRF2 receptor-linked sociability is independent of locomotor activity. The present findings highlight major functions for the CRF system in the regulation of social behavior. Moreover, they provide initial evidence of sex-linked roles for the CRF1 and the CRF2 receptor, emphasizing the importance of sex as a major biological variable to be taken into consideration in preclinical and clinical studies.