Increase in Comforting Behavior (Allogrooming) During Social Interaction in Male Mice Deficient for the Slp Gene of Complement Component C4

Background: Oxytocin (OT) is a nonapeptide hormone produced in the hypothalamus, released into the brain and peripheral circulation, and plays a key role in social behavior. Recent studies indicate that complement component C4a is an OT-binding protein, which modulates plasma OT concentrations in mice. However, the role of C4a is unclear as to whether it contributes to consolation behavior. Methods: Social behavior, especially allogrooming, which is a form of empathy that depends on detecting the emotional states of others, was measured in wild-type or C4a/Slp knockout (Slp−/−) male mice. Results: Observer mice of both genotypes exhibited comforting (allogrooming) behavior toward a cage-mate demonstrator during reunion after brief isolation of the demonstrator mice. When demonstrator mice experienced body restraint stress during isolation, the allogrooming behavior was significantly increased in both genotypes, with a markedly greater increase in Slp−/− than in Slp+/+ mice. Allogrooming behavior in observer Slp−/− mice was significantly suppressed by an OT receptor antagonist. Furthermore, immunohistochemical analysis revealed that activation was significantly elevated in OT-positive hypothalamic neurons in observer Slp−/− mice that interacted with stressed demonstrator mice. OT release from the isolated hypothalamus, stimulated via CD38 and TRPM2 channel activation, was greater in Slp−/− mice than in Slp+/+ mice. Conclusions: Our results highlight that the data are consistent with a potential role for C4a in modulating neural circuits, possibly via its peripheral action on OT bioavailability. Direct evidence for C4a’s action within the brain remains a hypothesis for future investigation, for example, via site-specific manipulations.