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

<b>Background</b>: 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. <b>Methods</b>: 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 <i>C4a/Slp</i> knockout (<i>Slp</i>^-/-) male mice. <b>Results</b>: 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 <i>Slp</i>^-/- than in <i>Slp</i>^+/+ mice. Allogrooming behavior in observer <i>Slp</i>^-/- 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 <i>Slp</i>^-/- mice that interacted with stressed demonstrator mice. OT release from the isolated hypothalamus, stimulated via CD38 and TRPM2 channel activation, was greater in <i>Slp</i>^-/- mice than in <i>Slp</i>^+/+ mice. <b>Conclusions</b>: 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.