Modulation of aggression by social novelty recognition memory in the hippocampal CA2 region

Abstract The dorsal CA2 subregion (dCA2) of the hippocampus exerts a critical role in social novelty recognition (SNR) memory and in the promotion of social aggression. Whether the social aggression and SNR memory functions of dCA2 are related or represent independent processes is unknown. Here we investigated the hypotheses that an animal is more likely to attack a novel compared to familiar animal and that dCA2 promotes social aggression through its ability to discriminate between novel and familiar conspecifics. To test these ideas, we conducted a multi-day resident intruder (R-I) test of aggression towards novel and familiar conspecifics. We found that mice were more likely to attack a novel compared to familiarized intruder and that silencing of dCA2 caused a more profound inhibition of aggression towards a novel than familiarized intruder. To explore whether and how dCA2 pyramidal neurons encode aggression, we recorded their activity using microendoscopic calcium imaging throughout the days of the R-I test. We found that a fraction of dCA2 neurons were selectively activated or inhibited during exploration, dominance, and attack behaviors and that these signals were enhanced during interaction with a novel compared to familiarized conspecific. Based on dCA2 population activity, a set of binary linear classifiers accurately decoded whether an animal was engaged in each of these forms of social behavior. Of particular interest, the accuracy of decoding aggression was greater with novel compared to familiarized intruders, with significant cross-day decoding using the same familiar animal on each day but not for a familiar-novel pair. Together, these findings demonstrate that dCA2 integrates information about social novelty with signals of behavioral state to promote aggression towards novel conspecifics.