Serotonergic modulation of attack behavior in social isolation mice

Background and Purpose: Intermittent explosive disorder is characterized by outbursts of rage and violence. While the 5HT receptor is linked to aggression reduction, its neural circuit mechanism remains unclear. Here, we explored the impact of the raphe nucleus projecting to the ventral hippocampus (vHip) on impulsive aggression. Experimental Approach: We used post-weaning social isolation (SI) mice as an animal model and employed the chemogenetic technique to specifically manipulate the activity of neural pathways projecting from either the dorsal raphe nucleus (DRN) or the median raphe nucleus (MRN) to the vHip. Combining with 5HT receptor (5HTR) agents, we investigated the impact of serotonergic inputs in the vHip on impulsive aggression. Key Results: By local infusion of Clozapine N-Oxide, activating either DRN soma or DRN nerve terminals in the vHip reduced impulsive aggression. 5-HTR antagonist SB-224289 nullified this aggression reduction. Activating the MRN→vHip pathway ameliorated depression-like behavior but not impulsive aggression. DRN→vHip activation decreased c-Fos levels in the vHip and the aggression-control area, the ventromedial hypothalamus (VMH). Intra-vHip infusion of 5-HTR agonists (anpirtoline, CP-93129) suppressed impulsive aggression and decreased c-Fos levels within the vHip neurons projecting to the VMH, suggesting an inhibition mechanism. Conclusion and Implications: Our findings indicate that activating the DRN, rather than MRN, projecting to the vHip is sufficient to inhibit impulsive aggression in a 5-HTR-dependent manner. Thus, targeting 5-HTR could serve as a promising therapeutic approach to ameliorate symptoms of impulsive aggression.