Identification of Serotonergic Neuronal Modules that Affect Aggressive Behavior

Escalated aggression can have devastating societal consequences, yet underlying neurobiological mechanisms are poorly understood. Here, we show significantly increased inter-male mouse aggression when neurotransmission is constitutively blocked from either of two subsets of serotonergic, Pet1⁺ neurons: one identified by dopamine receptor D1(Drd1a)::cre-driven activity perinatally, and the other by Drd2::cre from pre-adolescence onward. Blocking neurotransmission from other Pet1⁺ neuron subsets of similar size and/or overlapping anatomical domains had no effect on aggression compared with controls, suggesting subtype-specific serotonergic neuron influences on aggression. Using established and novel intersectional genetic tools, we further characterized these subtypes across multiple parameters, showing both overlapping and distinct features in axonal projection targets, gene expression, electrophysiological properties, and effects on non-aggressive behaviors. Notably, Drd2::cre marked 5-HT neurons exhibited D2-dependent inhibitory responses to dopamine in slices, suggesting direct and specific interplay between inhibitory dopaminergic signaling and a serotonergic subpopulation. Thus, we identify specific serotonergic modules that shape aggression.