A molecularly distinct cell type in the midbrain regulates intermale aggression behaviors in mice

Abstract Background The periaqueductal gray (PAG) is a central hub for regulation of aggression, while little is known on the circuitry and molecular mechanisms that govern this regulation. We investigate the role of a distinct cell type, Tachykinin 2 -expressing (Tac2 + ) neurons, located in the dorsomedial PAG (dmPAG), in modulating aggression in mice. Methods We combined activity mapping, in vivo Ca 2+ recording, chemogenetic and pharmacological manipulation, and a viral-based translating ribosome affinity purification (TRAP) profiling using a mouse resident-intruder model. Results We reveal that the dmPAG Tac2 neurons were selectively activated during fighting behaviors. Activation of the dmPAG Tac2 neurons evoked, while inhibition or genetic ablation of the dmPAG Tac2 neurons suppressed fighting behaviors. TRAP profiling of dmPAG Tac2 neurons revealed that fighting behaviors specifically induced enrichment of serotonin-associated transcripts to the dmPAG Tac2 neurons. Last, we validated these findings by selectively delivering pharmacological agent into the dmPAG and reversed the behavioral outcomes induced by chemogenetic manipulation. Conclusions We identify that the dmPAG Tac2 neuron can regulate mouse aggressive behavior and thus suggest a distinct molecular target for the treatment of exacerbated aggressive behaviors in populations that exhibit high-level of violence.