SUMMARY
Neuropeptides exert broad effects across the brain to influence behavior. However, the mechanism by which the brain uses neuropeptide signaling to exert top-down control over complex behavioral responses remains poorly understood. Prolonged social isolation induces a distinct internal state that results in sweeping changes to behavior, including increased aggression. Here, we find that isolation-induced aggression activates Tachykinin-2 expressing (Tac2 + ) neurons in the mouse medial prefrontal cortex (mPFC). Genetic characterization of Tac2 + cells in the mPFC reveals them to be a population of unexplored GABAergic neurons. In-depth behavioral analyses combined with in vivo recordings of neural activity demonstrate that mPFC Tac2 + neurons are tuned to distinct phases of isolation-induced aggression: investigatory behaviors that escalate to attack (aggression escalation) and attack itself (aggression release). Loss-of-function perturbations targeting the release of either Neurokinin B (NkB), the stimulatory peptide encoded by Tac2 , or the inhibitory neurotransmitter, GABA, reveal that these signaling molecules exert dissociable control over aggression escalation and release. These findings identify distinct roles for opposing signaling molecules co-released from the same population of cells. This suggests a surprising neurochemical mechanism by which neuropeptidergic populations in the prefrontal cortex exert top-down influence over complex behavior via the co-release of signaling molecules with opposing actions but coordinated impacts on behavior.