Co-release of opposing signaling molecules from cortical neurons controls the escalation and release of aggression

Prolonged social isolation induces a distinct state characterized by numerous impacts on behavior, including increased aggression and altered social behaviors, but the contributions of cortical circuits to these behaviors are poorly understood. Here, we find that social isolation promotes aggression and increases investigatory behaviors leading up to aggression in both males and female mice. Genetic characterization of the neuropeptidergic population of Tachykinin-2 expressing (Tac2 ⁺ ) neurons in the medial prefrontal cortex (mPFC) reveals a population of predominately early-layer GABAergic neurons that are activated by aggressive encounters in isolated mice. Cells expressing the Neurokinin 3 receptor, which binds the peptide product of Tac2 , are similarly activated by aggressive interactions in isolated mice. Loss of function perturbations targeting the co-release of Neurokinin B (NkB), the stimulatory peptide encoded by the gene Tac2, and the inhibitory neurotransmitter GABA from mPFC Tac2 ⁺ neurons, reveals dissociable functions for each signaling molecule in the distinct behaviors that tile an aggressive encounter. GABA transmission form Tac2 ⁺ neurons controls the release of aggression, whereas Tac2/NkB signaling controls the investigatory behaviors escalating to aggression. These findings reveal dissociable roles for opposing signaling molecules released from the same neuron in the control over aggression, suggesting a neurochemical mechanism by which internal states may exert coordinated, sequential effects on a broad array of behaviors.