Traumatic stress recruits an excitatory orbitofrontal–amygdala pathway to drive maladaptive aggression

Abstract Traumatic stress is a reliable predictor of heightened aggression, yet the mechanisms linking stress exposure to aggression remain poorly understood. We previously found that traumatic stress activates the posterior ventral segment of the medial amygdala (MeApv) to drive persistent increases in aggressive behavior. However, why traumatic stress would engage an aggression-promoting pathway is unclear. To address this, we mapped the inputs to the MeApv and identified a population of excitatory, but not inhibitory, neurons in Layer 5 of the medial orbitofrontal cortex (mOFC). The OFC is classically viewed as an inhibitory brake on amygdala-driven impulses, yet emerging evidence suggests it can also facilitate context-dependent emotional responses. Notably, traumatic stress is known to disrupt OFC function and its connectivity with the amygdala, implicating this circuit in pathological aggression. Using fiber photometry, we found that traumatic stress selectively activates these MeApv-projecting excitatory mOFC (mOFC MeApv ) neurons as well as their downstream MeApv outputs. Chemogenetic inhibition of the excitatory mOFC MeApv neurons during traumatic stress exposure prevented the subsequent increase in aggression while preserving non-aggressive social behavior. Together, these findings identify an excitatory cortical–amygdala pathway that is necessary for stress-induced aggression and support a model in which traumatic stress recruits, rather than suppresses, OFC output to drive maladaptive behavior.