A cortical insula-orbitofrontal circuit drives stress-induced dopamine system dysfunction.

Stress is a major risk factor for psychiatric disorders, including post-traumatic stress disorder (PTSD), depression, and psychosis, and is closely linked to dysregulation of the dopamine system. Psychosis is characterized by aberrant salience processing driven by elevated striatal dopamine transmission, and both clinical and preclinical studies demonstrate that acute stress increases dopamine release and induces behavioral alterations associated with psychosis. A key physiological substrate of this dysregulation is increased dopamine neuron population activity in the ventral tegmental area (VTA); however, the upstream circuits through which stress drives this pathological dopamine state remain poorly defined. Human neuroimaging studies implicate the insular cortex (IC), a core node of the salience network, with hyperactivity reported in PTSD. Preclinical studies similarly demonstrate that IC activity contributes to stress-induced fear and anxiety-like behaviors. Yet, whether the IC modulates dopamine neuron population activity has not been established. Here, we identified a previously unrecognized insula-orbitofrontal circuit (IC-OFC) that powerfully regulates VTA dopamine neuron population activity. Using in vivo extracellular electrophysiology in rats, we demonstrate that activation of the IC selectively increases VTA dopamine neuron population activity. This effect is replicated by selective, chemogenetic activation of the IC-OFC circuit. Importantly, inactivation of this pathway reverses stress-induced elevations in dopamine population activity and normalizes associated behavioral disruptions. Together, these findings identify an IC-OFC-VTA circuit through which stress drives pathological dopamine system activation, providing new mechanistic insight into stress-induced dopamine dysregulation and revealing a novel circuit target for intervention in stress-related psychiatric disorders.