A prefrontal cortex-lateral hypothalamus circuit controls stress-driven increased food intake

Abstract Stress can drive overconsumption of high-fat foods. The medial prefrontal cortex (mPFC) is implicated in such stress-eating, but the underlying circuit mechanisms remain unclear. Here, we show that mPFC projections to the lateral hypothalamus (LHA) are required for stress-induced fat intake in male mice. We find that mPFC-LHA stimulation in sated states increases fat intake. Social stress acutely engages mPFC-LHA neurons, and inhibiting this pathway selectively prevents stress-driven excess fat intake. Circuit mapping shows that mPFC neurons innervate GABAergic and glutamatergic LHA (LHA VGLUT2 ) neurons, but that social stress preferentially engages mPFC-LHA VGLUT2 neurons and causes plasticity at mPFC-LHA VGLUT2 synapses. Specifically, stress weakens mPFC synapses onto LHA VGLUT2 neurons that curtail food intake, while strengthening mPFC synapses onto midbrain-projecting LHA VGLUT2 neurons linked to stress-eating. We show that LHA VGLUT2 neurons are required downstream mPFC targets for transforming stress into heightened fat intake. Overall, we identify the mPFC-LHA as a multi-branched network, indispensable for stress-eating.