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

Stress can drive excessive intake of palatable high-caloric food. The medial prefrontal cortex (mPFC) is implicated in this, but through unknown downstream circuits and mechanisms. Here we show, in mice, that the projection from the mPFC to the lateral hypothalamus (LHA) is a critical substrate for stress-driven fat intake. We show that optogenetic stimulation of the mPFC-LHA increases fat intake under naïve conditions. Using in vivo electrophysiology and ensemble tagging, we demonstrate that the mPFC-LHA network acutely responds to social stress. Combining patch clamp and optogenetics, we show that after social stress plasticity occurs specifically at mPFC synapses onto LHA glutamatergic (but not GABAergic) neurons. Such stress primes the efficacy with which optogenetic stimulation of mPFC-LHA pathways drives fat intake, while chemogenetic inhibition of this network specifically blocks stress-driven increased fat intake. Our findings identify the mPFC as a top-down regulator of distinct LHA feeding networks, necessary for stress-eating behavior.