A prefrontal cortex-lateral hypothalamus circuit controls stress-driven increased food intake.
basic_science · Level V
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- Record sourced from PubMed, PMID 41912543.
- Also identified by DOI 10.1038/s41467-026-71073-z.
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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<sub>VGLUT2</sub>) neurons, but that social stress preferentially engages mPFC-LHA<sub>VGLUT2</sub> neurons and causes plasticity at mPFC-LHA<sub>VGLUT2</sub> synapses. Specifically, stress weakens mPFC synapses onto LHA<sub>VGLUT2</sub> neurons that curtail food intake, while strengthening mPFC synapses onto midbrain-projecting LHA<sub>VGLUT2</sub> neurons linked to stress-eating. We show that LHA<sub>VGLUT2</sub> 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.