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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月31日

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  • L. F. Supiot,
  • K. L. Kooij,
  • W. Du,
  • A. A. C. Benschop,
  • A. S. J. Nicolson,
  • R. Haak,
  • I. G. Wolterink-Donselaar,
  • M. C. M. Luijendijk,
  • D. Riga,
  • R. A. H. Adan,
  • R. B. Poorthuis,
  • F. J. Meye

摘要

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 (LHAVGLUT2) neurons, but that social stress preferentially engages mPFC-LHAVGLUT2 neurons and causes plasticity at mPFC-LHAVGLUT2 synapses. Specifically, stress weakens mPFC synapses onto LHAVGLUT2 neurons that curtail food intake, while strengthening mPFC synapses onto midbrain-projecting LHAVGLUT2 neurons linked to stress-eating. We show that LHAVGLUT2 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.