Integration of cortical inputs in the lateral hypothalamus is dominated by the medial prefrontal cortex

The lateral hypothalamus (LH) is a critical brain region orchestrating survival behaviours including feeding. Its sparse intrinsic synaptic connectivity allows long-range projections to modulate its activity. Some of these projections arise from the cerebral cortex, which is known to influence feeding. However, the functional and anatomical organization of cortico-hypothalamic pathways have remained poorly studied. We used anatomical and optogenetic mapping to show that the medial prefrontal cortex (mPFC) is the strongest cortical input source to the LH, followed by a lateral associative region including the insular cortex (IC), and the ventral subiculum. Input from the mPFC and IC had markedly different synaptic dynamics and were integrated supralinearly. IC input surpassed that of the mPFC in a subpopulation of highly excitable dorsal LH neurons which had a strong h-current. Input from the mPFC showed selective targeting to LH neurons which project back to the mPFC, suggesting the existence of a direct feedback loop. Overall, these results identify a direct prefrontal hypothalamic pathway which is poised to dominate rapid cortical control of hypothalamic activity.