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 local 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 has 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. Inputs 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. KEY POINTS: The lateral hypothalamus (LH) receives monosynaptic, excitatory cortical synaptic input from associative cortical regions and hippocampus. Cortical input is integrated temporally in a pathway-specific manner within individual LH neurons. Inputs from the medial prefrontal cortex (mPFC) and insula are integrated supralinearly. The mPFC is a dominant source targeting LH neurons projecting back to the mPFC.