Hypothalamic research since the middle of the 20th century shaped the view that the
lateral hypothalamic area (LHA) has a central role in controlling appetitive drives. The LHA is
anatomically positioned to receive converging axonal inputs which relay information about the
body’s metabolic state as well as descending projections from the cerebral hemispheres, which
encode cognitive and emotional states that inÀuence feeding. Cerebral inputs are capable of initiating
feeding despite the presence of competing satiety signals. Recent work has shown that medial
prefrontal cortical areas can drive feeding in sated animals, possibly by engaging hypothalamic
hypocretin/orexin (H/O)-expressing neurons, which are known to send projections to the cortex.
Neuroanatomical tract tracing was used, in rats, to test the hypothesis that there are bidirectional
monosynaptic connections between the medial prefrontal cortex and the lateral hypothalamic
area. To further examine hypothalamic-cortical interactions, prefrontal targets of H/O-containing
axons were described with cell-type precision by using immunohistochemistry and neuronal
reconstructions. Collectively, these experiments produced the highest spatial resolution maps of
prefrontal chemoarchitecture and connections with the LHA. Additionally, they provide novel
probe targets for future functional studies, which includes a previously unappreciated connection
between the infralimbic cortical area and the terete part of the hypothalamic tuberal nucleus.