The hypocretins: excitatory neuromodulatory peptides for multiple homeostatic systems, including sleep and feeding

The hypocretins are two neuropeptides of related sequence that are produced from a common precursor whose expression is restricted to 1, 100 large neurons of the rat dorsal-lateral hypothalamus. The hypocretins have been detected immunohistochemically in secretory vesicles at synapses of fibers that project to areas within the posterior hypothalamus that are implicated in feeding behaviors and hormone secretion and diverse targets in other brain regions and in the spinal cord, including several areas implicated in cardiovascular function and sleep-wake regulation. The hypocretin-producing cells have receptors for leptin and receive input from arcuate neuropeptide Y neurons. The peptides are excitatory when applied to cultured hypothalamic, cortical, or spinal cord neurons. Two G protein-coupled receptors for the hypocretins have been identified, and these have different distributions within the CNS and differential affinities for the two hypocretins. Administration of the hypocretins stimulates food intake; affects blood pressure, hormone secretion, and locomotor activity; and increases wakefulness while suppressing REM sleep. The hypocretin mRNA accumulates during food deprivation. An inactivating insertion into the hypocretin receptor 2 gene in dogs results in narcolepsy. Mice whose hypocretin gene has been inactivated exhibit a narcolepsy-like phenotype. Human patients with narcolepsy have greatly reduced levels of hypocretin peptides in their cerebral spinal fluid. One aspect of hypocretin activity is the direct excitation of noradrenergic neurons in the locus coeruleus to prevent entry into REM sleep. These peptides appear to be part of a complex circuit that integrates aspects of energy metabolism, cardiovascular function, hormone homeostasis, and sleep-wake behaviors.