Hypocretins/Orexins in Brain Function

Abstract

The hypocretins (also called the orexins) are two C-terminally amidated neuropeptides of related sequence. They are produced from a common precursor whose expression is restricted to a few thousand neurons of the rat dorsolateral hypothalamus. Two G‐protein‐coupled receptors (GPCRs) for the hypocretins have been identified, and these have different distributions within the CNS and differential affinities for the two hypocretins. The hypocretins have been detected in secretory vesicles at synapses of fibers that project to areas within the posterior hypothalamus that are implicated in feeding behaviors and hormone secretion. Hypocretin fibers also project to diverse targets in other brain regions and the spinal cord, including several areas implicated in cardiovascular function and sleep--wake regulation. The peptides are excitatory when applied directly in vivo and to cultured neurons and slices, although there is also evidence for some inhibitory signaling. Administration of the hypocretins stimulates food intake, affects blood pressure, hormone secretion, and locomotor activity, and increases wakefulness while suppressing rapid eye movement (REM) sleep. Inactivating mutations in the hypocretin receptor 2 gene (hcrtr 2) in dogs result in narcolepsy. Mice whose hypocretin gene has been inactivated exhibit a narcolepsy‐like phenotype. Most human patients with narcolepsy have greatly reduced levels of hypocretin peptides in their cerebrospinal fluid (CSF) and no or barely detectable hypocretin neurons in their hypothalami, suggestive of autoimmune attack. One aspect of hypocretin activity is the direct excitation of cholinergic forebrain neurons, brainstem monoaminergic REM‐off neurons in the locus coeruleus and dorsal raphe nucleus, and histaminergic tuberomammillary nucleus (TMN), which together suppress slow‐wave sleep. The hypocretins also modulate the activity of cholinergic REM‐on neurons in the brainstem, which gate REM entry. The effects on wakefulness appear to be the dominant activities of the hypocretin system and are twofold: maintenance of the waking state and suppression of REM entry.