THE NE SYSTEM AS A TARGET FOR HYPOCRETIN NEURONS: Implications for regulation of arousal

As described in detail elsewhere in this volume, hypocretin (Hcrt, also called orexin) is a neuropeptide discovered recently in brain by subtractive hybridization technology 1 and orphan receptor analysis. Anatomical studies revealed that this peptide is made only in a select group of neurons in the hypothalamus, which project widely throughout the neuraxis. Functional analyses initially revealed a potential role for Hcrt in food intake, but later studies showed an important role of this neuropeptide system in regulation of arousal and sleep-waking states. It now seems clear that interference with Hcrt neurotransmission at any of several steps in either animals or humans leads to a narcoleptic-like syndrome. Although Hcrt projections ramify widely in the CNS, they are particularly target brain systems associated with arousal and regulation of sleep and waking. Among these areas, the nucleus locus coeruleus (LC) is especially heavily innervated by Hcrt fibers 3 (Fig. 1). Studies have shown that noradrenergic neurons of the LC receive direct Hcrt inputs via asymmetrical synapses, and that Hcrt in slices directly depolarizes and activates LC neurons. Activation by Hcrt is also seen in 5HT histamine, and cholinergic brain neurons implicated in arousal mechanisms. Together with results showing that loss of Hcrt is associated with narcolepsy, these findings have led to the general view that Hcrt function is important in regulation or maintenance of arousal or waking. Here we review our recent work on the effects of this peptide on physiological properties of LC neurons, and the innervation of locus coeruleus in rat and monkey by