Hypocretin (Orexin) activation and synaptic innervation of the locus coeruleus noradrenergic system

Hypocretin has been identified as a regulator of metabolic and endocrine sy stems. Several brain regions involved in the central regulation of autonomi c and endocrine processes or attention are targets of extensive hypocretin projections. The most dense arborization of hypocretin axons in the brainst em was detected in the locus coeruleus (LC). Multiple labeling immunocytoch emistry revealed a massive synaptic innervation of catecholaminergic LC cel ls by hypocretin axon terminals in rats and monkeys. In both species, all t yrosine hydroxylase-immunopositive cells in the LC examined by electron mic roscopy were found to receive asymmetrical (excitatory) synaptic contacts f rom multiple axons containing hypocretin. In parallel electrophysiological studies with slices of rat brain, all LC cells showed excitatory responses to the hypocretin-2 peptide. Hypocretin-2 uniformly increased the frequency of action potentials in these cells, even in the presence of tetrodotoxin, indicating that receptors responding to hypocretin were expressed in LC ne urons. Two mechanisms for the increased firing rate appeared to be a reduct ion in the slow component of the afterhyperpolarization (AHP) and a modest depolarization. Catecholamine systems in other parts of the brain, includin g those found in the medulla, zona incerta, substantia nigra or olfactory b ulb, received significantly less hypocretin input. Comparative analysis of lateral hypothalamic input to the LC revealed that hypocretin-containing ax on terminals were substantially more abundant than those containing melanin -concentrating hormone. The present results provide evidence for direct act ion of hypothalamic hypocretin cells on the LC noradrenergic system in rats and monkeys. Our observations suggest a signaling pathway via which signal s acting on the lateral hypothalamus may influence the activity of the LC a nd thereby a variety of CNS functions related to noradrenergic innervation, including vigilance, attention, learning, and memory. Thus, the hypocretin innervation of the LC may serve to focus cognitive processes to compliment hypocretin-mediated activation of autonomic centers already described. (C) Wiley-Liss, Inc.