Trends in Neurosciences
ReviewThe hypocretin/orexin ligand–receptor system: implications for sleep and sleep disorders
Section snippets
Anatomy of the hypocretin/orexin system
The distribution of Hcrt/orexin-containing cells has been described both by in situ hybridization1, 7 and immunohistochemistry, using antibodies against prepro-hypocretin21, Hcrt1/orexin A (22, 23, 24, 25) and Hcrt2/orexin B (23, 26). Hcrt/orexin-containing cells are restricted to the tuberal region of the hypothalamus, specifically within the PFH and dorsomedial hypothalamic nuclei, and the dorsal and lateral hypothalamic areas, which encompass about 1 mm rostrocaudally in the rat brain (Fig. 2
Cellular effects of hypocretin/orexin
The effects of the Hcrt/orexin peptides have been uniformly reported as excitatory to date. The initial paper on the hypocretins demonstrated an excitatory effect of Hcrt2/orexin B on cultured hypothalamic cells using whole-cell patch recordings1. Subsequent studies have shown that, in addition to excitatory effects, Hcrt1/orexin A and Hcrt2/orexin B have neuromodulatory effects at nanomolar concentrations on both GABA- and glutamate-mediated neurotransmission in medial and lateral hypothalamic
Hypocretin/orexin and sleep
The widespread anatomical projections of the Hcrt/orexin neurons suggest that they might be involved in multiple functions. In addition to food intake regulation, the hypocretin/orexin system has been implicated in neuroendocrine40, 45, 46, 47, 48, cardiovascular12, 49 and gastrointestinal50 control, and in water balance51. However, two landmark papers52, 53 strongly indicate that dysfunction of the Hcrt/orexin system can result in the sleep disorder narcolepsy.
Narcolepsy is characterized by
Concluding remarks
Characterization of the discharge pattern of the Hcrt/orexin-containing cells across arousal states will be essential to understand the involvement of these cells in ‘normal’ sleep–wake regulation. Although the model proposed has focused on narcolepsy, it might be applicable to other pathophysiological conditions such as the disrupted sleep characteristic of aged individuals. Given the putative role of hypocretin/orexin in sleep–wakefulness, food intake regulation and other possible
Acknowledgements
The authors thank Jane Ding for preparation of Fig. 1. The authors’ research has been supported by NIH 1 R01HL/MH59658 and 1 R01MH61755.
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