The brain hypocretins and their receptors: mediators of allostatic arousal

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The hypocretins (abbreviated ‘Hcrts’ – also called ‘orexins’) are two neuropeptides secreted exclusively by a small population of neurons in the lateral hypothalamus. These peptides bind to two receptors located throughout the brain in nuclei associated with diverse cognitive and physiological functions. Initially, the brain Hcrt system was found to have a major role in the regulation of sleep/wake transitions. More recent studies indicate Hcrts may play a role in other physiological functions, including food intake, addiction, and stress. Taken together, these studies suggest a general role for Hcrts in mediating arousal, especially when an organism must respond to unexpected stressors and challenges in the environment.

Introduction

It has been a decade since the discovery of the hypocretins (Hcrts), and during the past ten years we have learned much about their expression, structure, and function. Almost immediately after their discovery, the important role of Hcrts in maintaining wakefulness was reported in multiple species including humans [1•, 2•, 3, 4, 5]. Subsequent years have only solidified the evidence that Hcrts are both necessary to maintain and sufficient to induce wakefulness, and they are now generally considered to be ‘arousal-promoting’ peptides [6•, 7•]. Recently, Hcrts have also been implicated in physiological functions and behaviors other than wakefulness. In this review, we provide an overview of the brain Hcrts and their receptors and survey the recent studies implicating a role for Hcrts in these diverse physiological functions. In trying to integrate these studies, we suggest that two general functions of Hcrts are to mediate wakefulness and allostatic arousal.

Section snippets

The hypocretins

The Hcrts were discovered independently by two groups in the late 1990s [8••, 9••]. They consist of a pair of secreted peptides, hypocretin-1 and hypocretin-2 (Hcrt1 and Hcrt2; also known as ‘orexin A’ and ‘orexin B’, respectively). These peptides are processed from the same genetic precursor, ‘preprohypocretin’ (ppHcrt) and are expressed exclusively in the perifornical lateral hypothalamic area of the brain [8••, 9••]. Hctrs and their receptors are also expressed in the periphery [10], but in

The hypocretin receptors

Both Hcrt peptides bind with different affinities to two Hcrt receptors, hypocretin receptor 1 (Hcrtr-1 – also called ‘OxR1’) and 2 (Hcrtr-2 – also called ‘OxR2’) [8••, 9••]. Hcrt-r1 binds Hcrt1 with high affinity and binds Hcrt2 with 100–1000-fold lower affinity [9••, 15]. Hcrt-r2 has a high affinity for both Hcrt1 and Hcrt2 (Figure 2).

The Hcrt receptors are located on postsynaptic terminals in a pattern consistent with the anterograde projections of hypocretin neurons described above (Figure 1

The crucial role of hypocretins in arousal stability

Extensive evidence demonstrates that Hcrts promote and maintain wakefulness, as described more thoroughly in other excellent reviews [6•, 7•, 13]. Major evidence stems from the original finding that impairment of the Hcrt system causes the sleep disorder narcolepsy in mice, dogs and humans [1•, 2•, 3, 4, 5]. Most human narcoleptics have decreased levels of Hcrt in their cerebrospinal fluid, and postmortem analysis reveals a reduction of Hcrt neurons in human narcoleptic brains [4, 5].

Other potential functions of the hypocretin system

Hcrts are implicated in many physiological functions other than maintaining wakefulness. For example, the alternate name of Hcrts, ‘orexins’, was designated because i.c.v. infusion of Hcrts increased food intake in rodents [9••]. These results are now considered to be an indirect effect of the wake-promoting effects of Hcrts, but this is still an active area of investigation. Microinjection of Hcrts into the arcuate nucleus stimulates orexigenic GABAergic neurons and inhibits anorexigenic

Hypocretins: regulators of arousal and allostasis

The role of the hypocretin system in promoting wakefulness is often described as a role in ‘arousal.’ Generalized arousal is marked by increased motor activity and heightened responsiveness to sensory and emotionally salient stimuli [37•, 38, 39, 40]. Less often emphasized, however, is that arousal systems are involved in much more than just regulating sleep/wake cycles, such as the vigilance, anxiety, and symptoms of many psychiatric disorders [41]. Importantly, brain structures implicated in

Conclusions

In the ten years since their discovery, we have learned much about the brain Hcrt system. Indeed, the role of Hcrts in promoting wakefulness is indisputable. This review suggests a framework for thinking about a general role for Hcrts in other behaviors as well. While more research is needed to elucidate the precise functions of Hcrts, perhaps the role of the Hcrt system will only be fully appreciated in the context of organismal homeostasis and allostasis. With sophisticated new imaging and

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

MEC and JSB are supported by Graduate Research Fellowship Awards from the National Science Foundation. MEC is also supported by a National Research Service Award from the National Institutes of Health. LdL is supported by grants from the National Institute on Drug Abuse, DARPA and NARSAD.

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