Abstract
Orexin is a neuropeptide produced by a specific subset of neurones located in the lateral hypothalamic area. Mice lacking either prepro-orexin or orexin receptor 2, as well as those in which orexin-producing neurones (orexin neurones) are deleted, share a common phenotype: altered sleep–wake regulation and the sudden onset of muscle atonia. These symptoms are similar to the human sleep disorder narcolepsy. In this review, we describe recent advances in the study of orexin function with a particular emphasis on microscopic techniques that better characterise the neuronal networks involving orexin neurones, as well as recent optogenetic approaches that allow for the activation or inhibition of specific neurones by expressing different light-activated proteins. In particular, the use of orexin/halorhodopsin and orexin/channelrhodopsin-2 transgenic mice has demonstrated an important role for orexin neurones in regulating the sleep–wake cycle and state of arousal in vivo. Further refinement of these in vitro and in vivo techniques will allow for a more detailed understanding of the interaction of orexin with other neurotransmitter pathways in the brain.
Highlights
New Approaches for the Study of Orexin FunctionThe use of orexin ⁄ halorhodopsin and orexin ⁄ channelrhodopsin-2 transgenic mice has demonstrated an important role for orexin neurones in regulating the sleep– wake cycle and state of arousal in vivo
Dense projections of orexin neurones are observed in the serotonergic dorsal raphe nucleus (DR), noradrenergic locus coeruleus (LC) and histaminergic tuberomammillary nucleus (TMN), and all of these nuclei are involved in promoting arousal
AVP is an anti-diuretic hormone released during dehydration, and these results suggest that the orexin system plays a key role in water deprivation-induced hyperlocomotor activity
Summary
The use of orexin ⁄ halorhodopsin and orexin ⁄ channelrhodopsin-2 transgenic mice has demonstrated an important role for orexin neurones in regulating the sleep– wake cycle and state of arousal in vivo Further refinement of these in vitro and in vivo techniques will allow for a more detailed understanding of the interaction of orexin with other neurotransmitter pathways in the brain. There are good data available indicating that orexin plays a role in regulating feeding behaviour; mice lacking the orexin peptide (prepro-orexin knockout mice) or OX2R (OX2R knockout mice), as well as those in which orexin-expressing neurones were deleted (orexin ⁄ ataxin-3 transgenic mice), demonstrate a phenotype remarkably similar to the human sleep disorder narcolepsy [10,11,12]. M2 and ⁄ or M4 receptors are likely to be involved because they are coupled to inhibitory Gi ⁄ Go type G proteins, whereas M1, M3 and M5 receptors are coupled to Gq ⁄ G11 type G proteins signalling molecules [24]
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