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      The neurobiological basis of narcolepsy.

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          Abstract

          Narcolepsy is the most common neurological cause of chronic sleepiness. The discovery about 20 years ago that narcolepsy is caused by selective loss of the neurons producing orexins (also known as hypocretins) sparked great advances in the field. Here, we review the current understanding of how orexin neurons regulate sleep-wake behaviour and the consequences of the loss of orexin neurons. We also summarize the developing evidence that narcolepsy is an autoimmune disorder that may be caused by a T cell-mediated attack on the orexin neurons and explain how these new perspectives can inform better therapeutic approaches.

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          Orexins and Orexin Receptors: A Family of Hypothalamic Neuropeptides and G Protein-Coupled Receptors that Regulate Feeding Behavior

          Takeshi Sakurai, Akira Amemiya, Makoto Ishii … (1998)
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            Neural substrates of awakening probed with optogenetic control of hypocretin neurons.

            Antoine Adamantidis, Feng Zhang, Alexander M Aravanis … (2007)
            The neural underpinnings of sleep involve interactions between sleep-promoting areas such as the anterior hypothalamus, and arousal systems located in the posterior hypothalamus, the basal forebrain and the brainstem. Hypocretin (Hcrt, also known as orexin)-producing neurons in the lateral hypothalamus are important for arousal stability, and loss of Hcrt function has been linked to narcolepsy. However, it is unknown whether electrical activity arising from Hcrt neurons is sufficient to drive awakening from sleep states or is simply correlated with it. Here we directly probed the impact of Hcrt neuron activity on sleep state transitions with in vivo neural photostimulation, genetically targeting channelrhodopsin-2 to Hcrt cells and using an optical fibre to deliver light deep in the brain, directly into the lateral hypothalamus, of freely moving mice. We found that direct, selective, optogenetic photostimulation of Hcrt neurons increased the probability of transition to wakefulness from either slow wave sleep or rapid eye movement sleep. Notably, photostimulation using 5-30 Hz light pulse trains reduced latency to wakefulness, whereas 1 Hz trains did not. This study establishes a causal relationship between frequency-dependent activity of a genetically defined neural cell type and a specific mammalian behaviour central to clinical conditions and neurobehavioural physiology.
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              A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains.

              C Peyron, J Faraco, W. Rogers … (2000)
              We explored the role of hypocretins in human narcolepsy through histopathology of six narcolepsy brains and mutation screening of Hcrt, Hcrtr1 and Hcrtr2 in 74 patients of various human leukocyte antigen and family history status. One Hcrt mutation, impairing peptide trafficking and processing, was found in a single case with early onset narcolepsy. In situ hybridization of the perifornical area and peptide radioimmunoassays indicated global loss of hypocretins, without gliosis or signs of inflammation in all human cases examined. Although hypocretin loci do not contribute significantly to genetic predisposition, most cases of human narcolepsy are associated with a deficient hypocretin system.
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                Author and article information

                Journal
                Journal ID (iso-abbrev): Nat. Rev. Neurosci.
                Title: Nature reviews. Neuroscience
                Publisher: Springer Science and Business Media LLC
                ISSN (Electronic): 1471-0048
                ISSN (Print): 1471-003X
                Publication date (Electronic): Feb 2019
                Volume: 20
                Issue: 2
                Affiliations
                [1 ] Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
                [2 ] Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
                [3 ] Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA. tscammel@bidmc.harvard.edu.
                Article
                Publisher Item ID: 10.1038/s41583-018-0097-x Mid ID: NIHMS1017577
                DOI: 10.1038/s41583-018-0097-x
                PMC ID: 6492289
                PubMed ID: 30546103
                SO-VID: 02835772-0ecf-4d28-bc6c-3fe9e68eae1c
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