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This chapter reviews the contribution of the human leukocyte antigen (HLA) molecule in narcolepsy in terms of genetic association, relationship to clinical characteristics, autoimmune hypothesis and molecular mechanisms. The HLA genotype has been related to sleep, even in healthy subjects. In 1983, a strong association was reported in Japanese narcolepsy patients with HLA. Narcolepsy is not limited to the core symptoms of lapsing into sleep and cataplexy, but also exhibits wide range of associated symptoms that are somatic and neuropsychiatric. Among known HLA-related diseases, the relative risk of narcolepsy is extremely high. Although, there is no direct evidence for autoimmunity, studies of environmental factors in narcolepsy have suggested that previous infectious diseases could be a trigger to develop narcolepsy. Association with the HLA complex is not limited to narcolepsy, and over 100 types of diseases are known to show significant associations with HLA.
In the first half of the twentieth century, research by von Economo and Walle Nauta implicated the hypothalamus in sleep and waking. In the subsequent 50 years the hypothalamus was abandoned and instead the pons was considered to house the neurons regulating states of consciousness. In 1999, the linkage of a hypothalamic peptide, hypocretin, with narcolepsy shifted the emphasis back to the hypothalamus. However, since REM sleep originates from the pons, we sought to identify how the hypothalamus links with the pons, which would elucidate a network map of regions responsible for all three states. In this review we summarize our hypothesis that hypothalamic wake and non-REM sleep active neurons link with a group of i nhibitory pontine neurons to gate the transition to REM sleep. This hypothesis was first publically presented by us at the Society for Neuroscience meeting in 2004. We suggest that the pontine areas inhibiting REM sleep (PAIRS) represent GABA neurons; that these neurons are activated by glucosensing neurons, and neurons involved in emotion and arousal, and that their purpose is to keep the animal upright, mobile, and vigilant as it forages for food.
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