The Hypocretin Model in Humans
The protein neurotransmitter or neuropeptide, hypocretin (also called orexin; see page on
Dr. Yanagisawa’s work) has been strongly associated with narcolepsy in dogs (thanks to the results of
Dr. Mignot’s work in Stanford) and has been found to also play a role in human narcolepsy. The function of hypocretin is an excitatory one, and this neurotransmitter promotes wakefulness in many different species. Hypocretinergic neurons (the cells that produce this
neuropeptide) are, for the most part, active during waking and inactive during sleep. Two different types of this neuropeptide are studied in relation to narcolepsy. They are hypocretin 1 and 2, also called orexin A and B, respectively.
In certain studies with a limited number of narcoleptic patients, approximately 85% of the subjects showed very low hypocretin levels in tests of their cerebrospinal fluid (CSF). Also, it was observed that the number of cells that produce hypocretin in the hypothalamus, especially the large concentration in the lateral hypothalamus, is much lower in narcoleptic patients than in normal or control subjects (refer to the image of brain tissue from the lateral hypothalamuses of a narcoleptic and a control subject stained for hypocretinergic neurons on the left). Hypocretin appears to modulate activity in the hypothalamus (which is associated with sleep regulation, other hormonal activity regulation, and appetite amongst other things), and hypocretin cells project to several different brain regions outside of the lateral hypothalamus including the brain stem. Some of these regions are described in our section on
The Brain and Narcolepsy. They include:
• The
tuberomammillary nucleus: a hypocretin deficiency results in lower levels of histamine, a neurotransmitter that promotes wakefulness.
• The
locus coeruleus: a hypocretin deficiency results in low levels of norepinephrine (commonly known as noradrenalin), a hormone important in alertness and arousal.
• The
dorsal pons and basal forebrain (part of the cerebral cortex): a hypocretin deficiency results in an decrease in acetylcholine activity, which affects REM sleep, alertness and behavioral arousal.
• The
raphe nuclei in the medullary and pontine regions of the reticular formation: a hypocretin deficiency results in lower serotonin activity, which reduces cortical arousal and interferes in locomotion.
A hypocretin deficiency in the brain, either due to a loss of hypocretinergic (hypocretin producing) cells in the lateral hypothalamus or a loss of hypocretin receptors in other brain areas, is said to affect narcolepsy by decreasing the overall monoaminergic tone in the central nervous system. This means that a hypocretin deficiency causes the lessening of activity in another group of neurotransmitters in the brain that are linked to arousal, and include dopamine, epinephrine, norepinephrine and serotonin. This decreased monoaminergic tone was one of the causes of narcolepsy that were suggested before the publication of Mignot Yanagisawa’s work, and could explain the effect of certain current
medical treatments for the disorder.
Thus we can see that a disruption of the hypocretin system in the central nervous system (CNS) leads to a great deal of interference in other chemical systems of sleep regulation in the brain. But what causes this initial disruption? For information on the possible ways in which hypocretinergic cells or receptors are lost in the CNS, browse to our sections on
The Genetics of Narcolepsy and the
Autoimmune Theory of Narcolepsy.
Back to Causes
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