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'Dissecting sleep' by studying the strange phenomenon of cataplexy

Cell Press

Measuring brain cell activity in dogs with a genetic form of narcolepsy, neurobiologists Jerome Siegel and his colleagues have presented evidence that wakefulness is maintained by the activity of neurons triggered by the neurotransmitter histamine. The discovery will be appreciated by anyone in whom antihistamines in allergy or over-the-counter sleep drugs cause drowsiness.

The findings offer new insights both into normal sleep and narcolepsy.

To "dissect" the neurological components of sleep, the scientists studied the phenomenon of cataplexy -- the abrupt loss of muscle tone while maintaining a state of complete wakefulness. The majority of narcoleptics suffer from this malady, in which a strong emotion, even a funny joke, can cause them to drop into a state of paralyzed awareness ranging from a few seconds to half an hour. Similarly, in narcoleptic dogs, emotional excitement, play, or even receiving a favorite food can trigger cataplexy.

The researchers have been using cataplexy as a unique natural "experiment" to distinguish the neural basis of loss of consciousness from that of skeletal muscle paralysis during sleep.

In their studies, they have concentrated on the role of three kinds of neurons in the brain's hypothalamus -- the central controlling region for sleep and wakefulness.

In their previous experiments, they found that noradrenalin- and serotonin-triggered neurons reduced their electrical activity during cataplexy. In the latest experiments, they measured the activity of histamine-triggered neurons when the dogs experienced cataleptic episodes when given a food treat or toy.

The scientists discovered that the histamine-triggered neurons maintained their normal waking-level activity during such cataplexy. What's more, when the researchers administered drugs that increased cataplexy, they found no effect on the histamine neurons. In contrast, a drug that affected the norepinephrine neurons aggravated cataplexy in the animals.

The researchers also conducted experiments that indicated how the histamine neurons are activated during cataplexy -- by the reduction in a key neurotransmitter chemical, gamma-aminobutyric acid.

The discovery of the key role of the histamine neurons is consistent with what is already known about the wiring of the brain's sleep centers, wrote the scientists. Researchers knew that the histamine neurons in the hypothalamus extend themselves into the areas of the forebrain and brainstem known to control sleep and wakefulness.

Their latest findings also offer insight into the basic molecular mechanism of narcolepsy and cataplexy. Humans with narcolepsy have reduced numbers of neurons that release small proteins called hypocretins, and it is the effect of these proteins on histamine cells that govern wakefulness.


Joshi John, Ming-Fung Wu, Lisa N. Boehmer, and Jerome M. Siegel: "Cataplexy-Active Neurons in the Hypothalamus: Implications for the Role of Histamine in Sleep and Waking Behavior"

Published in Neuron, Volume 42, Number 4, May 27, 2004, pages 619-634.

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