Identification of the neuronal suppressor of cataplexy, sudden weakening of muscle tone


Sleep is of absolute necessity for us humans, although if one falls asleep all of a sudden while being awoken, it would cause a big trouble. The brain is equipped with sleep mechanism and wakefulness mechanism, which are regulated to be on or off in an adequate manner.

Image: Scheme of the human brain an nacrolepsy patient; Copyright: Kanazawa University

External stimulus causing excitement such as laughter by a joke augments the amygdala activity. In narcolepsy patient (left) lacking orexin neurons, activities of the amygdala become excessive, causing cataplexy; ©Kanazawa University

It is orexin that is important in regulating this switch. If orexin neurons are lost, one suffers from narcolepsy, a sleep disorder, where sleep and wakefulness are inadequately switched on and off. The typical symptoms are excessive daytime sleepiness and cataplexy. Cataplexy takes place when one is very excited in terms of one's emotion and if severe, one may lose the muscle tone of the whole body and fall down. Sleep is categorized into two, REM sleep and non-REM sleep. Dreams are dreamt usually during REM sleep, where most of the muscles are controlled to be relaxed (called atonia) in order to prevent the dreamer to make real actions. Cataplexy attack is thought that atonia, a characteristics of REM sleep, takes place while one is awoken. The research team previously found two types of neurons preventing narcolepsy by receiving orexin from orexin neurons. The one is noradrenaline neurons in the locus coeruleus of the brain, suppressing strong sleepiness, and the other is serotonin neurons in the dorsal raphe nucleus of the brain, inhibiting cataplexy.

In this study, the international research team led by the researchers of Kanazawa University has discovered that serotonin neurons in the dorsal raphe nucleus inhibits catalepsy by reducing activities of the amygdala that controls emotion.

Serotonin neurons in the dorsal raphe nucleus extend projections throughout the brain and send information. In this study, with an optogenetic tool, the team has discovered that catalepsy was almost completely inhibited by artificial augmentation of serotonin release induced by selectively stimulating serotonin nerve terminals in the amygdala in the narcolepsy model mice. The same experimental operation in the other brain region that controls REM sleep did not inhibit cataplexy. In addition, the team found that serotonin release reduced the amygdala activity. When the amygdala activity was artificially reduced in a direct manner, cataplexy was inhibited, while artificially augmented, frequency of cataplexy attack increased. Furthermore, the effect of orexin neurons inhibiting cataplexy was found to be abolished when serotonin release was inhibited selectively in the amygdala.

Cataplexy takes place, triggered by a sudden emotional excitement of positive valence such as a big laughter. This study has revealed that serotonin neurons do not directly suppress muscle tone weakening but inhibit cataplexy by reducing and controlling activities of the amygdala, which is involved in communicating emotional excitement. In fact, it is known that the amygdala of narcolepsy patients without orexin neurons responds excessively when the patients see, for example, interesting photos. By identifying neuronal pathway, orexin neuron - serotonin neuron in the dorsal raphe nucleus - the amygdala, the team believes that the current study has made a big step forward to understanding of the whole picture of the narcolepsy mechanism. It is also highly expected that new therapy would be developed for cataplexy.; Source: Kanazawa University
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