How Dorsal Raphe Serotonin Neurons Suppress Cataplexy

Serotonin neurons in the brain inhibit cataplexy by reducing activity in the amygdala, an international research team has discovered.

Cataplexy is a sudden short term episode of muscle weakness accompanied by full conscious awareness. It is typically triggered by a sudden emotional excitement of positive valence such as laughter.

A new study, led by researchers at Kanazawa University, reveals that serotonin producing neurons do not directly suppress muscle tone weakening. Rather, they inhibit cataplexy by reducing and controlling activities of the amygdala.

The amygdala is a brain region that plays vital roles in processing emotional responses as well as in emotional memory. Emotion is accompanied with physical, physiological, and behavioral changes, and is distinguished from mood, that signifies weak feelings prevailing for a mid- and long-term in a mild manner.

Sleep And Wakefulness

Sleep is of absolute necessity for humans. But if you fall asleep all of a sudden while awake, it can cause major problems.

The brain is equipped with sleep mechanism and wakefulness mechanism, which are regulated to be on or off in an adequate manner. Orexin (also known as hypocretin), a neuropeptide, is important in regulating this switch. If orexin-sensitive neurons are lost, an individual can suffers from narcolepsy, a sleep disorder, where sleep and wakefulness are inadequately switched on and off.

Typical symptoms of narcolepsy include excessive daytime sleepiness and cataplexy. Cataplexy, if severe, may cause one to lose muscle tone through the whole body, resulting in collapse and potential injury.

narcolepsy cataplexy

Click to Enlarge. Credit: Kanazawa University

Sleep is categorized into 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. In a cataplexy episode, atonia, a characteristics of REM sleep, takes place while one is awake.

In previous work, the research team found that two types of neurons prevent narcolepsy by receiving orexin from orexin neurons. One type is noradrenaline neurons in the locus coeruleus of the brain, suppressing strong sleepiness. The other is serotoninergic neurons in the dorsal raphe nucleus of the brain, inhibiting cataplexy.

Orexin vs. Serotonin

Since the activities of serotonin neurons are high during wakefulness but low during sleep, serotonin is thought to be involved in regulating wakefulness and sleep. Serotonin neurons in the dorsal raphe nucleus extend projections throughout the brain and send information.

In this study, using optogenetics tools, the team has found that cataplexy was almost completely inhibited by selectively stimulating serotonin nerve terminals in the amygdala in 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.

Narcolepsy Pathway

Orexin A and orexin B are neuropeptides produced from a single gene in certain neurons of the hypothalamus. They consist of about 30 amino acid residues and function as neurotransmitters to convey information between neurons.

Orexin producing neurons extend nerve projections throughout the brain. Orexin released from the orexin nerve terminal exerts different functions in various regions of the brain. It prevents narcolepsy by stably maintaining wakefulness as well as to function for promotion of eating and metabolism and of response for reward.

It is known that the amygdala of narcolepsy patients without orexin neurons responds excessively when the patients see, for example, interesting photos. By identifying the neuronal pathway involving orexin neurons, serotonin neurons in the dorsal raphe nucleus, and the amygdala, the team believes that the current study has made a big step forward to understanding the whole picture of narcolepsy’s mechanism.

Top Image: Arran Lewis, Wellcome Images

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