New mouse study links nerve cells to sleep attacks and cataplexy

In narcolepsy, targeting specific nerve cells involved in sleep–wake transitions may offer a way to address excessive daytime sleepiness and cataplexy, a sudden loss of muscle tone that happens while a patient remains conscious, according to a study in mice.

Targeting these nerve cells could offer “a novel therapeutic target for the treatment of narcolepsy,” three researchers from the University of Toronto wrote in their study, “GABA neurons in the sublaterodorsal tegmental nucleus suppress wakefulness in healthy and narcoleptic mice,” published in PLOS Biology.

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How nerve cells regulate sleep and wakefulness

The sleep–wake cycle is controlled by networks of nerve cells, or neurons, that switch the brain between wakefulness, non-rapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep. NREM sleep includes stages ranging from light to deep sleep and plays an important role in physical restoration, while REM sleep is the stage when most dreaming occurs.

In narcolepsy, the sleep–wake cycle is disrupted. As a result, patients may experience overwhelming daytime sleepiness and sudden sleep attacks. The brainstem, located at the base of the brain where it connects to the spinal cord, contains important parts of the network that regulates sleep–wake transitions, but the precise mechanisms remain unclear. That uncertainty has limited the development of new narcolepsy treatments.

This study focused on a group of inhibitory nerve cells called GABA neurons in the sublaterodorsal tegmental nucleus (SLD), a brainstem region already known to help control REM sleep. GABAergic neurons reduce the activity of other nerve cells by releasing GABA, a chemical messenger that dampens neural activity.

To understand whether these SLD neurons contribute to narcolepsy, the researchers compared healthy mice with mice lacking orexin, a brain chemical that normally helps stabilize wakefulness. Loss of orexin, also called hypocretin, is a defining feature of narcolepsy type 1, the form commonly associated with cataplexy.

They used optogenetics, a technique that uses light to turn specific nerve cells on or off, while monitoring electrical activity in the brain with electroencephalography (EEG). They also used electromyography (EMG), which measures the electrical activity of muscles. This allowed them to see how activating or silencing GABA neurons in the SLD affected sleep, wakefulness, and muscle activity.

Turning off SLD GABA neurons triggered wakefulness

When the researchers turned off, or silenced, those neurons, healthy mice quickly woke up regardless of whether they were in NREM sleep or REM sleep. They also stayed awake longer when the nerve cells were silenced for longer periods. “Silencing the SLD GABA neurons reliably induced episodes of wakefulness,” the researchers wrote.

Silencing the SLD GABA neurons while the mice were awake also made them more alert. Their brains showed more fast-wave activity associated with active wakefulness and less slow-wave activity associated with sleep. Muscle activity also increased, and the mice were more likely to move around.

The researchers then activated the SLD GABA neurons, producing the opposite effect. Wakefulness decreased, while NREM sleep increased. Activating these nerve cells helped maintain NREM sleep by preventing mice from waking up, but it did not increase REM sleep. Cortical and muscle activity associated with wakefulness also decreased, supporting the conclusion that SLD GABA neurons suppress wakefulness.

The researchers also traced where these nerve cells project in the brain. They found traces of axonal projections to several regions involved in wakefulness, alertness, and movement. This suggests that SLD GABA neurons may suppress wakefulness by influencing multiple wake-promoting brain networks.

In an orexin-deficient mouse model of narcolepsy, activating the SLD GABA neurons caused the animals to suddenly enter NREM sleep within about five seconds, even while they were actively moving around. These episodes resembled sleep attacks in people with narcolepsy, in which sleep abruptly intrudes on wakefulness. Unlike cataplexy, the episodes could be interrupted by gently touching the mice.

When the researchers activated the same nerve cells during NREM sleep in orexin-deficient mice, the mice remained in NREM sleep longer, just as healthy mice did. Activating the SLD GABA neurons during REM sleep had little effect in either group. This suggests that activating these neurons mainly reinforces NREM sleep.

Silencing neurons ended sleep attacks and cataplexy

In orexin-deficient mice, silencing the SLD GABA neurons immediately ended sleep attacks, waking the animals and restoring brain and muscle activity associated with alert wakefulness. Silencing the neurons also prolonged wakefulness and increased the likelihood that the mice would remain awake, similar to what was seen in healthy mice.

The researchers also found that silencing these nerve cells immediately ended cataplexy by restoring movement and wakefulness. Overall, the study shows that SLD GABA neurons play a key role in regulating transitions among arousal states in mice. In healthy mice, they normally suppress wakefulness, while in orexin-deficient mice, they appear to contribute to sleep attacks and cataplexy.

“Collectively, these findings establish SLD GABA neurons as a key regulator of arousal state transitions,” the researchers wrote. “Our findings not only resolve a longstanding question about the function of SLD GABA neurons but also identify a potential intervention target to resolve the excessive sleepiness of narcolepsy.”