Sleep disturbances and impaired muscle control in ataxia may have a common cause

Ataxia affects people’s ability to walk, talk, and perform other motor functions. Genetic mutations that disrupt or destroy Purkinje cellsInhibitory neurons in the cerebellum, which coordinates movement and facilitates cognition and emotional processing, can cause this disorder.¹ However, one group has provided additional evidence that this brain structure may be involved in another non-motor function: sleep.

Reports sleep disorders sparked interest among people with ataxia Roy Sillitoeneuroscientist at Baylor College of Medicine.² When Luis Salazarwho had previously researched sleep, joined Sillitoe’s group as a graduate student, an exciting opportunity arose to explore this interaction. “This seemed like a really fruitful area to explore and study, and it had not been explored in the mouse models that we had in the lab,” explained Salazar, now co-founder of Sobek AI.

In an article published in Disease models and mechanisms, Salazar and colleagues demonstrated that Purkinje cells affected by ataxia also control aspects of the sleep cycle in mice.³ The findings help to better understand sleep disturbances in people with movement disorders such as ataxia, which affect their overall health and quality of life. “We can start thinking about how we can treat it: with drugs or neurostimulation,” he said. Amanda Brownneuroscientist and researcher in Sillitoe’s laboratory and co-author of the paper.

The team previously explored two models dystoniaanother movement disorder, and demonstrated that preventing brainstem neurons from communicating with the cerebellum disrupts sleep.⁴ “After that, the idea came to look for another mouse model first,” Salazar said. “And also trying to unravel a little bit of the cellular mechanisms that were at work here.”

To simulate ataxia, the team selectively silenced Purkinje cells in mice, which caused ataxia-like motor disorders.⁵ “We are using perhaps one of the purest models of ataxia currently known in mice,” Brown said.

Because sleep is controlled in part by the circadian rhythm, the team first examined changes in this internal clock in ataxic mice. They recorded how often the animals used the running wheel to establish their activity patterns, and after an acclimation period to a 12-hour light-dark cycle, they assessed changes in these patterns by placing the mice in constant darkness. Although suppressing Purkinje cell activity reduced the overall activity of ataxic mice, this manipulation did not affect the animals’ circadian rhythms.

The team then studied changes in the animals’ sleep cycles by studying electrical activity in the brain and muscles using electrodes. Mice have a normal sleep cycle contains the animal alternates between three stages: wakefulness, rapid eye movement (REM) and non-rapid eye movement (NREM).⁶

Mice with ataxia showed longer periods of each stage, although they had fewer periods of wakefulness and REM sleep, so overall these mice spent more time in slow-wave sleep compared to the awake or REM sleep stages. These mice also took longer to enter REM sleep. Notably, this REM sleep deficit reflects REM sleep disorders that occur in people with ataxia.⁷

“This provides a good scientific basis for further research,” he said. Sheng-Han Kuoneurologist and translational neuroscientist at Columbia University who was not involved in this study. He said that because movement disorders can have other interfering effects, investigating the role of Purkinje cells using specific approaches such as optogenetics could help further confirm their involvement in sleep regulation. Sillitoe’s group also wants to study the effects in more complex disease models that more closely resemble human disorders.

“Some very interesting next steps will be to study these abnormal signals and figure out how they affect sleep processes and other non-motor functions, especially in these neurological disorders,” Brown said.