Sleep disturbances in ataxic mice caused by dysfunction in the cerebellum


Patients with movement disorders such as ataxia, dystonia, and tremors often suffer from severe sleep disturbances which significantly affect their physical and mental health as well as their quality of life. The underlying cause of these secondary non-motor issues is not well understood. A recent study in mice from the laboratory of Dr. Roy V. Sillitoe, professor of Pathology and Neuroscience at Baylor College of Medicine and a principal investigator at the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital, provides new insights into the role of a specific region of the brain – the cerebellum - in regulating sleep and thus, highlights its importance as a source of sleep disruptions in motor disorders. The study was published in Disease Models and Mechanisms, a journal of The Company of Biologists.

“Our study shows that the dysfunction of a specific group of cells in the cerebellum called the Purkinje cells, which have long been known to disrupt movements, also alter sleep patterns,” Dr. Sillitoe said. “Our findings posit a connection between cerebellar dysfunction and disrupted sleep and thereby, underscores the importance of examining the role of cerebellum in different sleep disorders.”

Emerging roles for the cerebellum 

The cerebellum is the brain region that regulates many motor functions including coordination, balance, posture, and learning. However, there is emerging evidence suggesting it also plays a key role in certain non-motor functions such as cognitive and emotional processing, associative learning, and particularly, sleep and sleep-associated processes. Moreover, in patients with cerebellar ataxia, cognitive function, and depression correlate with sleep quality. 

So, in this study, the Sillitoe lab addressed an important question – does cerebellar dysfunction also impair sleep and if so, which cerebellar neurons are involved in the impairment of this non-motor function?

They focused their studies on Purkinje cells, the principal neurons of the cerebellum that play critical roles in motor function. “While previous studies have tested the role of the cerebellum in sleep regulation, little is known about how specific neurons in specific disease contexts are involved in this function,” Dr. Luis Salazar, lead author and a former graduate student in the Sillitoe lab, said.

Using a mouse ataxia model to solve the puzzle

To investigate the relationship between Purkinje cells and sleep, the Sillitoe lab used a well-established genetic switch to turn off the activity of these cerebellar neurons in the brains of mice. Since all Purkinje cells are inhibitory neurons and represent the sole output of the cerebellar cortex, this genetic manipulation effectively turned off all communication between these neurons and their downstream targets, the cerebellar nuclei. Based on previous studies of this mouse model, they saw that the resulting mutant mice had severe ataxic motor symptoms including lack of balance, coordination, and abnormal gait. In this new work, they found the ataxic mice also exhibited sleep impairments similar to those reported for human ataxia patients like excessive daytime fatigue and sleepiness and changes in sleep quality. 

Ataxic mice have altered sleep architecture

Sleep regulation is governed by two processes - the circadian clocks that regulate the timing of sleep and wakefulness based on a 24-hour biological clock and the homeostatic process that compensates for any lack of sleep due to extended periods of wakefulness. The team found that despite cerebellar and motor dysfunction, the circadian rhythms in these mice remained unchanged, indicating that their sleep impairments may be likely due to changes in the sleep-associated brain activity patterns. 

When we sleep, our brain cycles through four different states. The first three are considered non-rapid eye movement (NREM 1, 2, and 3) sleep or quiet sleep and the fourth is the rapid eye movement (REM) sleep, also known as active sleep. NREM 1 is the transitory phase from wakefulness to resting state while NREM 2, 3 and REM sleep stages are critical for conducting physical repairs; and processing/storage of factual and emotional memories. During a full night of uninterrupted sleep, a person may experience several cycles of these sleep stages, referred to as ‘sleep architecture’.

To understand and compare the sleep architecture of the ataxic mice to normal mice, the team placed electrodes on the surface of their brains to measure the electrical potentials associated with brain activity and also implanted electrodes into the muscles to monitor muscle activity associated with movement and relaxation. 

“Using these signals, we found that while the typical sleep stages were present in ataxic mice, the time they spent awake and in different sleep stages were altered compared to normal mice, indicating poor sleep quality,” Dr. Amanda Brown, co-author and postdoctoral fellow in the Sillitoe lab, said. “The ataxic mice had overall longer periods of NREM sleep with more frequent and longer bouts of NREM. On the other hand, they spent overall less time in awake or in REM sleep states because they had fewer cycles through these states and it took them longer to attain these states.”

The REM sleep is considered the deepest sleep and most restful state in which we dream and process emotions whereas the NREM sleep is akin to naps, which while restorative is not as rejuvenating as the deep REM sleep.

“We have discovered dysfunctional Purkinje cells in the cerebellum as the cause of sleep disturbances and poor-quality sleep in ataxic mice and likely, in patients with motor disorders,” Dr. Sillitoe said. “These findings not only expand our understanding of this particular non-motor complication in ataxia and other motor disorders, but also points to a much broader role for cerebellum and its circuits in acting as a nexus for various disease symptoms in motor disorders.

A complete list of authors and their institutional affiliations can be found here. This work was supported by Baylor College of Medicine (BCM), Texas Children’s Hospital, The Hamill Foundation, and grants from the National Institutes of Neurological Disorders and Stroke and Dystonia Medical Research Foundation. Research reported in the publication used the Animal Behavior Core and the Cell and Tissue Pathogenesis Core (BCM IDDRC) which is supported by Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health. It was also supported in part by the RNA In Situ Hybridization Core facility at Baylor College of Medicine, which is supported by a Shared Instrumentation grant from the NIH and the NIH IDDRC grant from the Eunice Kennedy Shriver National Institute of Child Health & Human Development.