Posts tagged cerebellar ataxia
Articles and news from the latest research reports.
Researchers find gene critical for development of brain motor centre
In a report published today in Nature Communications, an Ottawa-led team of researchers describe the role of a specific gene, called Snf2h, in the development of the cerebellum. Snf2h is required for the proper development of a healthy cerebellum, a master control centre in the brain for balance, fine motor control and complex physical movements.
Athletes and artists perform their extraordinary feats relying on the cerebellum. As well, the cerebellum is critical for the everyday tasks and activities that we perform, such as walking, eating and driving a car. By removing Snf2h, researchers found that the cerebellum was smaller than normal, and balance and refined movements were compromised.
Led by Dr. David Picketts, a senior scientist at the Ottawa Hospital Research Institute and professor in the Faculty of Medicine at the University of Ottawa, the team describes the Snf2h gene, which is found in our brain’s neural stem cells and functions as a master regulator. When they removed this gene early on in a mouse’s development, its cerebellum only grew to one-third the normal size. It also had difficulty walking, balancing and coordinating its movements, something called cerebellar ataxia that is a component of many neurodegenerative diseases.
"As these cerebellar stem cells divide, on their journey toward becoming specialized neurons, this master gene is responsible for deciding which genes are turned on and which genes are packed tightly away," said Dr. Picketts. "Without Snf2h there to keep things organized, genes that should be packed away are left turned on, while other genes are not properly activated. This disorganization within the cell’s nucleus results in a neuron that doesn’t perform very well—like a car running on five cylinders instead of six."
The cerebellum contains roughly half the neurons found in the brain. It also develops in response to external stimuli. So, as we practice tasks, certain genes or groups of genes are turned on and off, which strengthens these circuits and helps to stabilize or perfect the task being undertaken. The researchers found that the Snf2h gene orchestrates this complex and ongoing process. These master genes, which adapt to external cues to adjust the genes they turn on and off, are known as epigenetic regulators.
"These epigenetic regulators are known to affect memory, behaviour and learning," said Dr. Picketts. "Without Snf2h, not enough cerebellar neurons are produced, and the ones that are produced do not respond and adapt as well to external signals. They also show a progressively disorganized gene expression profile that results in cerebellar ataxia and the premature death of the animal."
There are no studies showing a direct link between Snf2h mutations and diseases with cerebellar ataxia, but Dr. Picketts added that it “is certainly possible and an interesting avenue to explore.”
In 2012, Developmental Cell published a paper by Dr. Picketts’ team showing that mice lacking the sister gene Snf2l were completely normal, but had larger brains, more cells in all areas of the brain and more actively dividing brain stem cells. The balance between Snf2l and Snf2h gene activity is necessary for controlling brain size and for establishing the proper gene expression profiles that underlie the function of neurons in different regions, including the cerebellum.
Neurologists at LMU have studied the role of the vestibular system, which controls balance, in optimizing how we direct our gaze. The results could lead to more effective rehabilitation of patients with vestibular or cerebellar dysfunction.
When we shift the direction of our gaze, head and eye movements are normally highly coordinated with each other. Indeed, from the many possible combinations of speed and duration for such movements, the brain chooses the one that minimizes the error in reaching the intended line of sight. Dr. Nadine Lehnen, who heads a research group based at LMU’s Center for Vertigo and Balance Disorders, in collaboration with her colleague Dr. Murat Saglam and Professor Stefan Glasauer of the Center for Sensorimotor Diseases at LMU, have now published a paper in the latest issue of the journal of Brain which investigates the significance of the vestibular system for this optimization of motor coordination. The vestibular system in the brain is mainly responsible for the maintenance of balance and posture. The new work focused on subjects suffering from bilateral defects in the vestibular system (a complete vestibulopathy) or lesions in the cerebellum, which is functionally linked to it.
The authors of the new study had previously developed a mathematical model that enabled them to predict the horizontal movements of the head and eyes in response to the presentation of an off-center stimulus. “When subjected to repeated trials, healthy subjects are able to select the combination of eye and head movements that minimizes gaze shift variability,” says Glasauer. They unconsciously choose the set of movements associated with the least error in the endpoint. Moreover, they can do this even when wearing a helmet with weights attached, which alters the moment of inertia of the head.
Learning to find the endpoint
However, patients who show defects in the vestibular system or the cerebellum have greater difficulty in controlling the direction of gaze in response to changes in their environment. “It turns out that information relayed from the balance organs to the vestibular system is essential for the optimization of gaze shifts,” says Nadine Lehnen. Patients with complete bilateral vestibular loss are therefore unable to perform such shifts in the most efficient way. “In striking contrast, patients with cerebellar damage can, to a certain extent, learn to optimize certain parameters of head and eye movements, by adjusting the velocity of head movement, for instance,” says Glasauer.
"These results provide the first evidence that the vestibular system is critical for optimizing voluntary movements“, says Dr. Kathleen E. Cullen from McGill University in Montreal in a scientific commentary to the study appearing in the print issue of Brain. The new findings are of relevance for the rehabilitation of patients who have suffered damage to the cerebellum and patients with incomplete vestibulopathies. “We assume that gaze shift control in these patients can be enhanced by a rehabilitation training based on active head movements,” says Nadine Lehnen. Head movements provide the vestibular feedback which generates the sensorimotor error messages that underlie the ability to learn how to optimize the coordination of eye and head movements. Instead of trying to hold their heads steady, these patients should be encouraged to actively move their heads, when they shift their gaze.
The question if patients with partial vestibulopathy can optimize gaze shift behavior by engaging in active head movements is now under investigation. This work forms part of a rehabilitation study which is being carried out at the Center for Vertigo and Balance Disorders at Munich University Hospitals, and is financed by the Federal Ministry for Education and Research.