Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - COSI (Cerebellar modules and the Ontogeny of Sensorimotor Integration)

Teaser

The perfect execution of a voluntary movement requires the appropriate integration of the current position of your body, information from your environment and the desired outcome. To assure that this motor output becomes and remains appropriate, the brain needs to learn from...

Summary

The perfect execution of a voluntary movement requires the appropriate integration of the current position of your body, information from your environment and the desired outcome. To assure that this motor output becomes and remains appropriate, the brain needs to learn from the result of previous outputs. The little brain, or cerebellum, plays a central role in sensorimotor integration, yet -despite decades of studies- there is no generally excepted theory for how the cerebellum functions.

When the function of the cerebellum is disrupted, for instance due to tumor or stroke, patients have enormous difficulties in speech, walking, maintaining balance, making directed movement, etc. These problem also occur as the result of mutations in certain genes, leading to e.g. spino-cerebellar ataxias (SCAs) and more recently the cerebellum has also been linked to neurodevelopmental disorders, for instance autism spectrum disorder (ASD). In order to provide to basis for understanding how these disorder result in their specific, sometimes very different problems, we study the functioning of the cerebellum.

We recently demonstrated that there are differences in the level of activity between two subgroups of cerebellar neurons. Our goal is to determine how the cerebellum functions and dysfunctions through a deeper analysis of the differences between cerebellar neurons, with a particular focus on the development of the brain. Our hypothesis is that these differences will explain existing controversies, and unify contradicting results into one central theory on cerebellar function.

To this end, we are working on three key objectives. First, we will look at the development of the connections and information flow towards the cerebellum, and determine if this differs between the two subgroups (key objective A). Next, we will compare the two subgroups in more detail, looking at the gene they express and how these determine their level of activity (key objective B). Finally, we will determine how the differences in connections and gene expression affect how the two subgroups control behavior (key objective C). This will be evaluated with more standard task testing motor coordination and learning, but also by testing more social and cognitive functions, as these functions in recent years have also been linked to the cerebellum.

By combining the information from these three key objectives, we aim to determine how the two subgroups develop and contribute to the different functions that the cerebellum is involved in. The ultimate goals is to produce a unifying theory for cerebellar functioning based on the development of the two subgroups. This knowledge is fundamental for the diagnosis and treatment of cerebellum-related neurodegenerative disorders, including SCAs, but also to understand the contribution of the cerebellum to the neurodevelopmental disorder, such as ASD.

Work performed

With respect to the three key objectives stated above the following results have been obtained:
1. We have and are still examining the input to the cerebellar cortex and nuclei and determined the temporal and spatial profile of connectivity.
2. We have determined the expression profiles of Purkinje cells in the two different modules and are verifying and further testing interesting candidate genes. We have determined the developmental onset and progress of activity for cerebellar neurons.
3. We have evaluated the contribution of distinct genes with a module-related expression or function to cerebellar neuronal activity and cerebellum-dependent behavior.

Final results

The project aims to achieve its three key objectives using a wide variety of techniques, many of which are novel, innovative and often still being developed. As this is a five year project, we will incorporate new developments and modifications of these techniques, where and when ever required. As an example of state of the art approaches, we are currently employing rabies-based viral tracing techniques for cerebellar anatomy, and combining this with light-sheet microscopy for optimal insight in the connections with and within the cerebellum.
Despite some minor setbacks, we are on track with the key objectives and expect to complete all three of them in the second half of the project period.

Website & more info

More info: http://schonewillelab.org.