Neural circuits operate to drive behaviour and can cause debilitating brain disorders when malfunctioning. However, how circuit activity is causing learning and action and which modifications underlie the development of a disease is mostly unknown. The cerebellum is an ideal structure to tackle this issue because of its well-characterised anatomy, established motor learning and control theories, and relevance to pervasive brain disorders like autism. However, our cellular and circuit-level understanding of the cerebellar roles in learning and modulating behaviour and in modifying disease is still not satisfactory, therefore the therapeutic potential of cerebellar intervention is underestimated.
In this proposal, I will address this potential by combining multi-colour two-photon imaging and optogenetic interrogation in the cerebellar cortex of wild type and disease model mice performing a multi-sensory association task.
My first goal is to characterise the circuit operation of the cerebellum at unprecedented resolution. I will record two identified neuronal inputs simultaneously using independent expression of green and red fluorescent probes in neurons in the cerebellar cortex to investigate how multi-modal sensory inputs are associated during motor adaptation. The second goal is to define detailed cerebellar circuit deficits by using above methods in autism model mice. Finally, I will establish the causal roles of these neuronal inputs for this adaptive behaviour. I will perturb these motor control- and learning-related neuronal inputs and outputs using optogenetics to probe their unique contribution. I will apply similar optogenetic manipulations to restore the function of the dysregulated cerebellar circuit in autism model mice. Ultimately, I will build a bridge between this experimental technique and a human-applicable method.
Together, this project will provide substantial insights into the implementation and refinement of clinical cerebellar manipulation.
Call for proposal
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