The neural basis of motor control and learning in the vestibulocerebellar system

This dissertation uses the vestibulocerebellar system to unravel the neural basis of accurate behavioral responses, adaptable motor learning and even non-motor functionalities. To this end, I have revealed cellular and synaptic mechanisms that underlie appropriate neuronal coding and sensorimotor integration and how these errors in this coding result in motor (learning) deficits and disease. In Chapter 1.2, we reviewed the anatomical and physiological characteristics of the components of the VOR circuit, and proposed that the two types of VOR adaptation are mediated via different pathways and encoded at different loci. This concept provides a novel insight in where and how specific form of motor learning helps us deal with the outside world. In Chapter 2, we addressed a sophisticated approach of targeted recording electrophysiological activity in vivo in the cerebellum in awake animals. By driving the expression of a fluorescent marker with the promotor of one of the differentiating genes, the presence of a fluorescence signal could be used to recognize and approach Purkinje cells, while specific features of the signal can be used as a marker to identify the two subpopulations. In Chapter 3, to decipher the relevance of zebrin-identified heterogeneity in Purkinje cells, we tested the function of TRPC3 by using mouse genetics and electrophysiology in vitro and in vivo. We found that TRPC3 predominantly had an impact on the firing activity of zebrin-negative Purkinje cells. More importantly, it could selectively affect the eyeblink conditioning which is zebrin-negative associated. These findings suggest that TRPC3 contributes to the cellular heterogeneity in that it introduces distinct physiological properties in the sub-population of Purkinje cells, thus conjuring functional heterogeneity in cerebellar sensorimotor integration. In Chapter 4, we clarify the anatomical and histological characteristics of the basal interstitial nucleus neurons. We demonstrate that they are GABAergic and glycinergic and receive a relevant and unique excitatory input from the medio-rostral medullary reticular formation. As a putatively novel inhibitory afferent system, this type of neurons may play an essential role in the proper conversion of mossy fiber activity into Purkinje cell firing in the flocculus. In Chapter 5, we focus on the relationship between Purkinje cell activity and behavior of the mouse. Chapter 5.1 reveals that the magnitude of the change in Purkinje cells simple spike activity correlates with learning ability, both in conditions of enhanced and reduced learning. Chapter 5.2 shows that directionality has behavioral and neuronal correlates. Specifically, the direction of vestibular input determines the efficiency of eye movement adaptation in mice, with larger changes during contraversive head rotation and, more importantly, that gain-increase paradigms induce increased simple spike activity in ipsilateral cerebellar Purkinje cells. In Chapter 6, we focus on the roles of synaptic proteins in motor learning and cerebellar development. By genetic manipulation of PP2B, Chapter 6.1 evaluates the developmental contribution to the initiation of eye movement baseline reflex and adaptations. Chapter 6.2 identifies the molecular mechanisms by which PP2B controls the integrity of PF-PC synapses and proposed a combined phosphatase and structural role of PP2B in governing synaptic function and learning. Chapter 6.3 shows that Shisa6 is crucial for Purkinje cell AMPA-receptor function, synaptic plasticity, and cerebellar motor learning. In Chapter 7, we extend the research beyond the motor domain. Through in vivo and in vitro electrophysiology on mice lacking the autism-related Shank2 gene, we found impairments in Purkinje cell intrinsic plasticity, LTP induction at the parallel fiber to Purkinje cell synapse, and simple spike regularity in predominantly zebrin-positive Purkinje cells. Purkinje cell-specific Shank2-mutants showed deficits in motor learning and even impaired social behavior, highlighting the importance of cerebellar pathology in the generation of autism spectrum disorder.

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