Effective coordination requires that the motor system predict proper movements. To make these predictions, the cerebellum integrates sensorimotor information and motor errors and, through a process of error-driven learning, build up feed-forward models of movement. Decades of cerebellar research have clarified a highly stereotyped circuit, identified roles for particular circuit elements, and suggested cellular mechanisms that might account for associative learning. However, fundamental questions remain unanswered. How do particular activity patterns in Purkinje neurons influence movement? What are the functional ramifications of the neurochemically-defined divisions in the motor map? Where within the cerebellar circuit do changes occur during cerebellum-dependent forms of motor learning? And finally, how do circuit changes alter cerebellum-dependent behavior? The following specific aims will be addressed in the project.
In Specific Aim 1, we will interrogate the organization of the motor map in the simplex lobe of the mouse cerebellum using optogenetic stimuli. Preliminary data show that Purkinje neuron inhibition triggers rapid, highly stereotyped movements. Using high speed videography and motion tracking we will measure movement trajectories and speeds in response to activation or inhibition in various cerebellar neurons with patterned illumination. We will also make electrophysiological recordings from cerebellar neurons in awake mice to examine the effects of manipulating PN excitability on the circuit.
In Specific Aim 2 we will test whether associative motor learning can be driven by pairing sensory stimuli with optogenetically-elicited reductions or increases in PN firing. In vivo electrophysiology will be used to determine how error signals contribute to this learning.
In Specific Aim 3 we will test the hypothesis that manipulation of PN firing alters a prediction signa giving rise to feed-forward error signals. These interrelated aims make use of a novel behavioral preparation applying sophisticated optical patterning, optogenetic, electrophysiological, and behavioral methods to awake mice in order to answer fundamental questions about cerebellar physiology. Together, the proposed experiments are designed to resolve issues that have been debated for decades within the cerebellar field. We expect that our results will yield a much improved understanding of basic cerebellar physiology and resolve some long-standing mysteries regarding cerebellum-dependent learning. In addition, these findings are likely to provide conceptual insights into cerebellar dysfunction caused by inherited and sporadic forms of ataxia.
The cerebellum is critically important for motor coordination, balance, and eye movements and its function is impaired by tumors, strokes, various genetic diseases, and toxins. We propose to combine cutting edge optical, neurophysiological, and behavioral approaches to explore cerebellar circuits in order to learn how they control motor behavior and participate in the types of motor learning that are required for proper coordination. Our findings will provide fundamental insights into the basic function and pathology of cerebellum allowing us to better understand mechanisms of cerebellar learning and disease.
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