Early development of the cerebellar circuits

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The overall goal of my research program is to understand the mechanism driving early cerebellar development and circuit formation. The cerebellum is a part of the brain that is important for coordinating movements, emotion and cognition. Two types of neurons are central in regulating cerebellar function: cerebellar nuclei (CN) neurons and Purkinje cells (Pcs). The CN neurons and Pcs are the only neuronal populations that exist during early cerebellar development. Although the CN are the main output neurons of the cerebellum, little is known about their formation and their connectivity in early neural circuit development. We have discovered that a subset of CN neurons that express SNCA/Otx2/P75ntr (hereafter called “A-cells”) originates from the mesencephalon and migrates into the developing cerebellum. We have also provided novel information that the trigeminal nerve projects pioneer axons to the cerebellar primordium, targets A-cells. These data raise the possibility that early cerebellar circuit development depends on the trigeminal nerve, not the vestibular nerve as traditionally thought. My research will investigate how early cerebellar circuits regulate cerebellar morphogenesis and provide a migratory substrate for CN neurons. To achieve this goal I will use a combination of in vitro and in vivo models including mouse genetics, embryonic and primary cerebellar culture, whole mount and section immunohistochemistry, in situ hybridization (RNAscope), Western blotting, neuronal tract tracing, and a 3D micro-engineered model of neuronal migration. Important questions to be answered include: Do A-cells originate from mesencephalic neural crest? Do rhombic lip-derived CN neurons use A-cells/pioneer axons for migration? What is the fate of A-cells in the developing cerebellum? The proposed research will enhance our understanding of how early pioneer axons and their target neurons play intrinsic organizer roles in the developing cerebellum. I will investigate if A-cells are temporarily present and with pioneer axons from the trigeminal nerve test if they establish cerebellar circuit. The mechanism I propose deviates from the traditional model. I will also investigate if these new A-cells/pioneer axon combination provide a migratory substrate for the rhombic lip-derived cells to their destination. Elucidating the role of this intrinsic organizer will answer key questions about the basic biology of early cerebellar morphogenesis and development. The proposed research will be used as a vehicle to train HQP in the broad areas of developmental neurobilogy and for research scientists in the field of neuroscience.