The goal of this research proposal is to understand how complex neuronal circuits form in the developing brain. The precise mechanisms that underlie this developmental program, and how it can go awry in certain disorders, are not well-understood. It seems clear that a certain amount of reorganization occurs as neuronal circuits progress from nascent to highly specific and mature. The process of synaptic reorganization has been studied extensively in relatively simple circuits of the peripheral nervous system, but is poorly understood for more complex circuits in the central nervous system. New tools recently developed in the laboratory provide clear identification of many individual circuit components and allow one to begin to ask detailed questions about complex circuitry in the central nervous system. ? This research proposal focuses on the cerebellum, a region of the brain crucial for motor learning and coordination. The cerebellum provides an ideal model for circuitry analysis due to the presence of several different circuits at progressive stages of complexity. In newly developed Brainbow transgenic multicolor fluorescent mice, high-resolution imaging and three-dimensional digital reconstruction techniques will be used to construct detailed circuitry maps at various stages throughout development, including the adult. Analysis will involve the quantification of the convergent and divergent properties within the mossy fiber-to-granule cell circuit. These investigations will help determine what mechanisms underlie the development of this cerebellar circuit, and precisely when circuit maturation is complete. Also planned is an investigation of a mouse model of the human disease developmental cerebellar ataxia, a devastating condition in which children progressively lose motor control and coordination. A systematic comparison of the development of circuitry within the ataxic and normal brain will be done in order to investigate how the process of circuit development may go awry in the disease state. This research will help to provide a better understanding of how neuronal circuits form in the mammalian brain. ? The goal of this work is to understand how complex circuits form in the developing brain. There are a great deal of human disorders that arise when development goes awry (e.g., in childhood cerebellar ataxia); a better understanding of brain circuitry can lead to appropriate treatments for disease. This research will help to delineate the developmental mechanisms that lead to normal and abnormal connectivity within the brain. ? ?
