Cerebellar Microcircuits: Organization & Development

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The Unipolar Brush Cells (UBCs) are interneurons situated in the cerebellar granular layer and in granule cell containing regions of the cochlear nuclear complex. In the cerebellar cortex, UBCs and granule cells share mossy fiber inputs and represent the only two excitatory glutamatergic neuron classes. In rodents, UBCs have a more restricted distribution than in other mammals and abound in vestibulo-cerebellar lobules, with minor contingents in other lobules of the midline vermis. Across mammalian species, UBCs are preferentially associated with sensory input systems, while they appear to eschew regions targeted primarily by the cortico-ponto-cerebellar pathway. The UBC has typically only one dendrite that terminates with a brush of dendrioles; these establish a giant excitatory synapse with the rosette-like terminal of a mossy fiber; UBC axons ramify among granule cells and form a strikingly unique, cortex-intrinsic system of mossy fiber-like branches. The UBC, with its one-to-one giant synapse, is thought to amplify the input of an individual fiber and synchronize the activity of hundreds of target granule cells, thus influencing the firing pattern of subsets of overlying Purkinje cells. While in cerebellum UBCs are highly enriched in the caudal vermal and lateral lobules densely innervated by primary and secondary vestibular fibers, in the cochlear nuclear complex their density is highest in the polysensory innervated dorsal nucleus. Consequently, the notion has been put forward that these unique neurons are important for regulating head position in space, influencing posture and eye movements and improving auditory performance. Previous evidence indicates the UBC population is chemically heterogeneous and consists of two main chemotypes, a subset expressing the calcium binding protein calretinin, and a calretinin-negative subset expressing the metabotropic glutamate receptor mGluR1a. In this competitive renewal, the P.I. and his collaborators propose to test individual facets of the hypotheses that the properties of UBCs subclasses are related to specific types of inputs, that additional subclass specific chemotypes exist, and that input qualities transmitted by the UBC axon affect the cerebellar network. Specific aims will analyze possible sublineage specific inputs of UBCs, investigate their developmental plasticity and electrophysiologic properties, search for novel UBC chemotypes and study the network impact of UBC excitation. The proposed research is based on multidisciplinary approaches and will be primarily centered on mice to take advantage of the availability of strains of mutant animals with genetically transmitted neurological defects as well as of bacterial artificial chromosome (BAC)-transgenic mice expressing enhanced green fluorescent protein (eGFP) under the control of a specific promoter.