Cerebellar Microcircuits: Organization and Development

Northwestern University At Chicago, Evanston IL

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Abstract

DESCRIPTION (provided by applicant): This competitive renewal application proposes a series of studies intended to further clarify the typology of the cerebellar unipolar brush cell (UBC), a type of granular layer interneuron that has been promoted by the applicant's laboratory over the last several years. These studies are predicated upon the recent discovery of two subsets of these neurons, one of which is immunoreactive for the calcium binding protein calretinin and the other for the metabotropic glutamate receptor mGluR1 alpha, and upon a new bromodeoxyuridine study, which together with previous investigations using [3H]-thymidine labeling indicates that the two UBCs originate from the proliferative matrix of the ventricular zone within different, but overlapping, time windows. A goal of the proposed research is to test the alternative hypotheses that: a) categories of mossy fibers differentially regulate the chemical phenotypes of UBCs as they establish synaptic connections during development, and b) UBCs "autonomously" expressing different phenotypes match with different types of mossy fibers as they reach the cerebellar cortex. Another goal is to identify other chemical phenotypes of UBCs and their relation to the cells' functional properties. It is hypothesized that the two main subsets of UBCs express different cohorts of genes resulting in diversity of spontaneous activity and responses to synaptic activation, although they may share other genes presiding over fundamental aspects of morphological differentiation. The proposed studies will generate insight into the neural mechanisms of the posterior vermis, which is now thought to hold a representation of head orientation in space. The research will be conducted in vivo and in vitro, and primarily in mice and rats, using a combination of morphological, molecular, and electrophysiological approaches.