ABNORMAL ONTOGENY AND CORTICAL FUNCTION IN A MOUSE MODEL

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Early insult or injury to the brain is involved in many debilitating developmental disorders including severe learning disabilities and mental retardation. A common feature of many of these disorders is abnormal morphogenesis of the cerebral cortex. Clinical observers have long presumed that abnormal cortical cytomorphology is responsible for the behavioral changes and cognitive deficits in developmental brain disorders. However, few attempts have been made to experimentally test this hypothesis. Here we utilizes a mouse model to address the hypothesis that abnormal cortical cytomorphology can be correlated with impaired cognitive behavior. In mice, cholinergic projections from the nucleus basalis area [nBM] invade neocortex at birth and are temporally and spatially well suited to play a modulatory role in morphogenesis. When lesions are performed in the nBM area at birth, a transient depletion of cortical cholinergic markers ensues which is accompanied by retarded neuronal maturation. Cortical cytoarchitecture and connectivity remain permanently altered into adulthood despite cholinergic re-innervation of neocortex. Recent behavioral experiments with mice that received bilateral nBM lesions at birth show deficits in memory and learning in these animals by adulthood. Preliminary results suggest that these behavioral deficits are correlated with specific morphological and neurochemical features in cerebral cortex. This project is designed to l) examine and quantify the key morphological and neurochemical features in the cortex of neonatally nBM lesioned mice after they have concluded behavioral testing in early adulthood; these data will than be examined for correlations with behavioral testing scores; 2) to investigate whether abnormal cortical morphogenesis following neonatal lesions to the nBM area in mouse is the result of selective depletion of cholinergic afferent fibers and/or neurotransmission and 3) to train minority students in basic laboratory and research skills through their participation in a biomedically relevant research project