The striatum (caudate-putamen), a brain area involved in the control of movement and cognitive processes receives a massive excitatory input from the cerebral cortex. The research described in this application is concerned with the hypothesis that cortical lesions result in prolonged molecular changes in neurons of the striatum and its target areas, the pallidum and the substantia nigra. This hypothesis is derived from results showing that levels of neuropeptides are altered in striatal efferent neurons after cortical lesions, both in humans and in experimental animals. We have shown that, in the rat, these changes are related to modifications of the level of messenger RNAs (mRNAs) encoding these neurotransmitters, suggesting that plasticity of striatal gene expression is a consequence of cortical lesions. This may play a critical role in the long-term consequences of cortical lesions on subcortical structures, and have implications for the overall pattern of motor and cognitive disturbances occurring after cortical injury. We will further characterize the molecular effects of cortical lesions on striatal neurons, their topography, time course, and consequences on pallidal and nigral neurons. Specifically, we will measure the level of mRNAs encoding neurotransmitters and neurotransmitter-related enzymes by in situ hybridization histochemistry and quantitative autoradiography in topographically identified neurons of the striatum, pallidum, and substantia nigra of adult rats after lesions of the cerebral cortex. Results will be compared with changes in the level of the peptides or proteins encoded by these mRNAs and in the characteristics of the corresponding neurotransmitter receptors. The potential for recovery of striatal neurotransmitter systems after cortical lesions will be determined by analyzing results obtained after different survival time. Because previous results suggest that restricted cortical lesions result in an activation of striatal neurons, we will investigate the potential role of remaining striatal inputs and excess glutamate release in the generation of these effects. This will be done by repeating the experiments after bilateral cortical lesions, combined nigral and cortical lesions, and administration of glutamate antagonists. The results of these experiments will provide new insights into the molecular effects of cortical lesions on striatal neurotransmitter systems and, more generally, the plasticity of gene expression in the brain. They will help to identify new directions in the treatment of striatal dysfunction resulting from cortical alterations such as those occurring in stroke and other brain injuries.
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