Gene expression and behavior in animal models of movement disorders

The overall goal of this thesis was to examine the regulation of gene expression with respect to behavior in animal models of movement disorders. These studies examined the effects of pharmacological treatments producing different behavioral outcomes on gene expression in neurons of the basal ganglia. Further experiments examined the regulation of gene expression following lesions of the nigrostriatal pathway. Quantitative in situ hybridization histochemistry was used to measure the levels of mRNA encoding glutamic acid decarboxylase (GAD), the rate-limiting enzyme in GABA synthesis, in pallidal neurons. In addition, the levels of enkephalin and substance P mRNA were measured in striatopallidal neurons. These molecular markers were used as an indication of long-term changes in neuronal activity which could then be related to the behavioral effects of the treatments. The findings are as follows: (1) Short- and long-term haloperidol treatments, which induced catalepsy and orofacial dyskinesia, respectively, had identical effects on gene expression in the striatum and entopeduncular nucleus, but opposite effects on GAD mRNA levels in the globus pallidus. (2) The muscarinic antagonist scopolamine blocked haloperidol-induced catalepsy and increases in GAD mRNA in the globus pallidus, but not enkephalin or GAD mRNA in the striatum. (3) Treatments which increased striatal enkephalin mRNA resulted in down-regulation of $\mu$ opioid receptor mRNA in the globus pallidus. (4) Lesions of the subthalamic nucleus blocked nigrostriatal lesion-induced increases in GAD mRNA in the globus pallidus. (5) Nigrostriatal lesions induced bilateral increases in GAD mRNA in the reticular thalamic nucleus. The results reveal that changes in gene expression in the globus pallidus are better correlated with the behavioral outcome of pharmacological treatments than in the striatum. Furthermore, these findings suggest that polysynaptic pathways regulated by the subthalamic nucleus are involved in changes elicited by nigrostriatal dopamine depletion. Taken together, the results suggest that structures further downstream from the striatum, especially the globus pallidus and subthalamic nucleus, are critically involved in the generation of movement disorders. These results challenge the existing views of the basal ganglia circuitry in relation to movement disorders