Cerebello-Basal Ganglia Interactions

DESCRIPTION (provided by applicant): Dystonias comprise a diverse group of movement disorders that are often characterized by prolonged contraction of muscles. The most common dystonias are idiopathic. Nonetheless, several genes have been implicated in dystonia. The most prevalent cause of nonidiopathic dystonia is damage to the basal ganglia. Recently, however, evidence has amassed in support of the notion that in some cases cerebellar dysfunction may also contribute to (or even instigate) dystonia. Our working hypothesis is that aberrant cerebellar activity dynamically alters the physiologic function of the basal ganglia thus resulting in dystonia. An anatomical substrate for a direct disynaptic connection from the cerebellum to the basal ganglia via the centrolateral nucleus of the thalamus has been described both in rodents and primates. In this proposal we wish to test the hypothesis that in healthy individuals this disynaptic connection allows for rapid communication between the cerebellum and the basal ganglia. Further, we will test the hypothesis that this disynaptic pathway provides the primary conduit through which aberrant cerebellar activity forces erratic burst firing in the basal ganglia neurons thereby causing dystonia. Successful completion of this proposal will advance our understanding of the nature of interactions between the cerebellum and basal ganglia for motor coordination. Additionally, it may also provide a detailed mechanistic insight as to how aberrant cerebellar activity instigates dystonia. PUBLIC HEALTH RELEVANCE: Dystonias are the third most common movement disorder and are characterized by prolonged contraction of muscles. The most prevalent cause of dystonia is damage to the basal ganglia. Recent evidence, however, suggests that in some cases cerebellar dysfunction may also contribute to (or even instigate) dystonia. Here we will test the working hypothesis that, to cause dystonia, aberrant cerebellar activity dynamically alters the physiologic function of the basal ganglia neurons via a disynaptic pathway routed through the thalamus. Successful completion of this proposal will advance our understanding of the nature of interactions between the cerebellum and basal ganglia for motor coordination and may provide a detailed mechanistic insight as to how aberrant cerebellar activity instigates dystonia. This information would be invaluable for designing rational therapeutic interventions for the treatment of cerebellar-induced dystonia.