Dystonia is a movement disorder characterized by simultaneous and prolonged co-contraction of agonist and antagonist muscles, causing patients to adopt painful twisting postures. The dystonias are heterogeneous in their etiologies and few of these are well understood. Dystonia can be generated by lesions in the basal ganglia and many genetic and secondary dystonias are associated with altered basal ganglia activity suggesting the basal ganglia plays a role in this disorder. Certain dystonias present after cerebellar insult and others are relieved by lesion of the cerebellar output nuclei suggesting that the cerebellum may be involved in certain cases of dystonia. In rodents, perfusing a selective Na/K ATPase (sodium pump) blocker ouabain into the cerebellum results in dystonia. Studies in our lab suggest this mechanism of dystonia generation may be important in a particular genetic dystonia, DYT12 or Rapid-Onset Dystonia- Parkinsonism. We suggest that in this model, aberrant activity in the cerebellum is transferred to the basal ganglia and mediates the observed dystonia. A disynaptic connection between the cerebellar output nuclei and basal ganglia input nuclei has been identified in rodents and primates. The physiologic role of this pathway is currently unknown. In this proposal we evaluate the role of this disynaptic pathway and specifically one of its intermediate nuclei, the centrolateral nucleus of the thalamus (CL), in dystonia induced by ouabain administration to the cerebellum. Preliminary studies suggest that lesioning of CL prior to ouabain perfusion prevents the generation of dystonia. In this proposal we will test if this prevention is long term and if it is accompanied by other motor abnormalities. We will also explore CL as a potential site of intervention after animals already have dystonia. Finally we will determine how CL neuron firing changes in response to ouabain perfusion onto the cerebellum. This should give us insight into the role of the disynaptic pathway through CL in diseased animals and help up develop new interventions to test on dystonic ouabain perfused mice including pharmacologic treatments and deep brain stimulation. These experiments together will help define one mechanism of dystonia induction and suggest new methods to alleviate dystonia in certain human cases.
Dystonia is a common movement disorder whose etiology is varied and poorly understood. We will test the hypothesis that aberrant communication between the cerebellum and basal ganglia through the thalamus may mediate certain forms of dystonia. We will also determine the relevance of this pathway as a site of intervention by asking if disruption of this pathway can be used to prevent or alleviate dystonia.
|Fremont, Rachel; Tewari, Ambika; Khodakhah, Kamran (2015) Aberrant Purkinje cell activity is the cause of dystonia in a shRNA-based mouse model of Rapid Onset Dystonia-Parkinsonism. Neurobiol Dis 82:200-12|
|Fremont, Rachel; Calderon, D Paola; Maleki, Sara et al. (2014) Abnormal high-frequency burst firing of cerebellar neurons in rapid-onset dystonia-parkinsonism. J Neurosci 34:11723-32|
|Chen, Christopher H; Fremont, Rachel; Arteaga-Bracho, Eduardo E et al. (2014) Short latency cerebellar modulation of the basal ganglia. Nat Neurosci 17:1767-75|