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dc.contributor.authorTewari, Ambika
dc.identifier.citationSource: Dissertation Abstracts International, Volume: 79-07(E), Section: B.;Advisors: Kamran Khodakhah.
dc.description.abstractThe cerebellum has an established role in movement control and maintenance of balance and posture. This prevailing view of the cerebellum comes from several landmark studies showing that damage to the cerebellum results in uncoordinated activity known as ataxia. To date, almost one hundred different types of ataxias are recognized. To determine the pathophysiological mechanisms underlying various ataxias of known etiology, several labs have employed genetic manipulations in rodents to produce models recapitulating the phenotype observed in human patients. However, there are some disorders in which producing animal models that faithfully recapitulate the human phenotype has proven to be a challenge. In such cases, we hypothesized that the absence of a neurological phenotype is due to compensation that can occur when a gene is knocked out early in development.;We employed an acute knockdown approach in the cerebellum of adult mice to bypass this compensation. Using this technique, we successfully recapitulated dystonic postures seen in human patients in mouse models of Rapid-onset Dystonia Parkinsonism (RDP) and in DYT1 establishing a causal role for the cerebellum in certain types of dystonia. However, acute knockdown of ATM in the adult cerebellum was not sufficient to model the neurological features of Ataxia-telangiectasia (A-T) indicating that compensation is not sufficient to explain the challenge in modeling the neurological phenotype of A-T in rodents. To elucidate the pathophysiological mechanisms underlying ataxia and cerebellar-induced dystonia, we recorded from the deep cerebellar nuclei in established genetic mouse models and acute knockdown models of ataxia and dystonia. We found that cerebellar output is affected in these various models and that the irregularity of this output could be used to predict the severity of the motor phenotype.
dc.publisherProQuest Dissertations & Theses
dc.titleAbnormal cerebellar output can predict the severity of cerebellar-induced motor disorders

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