Adult-onset Purkinje cell loss in cerebellar dysfunction

点击翻译按钮获取中文摘要

PROJECT SUMMARY/ABSTRACT Neurodegeneration underlies many major neurological diseases. Cerebellar Purkinje cell degeneration is a hallmark of ataxia, a disorder that entails poor motor coordination. However, a growing consensus argues that conditions traditionally thought of as circuit disorders, such as tremor and dystonia, may also involve cerebellar degeneration. This debate is due in part to technical limitations. Current human imaging techniques lack the single-cell resolution necessary to reveal localized cell loss, and postmortem studies only inform the end-state of disease and suffer from a scarcity of tissue samples, particularly from dystonia patients. Meanwhile, rodent work suggests that Purkinje cell loss has diverse effects on behavior, although these studies often involve the disruption of multiple cell types and prolonged developmental deficits, which make directly attributing behavioral outcomes to Purkinje cell death difficult. To address these challenges, we use a genetic mouse model that initiates Purkinje cell-specific death with temporal precision. Preliminary data suggests that adult-onset Purkinje cell death causes progressive motor dysfunction that transitions through ataxia, tremor, and dystonia. This proposal tests the hypothesis that Purkinje cell loss drives progressive functional changes that uniquely impact motor behavior. Different regions of the cerebellum control distinct behaviors. Therefore, the first aim tests whether adult-onset Purkinje cell loss causes behavioral defects depending on the region affected. A battery of behavioral tests will track how motor dysfunction emerges, and immunohistochemistry and neural tracing will reveal how cerebellar circuit architecture changes with degeneration and motor function deterioration. The second aim tests how progressive Purkinje cell loss impacts the firing activity of the cerebellar nuclei, which receive Purkinje cell input and project to other parts of the motor circuit. In vivo electrophysiological recordings from the cerebellar nuclei of awake mice experiencing degeneration-induced motor defects will be used to determine how Purkinje cell loss dynamically shapes neuronal dysfunction. In addition, this aim will determine whether the beneficial effects of deep brain stimulation to the cerebellar nuclei in motor dysfunction hold true during Purkinje cell loss. The completion of these aims will define the impact of Purkinje cell death in ataxia, tremor, and dystonia and the mechanisms by which a single insult to a circuit can exert diverse consequences on motor function. The fellowship training plan includes designing and performing these experiments, analyzing the data, and writing and presenting the work in a supportive, resource-filled training environment.