Graduation Year

2015

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Medical Sciences

Major Professor

Lynn Wecker, Ph.D.

Committee Member

Rex Philpot, Ph.D.

Committee Member

Seok Hun Kim, P.T., Ph.D.

Committee Member

Paula Bickford, Ph.D.

Committee Member

Craig Doupnik, Ph.D.

Committee Member

Theresa Zesiewicz, M.D.

Keywords

Cumulative Gait Index, gait analysis, Neuroscience, Pharmacology, Principal Component Analysis, treadmill

Abstract

Numerous studies suggest that modulation of the cholinergic system through the use of nicotinic agonists can improve motor function in humans or animals with motor disorders. Specifically, although there are no approved therapeutics for patients with ataxia, the nicotinic receptor agonist varenicline has demonstrated efficacy to improve coordination and gait in several groups of patients with different subtypes of ataxia. Importantly, the mechanism underlying the varenicline’s mechanism of action to improve motor function remains to be elucidated. Thus, the purpose of these experiments was to first quantify gait impairments in rats with olivocerebellar ataxia utilizing an objective treadmill-based system to investigate temporospatial aspects of animals’ gait. These results were used to calculate an index that characterizes deviations from ‘normal’ gait, as similarly employed in clinical studies. The translational validity of this method of gait assessment was investigated by comparing gait impairments between these animals and those reported for humans with ataxia. It was next investigated whether varenicline could attenuate any gait impairments and thus improve motor functioning in these animals, as suggested by clinical findings. Finally, varenicline’s mechanism of action was investigated by attempting to block its effects by pretreating animals with the nicotinic antagonist mecamylamine. Thus, these studies demonstrate the involvement of nicotinic acetylcholine receptors in the mechanism of varenicline’s effects to improve motor functioning. Moreover, these results provide translational methods by which the efficacy of other, more selective nicotinic agonists to improve motor functioning can be tested preclinically prior to their use in humans with ataxia.

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Neurosciences Commons

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