Date of Award

January 2013

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Joshua T. Dudman

Second Advisor

Gordon Buchanan

Subject Area(s)

Neurosciences

Abstract

Implicit and explicit motivation in a murine model of Parkinson's disease

Babita Panigrahi (1,2), Alla Y. Karpova (1), and Joshua T. Dudman (1) (Sponsored by Gordon Buchanan, 2)

1, Howard Hughes Medical Institute, Janelia Farm Research

Campus, Ashburn, Virginia, USA

2, Department of Neurology, Yale University School of Medicine, New Haven, CT

Parkinson's disease (PD) is the second most common neurodegenerative disorder, affecting over 6 million worldwide. Its pathogenesis involves degeneration of midbrain neurons that synthesize and release dopamine (DA). DA transmission in the basal ganglia has been implicated in multiple aspects of the control of motivated, voluntary behaviors. Studies of patients with PD have revealed deficits in the adaptation of movement vigor to task demands (implicit motivation). By contrast, studies in rodent models of PD have revealed deficits in the willingness to perform movements or actions required for reward (explicit motivation). The distinction between these functionally unique forms of motivation is even more difficult in rodent models, where disease pathophysiology is often first explored.

A comprehensive understanding of the progression and pathology of PD requires animal models that account for all behavioral and neuronal deficits observed in humans, including the motor, cognitive, and physiological aspects of disease. Along these lines, we used a combination of behavioral assays in a mouse model of progressive PD to assess the gross motor deficits of PD in an open field task, the fine motor deficits of PD in a reaching task, and the electrophysiological basis of disease with extracellular recordings in the striatum during these behaviors. Through these measures, we asked whether (1) what appears to be explicit motivation in rodents could reflect a deficit in implicit motivation and (2) whether deficits in implicit motivation emerge concomitantly with more traditional measures of motor impairment. Our results suggest that deficits in implicit motivation can explain an apparent deficit in explicit motivation in mice lacking midbrain dopamine neurons. This is the first longitudinal study of two distinct motivational states in a progressive rodent model of PD, opening the door to future insights in human pathology.

Comments

This thesis is restricted to Yale network users only. This thesis is permanently embargoed from public release.

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