Doctoral Dissertations

Karen C. Goss

Date of Award

5-1996

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Comparative and Experimental Medicine

Major Professor

Carmen Lozzio

Committee Members

Karla Matteson, Nick Potter, Susan Orosz

Abstract

The efficacy of certain treatment techniques used by physical and occupational therapists is controversial due to the subjective manner in which data is collected when studying human subjects. Motor learning in human subjects is difficult to measure directly and is usually inferred based on changes in behavior. Research data in the area of motor learning in humans is insufficient with regard to plasticity, adaptation and synaptogenesis in the central nervous system. The obvious limitations when working with human subjects makes it difficult to establish the basis for and relevance of certain treatment strategies for improvement of motor learning. Due to the limitations and constraints when working with humans, a mutant mouse was chosen to investigate central nervous system changes.

For over three decades animal models have been used as tools for studying the development and function of the human nervous system. Mutant animal models that have nervous system disorders comparable to those found in humans have been used to study nervous system diseases and their progression. Lurcher mutant mice have ataxic gaits and poor balance and coordination skills due to a genetic disorder which results in progressive Purkinje cell loss in the cerebellum. Purkinje cell loss produces motor deficits in humans which are similar to those found in the Lurcher. Human loss of cerebellar Purkinje cells can be the result of various problems including inherited disorders or damage to the cerebellum from injury or alcoholism. In this study the Lurcher was used as a testing model to determine whether motor enrichment training leads to improvement in motor learning, motor control, and motor performance as measured with behavioral and histological changes.

Lurcher mutants were exposed to a structured regime of novel motor activities daily for a 30 day period to determine if motor behavior is affected and if structural changes occur in the cerebellum after actively participating in motor enrichment sessions. Behavioral performance and histological studies of the cerebellum and associated motor cortex of Lurcher and normal litter mates who were exposed to motor enriched- environments were objectively (statistically) compared to Lurcher mutants and normal non-trained mice that did not receive any type of motor stimulation outside of normal cage activity.

Behaviorally, the Lurchers and normal mice, exposed to the motor enriched environment (trained group) performed significantly better than did their non-trained litter mates (non-trained group) on motor evaluations in regard to speed, time to complete the task, falls, and compensation ability. Histologically, at the light level, structural differences were found in increased depth of the molecular layer of the cerebellum of mice exposed to the motor learning environment. The area of the Purkinje cell dendritic fields of normal mice exposed to the motor enrichment activities were significantly larger when compared to non-trained normal mice that were not exposed to motor learning. Purkinje cell dendritic areas could not be evaluated in either trained or non-trained Lurcher mutants, due to the massive loss of Purkinje cells in both groups. There was no difference between the Lurcher groups (trained or non-trained) in number of surviving Purkinje cells.

Golgi analysis in the motor association cortex revealed an increase in complexity of dendritic branching of pyramidal cells of the trained normal mice as well as both groups of Lurcher mice (trained and non-trained). The normal mice exposed to motor learning had the most complex dendritic branching. The Lurcher group exposed to the motor learning environment and the non-trained Lurcher group were approximately equalivant in dendritic branching complexity of pyramidal cells. The normal non-trained mice had the least complex dendritic branching in the pyramidal cells.

Histologically this study shows that motor learning can be achieved in spite of massive Purkinje cell loss and that exposure to novel motor experiences can contribute to more normal organization of the structure of the cerebellum as well as changes in the motor cortex. When results are extrapolated to humans the study provides a solid cellular and behavioral basis for motor-enrichment treatment of patients who have related disorders of the cerebellum.

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