1996 - Dalhousie University

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Transcript of 1996 - Dalhousie University

by
Valerie J. Bolivar
Submitted in partial fulfillment of the requirements for the Ph.D degree
at
1996
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ISBN 0-612-16015-7
Canada
Nome Valerie Bolivar Dissertation Abstracts International and Masters Abstracts International are a r r a n g e d b y b r o a d g e n e r a l subject categories. Please select the o n e subject which most n e a r l y describes the content o f y o u r dissertation o r thesis. Enter the corresponding (bur-digit code in t h e spaces provided.
Psychology SUBJECT TERM
Subject Categories
THE HUMANITIES AND SOCIAL SCIENCES COMMUNICATIONS AND THE ARTS Architecture 0729 Art History 0377 Cinema 0900 Danes 0378 Fin* Arts 0357 Information Science 0723 Journalism 0391 Library Science 0399 Mess Communication! 0708 Musk. .. 0413 Speech Communication 0459 Theater 0465
EDUCATION General 0515 Administration 0514 Adult and Continuing 0516 Agricultural 0517 Art 0273 Bilingual anr! Multicultural 0282 Business 0688 Coimiunily College 0275 Curriculum and Instruction 0727 Early Childhood 0518 Elementary 0524 Finance 0277 Guidance and Counseling 0519 Health !. 0680 Higher 0745 History of 0520 Home Economics 0278 Industrial 0521 Language and literature 0279 Mathematics 0280 Music 0522 Philosophy of 0998 Physical.... 0523
p»y<i»fc>gy 0525 Reading 0535 Religious 0527 Science* - 0714 Secondary 0533 Social Sconces 0534 Sociology of 0340 Special 0529 Teacher Training 0530 Technology ... 0710 Tests and Measurements 0288 Vocational 0747
LANGUAGE, LITERATURE AND LINGUISTICS
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literature General 0401 Classical 0294 Comparative 0295 Medieval 0297 Modem 0298 African 0316 American 0591 Asian, 0305 Canadian (English) 0352 Canadian (French) 0355 English 0593 Germanic 0311 Latin American 0312 Middle Eastern 0315 Romance 0313 Slavic arte "ait European 0314
PHILOSOPHY, RELIGION AND THEOLOGY Philosophy 0422 Religion
General 0318 Biblical Studies 0321 Clergy 0319 History of 0320 Philosophy of 0322
Theology. 0469
Business Administration General 0310 Accounting 0272 Barking 0770 Management 0454 Marketing 033ft
Canadian Studies 0385 Economics
General 0501 Agricultural 0503 Commerce-Business 0505 Finance 0508 History 0509 Labor 0510 Theory 0511
Folklore 0358 Geography 0366 Gerontology 0351 History
General 0578
Ancient 0579 Medieval 0581 Modern 0582 Black 0328 African 0331 Asia, Australia and Oceania 0332 Canadian 0334 European.. 03J5 Latin American 0336 Middle Eastern 0333 United Stales 0337
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General 0615 International Law and
Relations 0616 Public Administration 0617
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Genera! , 0626 OiminoJogy and Penology.,. 0627 L^rregxaphV 0938 Ethnic and Racial Studies 0631 Individual and Family
.""vdies 0628 '.vjrslrial and Labor
Kelations 0629 Public and Social Welfare ....0630 Social Structure and
Development 0700 Theory and Methods 0344
Transportation 0709 Urban and Regional Planning ....0999 Women's Studies 0453
THE SCIENCES AND ENGINEERING BIOLOGICAL SCIENCES Agriculture
General 0473 Agronomy. 0285 Animal Culture and
Nutrition 0475 Animal Pathology 0476 Food Science and
Tedinology 0359 Forestry and Wildlife 0478 Plant Culture 0479 Plant Pathology 0480 Plant Physiology 0817 Range Management 0777 Wood Technology 0746
Biology General 0306 Anatomy 0287 Bioslatislics 0308 Botany 0309 Cell... 0379 Ecology 0329 Entomology 0353 Genetics 0369 LLinology 0793 Mierciiology 0410 Molecular" 0307 Neuroscience 0317 Oceanography 0416 Physiology 0433 Rddiolion. 0821 Veterinary Science „ 0778 Zoology 0472
Biophysics General 0786 Medical 0760
EARTH SCIENCES Biogeochemishy 0425 Geochemistry 0996
Geodesy 0370 Geology 0372 Geophysics 0373 Hycfclogy 0388 Mineralogy 0411 Paleobotany 0345 Paleoecology 0426 Paleontology 0418 Paleozoology 0985 Palynoiogy 0427 Physical Geography 0368 Physical Oceanography 0415
HEALTH AND ENVIRONMENTAL SCIENCES Environmental Sciences 0768 Health Sciences
General 0566 Audio logy 0300 Chemotherapy 0992 Dentistry ..Z... 0567 Education 0350 Hospital Management 0769 Human Development 0758 Immunology 0982 Medicine and Surgery 0564 Mental Health 0347 Nursing 0569 Nutrition 0570 Obstetrics and Gynecology ..0380 Occupational Health and
Therapy 0354 Cphmalmology .0381 Pathology ....!.. 0571 Pharmacology 0419 Pharmacy 0572 Physical Therapy 0382 Public Health .„ 0573 Radiology 0574 Recreation 0575
Speech Pathology 0460 Toxicology 0383
Home Economics 0386
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High Energy 0798 Fluid and Plasma 0759 Molecular 0609 Nuclear 0610 Optics 0752 Radiation 0756 Solid Stale 0611
Statistics 0463
Applied Sciences Applied Mechanics 0346 Computer Science .....0984
Engineering General 0537 Aerospace 0538 Agricultural 0539 Automotive 0540 Biomedical 0541 Chemical 0542 Civil 0543 Electronics and Electrical 0544 Heat and Thermodynamics... 0348 Hydraulic 0545 Industrial 0546 Marine 0547 Materials Science 0794 Mechanical 0548 Metallurgy 0743 Mining 0551 N u c l e i 0552 Packaging 0549 Petroleum 0765 Sanitary and Municipal 0554 System Science 0790
Geotechnology 0428 Operations Research 0796 Plastics Technology 0795 Textile Technology 0994
PSYCHOLOGY General 0621 Behavioral 0384 Clinical 0622 Developmental 0620 Experimental 0623 Industrial 0624 Personality 0625 Physiological 0989 Psychobiology 0349 Psychomelrics 0632 Social 0451
dedicated with love to my parents and husband
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Movement Analysis The Ontogeny of Movement Patterns
Terrestrial Locomotion Grooming Swimming
Research Objectives General Developmental Hypotheses Genotype Related Hypotheses
METHOD Subjects Apparatus Behavioral Testing Swimming Style Coding Analysis Measures of Individual Limb Movement
Duration Measurement of Velocity Missed Strokes
Measures of Interlimb Coordination Latency Phase
Measures of Consistency Statistical An" "yses
RESULTS Weight Swimming Style Forelimb Stroke-Cycle Analyses
Duration Right Forelimb Mean Velocity Right Forelimb Maximum Velocity
Hindlimb Stroke-Cycle Analyses Duration Right Hindlimb Mean Velocity
Missed Strokes Forelimbs
Interlimb Coordination Measures
Bilateral Forelimb Pair Latency 98 Bilateral Hindlimb Pair Latency 98 Ipsilateral and Contralateral Limb Pair Latencies 100 Phase 105
Bekoff and Trainer (1979) Method 105 Bilateral Forelimb Pair (Bekoff & Trainer Method) 105 Bilateral Forelimb Pair (Corrected Method) 107 Bilateral Hindlimb Pair (Bekoff & Trainer Method) 109 Bilateral Hindlimb Pair (Corrected Method) 111 Ipsilateral Limb Pair Phase (Bekoff & Trainer Method) 113 Ipsilateral Limb Pair Phase (Corrected Method) 113 Contralateral Limb Pair Phase (Bekoff & Trainer Method) 116
Contralateral Limb Pair Phase (Corrected Method) 118 Summary of Phase Comparisons 120 Consistency 121
Forelimb Durations 121 Hindlimb Durations 122 Bilateral Forelimb Phase 126 Bilateral Hindlimb Phase 126 Ipsilateral Limb Phase 129 Contralateral Limb Phase 129
DISCUSSION 133 Weight Profiles and Their Relation to Basic Movements 133 Swim Styles in nelation to Individual Limb Parameters 135 Interlimb Coordination: Latencies 138 Interlimb Coordination: Phase Relationships 139 Consistency 144 The Importance of Multiple Behavioral Measures 147 Future Research 151 Conclusions 153
REFERENCES 156
8
Mean Weight (± SEM) for control and jimpy Op/Y) mice from 3 to 21 days of age. 67
The progression of swimming styles of jimpy Op/Y) and control mice from 3 to 21 days of age. 68
Mean swim maturity scores (± SEM) for control and jimpy O'p/Y) mice from 3 to 21 days of age. 70
Mean stroke-cycle duration (± SEM) of the forelimbs for control and jimpy Op/Y) mice from 3 to 13 days of age. 73
Mean stroke-cycle duration (± SEM) of the right forelimb for control and jimpy Op/Y) mice from 3 to 13 days of age. 74
Mean stroke-cycle duration (± SEM) of the left forelimb for control and jimpy Op/Y) mice from 3 to 13 days of age. 76
Mean velocity (± SEM) of the right forelimb, during the ten stroke swim session, for control and jimpy (jp/Y) mice from 3 to 13 days of age. 77
Mean maximum velocity (± SEM) of the right forelimb, during the onset of the swim stroke, for control and jimpy Op/Y) mice from 3 to 13 days of age. 79
9 Mean stroke-cycle duration (± SEM) of the hindlimbs for control and jimpy Op/Y) mice from 3 to 21 days of age. 81
10 Mean stroke-cycle duration (± SEM) of the right hindlimb for control and jimpy Op/Y) mice from 3 to 21 days of age. 83
11 Mean stroke-cycle duration (± SEM) of the left hindlimb for control and jimpy Op/Y) mice from 3 to 21 days of age. 84
12 Mean velocity (± SEM) of the right hindlimb, during the ten stroke swim session, for control and jimpy Op/Y) mice from 3 to 21 days of age. 86
13 Mean maximum velocity (± SEM) of the right hindlimb, during the onset of the swim stroke, for control and jimpy Op/Y) mice from 3 to 21 days of age. 88
VII
14 Mean number of strokes missed (± SEM) by the forelimbs, in a ten stroke session, for control and jimpy Qp/Y) mice from 3 to 13 days of age. 89
15 Mean number of strokes missed (± SEM) by the right forelimb, in a ten stroke session, for control and jimpy Op/Y) mice from 3 to 13 days of age. 91
16 Mean number of strokes missed (± SEM) by the left forelimb, in a ten stroke session, for control and jimpy Qp/Y) mice from 3 to 13 days of age. 92
17 Mean number of strokes missed (± SEM) by the hindlimbs, in a ten stroke session, for control and jimpy Op/Y) mice from 3 to 21 days of age. 94
18 Mean number of strokes missed (± SEM) by the right hindlimb, in a ten stroke session, for control and jimpy Qp/Y) mice from 3 to 21 days of age. 96
19 Mean number of strokes missed (± SEM) by the left hindlimb, in a ten stroke session, for control and jimpy Op/Y) mice from 3 to 21 days of age. 97
20 Mean stroke latency (± SEM) of the left forelimb relative to the right forelimb for control and jimpy Op/Y) mice from 3 to 13 days of age. 99
21 Mean stroke latency (± SEM) of the left hindimb relative to the right hindlimb for control and jimpy Op/Y) mice from 3 to 21 days of age. 101
22 Mean stroke latency (± SEM) of the right hindlimb relative to the right forelimb for control and jimpy Op/Y) mice from 3 to 13 days of age. 102
23 Mean stroke latency (± SEM) of the left hindlimb relative to the right forelimb for control and jimpy Op/Y) mice from 3 to 13 days of age. 104
24 Mean phase value (± SEM) of the left forelimb relative to the right forelimb for control and jimpy Qp/Y) mice from 3 to 13 days of age calculated (Bekoff & Trainer Method). 106
25 Mean phase value (± SEM) of the left forelimb relative to the right forelimb for control and jimpy Op/Y) mice from 3 to 13 days of age (Corrected Method). 108
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26 Mean phase value (± SEM) of the left hindlimb relative to the right hindlimb for control and jimpy Qp/Y) mice from 3 to 21 days of age (Bekoff & Trainer Method). 110
27 Mean phase value (± SEM) of the left hindlimb relative to the right hindlimb for control and jimpy Qp/Y) mice from 3 to 21 days of age (Corrected Method). 112
28 Mean phase value (+ SEM) of the right hindlimb relative to the right forelimb for control and jimpy Qp/Y) mice from 3 to 13 days of age (Bekoff & Trainer Method). 114
29 Mean phase value (± SEM) of the right hindlimb relative to the right forelimb for control and jimpy Qp/Y) mice from 3 to 13 days of age (Corrected Method). 115
30 Mean phase value (+ SEM) of the left hindimb relative to the right forelimb for control and jimpy Qp/Y) mice from 3 to 13 days of age (Bekoff & Trainer M ethod). 117
31 Mean phase value (± SEM) of the left hindimb relative to the right forelimb for control and jimpy Qp/Y) mice from 3 to 13 days of age (Corrected Method). 119
32 Mean coefficient of variation (± SEM) of the right forelimb durations for control and jimpy Qp/Y) mice from 3 to 13 days of age. 123
33 Mean coefficient of variation (± SEM) of the left forelimb durations for control and jimpy Qp/Y) mice from 3 to 13 days of age. 124
34 Mean coefficient of variation (± SEM) of the right hindlimb durations for control and jimpy Qp/Y) mice from 3 to 21 days of age. 125
35 Mean coefficient of variation (± SEM) of the left hindlimb durations for control and jimpy Qp/Y) mice from 3 to 21 days of age. 127
36 Mean standard deviation (± SEM) of the forelimb bilateral phase values for control and jimpy Qp/Y) mice from 3 to 13 days of age. 128
37 Mean standard deviation (± SEM) of the hindlimb bilateral phase values for control and jimpy Qp/Y) mice from 3 to 21 days of age. 130
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38 Mean standard deviation (± SEM) of the ipsilateral limb phase values for control and jimpy Qp/Y) mice from 3 to 13 days of age. 131
39 Mean standard deviation (± SEM) of the contralateral limb phjse values for control and jimpy Qp/Y) mice from 3 to 13 days of age. 132
w
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ABSTRACT
Neurological mutant mice provide an imperfectly explored and potentially important way to examine the effects of single gene mutations on motor behavior. This thesis research concerns the swimming behavior of one neurological mutant, the dysmyelinating jimpy mouse. The jimpy mutation (jp/Y) results from a single base change within the proteolipid protein gene and causes severe dysmyelination throughout the central nervous system while not affecting the peripheral nervous system. Examination of this mutant with a refined swimming test during the early postnatal period allowed the study of developmental effects of dysmyelination on a basic rhy'lnmical motor behavior. Male jimpy mouse pups and their littermate controls w re videotaped every second day from postnatal day 3 to 21. Detailed examinations of the movements made during swimming were accomplished by frame-by-frame analyses of the videotaped swimming sessions. Swimming behavior was examined in terms of general swimming style (limb usage), individual limb timing and interlimb coordination. These combined measures of swimming ability were used to provide a richer picture of swimming behavior in these mutants than previously provided.
Although generalized swimming style measures did not show significant differences between jimpy and control groups, more fine-grained analyses did. Jimpy mice displayed stroke duration and velocity deficits in hindlimb movements. However, these deficits did not become apparent until postnatal days 11 and 13. When examining the coordination between pairs ot limbs it became evident that jimpy mice were less able to maintain a coordinated swim involving both the forelimbs and hindlimbs. Coordination distinctions may reflect imperfect neural transmission in the jimpy mutant. Further, messages that have to travel the full length of a dysmyelinated spinal cord become temporally delayed, thereby resulting in a lack of normal swimming coordination. My data confirm the importance of detailed behavioral analyses to improve our understanding of how single gene mutations affect motor behavior.
xi
ACKNOWLEDGMENTS
I would like to thank my supervisor John Fentress for introducing me to
neurological mutant mice. Little did either of us know that what started as a
comprehensive project would change the direction of my academic interests and
career. I thank all my thesis committee members, John Barresi, Richard Brown,
Jim Clark and John Fentress, for their helpful comments and criticisms on drafts
of my thesis. I would especially like to thank my external examiner Richard
Sidman for his supportive comments on my thesis research.
Vem Fraser and the other animal care staff desen/e special thanks, especially
Ross Burgess for taking special caro of my "little guys". Thanks go to Wanda
Danilchuck for help with everything from filming to proofreading, and especially for
her assistance in that last minute rush to get the thesis off to the external
examiner.
I thank my parents, who have helped so much both financially and
emotionally over the past few years. Yes, Dad I did "finish what I started".
Special thanks go to Tigger for always knowing just when to be a welcome
distraction. Last, but absolutely not least, I thank my husband Kevin, for his
hundreds (or was it thousands?) of hours of technical support. Your hours of
technical help are surpas 3d only by your hours of emotional support. In return
all I can say is, "It is finally over!!"
xii
INTRODUCTION
Nothing in neurobiology makes sense except in the light of
behavior.
This thesis concerns the behavioral (motor) development of a neurological
mutant mouse strain Qimpy), on the conviction that behavior provides the
fundamental assay of integrated nervous system action (Fentress, 1991).
Movement reveals many problems and patterns of organization that can help
link issues that are otherwise often separate in traditional neurobiological and
behavioral disciplines. The potential for linking genes and behavior has
received increasing appreciation in recent years, as symbolized by volume
264 of Science (June, 1994) on the subject. However, for both invertebrate
and vertebrate species reviewed in that issue, the lack of quantification of
developmental details in overt behavior remains disappointing. As noted in
the introduction of this special issue (Mann, 1994), behavioral traits have for
the most part been "inexactly defined" (p. 1688).
Movement provides the most obvious assay of the integrated nervous
system operations that make adaptive behavior possible (Cordo & Hamad,
1994). Developmental analyses provide a natural dissection of these
individual operations as well as their rules of combination over time (Fentress
& Bolivar, 1996). Neurological mutant mice in turn allow the investigator to
trace these events in animals that have previously been characterized in detail
at cellular and biochemical levels (Sidman, 1983). It is hoped that the
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molecularly oriented research at the neurobiological level (Churchland &
Sejnowski, 1992). The potential for combining multiple assays of mutant
phenotypes in mice has been reviewed by Takahashi, Pinto and Vitatema
(1994).
tool for linking genes with their cellular, neuroanatomical and biochemical
effects. The techniques used to determine deficits at any of these levels of
analysis have become sophisticated and enable precise measurements (e.g.,
Dautigny et al., 1986; Fannon, Mastronardi & Moscarello, 1994; Skoff &
Knapp, 1990). Some neurological mutants have also been categorized as
rodent models of human genetic disorders (e.g., the jimpy mouse for
Pelizaeus-Merzbacher disease, the twitcher mouse for infantile Krabbe's
disease) and emphasis is placed on how well the mouse disorder matches the
human one. As outlined by Sidman (1983), it is important to recognize that
due to the developmental and organizational differences between species,
these models may have limited generality. Instead, the critical importance of
these neurological mutant mice to date has been the insight they provide at
more fundamental levels of analysis. These include insights into formal
genetics (intragenetic structure and neighboring genetic loci and chromosomal
map position), homologous gene products and their target cells and
3
developmental and physiological time courses given the specific deficits
involved (Sidman, 1983). When considered in this more fundamental
framework, even those mutations…