AN EVALUATION OF COGNITIVE DEFICITS IN A RAT - MODEL OF HUNTINTONS'S DISEASE
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Author
Presented To
Department of Psychology
Abstract
The purpose of this thesis was to develop methodology by which treatments for the
cognitive impairments in Huntington's disease (HD) could be tested. As such, the thesis focused
mainly on evaluating rats with quinolinic acid (QA) lesions of the striatum, as this manipulation
mimics some aspects of the neural damage in Huntington's disease, to try to identify cognitive
deficits of HD resulting from cell loss in the striatum.
In the first part (Chapters 3-5), the role of the striatum in implicit memory was
investigated. Chapter 3 compared the performance of rats and humans on a reaction time task
that evaluated implicit memory by presenting visual stimuli with differing probabilities which
change over time. Although rats made higher percentage of incorrect responses and late errors,
both groups showed a similar pattern of reaction times. Chapter 4 investigated whether implicit
memory (the computation of probabilities to predict the location of a stimulus) was affected by
selective blockade of dopaminergic transmission at the D1 or D2 receptors by SCH-23390 and
raclopride, respectively. Reaction times were slower with SCH-23390 and raclopride, but only
SCH-23390 reduced errors to the least probable target location. Chapter 5 used the same task to
evaluate implicit memory in rats with QA lesions of the dorsomedial striatum (DMS). Implicit
memory was not affected by lesions of the DMS, which suggested that once a task that requires
implicit memory has been learned, the DMS was not involved in sustaining the performance of
the task. The second part of this thesis (Chapter 6), explored the contribution of the DMS in
habit formation. DMS lesioned rats did not show habitual responding, and were not impaired in
learning a new goal-directed behaviour. The third part (Chapters 7 and 8), investigated the role
of the dorsal striatum in reversal learning, attentional set-formation, and set-shifting. Dorsal
striatum lesioned rats were not impaired in reversal learning, but had a diminished shift-cost,
which suggested that dorsal striatum lesions disrupted the formation of attentional sets.
These results showed that although QA lesions of the dorsal striatum mimic some aspects
of the neural damage in HD, they did not result in the same cognitive deficits observed in
patients with HD, at least using the tasks presented in this thesis. However, other animal models
of HD could be evaluated using the different tasks presented in this thesis to continue the search
of a reliable animal model of HD in which treatments for the disease could be evaluated.
Table of Contents
Abstract v
Acknowledgements vii
Chapter 1
General Introduction 15
Huntington's disease
17
11 Introduction 17
12 Epidemiology 17
13 Genetics 18
14 Neuropathology 19
141 Organisation of the basal ganglia 20
15 Symptoms 24
151 Motor symptoms 25
152 Psychiatric and mood symptoms 26
153 Cognitive symptoms 28
16 Treatment - 35
17 Choosing an animal model for the study of Huntington's disease 35
171 Quinolinic acid (QA) lesions of the rat striatum: an animal model of Huntington's
disease 40
18 Behavioural paradigms used in this thesis to evaluate QA lesioned rats 43
181 Implicit memory tasks 44
182 Habit formation tasks 51
183 Attentional set-shifting tasks 55
19 Outline of experimental work in this thesis 65
Chapter 2
2 General Methods 67
211 Animals 69
212 Surgery 70
213 Histology 71
214 Data analyses 73
Chapter 3
3 Spatiotemporal Target Probability Signal Reaction Time Task: Performance of Rats and
Humans - 75
31 Introduction 77
32 Method 78
321 Subjects 78
322 Apparatus 79
323 Procedure 80
324 Data Analysis 87
33 Results 88
34 Discussion 94
Chapter 4
4 Selective Effects of D1 or D2 Dopamine Receptor Antagonism in the Spatiotemporal Target
Probability Signal Reaction Time Task in Rats 99
41 Introduction 101
42 Method 102
421 Animals 102
422 Apparatus 102
423 Procedure 103
424 Data Analysis 105
43 Results 105
431 Raclopride 105
432 SCH-23390 - 108
44 Discussion 114
Chapter 5
5 The Effects of Bilateral Quinolinic Acid Lesions of the Dorsomedial Striatum in the
Spatiotemporal Target Probability Signal Reaction Time Task 121
51 Introduction 123
52 Method 124
521 Animals 124
522 Apparatus 124
523 Procedure 124
524 Data analysis 125
53 Results 126
531 Histology 126
532 Behavioural performances 129
54 Discussion 138
Chapter 6
6 Goal-Directed and Habitual Responding in Rats with Bilateral Quinolinic Acid Lesions of
the Dorsomedial Striatum: Implications for Huntington's disease 143
61 Introduction 145
62 Method 147
621 Animals 147
622 Apparatus 148
623 Procedure 149
624 Data analysis 152
63 Results 154
631 Histology 154
632 Behavioural performances 157
64 Discussion 166
Chapter 7
7 Attentional Set-Shifting in Rats with Bilateral Quinolinic Acid Lesions of the Dorsomedial
Striatum 173
71 Introduction 175
72 Method 177
721 Animals 177
722 Apparatus 177
723 Procedure 178
724 Data analysis 183
73 Results 184
731 Histology 184
732 Behavioural performances 184
74 Discussion 187
Chapter 8
8 The Effects of Lesions of the Dorsal Striatum in Reversal Learning, Attentional Set-
Formation and Set-Shifting 195
81 Introduction 197
Experiment 1 Standard 7-stage attentional set-shifting task 199
82 Method 199
821 Animals 199
822 Apparatus 199
823 Procedure 200
824 Data analysis 201
83 Results 203
831 Histology 203
832 Behavioural performances 206
84 Discussion 208
Experiment 2 Effects of early reversal vs late reversal stage in set-formation 210
85 Introduction 210
86 Method 213
861 Procedure 213
862 Data Analysis 215
87 Results 217
871 Early reversal stage task 217
872 Late reversal stage task - 219
873 Early reversal vs late reversal stage 221
88 Discussion 222
Experiment 3 The probe stage attentional set-formation task 229
89 Introduction 229
810 Method 231
8101 Procedure 231
8102 Data analysis 234
811 Results 235
8111 Effects of repeated testing in the standard 7-stage Attentional Set-Shifting task 235
8112 Probe stage attentional set-shifting task 236
812 Discussion 239
Overall summary and conclusion 241
Chapter 9
9 General Discussion 245
91 Introduction 247
92 Summary of results 248
921 Role of the dorsomedial striatum in implicit memory 248
922 Role of the dorsomedial striatum in goal-directed and habitual responding - 250
923 Role of the dorsal striatum in attentional set-shifting, set-formation and reversal
learning 252
93 Contributions, limitations and future research directions 254
931 Spatiotemporal Target Probability Signal Reaction Time Task 254
932 Goal-directed and habit formation - 257
933 Attentional Set-shifting task 258
934 Quinolinic acid lesions of the rat striatum as an animal model of Huntington's disease
262
94 Conclusion 265
References 267
Appendix 291
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