Investigating the Effects of Specific Acetylcholine Receptor Activation on Hippocampal Function for the Treatment of Alzheimer's Disease Público
Galloway, Claire Rebecca (2017)
Abstract
Drugs that selectively increase the activity of M1 or M4 muscarinic acetylcholine (ACh) receptors represent potential therapies for memory impairments in Alzheimer's disease (AD), but little is known about how these muscarinic activators influence memory-related neural circuitry in vivo. The hippocampus is essential for linking individual items into a spatiotemporal context that supports memory for information about objects in their location, and is disproportionately impacted in AD. Oscillatory synchrony between the CA1 and CA3 subregions of the hippocampus and the spatial fidelity of hippocampal place cells, which fire preferentially within specific locations of a given environment, are useful metrics of hippocampal network activity that relates to memory. Three experiments were conducted in rats to investigate if selectively increasing the activity of M1 or M4 can influence hippocampal function in healthy rats, and to test an M1 agonist as a potential acute therapy for ameliorating hippocampal dysfunction in a new transgenic rat model of AD. In the first experiment (Chapter 2), the results indicated that the activity of CA1 and CA3 of the hippocampus was more synchronous when rats were exploring novel objects, but this increase was similar across drug conditions. In the second experiment (Chapter 3), the results showed that AD rats developed an age-dependent impairment in spatial memory by 9-12 months of age, when non-spatial memory performance of AD rats was still intact. In the third experiment (Chapter 4), the results showed that hippocampal place cells of AD rats had reduced spatial fidelity that was best characterized by decreased signal-to-noise ratio of firing rates, and an M1 agonist may help improve the signal-to-noise ratio of hippocampal place cells in AD rats. The results of the experiments advance our understanding of how muscarinic drug therapies affect hippocampal function in healthy and AD rats and shed light on the nature of hippocampal dysfunction that underlies memory impairments in Alzheimer's disease.
Table of Contents
Chapter 1: General Introduction 1
Memory and the hippocampus 2
Local field potentials in the hippocampus 4
Place cells in the hippocampus 6
Acetylcholine 7
Alzheimer's disease 10
Animal models of AD 11
Hippocampus and memory in AD 12
The cholinergic hypothesis of AD cognitive deficits 13
Object Recognition Memory Tasks 14
Summary 16
References 18
Chapter 2: M1 and M4 Effects on Hippocampal Function 34
Abstract 35
Introduction 36
Method 39
Subjects 39
Drugs 39
Surgery 40
Procedure 42
Analyses 43
Results 46
CA1 and CA3 power 47
CA3-CA1 coherence 55
Discussion 58
References 71
Chapter 3: Longitudinal Assessment … Memory in … Model of Alzheimer's … 80
Abstract 81
Introduction 82
Method 84
Subjects 84
Procedure 84
Analyses 86
Results 87
Discussion 88
References 94
Chapter 4: Hippocampal dysfunction and M1 agonism in … Alzheimer's … 98
Abstract 99
Introduction 100
Method 104
Subjects 104
Drugs 105
Surgery 105
Procedure 107
Analyses 109
Results 113
Place cell testing 113
Recognition memory testing 124
Discussion 125
References 146
Chapter 5: General Discussion 155
Summary of Chapter 2 156
Summary of Chapter 3 157
Summary of Chapter 4 158
Implications for network level mechanisms underlying AD 159
Implications for muscarinic therapies for AD 162
Implications for muscarinic therapies in relation to other pathological factors in AD 164
Conclusion 166
References 168
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