Investigating the Effects of Specific Acetylcholine Receptor Activation on Hippocampal Function for the Treatment of Alzheimer's Disease Open Access

Galloway, Claire Rebecca (2017)

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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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