Behavioral and Physiological Consequences of Microembolic Stroke Open Access

Nemeth, Christina Linnea (2014)

Permanent URL: https://etd.library.emory.edu/concern/etds/4f16c340f?locale=en
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Abstract

An estimated 15% of the population over age 65 suffers from some form of depression and the risk of depression increases with age. The already multifarious nature of depressive disorders makes it especially difficult to diagnose and treat in the elderly due to pre-existing health conditions, related medications, and concurrent anhedonia associated with aging in many individuals. Silent cerebral infarction, or microembolic stroke, stems from arteriosclerotic risk factors and occurs frequently within the general population. Microembolic stroke correlates highly with the manifestation of depression and cognitive decline. To explore this relationship, we used a microsphere embolism model to induce behavioral disruption in adult rats in order to study the mechanisms of acute ischemic damage. We found that while the degree or location of microvascular injury did not correlate with altered behavior, ME procedures did lead to the increased expression of several inflammatory markers at a time-point that correlates with behavior. Inhibition of inflammatory activity via the use of specific and generalized anti-inflammatory therapeutics reverses behavioral deficits; however, timing of pharmacological intervention, with respect to injury, is important. These findings shed light on a common, but under-appreciated, model of depression and suggest that depression and cognitive dysfunction of a vascular origin may be ameliorated by careful control of cardiovascular risk factors and by anti-inflammatory therapeutics.

Table of Contents

CHAPTER ONE 1

Heartsick: psychiatric implications of cerebromicrovascular disease 1

Cerebral Microvascular Disease: An Epidemic 1

A Succinct Review of Blood Vessels in the Body 2

Cerebral (Macro) Vasculature 2

Cerebral Microvasculature 4

Vascular-Induced Behavioral Disruption: Evolution of the Vascular Depression Hypothesis 6

Vascular-Induced Behavioral Disruption: Mechanisms 7

Vascular-Induced Behavioral Disruption: An Inflammatory Disease? 11

Vascular-Induced Behavioral Disruption: In the Lab 13

Vascular-Induced Behavioral Disruption: In the Clinic 14

Vascular-Induced Behavioral Disruption: Call for Translation 17

Summary 18

CHAPTER TWO 20

Microembolism infarcts lead to delayed changes in affective-like behaviors followed by spatial memory impairment 20

Materials and Methods 22

Results 30

Discussion 36

CHAPTER THREE 42

Microembolism infarcts induce a functional and histological response that is sexually dimorphic 42

Materials and Methods 44

Results 47

Discussion 50

CHAPTER FOUR 56

Microembolism infarcts induce anhedonia but no detectable changes in white matter integrity in aged rats 56

Materials and Methods 58

Results 62

Discussion 68

CHAPTER FIVE 77

Microembolism infarcts and behavior: influence of the hypothalamic-pituitary-adrenal axis 77

Materials and Methods 78

Results 81

Discussion 85

CHAPTER SIX 92

Microembolism infarcts induce long-term neuroinflammation 92

Materials and Methods 94

Results 97

Discussion 103

CHAPTER SEVEN 108

Inhibition of soluble tnf attenuates microembolism-induced neuroinflammation and improves behavioral outcome 108

Materials and Methods 110

Results 113

Discussion 116

CHAPTER EIGHT 119

Microembolism infarcts induce functional deficits that are attenuated by anti-inflammatory, but not anti-depressant, treatment 119

Materials and Methods 120

Results 124

Discussion 127

CHAPTER NINE 130

GENERAL DISCUSSION 130

Searching for a Mechanism 133

Putting the Mechanism to the Test: Reversal 136

Important Considerations: Interactions of Age and Sex 139

Future Directions 145

References 149

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