Behavioral and Physiological Consequences of Microembolic Stroke Open Access
Nemeth, Christina Linnea (2014)
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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