The role of noradrenergic-derived galanin in stress-related behavior Open Access

Tillage, Rachel (Fall 2020)

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Stress is a primary risk factor for many neuropsychiatric disorders, including affective and anxiety disorders. Although these conditions are highly prevalent and are a leading cause of disability worldwide, the current therapeutic treatments available are often ineffective for many people and carry adverse side effects. Furthermore, the neurobiological mechanisms underlying stress-related neuropsychiatric disorders are not well understood. The neuropeptide galanin has been implicated in the pathophysiology of affective and anxiety disorders in both human and animal studies. Galanin is abundantly expressed in the main noradrenergic nucleus, the locus coeruleus, which is an important node in the stress response and is dysregulated in stress-related neuropsychiatric disorders. However, we currently lack a comprehensive understanding of the specific role noradrenergic-derived galanin plays in regulating stress-related behaviors. Here, we addressed this knowledge gap by using genetic and environmental manipulations of the galanin system to improve our understanding of how galanin from the locus coeruleus modulates stress-induced behaviors. We examined how chronic lack of galanin in noradrenergic neurons affects both neurochemistry and behavior using mice that lack galanin expression specifically in noradrenergic neurons. We found that noradrenergic neurons are a significant source of galanin to the hippocampus and prefrontal cortex, and that noradrenergic-derived galanin regulates behavioral coping responses. Next, we attempted to disentangle the roles of noradrenergic-derived galanin and norepinephrine in regulating behavioral responses to stress using mice that lack either norepinephrine or noradrenergic-derived galanin. Our data suggest that norepinephrine is important for acute stress-induced anxiety-like behavior, while both norepinephrine and noradrenergic-derived galanin participate in prolonged behavioral changes after a stressor. Finally, we examined how chronic elevation of noradrenergic galanin affects stress resilience. We found that chronic wheel running increased galanin expression in the locus coeruleus of mice and conferred resilience to a stressor, and galanin abundance predicted the degree of stress resilience. The beneficial effects of exercise were phenocopied by transgenic overexpression of galanin in noradrenergic neurons. Together, these studies provide new information about the complex role of noradrenergic-derived galanin in regulating stress-related behaviors and indicate the importance of continuing this line of research for developing new therapeutics to treat affective and anxiety disorders.

Table of Contents

Introduction 1

Stress-related neuropsychiatric disorders 2

Epidemiology 2

Current treatments 4

Animal models of stress 6

The noradrenergic system 8

Norepinephrine synthesis, signaling, and functions 8

Locus coeruleus anatomy and physiology 10

The role of the LC-NE system in the stress response 12

Galanin 16

Galanin synthesis and expression patterns 16

Galanin signaling and functions 18

Galanin in neuropsychiatric disorders 20

Galanin and stress resilience 21

Summary and thesis aims 23

Elimination of galanin synthesis in noradrenergic neurons reduces galanin in select brain areas and promotes active coping behaviors 26

Abstract 27

Introduction 28

Methods 30

Results 42

Discussion 47

Disentangling the functional roles of co-transmitters norepinephrine and galanin in stress-induced behavior 62

Abstract 63

Introduction 64

Methods 66

Results 70

Discussion 73

Chronic environmental or genetic elevation of galanin in noradrenergic neurons confers stress resilience in mice 86

Abstract 87

Introduction 88

Methods 90

Results 92

Discussion 99

General Discussion and Future Directions 112

Summary 113

Integration of key findings and future directions 114

Clinical implications 123

Conclusion 126

References 129

Appendix 159

Inflammation-induced depressive-like behavior 160

Abstract 161

Introduction 162

Methods 165

Results 167

Discussion 170

Appendix References 178

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