The role of noradrenergic-derived galanin in stress-related behavior Pubblico
Tillage, Rachel (Fall 2020)
Abstract
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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