Drosophila melanogaster as a model to investigate lifelong brain deficits and underlying mechanisms following repetitive mild head trauma Öffentlichkeit

Abstract

Mild head trauma, including concussion, can lead to chronic brain dysfunction and degeneration but the underlying mechanisms remain poorly understood. Here, we report the utilization of a novel head impact system to investigate the long-term effects of mild head trauma on brain structure and function, as well as the underlying mechanisms in Drosophila melanogaster. We find that Drosophila subjected to repetitive head impacts develop long-term deficits, including impaired startle-induced climbing, progressive brain degeneration, and shortened lifespan, all of which are substantially exacerbated in female flies. Interestingly, head impacts elicit an elevation in neuronal activity and its acute suppression abrogates the detrimental effects in female flies. Together, our findings validate Drosophila as a suitable model system for investigating the long-term effects of head trauma, suggest an increased vulnerability in brain injury in female flies, and indicate that early altered neuronal excitability may be a key mechanism linking mild brain trauma to chronic degeneration. 

Table of Contents

Chapter 1 An Introduction to Traumatic Brain Injury. 1

1.1        Introduction and Epidemiology. 1

1.2        Traumatic Brain Injury Classification. 2

1.3        A Historical Perspective on Mild Traumatic Brain Injury. 4

1.4        Pathophysiology of Traumatic Brain Injury. 7

1.5        Mild TBI Signs and Symptoms. 10

1.6        TBI Risk Factors. 11

Chapter 2 Preclinical Modeling of Traumatic Brain Injury. 17

2.1        In Vitro Trauma Models. 18

2.2        Mammalian Models. 19

2.3        Non-Mammalian (Invertebrate) Models. 22

2.3.1      A Quick Primer on Drosophila Melanogaster Neurobiology. 23

2.3.2      Benefits of Drosophila Melanogaster. 24

2.3.3      Existing Drosophila Head Injury Models. 25

2.4        Our Novel Repetitive Mild Traumatic Brain Injury Drosophila Model 28

2.4.1      Results. 29

2.4.2      Discussion. 33

2.4.3      Methods. 34

Chapter 3 Long-Term Function Following Repetitive Head Injury. 37

3.1        Introduction. 37

3.2        Mammalian Behavioral Paradigms. 38

3.3        Drosophila Behavioral Paradigms. 40

3.4        Longitudinal Measurement of Motor Deficits in Drosophila Following Injury. 42

3.4.1      Results. 42

3.4.2      Discussion. 51

3.4.3      Methods. 53

Chapter 4 Brain Degeneration Following Head Injury. 55

4.1        Linking Head Trauma to Neurodegeneration. 55

4.2        Cellular and Molecular Pathology of Mild Traumatic Brain Injury. 61

4.3        Measuring Neurodegeneration in Drosophila. 69

4.4        Repetitive Head Impacts Exacerbate Age-Related Brain Degeneration. 69

4.4.1      Results. 69

4.4.2      Discussion. 71

4.4.3      Methods. 78

Chapter 5 Neuronal Activity in Long-Term Deficits of Repetitive Head Injury. 80

5.1        Aberrant Excitability in Brain Aging and Neurodegeneration. 80

5.2        Hyperexcitability Following Traumatic Brain Injury. 80

5.3        Activity-Mediated Effects of Repetitive Mild Head Trauma. 83

5.3.1      Results. 83

5.3.2      Discussion. 92

5.3.3      Methods. 97

Chapter 6 Future Directions and Conclusions. 98

6.1        Sexually Dimorphic Effects. 98

6.2        Glial Contributions. 99

6.3        Mitochondrial Function Following Injury. 100

6.4        CNS Remodeling Following Repetitive Mild Head Trauma. 100

6.5        Mitigating Risks Associated with Head Trauma. 102

6.6        Conclusions. 103

References 107

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Neuroscience
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Biology, Neuroscience
Stichwort	neurodegeneration mild traumatic brain injury Drosophila melanogaster
Committee Chair / Thesis Advisor	James Q. Zheng, PhD, Emory University
Committee Members	Victor Faundez, MD, PhD, Emory University Zixu Mao, MD, PhD, Emory University David Rye, MD, PhD, Emory University Kenneth H. Moberg, PhD, Emory University

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Supplemental Files

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	Video S1 (Demonstration of headfirst impacts using our novel Drosophila model)	2021-04-02 11:34:16 -0400	Press to Select an action Download
	Video S2 (Head impacts elicit immediate concussive-like behavior)	2021-04-02 11:34:30 -0400	Press to Select an action Download
	Video S3 (Automated tracking of fly climbing using idtracker.ai)	2021-04-02 11:34:40 -0400	Press to Select an action Download
	Video S4 (Novel approach to measure frank neurodegeneration in Drosophila whole-brain mounts)	2021-04-02 11:34:49 -0400	Press to Select an action Download
	Video S5 (Conditional suppression of neuronal activity via pan-neuronal expression of Shibirets1)	2021-04-02 11:34:58 -0400	Press to Select an action Download