Contributions of age and sex in the emergence of neurodegenerative conditions following mild head trauma in Drosophila Melanogaster Open Access

Abstract

Environmental insults, including those of physical nature, pose a significant risk for neurodegenerative disorders. Even seemingly innocuous hits to the head are believed to have long-lasting detrimental effects on brain function, which can emerge years after incident. However, it remains challenging to establish a causative connection between early-life exposure to mild head trauma and late-life emergence of neurodegenerative conditions. Furthermore, sex and age compound the outcome. Using our Drosophila head-impact model, we showed that early exposure to mild head trauma caused neurodegenerative conditions which only emerged in advanced ages and affected females disproportionately. Moreover, increasing age-at-injury further exacerbated the sexually dimorphic, late-life neurodegeneration. Next, we showed that mating is a primary cause for increased neurodegeneration in females. Specifically, Sex Peptide (SP) signaling in females was responsible for elevating vulnerability of the brain. Finally, RNA sequencing revealed a selected set of transcripts involved in the innate immune defense that were only altered in females. These transcriptomic changes exhibited a delayed onset and were only identified at chronic timepoints after injury in mated females, suggesting their role in the female-specific chronic responses to injury. Collectively, our findings established a causative link between early mild head trauma exposure and late-life neurodegeneration, affirmed the existence of sex differences in response to injury, and illuminated the critical contribution of age to the manifestation of neurodegenerative conditions. The identification of SP signaling in elevated female vulnerability also supports the emerging view that female reproductive processes may increase the risk for neurodegeneration.  

Table of Contents

Chapter 1 An Introduction to Traumatic Brain Injury and Subsequent Neurodegeneration

1.1       Introduction to Traumatic Brain Injury

1.2       Age as a Risk Factor in Brain Injury-Induced Neurodegeneration

1.3       Sex as a Risk Factor in Brain Injury-Induced Neurodegeneration

Chapter 2 Drosophila Melanogaster as a Model for Neurodegenerative Diseases and Traumatic Brain Injury

2.1       Drosophila melanogaster as a model for neurodegenerative diseases

2.2       Drosophila melanogaster as a model for TBI

2.3       Use of Drosophila Melanogaster to study aging

2.4       Sex dimorphism in Drosophila and neurodegeneration

2.5       HIFLI model

Chapter 3 Behavioral Deficits Following Head Injury

3.1       Introduction

3.2       Behavioral paradigms using Drosophila

3.3       Sensorimotor deficits following head injury

3.3.1 Introduction

3.3.2 Methods

3.3.3 Results

3.4       Sleep deficits following head injury

3.4.1 Introduction

3.4.2 Methods

3.4.3 Results

Chapter 4 Brain Pathology Following Head Injury

4.1       Introduction

4.2       Assessing neurodegenerative pathology in Drosophila TBI models

4.2.1 Methods

4.2.2 Results

4.2.3 Discussion

Chapter 5 Sex Peptide Mediates Female Vulnerability

5.1       Virgin females are resilient to neurodegeneration following injury

5.1.1 Introduction

5.1.2 Methods

5.1.3 Results

5.1.4 Discussion

5.2       Sex peptide alters female susceptibility to neurodegeneration

5.2.1 Introduction

5.2.2 Methods

5.2.3 Results

5.2.4 Discussion

5.3       Sex peptide does not affect male susceptibility to neurodegeneration

5.3.1 Introduction

5.3.2 Methods

5.3.3 Results

Chapter 6 Transcriptomic Changes in the Brain are Dependent on Sex and Reproductive Status

6.1       Introduction to transcriptomic changes in the brain following traumatic brain injury

6.2       Sexually dimorphic and reproductive status-dependent transcriptomic changes may underlie neurodegenerative conditions

6.2.1 Methods

6.2.2 Results

6.2.3 Discussion

Chapter 7 Conclusions and Future Directions

7.1       Summary and Conclusions

7.2       Future directions

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
Keyword	Sex differences Neurodegeneration Drosophila Mild head injury
Committee Chair / Thesis Advisor	James Q. Zheng, Emory University
Committee Members	Jie Jiang, Emory University Shirley Zhang, Emory University Zhexing Wen, Emory University Kenneth H. Moberg, Emory University Steven A. Sloan, Emory University

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	RNA-seq gene changes (This excel sheet contains all differentially expressed genes as a result of injury, in various genotypes, different injury groups, andcollected at various timepoints. )	2024-04-11 21:14:40 -0400	Press to Select an action Download