Drosophila melanogaster as a model to study age and sex differences in brain injury and neurodegeneration after mild head trauma

Abstract

Repetitive physical insults to the head, including those that elicit mild traumatic brain injury (mTBI), are a known risk factor for a variety of neurodegenerative conditions including Alzheimer’s disease (AD), Parkinson’s disease (PD), and chronic traumatic encephalopathy (CTE). Although most individuals who sustain mTBI typically achieve a seemingly full recovery within a few weeks, a subset experience delayed-onset symptoms later in life. As most mTBI research has focused on the acute phase of injury, there is an incomplete understanding of mechanisms related to the late-life emergence of neurodegeneration after early exposure to mild head trauma. The recent adoption of Drosophila-based brain injury models provides several unique advantages over existing preclinical animal models, including a tractable framework amenable to high-throughput assays and short relative lifespan conducive to lifelong mechanistic investigation. The use of flies also provides an opportunity to investigate important risk factors associated with neurodegenerative conditions, specifically age and sex. In this review, we survey current literature that examines age and sex as contributing factors to head trauma-mediated neurodegeneration in humans and preclinical models, including mammalian and Drosophila models. We discuss similarities and disparities between human and fly in aging, sex differences, and pathophysiology. Finally, we highlight Drosophila as an effective tool for investigating mechanisms underlying head trauma-induced neurodegeneration and for identifying therapeutic targets for treatment and recovery.

Polypathologies and Animal Models of Traumatic Brain Injury

“…Drosophila melanogaster flies are used as an animal model that has 70% genetic overlap, a nervous system with glial cells, similar diversity of neurotransmitters, and exhibits most of the behavioural impairment displayed by humans [50]. Using Drosophila flies will augment our ability to explore TBI more efficiently for high-throughput screening of therapeutic compounds, with numerous different models of injury being developed like the omni bead ruptor model for mTBI [49].…”

“…Zebrafish have a shorter lifespan which allows for greater flexibility to use existing weight drop models to investigate the impact of ageing on TBI outcomes [49]. Similarly, Xenopus tadpoles have been shown to demonstrate a wide range of TBI pathologies in response to a focal impact injury model [50]. The variety of models being produced for each non-mammalian species does present a challenge for reducing heterogeneity within the field, as the models have not been characterised as extensively as rodent models of TBI and require further scrutiny as to their utility [49].…”

Sexual Dimorphism in Age-Dependent Neurodegeneration After Mild Head Trauma inDrosophila: Unveiling the Adverse Impact of Female Reproductive Signaling

“…Recently, several Drosophila head injury models have developed that recapitulate several key findings from traumatic brain injury (TBI) in humans and other preclinical models and help gaining significant insights into the potential molecular and genetic underpinnings of injury responses [22][23][24][25][26][27][28] . We recently developed a novel Drosophila model (HIFLI: Headfirst Impact FLy Injury) in which mild repetitive head-specific impacts can be delivered to multiple awake and unrestricted adult flies of both sexes 28 .…”

“…Importantly, the fruit fly's relatively short lifespan enables longitudinal interrogation of disease progression from the initial trigger to the late-life emergence of neurodegenerative conditions such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) [17][18][19][20][21] . Recently, several Drosophila head injury models have been developed that recapitulate key findings from traumatic brain injury (TBI) in humans and other preclinical models, revealing significant insights into the potential molecular and genetic underpinnings of injury responses [22][23][24][25][26][27][28] . We recently developed a novel Drosophila model (HIFLI: Headfirst Impact FLy Injury) in which mild repetitive head-specific impacts can be delivered to multiple awake and unrestricted adult flies of both sexes 28 .…”