Using Drosophila as an integrated model to study mild repetitive traumatic brain injury

Abstract

Traumatic brain injury (TBI) is a major cause of morbidity and mortality worldwide. In addition, there has been a growing appreciation that even repetitive, milder forms of TBI (mTBI) can have long-term deleterious consequences to neural tissues. Hampering our understanding of genetic and environmental factors that influence the cellular and molecular responses to injury has been the limited availability of effective genetic model systems that could be used to identify the key genes and pathways that modulate both the acute and long-term responses to TBI. Here we report the development of a severe and mild-repetitive TBI model using Drosophila. Using this system, key features that are typically found in mammalian TBI models were also identified in flies, including the activation of inflammatory and autophagy responses, increased Tau phosphorylation and neuronal defects that impair sleep-related behaviors. This novel injury paradigm demonstrates the utility of Drosophila as an effective tool to validate genetic and environmental factors that influence the whole animal response to trauma and to identify prospective therapies needed for the treatment of TBI.

Expansion of a fly TBI model to four levels of injury severity reveals synergistic effects of repetitive injury for moderate injury conditions

“…Flies are well-known to exhibit motor dysfunction following TBI (Katzenberger et al 2013; Barekat et al 2016; Anderson et al 2018). However, the time-course of motor dysfunction across the primary and secondary injury periods, and for TBI of varying severities is not well-characterized.…”

“…Fruit flies offer an accessible model to study TBI. Two models of conducting TBI studies in fruit flies are the high-impact trauma (HIT) method and the Bead Ruptor method (Katzenberger et al 2013; Barekat et al 2016). One advantage to the Bead Ruptor method is the ease of scaling the primary injuries (Barekat et al 2016).…”

“…Two models of conducting TBI studies in fruit flies are the high-impact trauma (HIT) method and the Bead Ruptor method (Katzenberger et al 2013; Barekat et al 2016). One advantage to the Bead Ruptor method is the ease of scaling the primary injuries (Barekat et al 2016). We addressed this gap in methodology and expanded upon the original HIT method by adding selectable stopping points to reproducibly perform injury at four levels of injury severity.…”

“…Two models for studying TBI have been developed for the fruit fly ( Drosophila melanogaster ): the high-impact trauma (HIT) method, which uses a spring-based device deflected to 90°, and the Bead Ruptor homogenizer method, which uses a programmable homogenizer that can be set to various speeds and durations (Katzenberger et al 2013; Barekat et al 2016). Importantly, use of each method results in classic post-TBI symptoms including impaired locomotion, shortened lifespan, neurodegeneration, intestinal barrier disruption, and activation of immune and autophagy processes (Katzenberger et al 2013; Barekat et al 2016; Anderson et al 2018). While the Bead Ruptor method offers potential advantages in the ease of scaling primary injuries and inter-experiment standardization, the HIT method is simple, cost-effective, and better characterized to date (Katzenberger et al 2013, 2015, 2016; Barekat et al 2016; Anderson et al 2018).…”

A cost effective high-resolution climbing assay applied to Drosophila Parkinson’s and proprioception mutants reveal novel behavioural phenotypes

“…For example, most common climbing assays employ tapping down of the flies onto hard glass/polystyrene surface of test tubes (6,8). This regime of coercing flies to the bottom of the test tubes indeed is very effective for multiple repeats but could also induce physical stress and trauma to the flies (9).…”