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.
Highlights
Are increased following Traumatic brain injury (TBI) and recent work has shown that this is due to defects in lysosomal function, which leads to the accumulation of dysfunctional autophagosomes[11,14]
Given the acute mortality of flies at 4.35 m/s intensity, the high impact or severe TBI studies were standardized to this intensity
Repetitive, mild TBI is relatively common and can be experienced by individuals participating in activities such as contact sports[19]
Summary
Are increased following TBI and recent work has shown that this is due to defects in lysosomal function, which leads to the accumulation of dysfunctional autophagosomes[11,14]. The individual TBI outcomes are often highly heterogeneous, due to variations in the location and extent of the primary damage This heterogeneity reflects the complexity of the nervous system, and includes genetic and environmental factors that influence the cellular and molecular responses to damage[8,15]. Another important factor is age, with older individuals typically having more serious complications and worse outcomes following TBI16. Our unique injury paradigm will facilitate the systematic characterization of genetic, age-related and environmental factors that can influence the acute and long-term response to neural injury
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