Glial immune-related pathways mediate effects of closed head traumatic brain injury on behavior and lethality in Drosophila.

Bart Van Alphen,Sydney Rozenfeld,Fangke Xu,Marta Iwanaszko,Keyin Li,Taichi Q Itoh,Samuel Stewart,Anujaianthi Ramakrishnan,Bridget C Lear,Ravi Allada,Zuoheng Qin,Shiju Sisobhan,The Plos Biology Editors The Plos Biology Editors

doi:10.1371/journal.pbio.3001456

Abstract

In traumatic brain injury (TBI), the initial injury phase is followed by a secondary phase that contributes to neurodegeneration, yet the mechanisms leading to neuropathology in vivo remain to be elucidated. To address this question, we developed a Drosophila head-specific model for TBI termed Drosophila Closed Head Injury (dCHI), where well-controlled, nonpenetrating strikes are delivered to the head of unanesthetized flies. This assay recapitulates many TBI phenotypes, including increased mortality, impaired motor control, fragmented sleep, and increased neuronal cell death. TBI results in significant changes in the transcriptome, including up-regulation of genes encoding antimicrobial peptides (AMPs). To test the in vivo functional role of these changes, we examined TBI-dependent behavior and lethality in mutants of the master immune regulator NF-κB, important for AMP induction, and found that while sleep and motor function effects were reduced, lethality effects were enhanced. Similarly, loss of most AMP classes also renders flies susceptible to lethal TBI effects. These studies validate a new Drosophila TBI model and identify immune pathways as in vivo mediators of TBI effects.

Highlights

Traumatic brain injury (TBI) is one of the major causes of death and disability in the developed world [1,2,3]
We have developed a straightforward and reproducible Drosophila model for closed head TBI where we deliver precisely controlled strikes to the head of individually restrained, unanesthetized flies
This TBI paradigm is validated by recapitulating many of the phenotypes observed in mammalian TBI models, including increased mortality, increased neuronal cell death, impaired motor control, decreased/fragmented sleep, and hundreds of TBI-induced changes to the transcriptome, including the activation of many antimicrobial peptides (AMPs), indicating a strong activation of the immune response

Summary

Introduction

Traumatic brain injury (TBI) is one of the major causes of death and disability in the developed world [1,2,3]. Neuroinflammation is beneficial when it is promoting clearance of debris and regeneration [14] but can become harmful, mediating neuronal death, progressive neurodegeneration, and neurodegenerative disorders [15,16,17,18] The mechanisms underlying these opposing outcomes are largely unknown but are thought to depend of the location and timing of the neuroinflammatory response [19,20]. It remains to be determined what the relative roles of TBI-induced neuroinflammation and other TBI-induced changes are in mediating short- and long-term impairments in brain function in vivo

Methods

Results

Conclusion