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

Bart van Alphen; Samuel Stewart; Marta Iwanaszko; Fangke Xu; Keyin Li; Sydney Rozenfeld; Anujaianthi Ramakrishnan; Taichi Q. Itoh; Shiju Sisobhan; Zuoheng Qin; Bridget C. Lear; Ravi Allada

doi:10.1371/journal.pbio.3001456

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

Bart van Alphen, Samuel Stewart, Marta Iwanaszko, Fangke Xu, Keyin Li, Sydney Rozenfeld, Anujaianthi Ramakrishnan, Taichi Q. Itoh, Shiju Sisobhan, Zuoheng Qin, Bridget C. Lear, Ravi Allada^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

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.

Original language	English (US)
Article number	e3001456
Journal	PLoS biology
Volume	20
Issue number	1
DOIs	https://doi.org/10.1371/journal.pbio.3001456
State	Published - Jan 2022

Funding

This study was funded by the Department of Defense (W81XWH-20-1-0211 and W81XWH-16-1-0166 to RA) and the Defense Advanced Research Projects Agency (D12AP00023). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors thank Eugenie Bang for conducting the experiments that assessed TBI susceptibility and sleep and motor impairments in wild-type and NF-\u03BAB null flies. The authors thank Dr. Rosemary Braun for supervising the bioinformatic analyses and reviewing the initial draft of this manuscript.

ASJC Scopus subject areas

General Neuroscience
General Biochemistry, Genetics and Molecular Biology
General Immunology and Microbiology
General Agricultural and Biological Sciences

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van Alphen, B., Stewart, S., Iwanaszko, M., Xu, F., Li, K., Rozenfeld, S., Ramakrishnan, A., Itoh, T. Q., Sisobhan, S., Qin, Z., Lear, B. C., & Allada, R. (2022). Glial immune-related pathways mediate effects of closed head traumatic brain injury on behavior and lethality in Drosophila. PLoS biology, 20(1), Article e3001456. https://doi.org/10.1371/journal.pbio.3001456

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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.",

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AU - Stewart, Samuel

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AU - Lear, Bridget C.

AU - Allada, Ravi

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Y1 - 2022/1

N2 - 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.

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

Abstract

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