Loss of highwire Protects Against the Deleterious Effects of Traumatic Brain Injury in Drosophila Melanogaster

Following traumatic brain injury (TBI), the time window during which secondary injuries develop provides a window for therapeutic interventions. During this time, many TBI victims undergo exposure to hyperoxia and anesthetics. We investigated the effects of genetic background on the interaction of oxygen and volatile general anesthetics with brain pathophysiology after closed-head TBI in the fruit fly Drosophila melanogaster. To test whether sevoflurane shares genetic risk factors for mortality with isoflurane and whether locomotion is affected similarly to mortality, we used a device that generates acceleration–deceleration forces to induce TBI in ten inbred fly lines. After TBI, we exposed flies to hyperoxia alone or in combination with isoflurane or sevoflurane and quantified mortality and locomotion 24 and 48 h after TBI. Modulation of TBI–induced mortality and locomotor impairment by hyperoxia with or without anesthetics varied among fly strains and among combinations of agents. Resistance to increased mortality from hyperoxic isoflurane predicted resistance to increased mortality from hyperoxic sevoflurane but did not predict the degree of locomotion impairment under any condition. These findings are important because they demonstrate that, in the context of TBI, genetic background determines the latent toxic potentials of oxygen and anesthetics.

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Loss of highwire protects against the deleterious effects of traumatic brain injury in Drosophila Melanogaster

10.21203/rs.3.rs-18169/v1 ◽

2020 ◽

Author(s):

Ciaran Scott Hill ◽

Andrea Loreto ◽

Jemeen Sreedha ◽

David Menon ◽

Michael Coleman

Keyword(s):

Traumatic Brain Injury ◽

Drosophila Melanogaster ◽

Brain Injury ◽

Therapeutic Target ◽

Traumatic Injury ◽

Underlying Mechanism ◽

High Impact ◽

Synaptic Proteins ◽

Loss Of Function ◽

Climbing Ability

Abstract BackgroundTraumatic brain injury (TBI) is a major global cause of death and disability. Axonal injury is a major underlying mechanism of TBI and could represent a major therapeutic target. We provide evidence that targeting the axonal death pathway known as Wallerian degeneration (WD) improves outcome in a Drosophila Melanogaster model of high impact trauma. This cell-autonomous neurodegenerative pathway is initiated following axon injury, and in Drosophila, involves activity of the E3 ubiquitin ligase highwire. In this study we explore the effects of that a loss-of-function mutation in the highwire gene has on a range of outcomes following high impact trauma.ResultsResults demonstrate that a loss-of-function mutation in the highwire gene rescues deleterious effects of a traumatic injury, including - improved functional outcomes including climbing ability and flight maintenance, lifespan, survival of a subset of dopaminergic neurons, and retention of synaptic proteins.ConclusionWe demonstrate that a loss-of-function mutation in the highwire gene rescues deleterious effects of a traumatic injury. This data suggests that highwire represents a potential therapeutic target in traumatic injury.

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Loss of the Antimicrobial Peptide Metchnikowin Protects Against Traumatic Brain Injury Outcomes in Drosophila melanogaster

G3 Genes|Genome|Genetics ◽

10.1534/g3.120.401377 ◽

2020 ◽

Vol 10 (9) ◽

pp. 3109-3119 ◽

Cited By ~ 2

Author(s):

Laura C Swanson ◽

Stacey A Rimkus ◽

Barry Ganetzky ◽

David A Wassarman

Keyword(s):

Traumatic Brain Injury ◽

Immune Response ◽

Drosophila Melanogaster ◽

Transcription Factors ◽

Brain Injury ◽

Innate Immune Response ◽

Defense Mechanisms ◽

Innate Immune ◽

Injury Outcomes ◽

The Brain

Abstract Neuroinflammation is a major pathophysiological feature of traumatic brain injury (TBI). Early and persistent activation of innate immune response signaling pathways by primary injuries is associated with secondary cellular injuries that cause TBI outcomes to change over time. We used a Drosophila melanogaster model to investigate the role of antimicrobial peptides (AMPs) in acute and chronic outcomes of closed-head TBI. AMPs are effectors of pathogen and stress defense mechanisms mediated by the evolutionarily conserved Toll and Immune-deficiency (Imd) innate immune response pathways that activate Nuclear Factor kappa B (NF-κB) transcription factors. Here, we analyzed the effect of null mutations in 10 of the 14 known Drosophila AMP genes on TBI outcomes. We found that mutation of Metchnikowin (Mtk) was unique in protecting flies from mortality within the 24 h following TBI under two diet conditions that produce different levels of mortality. In addition, Mtk mutants had reduced behavioral deficits at 24 h following TBI and increased lifespan either in the absence or presence of TBI. Using a transcriptional reporter of gene expression, we found that TBI increased Mtk expression in the brain. Quantitative analysis of mRNA in whole flies revealed that expression of other AMPs in the Toll and Imd pathways as well as NF-κB transcription factors were not altered in Mtk mutants. Overall, these results demonstrate that Mtk plays an infection-independent role in the fly nervous system, and TBI-induced expression of Mtk in the brain activates acute and chronic secondary injury pathways that are also activated during normal aging.

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Cognitive control constrains memory attributions

Behavioral and Brain Sciences ◽

10.1017/s0140525x19001869 ◽

2019 ◽

Vol 42 ◽

Author(s):

Colleen M. Kelley ◽

Larry L. Jacoby

Keyword(s):

Alzheimer’S Disease ◽

Older Adults ◽

Alzheimer's Disease ◽

Traumatic Brain Injury ◽

Brain Injury ◽

Cognitive Control

Abstract Cognitive control constrains retrieval processing and so restricts what comes to mind as input to the attribution system. We review evidence that older adults, patients with Alzheimer's disease, and people with traumatic brain injury exert less cognitive control during retrieval, and so are susceptible to memory misattributions in the form of dramatic levels of false remembering.

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Lessons Learned From Coaching Postsecondary Students With Traumatic Brain Injury

Perspectives of the ASHA Special Interest Groups ◽

10.1044/2019_persp-19-00092 ◽

2020 ◽

Vol 5 (1) ◽

pp. 88-96

Author(s):

Mary R. T. Kennedy

Keyword(s):

College Students ◽

Traumatic Brain Injury ◽

Brain Injury ◽

Sense Of Self ◽

Scientific Evidence ◽

Sudden Onset ◽

Lessons Learned ◽

Speech Language Pathologists ◽

The Brain ◽

Exhaustive List

Purpose The purpose of this clinical focus article is to provide speech-language pathologists with a brief update of the evidence that provides possible explanations for our experiences while coaching college students with traumatic brain injury (TBI). Method The narrative text provides readers with lessons we learned as speech-language pathologists functioning as cognitive coaches to college students with TBI. This is not meant to be an exhaustive list, but rather to consider the recent scientific evidence that will help our understanding of how best to coach these college students. Conclusion Four lessons are described. Lesson 1 focuses on the value of self-reported responses to surveys, questionnaires, and interviews. Lesson 2 addresses the use of immediate/proximal goals as leverage for students to update their sense of self and how their abilities and disabilities may alter their more distal goals. Lesson 3 reminds us that teamwork is necessary to address the complex issues facing these students, which include their developmental stage, the sudden onset of trauma to the brain, and having to navigate going to college with a TBI. Lesson 4 focuses on the need for college students with TBI to learn how to self-advocate with instructors, family, and peers.

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The Speech-Language Pathologists' Role in Mild Traumatic Brain Injury for Middle and High School–Age Children: Viewpoints on Guidelines From the Centers for Disease Control and Prevention

American Journal of Speech-Language Pathology ◽

10.1044/2019_ajslp-18-0296 ◽

2019 ◽

Vol 28 (3) ◽

pp. 1363-1370 ◽

Cited By ~ 2

Author(s):

Jessica Brown ◽

Katy O'Brien ◽

Kelly Knollman-Porter ◽

Tracey Wallace

Keyword(s):

High School ◽

Traumatic Brain Injury ◽

Brain Injury ◽

Disease Control ◽

Mild Traumatic Brain Injury ◽

School Age Children ◽

School Age ◽

Speech Language Pathologists ◽

Control And Prevention ◽

Centers For Disease Control

Purpose The Centers for Disease Control and Prevention (CDC) recently released guidelines for rehabilitation professionals regarding the care of children with mild traumatic brain injury (mTBI). Given that mTBI impacts millions of children each year and can be particularly detrimental to children in middle and high school age groups, access to universal recommendations for management of postinjury symptoms is ideal. Method This viewpoint article examines the CDC guidelines and applies these recommendations directly to speech-language pathology practices. In particular, education, assessment, treatment, team management, and ongoing monitoring are discussed. In addition, suggested timelines regarding implementation of services by speech-language pathologists (SLPs) are provided. Specific focus is placed on adolescents (i.e., middle and high school–age children). Results SLPs are critical members of the rehabilitation team working with children with mTBI and should be involved in education, symptom monitoring, and assessment early in the recovery process. SLPs can also provide unique insight into the cognitive and linguistic challenges of these students and can serve to bridge the gap among rehabilitation and school-based professionals, the adolescent with brain injury, and their parents. Conclusion The guidelines provided by the CDC, along with evidence from the field of speech pathology, can guide SLPs to advocate for involvement in the care of adolescents with mTBI. More research is needed to enhance the evidence base for direct assessment and treatment with this population; however, SLPs can use their extensive knowledge and experience working with individuals with traumatic brain injury as a starting point for post-mTBI care.

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