CoChat
Sign Up
Cited by 87Traumatic Brain Injury and Neurovascular DisturbancesTraumatic Brain Injury ResearchNeurobiology and Insect Physiology Research

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

Open access
Barekat, Ayeh, Gonzalez, Arysa, Mauntz, Ruth E., Kotzebue, Roxanne W., Molina, Brandon, El-Mecharrafie, Nadja, Conner, Catherine J., Garza, Shannon +5 more·2016·Scientific Reports
DOI 10.1038/srep25252PMC PMC4855207
Open this paper in CoChat — free accountOpen PDF

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/srep25252

Cites

5 of 5 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Animal models recapitulate sleep phenotypes of disordered sleep in humans, especially excessive daytime sleepiness.

    “Animal models recapitulate sleep phenotypes of disordered sleep in humans, especially that of EDS.22,44,45,48,49,64–73”

    From Effects of Traumatic Brain Injury on the Orexin/Hypocretin System (2025) · cites this paper as [64]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 50

  1. Xiong Y., Mahmood A. & Chopp M. Animal models of traumatic brain injury. Nat Rev Neurosci 14, 128– 142, doi: 10.1038/nrn3407 (2013). 23329160 PMC3951995 · DOI
  2. Kane M. J.. A mouse model of human repetitive mild traumatic brain injury. J Neurosci Methods 203, 41– 49, doi: 10.1016/j.jneumeth.2011.09.003 (2012). 21930157 PMC3221913 · DOI
  3. Mouzon B.. Repetitive mild traumatic brain injury in a mouse model produces learning and memory deficits accompanied by histological changes. J Neurotrauma 29, 2761– 2773, doi: 10.1089/neu.2012.2498 (2012). 22900595 PMC13588329 · DOI
  4. Landre N., Poppe C. J., Davis N., Schmaus B. & Hobbs S. E. Cognitive functioning and postconcussive symptoms in trauma patients with and without mild TBI. Arch Clin Neuropsychol 21, 255– 273, doi: 10.1016/j.acn.2005.12.007 (2006). 16716563 · DOI
  5. Stern R. A.. Long-term consequences of repetitive brain trauma: chronic traumatic encephalopathy. PM R 3, S460– 467, doi: 10.1016/j.pmrj.2011.08.008 (2011). 22035690 · DOI
  6. Laskowski R. A., Creed J. A. & Raghupathi R. In Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects Frontiers in Neuroengineering (ed Kobeissy F. H.) (2015). 26269865
  7. Lozano D.. Neuroinflammatory responses to traumatic brain injury: etiology, clinical consequences, and therapeutic opportunities. Neuropsychiatr Dis Treat 11, 97– 106, doi: 10.2147/NDT.S65815 (2015). 25657582 PMC4295534 · DOI
  8. Faden A. I., Wu J., Stoica B. A. & Loane D. J. Progressive inflammation-mediated neurodegeneration after traumatic brain or spinal cord injury. Br J Pharmacol, doi: 10.1111/bph.13179 (2015). PMC4742301 25939377 · DOI
  9. Lipinski M. M., Wu J., Faden A. I. & Sarkar C. Function and Mechanisms of Autophagy in Brain and Spinal Cord Trauma. Antioxid Redox Signal 23, 565– 577, doi: 10.1089/ars.2015.6306 (2015). 25808205 PMC4545370 · DOI
  10. He C. & Klionsky D. J. Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 43, 67– 93, doi: 10.1146/annurev-genet-102808-114910 (2009). 19653858 PMC2831538 · DOI · Paper page
  11. Klionsky D. J.. Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy 4, 151– 175 (2008). 18188003 PMC2654259
  12. Sarkar C.. Impaired autophagy flux is associated with neuronal cell death after traumatic brain injury. Autophagy 10, 2208– 2222, doi: 10.4161/15548627.2014.981787 (2014). 25484084 PMC4502690 · DOI
  13. Lipinski M. M. & Wu J. Modification of autophagy-lysosomal pathway as a neuroprotective treatment for spinal cord injury. Neural Regen Res 10, 892– 893, doi: 10.4103/1673-5374.158344 (2015). 26199601 PMC4498346 · DOI
  14. Susman M.. Traumatic brain injury in the elderly: increased mortality and worse functional outcome at discharge despite lower injury severity. J Trauma 53, 219– 223, discussion 223– 214 (2002). 12169925
  15. Katzenberger R. J.. A Drosophila model of closed head traumatic brain injury. Proc Natl Acad Sci USA 110, E4152– 4159, doi: 10.1073/pnas.1316895110 (2013). 24127584 PMC3816429 · DOI
  16. Katzenberger R. J.. Death following traumatic brain injury in Drosophila is associated with intestinal barrier dysfunction. Elife 4, doi: 10.7554/eLife.04790 (2015). PMC4377547 25742603 · DOI
  17. McCrea M.. Standardized assessment of concussion (SAC): on-site mental status evaluation of the athlete. J Head Trauma Rehabil 13, 27– 35 (1998). 9575254
  18. Simon A. F., Liang D. T. & Krantz D. E. Differential decline in behavioral performance of Drosophila melanogaster with age. Mech Ageing Dev 127, 647– 651, doi: 10.1016/j.mad.2006.02.006 (2006). 16616306 · DOI
  19. Ratliff E. P.. Aging and Autophagic Function Influences the Progressive Decline of Adult Drosophila Behaviors. Plos One 10, e0132768, doi: 10.1371/journal.pone.0132768 (2015). 26182057 PMC4504520 · DOI
  20. Talavage T. M.. Functionally-detected cognitive impairment in high school football players without clinically-diagnosed concussion. J Neurotrauma 31, 327– 338, doi: 10.1089/neu.2010.1512 (2014). 20883154 PMC3922228 · DOI
  21. Onyszchuk G., He Y. Y., Berman N. E. & Brooks W. M. Detrimental effects of aging on outcome from traumatic brain injury: a behavioral, magnetic resonance imaging, and histological study in mice. J Neurotrauma 25, 153– 171, doi: 10.1089/neu.2007.0430 (2008). 18260798 · DOI
  22. Peschel N. & Helfrich-Forster C. Setting the clock–by nature: circadian rhythm in the fruitfly Drosophila melanogaster. FEBS Lett 585, 1435– 1442, doi: 10.1016/j.febslet.2011.02.028 (2011). 21354415 · DOI
  23. Rieger D., Shafer O. T., Tomioka K. & Helfrich-Forster C. Functional analysis of circadian pacemaker neurons in Drosophila melanogaster. J Neurosci 26, 2531– 2543, doi: 10.1523/JNEUROSCI.1234-05.2006 (2006). 16510731 PMC6793667 · DOI
  24. Jackson G. R.. Human wild-type tau interacts with wingless pathway components and produces neurofibrillary pathology in Drosophila. Neuron 34, 509– 519 (2002). 12062036
  25. Genis L., Chen Y., Shohami E. & Michaelson D. M. Tau hyperphosphorylation in apolipoprotein E-deficient and control mice after closed head injury. J Neurosci Res 60, 559– 564 (2000). 10797559
  26. Tran H. T., LaFerla F. M., Holtzman D. M. & Brody D. L. Controlled cortical impact traumatic brain injury in 3×Tg-AD mice causes acute intra-axonal amyloid-beta accumulation and independently accelerates the development of tau abnormalities. J Neurosci 31, 9513– 9525, doi: 10.1523/JNEUROSCI.0858-11.2011 (2011). 21715616 PMC3146343 · DOI · Paper page
  27. Simonsen A.. Promoting basal levels of autophagy in the nervous system enhances longevity and oxidant resistance in adult Drosophila. Autophagy 4, 176– 184 (2008). 18059160
  28. Rera M.. Modulation of longevity and tissue homeostasis by the Drosophila PGC-1 homolog. Cell Metab 14, 623– 634, doi: 10.1016/j.cmet.2011.09.013 (2011). 22055505 PMC3238792 · DOI · Paper page
  29. Rera M., Clark R. I. & Walker D. W. Intestinal barrier dysfunction links metabolic and inflammatory markers of aging to death in Drosophila. Proc Natl Acad Sci USA 109, 21528– 21533, doi: 10.1073/pnas.1215849110 (2012). 23236133 PMC3535647 · DOI
  30. Nonaka M.. Prolonged activation of NF-kappaB following traumatic brain injury in rats. J Neurotrauma 16, 1023– 1034 (1999). 10595819
  31. Hoffmann J. A. The immune response of Drosophila. Nature 426, 33– 38, doi: 10.1038/nature02021 (2003). 14603309 · DOI · Paper page
  32. Gyoneva S. & Ransohoff R. M. Inflammatory reaction after traumatic brain injury: therapeutic potential of targeting cell-cell communication by chemokines. Trends Pharmacol Sci 36, 471– 480, doi: 10.1016/j.tips.2015.04.003 (2015). 25979813 PMC4485943 · DOI
  33. Luo C. L.. Autophagy is involved in traumatic brain injury-induced cell death and contributes to functional outcome deficits in mice. Neuroscience 184, 54– 63, doi: 10.1016/j.neuroscience.2011.03.021 (2011). 21463664 · DOI
  34. Sadasivan S., Dunn W. A. Jr., Hayes R. L. & Wang K. K. Changes in autophagy proteins in a rat model of controlled cortical impact induced brain injury. Biochem Biophys Res Commun 373, 478– 481, doi: 10.1016/j.bbrc.2008.05.031 (2008). 18486600 · DOI
  35. Mizushima N. Autophagy: process and function. Genes Dev 21, 2861– 2873, doi: 10.1101/gad.1599207 (2007). 18006683 · DOI
  36. Nagy P., Varga A., Kovacs A. L., Takats S. & Juhasz G. How and why to study autophagy in Drosophila: it’s more than just a garbage chute. Methods 75, 151– 161, doi: 10.1016/j.ymeth.2014.11.016 (2015). 25481477 PMC4358840 · DOI
  37. Takats S.. Autophagosomal Syntaxin17-dependent lysosomal degradation maintains neuronal function in Drosophila. J Cell Biol 201, 531– 539, doi: 10.1083/jcb.201211160 (2013). 23671310 PMC3653357 · DOI
  38. Nezis I. P.. Ref(2)P, the Drosophila melanogaster homologue of mammalian p62, is required for the formation of protein aggregates in adult brain. J Cell Biol 180, 1065– 1071, doi: 10.1083/jcb.200711108 (2008). 18347073 PMC2290837 · DOI · Paper page
  39. Nezis I. P. Selective autophagy in Drosophila. Int J Cell Biol 2012, 146767, doi: 10.1155/2012/146767 (2012). 22567011 PMC3332208 · DOI
  40. DeVorkin L. & Gorski S. M. Monitoring autophagic flux using Ref(2)P, the Drosophila p62 ortholog. Cold Spring Harb Protoc 2014, 959– 966, doi: 10.1101/pdb.prot080333 (2014). 25183816 · DOI
  41. Klemenhagen K. C., O’Brien S. P. & Brody D. L. Repetitive concussive traumatic brain injury interacts with post-injury foot shock stress to worsen social and depression-like behavior in mice. Plos One 8, e74510, doi: 10.1371/journal.pone.0074510 (2013). 24058581 PMC3776826 · DOI
  42. Yang Z.. Temporal MRI characterization, neurobiochemical and neurobehavioral changes in a mouse repetitive concussive head injury model. Sci Rep 5, 11178, doi: 10.1038/srep11178 (2015). 26058556 PMC4461921 · DOI
  43. Lim M. M.. Dietary therapy mitigates persistent wake deficits caused by mild traumatic brain injury. Sci Transl Med 5, 215ra173, doi: 10.1126/scitranslmed.3007092 (2013). PMC3951738 24337480 · DOI · Paper page
  44. Verma A., Anand V. & Verma N. P. Sleep disorders in chronic traumatic brain injury. J Clin Sleep Med 3, 357– 362 (2007). 17694723 PMC1978305
  45. Kempf J., Werth E., Kaiser P. R., Bassetti C. L. & Baumann C. R. Sleep-wake disturbances 3 years after traumatic brain injury. J Neurol Neurosurg Psychiatry 81, 1402– 1405, doi: 10.1136/jnnp.2009.201913 (2010). 20884672 · DOI
  46. Sehgal A. & Mignot E. Genetics of sleep and sleep disorders. Cell 146, 194– 207, doi: 10.1016/j.cell.2011.07.004 (2011). 21784243 PMC3153991 · DOI
  47. Blake M. R.. Manipulations of amyloid precursor protein cleavage disrupt the circadian clock in aging Drosophila. Neurobiol Dis 77, 117– 126, doi: 10.1016/j.nbd.2015.02.012 (2015). 25766673 PMC4402283 · DOI
  48. Katzenberger R. J., Ganetzky B. & Wassarman D. A. The gut reaction to traumatic brain injury. Fly (Austin), 0, doi: 10.1080/19336934.2015.1085623 (2015). PMC5019014 26291482 · DOI
  49. Mullington J. M., Simpson N. S., Meier-Ewert H. K. & Haack M. Sleep loss and inflammation. Best Pract Res Clin Endocrinol Metab 24, 775– 784, doi: 10.1016/j.beem.2010.08.014 (2010). 21112025 PMC3548567 · DOI · Paper page
  50. Koh K., Evans J. M., Hendricks J. C. & Sehgal A. A Drosophila model for age-associated changes in sleep:wake cycles. Proc Natl Acad Sci USA 103, 13843– 13847, doi: 10.1073/pnas.0605903103 (2006). 16938867 PMC1564207 · DOI

Cited by

Sorted by citations

Authors
Barekat, A., Gonzalez, A., Mauntz, R. E., Kotzebue, R. W., Molina, B., El-Mecharrafie, N., Conner, C. J., Garza, S., Melkani, G. C., Joiner, W. J., Lipinski, M. M., Finley, K. D., & Ratliff, E. P.
Affiliations
  • San Diego State University (US)
  • University of California San Diego (US)
  • University of Maryland, Baltimore (US)
Corresponding author
  • Finley, Kim D.
  • Ratliff, Eric P.
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2016-05-04
Volume
6
Issue
1
Pages
25252-25252
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/srep25252
PMC
PMC4855207
OpenAlex
W2345431871
Cited by
87
References
5
Citations by year
2026: 5 · 2025: 6 · 2024: 14 · 2023: 12 · 2022: 6 · 2021: 12 · 2020: 12 · 2019: 7 · 2018: 6 · 2017: 6 · 2016: 1
FWCI
5.01
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Institutes of Health
  • National Institute on Aging (R01AG039628)
  • National Institute of Neurological Disorders and Stroke (R01NS091218)
Topics
  • Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
  • Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurobiology and Insect Physiology Research
Keywords
mild traumatic brain injury, Drosophila model, neuroinflammation, autophagy, tau phosphorylation, sleep behavior, neuronal dysfunction
MeSH terms
Brain Injuries, Traumatic, Animals, Disease Models, Animal, Drosophila

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review