{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T22:19:09Z","timestamp":1792448349154,"version":"4.5.0"},"reference-count":96,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2021,5,7]],"date-time":"2021-05-07T00:00:00Z","timestamp":1620345600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Mackay Hospital and Health Service and the Mackay Institute of Research and Innovation"},{"name":"Australian Government Research Training Scheme"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>The cumulative effect of mild traumatic brain injuries (mTBI) can result in chronic neurological damage, however the molecular mechanisms underpinning this detriment require further investigation. A closed head weight drop model that replicates the biomechanics and head acceleration forces of human mTBI was used to provide an exploration of the acute and chronic outcomes following single and repeated impacts. Adult male C57BL\/6J mice were randomly assigned into one of four impact groups (control; one, five and 15 impacts) which were delivered over 23 days. Outcomes were assessed 48 hours and 3 months following the final mTBI. Hippocampal spatial learning and memory assessment revealed impaired performance in the 15-impact group compared with control in the acute phase that persisted at chronic measurement. mRNA analyses were performed on brain tissue samples of the cortex and hippocampus using quantitative RT-PCR. Eight genes were assessed, namely MAPT, GFAP, AIF1, GRIA1, CCL11, TARDBP, TNF, and NEFL, with expression changes observed based on location and follow-up duration. The cortex and hippocampus showed vulnerability to insult, displaying upregulation of key excitotoxicity and inflammation genes. Serum samples showed no difference between groups for proteins phosphorylated tau and GFAP. These data suggest that the cumulative effect of the impacts was sufficient to induce mTBI pathophysiology and clinical features. The genes investigated in this study provide opportunity for further investigation of mTBI-related neuropathology and may provide targets in the development of therapies that help mitigate the effects of mTBI.<\/jats:p>","DOI":"10.1371\/journal.pone.0251315","type":"journal-article","created":{"date-parts":[[2021,5,7]],"date-time":"2021-05-07T18:41:37Z","timestamp":1620412897000},"page":"e0251315","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":29,"title":["Repetitive mild traumatic brain injury affects inflammation and excitotoxic mRNA expression at acute and chronic time-points"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7054-1492","authenticated-orcid":true,"given":"Matthew I.","family":"Hiskens","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony 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Res"},{"key":"pone.0251315.ref015","doi-asserted-by":"crossref","first-page":"184","DOI":"10.4103\/2152-7806.147566","article-title":"The pathophysiology underlying repetitive mild traumatic brain injury in a novel mouse model of chronic traumatic encephalopathy","volume":"5","author":"AL Petraglia","year":"2014","journal-title":"Surg Neurol Int"},{"key":"pone.0251315.ref016","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.jneumeth.2015.10.002","article-title":"The direction of the acceleration and rotational forces associated with mild traumatic brain injury in rodents effect behavioural and molecular outcomes","volume":"257","author":"R Mychasiuk","year":"2016","journal-title":"J Neurosci Methods"},{"issue":"7","key":"pone.0251315.ref017","doi-asserted-by":"crossref","first-page":"2407","DOI":"10.1111\/ejn.13360","article-title":"Reducing the time interval between concussion and voluntary exercise restores motor impairment, short-term memory, and alterations to gene 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neuroprotection","volume":"1","author":"M Hiskens","year":"2021","journal-title":"Trauma Care"},{"issue":"1","key":"pone.0251315.ref024","article-title":"Purification of nucleic acids by extraction with phenol:chloroform","volume":"2006","author":"J Sambrook","year":"2006","journal-title":"CSH protocols"},{"issue":"4","key":"pone.0251315.ref025","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method","volume":"25","author":"KJ Livak","year":"2001","journal-title":"Methods (San Diego, Calif)"},{"issue":"9","key":"pone.0251315.ref026","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1089\/neu.2012.2349","article-title":"Challenges in the development of rodent models of mild traumatic brain injury","volume":"30","author":"DS Dewitt","year":"2013","journal-title":"J Neurotrauma"},{"key":"pone.0251315.ref027","doi-asserted-by":"crossref","first-page":"223","DOI":"10.3389\/fneur.2015.00223","article-title":"Modeling Chronic Traumatic Encephalopathy: The Way Forward for Future Discovery","volume":"6","author":"RC Turner","year":"2015","journal-title":"Front Neurol"},{"issue":"10","key":"pone.0251315.ref028","doi-asserted-by":"crossref","first-page":"S460","DOI":"10.1016\/j.pmrj.2011.08.008","article-title":"Long-term consequences of repetitive brain trauma: chronic traumatic encephalopathy","volume":"3","author":"RA Stern","year":"2011","journal-title":"PM R"},{"issue":"11","key":"pone.0251315.ref029","doi-asserted-by":"crossref","first-page":"2869","DOI":"10.1016\/j.ajpath.2016.07.013","article-title":"Prolonged Repetitive Head Trauma Induces a Singular Chronic Traumatic Encephalopathy-Like Pathology in White Matter Despite Transient Behavioral Abnormalities","volume":"186","author":"DI Briggs","year":"2016","journal-title":"The American journal of pathology"},{"issue":"1","key":"pone.0251315.ref030","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1186\/1750-1326-9-55","article-title":"Merging pathology with biomechanics using CHIMERA (Closed-Head Impact Model of Engineered Rotational Acceleration): a novel, surgery-free model of traumatic brain injury","volume":"9","author":"DR Namjoshi","year":"2014","journal-title":"Mol Neurodegener"},{"key":"pone.0251315.ref031","doi-asserted-by":"crossref","first-page":"1707","DOI":"10.12659\/MSM.901124","article-title":"Long-Term Kinetics of Immunologic Components and Neurological Deficits in Rats Following Repetitive Mild Traumatic Brain Injury","volume":"23","author":"R Bai","year":"2017","journal-title":"Medical science monitor: international medical journal of experimental and clinical research"},{"key":"pone.0251315.ref032","article-title":"Differential responses to increasing numbers of mild traumatic brain injury in a rodent closed-head injury model","author":"B Fehily","year":"2019","journal-title":"J Neurochem"},{"issue":"4","key":"pone.0251315.ref033","doi-asserted-by":"crossref","first-page":"37","DOI":"10.3390\/diagnostics6040037","article-title":"Fluid Biomarkers of Traumatic Brain Injury and Intended Context of Use","volume":"6","author":"T Bogoslovsky","year":"2016","journal-title":"Diagnostics (Basel)."},{"issue":"13","key":"pone.0251315.ref034","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1089\/neu.2013.3255","article-title":"The spectrum of neurobehavioral sequelae after repetitive mild traumatic brain injury: a novel mouse model of chronic traumatic encephalopathy","volume":"31","author":"AL Petraglia","year":"2014","journal-title":"J Neurotrauma"},{"issue":"6","key":"pone.0251315.ref035","doi-asserted-by":"crossref","first-page":"1342","DOI":"10.3171\/2014.7.JNS14272","article-title":"Chronic gliosis and behavioral deficits in mice following repetitive mild traumatic brain injury","volume":"121","author":"R Mannix","year":"2014","journal-title":"J Neurosurg"},{"issue":"4","key":"pone.0251315.ref036","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1227\/NEU.0b013e318265a439","article-title":"3rd, Zhang J, Mannix R, Whalen MJ. Increasing recovery time between injuries improves cognitive outcome after repetitive mild concussive brain injuries in mice","volume":"71","author":"WP Meehan","year":"2012","journal-title":"Neurosurgery"},{"issue":"3","key":"pone.0251315.ref037","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1001\/2013.jamaneurol.340","article-title":"Neuroimaging of cognitive dysfunction and depression in aging retired National Football League players: a cross-sectional study","volume":"70","author":"J Hart","year":"2013","journal-title":"JAMA Neurol"},{"issue":"3","key":"pone.0251315.ref038","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1093\/brain\/awn347","article-title":"Brain function decline in healthy retired athletes who sustained their last sports concussion in early adulthood","volume":"132","author":"L De Beaumont","year":"2009","journal-title":"Brain"},{"issue":"107","key":"pone.0251315.ref039","doi-asserted-by":"crossref","first-page":"107","DOI":"10.4103\/2152-7806.83391","article-title":"Immunoexcitotoxicity as a central mechanism in chronic traumatic encephalopathy-A unifying hypothesis","volume":"2","author":"RL Blaylock","year":"2011","journal-title":"Surg Neurol Int"},{"issue":"9","key":"pone.0251315.ref040","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.2174\/092986712799462711","article-title":"The glutamatergic neurotransmission in the central nervous system","volume":"19","author":"P Marmiroli","year":"2012","journal-title":"Current medicinal chemistry"},{"key":"pone.0251315.ref041","first-page":"140","article-title":"GABA and glutamate transporters in brain","author":"Y Zhou","year":"2014","journal-title":"Astrocytic-neuronal-astrocytic Pathway Selection for Formation and Degradation of Glutamate\/GABA"},{"issue":"7","key":"pone.0251315.ref042","first-page":"751","article-title":"Pathophysiology of neurodegeneration following traumatic brain injury","volume":"61","author":"MA Freire","year":"2012","journal-title":"West Indian Med J"},{"issue":"8","key":"pone.0251315.ref043","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1016\/0896-6273(88)90162-6","article-title":"Glutamate neurotoxicity and diseases of the nervous system","volume":"1","author":"DW Choi","year":"1988","journal-title":"Neuron"},{"issue":"9","key":"pone.0251315.ref044","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/0165-6147(90)90184-A","article-title":"Excitatory amino acid neurotoxicity and neurodegenerative disease","volume":"11","author":"B Meldrum","year":"1990","journal-title":"Trends Pharmacol Sci"},{"issue":"1","key":"pone.0251315.ref045","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.neuropharm.2008.08.006","article-title":"The history of the pharmacology and cloning of ionotropic glutamate receptors and the development of idiosyncratic nomenclature","volume":"56","author":"D Lodge","year":"2009","journal-title":"Neuropharmacology"},{"issue":"5","key":"pone.0251315.ref046","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1254\/jphs.CPJ06007X","article-title":"Molecular mechanism of neuronal plasticity: induction and maintenance of long-term potentiation in the hippocampus","volume":"100","author":"E Miyamoto","year":"2006","journal-title":"J Pharmacol Sci"},{"issue":"2","key":"pone.0251315.ref047","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1016\/j.expneurol.2008.06.013","article-title":"Exacerbated glial response in the aged mouse hippocampus following controlled cortical impact injury","volume":"213","author":"R Sandhir","year":"2008","journal-title":"Exp Neurol"},{"issue":"8504","key":"pone.0251315.ref048","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1016\/S0140-6736(86)92134-3","article-title":"Defective brain microtubule assembly in Alzheimer\u2019s disease","volume":"2","author":"K Iqbal","year":"1986","journal-title":"Lancet (London, England)"},{"issue":"7","key":"pone.0251315.ref049","doi-asserted-by":"crossref","first-page":"a006247","DOI":"10.1101\/cshperspect.a006247","article-title":"Biochemistry and cell biology of tau protein in neurofibrillary degeneration","volume":"2","author":"EM Mandelkow","year":"2012","journal-title":"Cold Spring Harb Perspect Med"},{"issue":"1","key":"pone.0251315.ref050","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1007\/s00401-015-1515-z","article-title":"The first NINDS\/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy","volume":"131","author":"AC McKee","year":"2016","journal-title":"Acta Neuropathol"},{"issue":"7","key":"pone.0251315.ref051","doi-asserted-by":"crossref","first-page":"e0132177","DOI":"10.1371\/journal.pone.0132177","article-title":"Comparative Assessment of the Prognostic Value of Biomarkers in Traumatic Brain Injury Reveals an Independent Role for Serum Levels of Neurofilament Light","volume":"10","author":"F Al Nimer","year":"2015","journal-title":"PLoS One"},{"issue":"5","key":"pone.0251315.ref052","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1177\/1352458512443092","article-title":"Neurofilaments as biomarkers in multiple sclerosis","volume":"18","author":"CE Teunissen","year":"2012","journal-title":"Mult Scler"},{"issue":"4","key":"pone.0251315.ref053","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1080\/02699052.2019.1565895","article-title":"NFL blood levels are moderated by subconcussive impacts in a cohort of college football players","volume":"33","author":"LH Rubin","year":"2019","journal-title":"Brain Inj"},{"issue":"1","key":"pone.0251315.ref054","doi-asserted-by":"crossref","DOI":"10.3390\/brainsci10010023","article-title":"Towards the Development of an Integrative, Evidence-Based Suite of Indicators for the Prediction of Outcome Following Mild Traumatic Brain Injury: Results from a Pilot Study","volume":"10","author":"A Gozt","year":"2020","journal-title":"Brain sciences"},{"issue":"1","key":"pone.0251315.ref055","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s40478-018-0649-3","article-title":"Increased plasma neurofilament light chain concentration correlates with severity of post-mortem neurofibrillary tangle pathology and neurodegeneration","volume":"7","author":"NJ Ashton","year":"2019","journal-title":"Acta neuropathologica communications"},{"issue":"7","key":"pone.0251315.ref056","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1515\/hsz-2012-0115","article-title":"TDP-43 in central nervous system development and function: clues to TDP-43-associated neurodegeneration","volume":"393","author":"CF Sephton","year":"2012","journal-title":"Biol Chem"},{"issue":"12","key":"pone.0251315.ref057","doi-asserted-by":"crossref","first-page":"2006","DOI":"10.1007\/s11064-007-9318-9","article-title":"Temporal profiles of cytoskeletal protein loss following traumatic axonal injury in mice","volume":"32","author":"G Serbest","year":"2007","journal-title":"Neurochem Res"},{"key":"pone.0251315.ref058","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.brainres.2009.07.023","article-title":"Cytosolic TDP-43 expression following axotomy is associated with caspase 3 activation in NFL-\/- mice: support for a role for TDP-43 in the physiological response to neuronal injury","volume":"1296","author":"K Moisse","year":"2009","journal-title":"Brain Res"},{"issue":"5","key":"pone.0251315.ref059","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1016\/j.semcdb.2011.04.002","article-title":"Misfolded protein aggregates: mechanisms, structures and potential for disease transmission","volume":"22","author":"I Moreno-Gonzalez","year":"2011","journal-title":"Seminars in cell & developmental biology"},{"issue":"9","key":"pone.0251315.ref060","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1097\/NEN.0b013e3181ee7d85","article-title":"TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy","volume":"69","author":"AC McKee","year":"2010","journal-title":"Journal of neuropathology and experimental neurology"},{"issue":"4","key":"pone.0251315.ref061","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1111\/j.1440-1789.2009.01085.x","article-title":"Abnormal TDP\u201043 expression is identified in the neocortex in cases of dementia pugilistica, but is mainly confined to the limbic system when identified in high and moderate stages of Alzheimer\u2019s disease","volume":"30","author":"A King","year":"2010","journal-title":"Neuropathology"},{"issue":"5","key":"pone.0251315.ref062","first-page":"305","article-title":"The role of glial cells in Alzheimer disease: potential therapeutic implications","volume":"29","author":"I Lopategui Cabezas","year":"2014","journal-title":"Neurologia"},{"issue":"5","key":"pone.0251315.ref063","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1001\/jamaneurol.2016.0039","article-title":"Time Course and Diagnostic Accuracy of Glial and Neuronal Blood Biomarkers GFAP and UCH-L1 in a Large Cohort of Trauma Patients With and Without Mild Traumatic Brain Injury","volume":"73","author":"L Papa","year":"2016","journal-title":"JAMA Neurol"},{"issue":"1","key":"pone.0251315.ref064","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1007\/s00401-009-0619-8","article-title":"Astrocytes: biology and pathology","volume":"119","author":"MV Sofroniew","year":"2010","journal-title":"Acta Neuropathol"},{"issue":"6","key":"pone.0251315.ref065","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/j.annemergmed.2011.08.021","article-title":"Elevated levels of serum glial fibrillary acidic protein breakdown products in mild and moderate traumatic brain injury are associated with intracranial lesions and neurosurgical intervention","volume":"59","author":"L Papa","year":"2012","journal-title":"Annals of emergency medicine"},{"issue":"9","key":"pone.0251315.ref066","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1016\/S1474-4422(18)30231-X","article-title":"Serum GFAP and UCH-L1 for prediction of absence of intracranial injuries on head CT (ALERT-TBI): a multicentre observational study","volume":"17","author":"JJ Bazarian","year":"2018","journal-title":"The Lancet Neurology"},{"issue":"18","key":"pone.0251315.ref067","doi-asserted-by":"crossref","first-page":"1428","DOI":"10.1212\/WNL.0b013e318253d5c7","article-title":"GFAP and S100B in the acute phase of mild traumatic brain injury","volume":"78","author":"Z Metting","year":"2012","journal-title":"Neurology"},{"issue":"1","key":"pone.0251315.ref068","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1089\/neu.2015.4333","article-title":"Increases of Plasma Levels of Glial Fibrillary Acidic Protein, Tau, and Amyloid beta up to 90 Days after Traumatic Brain Injury.","volume":"34","author":"T Bogoslovsky","year":"2017","journal-title":"J Neurotrauma"},{"issue":"Pt 3:","key":"pone.0251315.ref069","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1016\/j.expneurol.2015.08.018","article-title":"Microglia in the TBI brain: The good, the bad, and the dysregulated","volume":"275","author":"DJ Loane","year":"2016","journal-title":"Exp Neurol"},{"issue":"1","key":"pone.0251315.ref070","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.cell.2014.06.008","article-title":"Sublime microglia: expanding roles for the guardians of the CNS","volume":"158","author":"MW Salter","year":"2014","journal-title":"Cell"},{"issue":"40","key":"pone.0251315.ref071","first-page":"9275","article-title":"Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration. The Journal of neuroscience: the official journal of the","volume":"25","author":"C Cunningham","year":"2005","journal-title":"Society for Neuroscience"},{"key":"pone.0251315.ref072","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1186\/s12974-015-0457-7","article-title":"Progesterone treatment reduces neuroinflammation, oxidative stress and brain damage and improves long-term outcomes in a rat model of repeated mild traumatic brain injury","volume":"12","author":"KM Webster","year":"2015","journal-title":"J Neuroinflammation"},{"issue":"4","key":"pone.0251315.ref073","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1111\/bph.13179","article-title":"Progressive inflammation-mediated neurodegeneration after traumatic brain or spinal cord injury","volume":"173","author":"AI Faden","year":"2016","journal-title":"British journal of pharmacology"},{"issue":"3","key":"pone.0251315.ref074","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1001\/jamaneurol.2014.3558","article-title":"Inflammation and neuroprotection in traumatic brain injury","volume":"72","author":"KN Corps","year":"2015","journal-title":"JAMA Neurol"},{"issue":"6","key":"pone.0251315.ref075","doi-asserted-by":"crossref","first-page":"1410","DOI":"10.1007\/s11064-019-02721-8","article-title":"Inflammation in Traumatic Brain Injury: Roles for Toxic A1 Astrocytes and Microglial\u2013Astrocytic Crosstalk","volume":"44","author":"DP Clark","year":"2019","journal-title":"Neurochemical research"},{"issue":"1","key":"pone.0251315.ref076","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.neulet.2009.06.065","article-title":"Rotenone and paraquat do not directly activate microglia or induce inflammatory cytokine release","volume":"462","author":"H Klintworth","year":"2009","journal-title":"Neurosci Lett"},{"issue":"1","key":"pone.0251315.ref077","first-page":"18","article-title":"The role of markers of inflammation in traumatic brain injury","volume":"4","author":"T Woodcock","year":"2013","journal-title":"Front Neurol"},{"issue":"4","key":"pone.0251315.ref078","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1038\/jcbfm.1994.76","article-title":"Closed head injury triggers early production of TNF alpha and IL-6 by brain tissue","volume":"14","author":"E Shohami","year":"1994","journal-title":"Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism"},{"issue":"11","key":"pone.0251315.ref079","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.1080\/02699052.2017.1363407","article-title":"Staying in the game: a pilot study examining the efficacy of protective headgear in an animal model of mild traumatic brain injury (mTBI).","volume":"31","author":"S Candy","year":"2017","journal-title":"Brain Inj"},{"issue":"1\u20132","key":"pone.0251315.ref080","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/S0165-5728(98)00273-2","article-title":"Early neuronal expression of tumor necrosis factor-alpha after experimental brain injury contributes to neurological impairment","volume":"95","author":"SM Knoblach","year":"1999","journal-title":"J Neuroimmunol"},{"issue":"2","key":"pone.0251315.ref081","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/S0165-5728(99)00148-4","article-title":"IL-10 levels in cerebrospinal fluid and serum of patients with severe traumatic brain injury: relationship to IL-6, TNF-\u03b1, TGF-\u03b21 and blood\u2013brain barrier function","volume":"101","author":"E Csuka","year":"1999","journal-title":"Journal of neuroimmunology"},{"key":"pone.0251315.ref082","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1186\/1742-2094-8-139","article-title":"Brain microvascular pericytes are immunoactive in culture: cytokine, chemokine, nitric oxide, and LRP-1 expression in response to lipopolysaccharide","volume":"8","author":"A Kovac","year":"2011","journal-title":"J Neuroinflammation"},{"issue":"12","key":"pone.0251315.ref083","doi-asserted-by":"crossref","first-page":"2274","DOI":"10.1002\/glia.22892","article-title":"CCL11 enhances excitotoxic neuronal death by producing reactive oxygen species in microglia","volume":"63","author":"B Parajuli","year":"2015","journal-title":"Glia"},{"issue":"7362","key":"pone.0251315.ref084","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1038\/nature10357","article-title":"The ageing systemic milieu negatively regulates neurogenesis and cognitive function","volume":"477","author":"SA Villeda","year":"2011","journal-title":"Nature"},{"issue":"9","key":"pone.0251315.ref085","doi-asserted-by":"crossref","first-page":"e0185541","DOI":"10.1371\/journal.pone.0185541","article-title":"CCL11 is increased in the CNS in chronic traumatic encephalopathy but not in Alzheimer\u2019s disease","volume":"12","author":"JD Cherry","year":"2017","journal-title":"PLoS One"},{"issue":"3","key":"pone.0251315.ref086","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1080\/1354750X.2020.1735521","article-title":"Blood biomarkers for assessment of mild traumatic brain injury and chronic traumatic encephalopathy","volume":"25","author":"MI Hiskens","year":"2020","journal-title":"Biomarkers"},{"issue":"9","key":"pone.0251315.ref087","doi-asserted-by":"crossref","first-page":"e25475","DOI":"10.1371\/journal.pone.0025475","article-title":"Distinct temporal and anatomical distributions of amyloid-beta and tau abnormalities following controlled cortical impact in transgenic mice","volume":"6","author":"HT Tran","year":"2011","journal-title":"PLoS One"},{"issue":"4","key":"pone.0251315.ref088","doi-asserted-by":"crossref","first-page":"e33606","DOI":"10.1371\/journal.pone.0033606","article-title":"CSF-biomarkers in Olympic boxing: diagnosis and effects of repetitive head trauma","volume":"7","author":"S Neselius","year":"2012","journal-title":"PloS one"},{"issue":"6","key":"pone.0251315.ref089","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1001\/jamaneurol.2014.367","article-title":"Blood biomarkers for brain injury in concussed professional ice hockey players","volume":"71","author":"P Shahim","year":"2014","journal-title":"JAMA Neurol"},{"key":"pone.0251315.ref090","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.dadm.2016.11.003","article-title":"Repetitive head impact exposure and later-life plasma total tau in former National Football League players","volume":"7","author":"ML Alosco","year":"2017","journal-title":"Alzheimers Dement (Amst)"},{"issue":"10","key":"pone.0251315.ref091","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1001\/jamaneurol.2015.1383","article-title":"Peripheral Total Tau in Military Personnel Who Sustain Traumatic Brain Injuries During Deployment","volume":"72","author":"A Olivera","year":"2015","journal-title":"JAMA Neurol"},{"issue":"10","key":"pone.0251315.ref092","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1038\/nrneurol.2016.127","article-title":"Fluid biomarkers for mild traumatic brain injury and related conditions","volume":"12","author":"H Zetterberg","year":"2016","journal-title":"Nature reviews Neurology"},{"issue":"6","key":"pone.0251315.ref093","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1242\/dmm.011320","article-title":"Towards clinical management of traumatic brain injury: a review of models and mechanisms from a biomechanical perspective","volume":"6","author":"DR Namjoshi","year":"2013","journal-title":"Dis Model Mech"},{"issue":"7500","key":"pone.0251315.ref094","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1038\/509282a","article-title":"Policy: NIH to balance sex in cell and animal studies","volume":"509","author":"JA 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