title: Repetitive Closed-Head Impact Model of Engineered Rotational Acceleration Induces Long-Term Cognitive Impairments with Persistent Astrogliosis and Microgliosis in Mice.
abstract: Repeated mild traumatic brain injury (rmTBI) has been identified by epidemiology as a high-risk factor for dementia at a later stage in life. Animal models to replicate complex features of human rmTBI and/or to evaluate long-term effects on brain function have not been established. In this study, we used a novel closed-head impact model of engineered rotational acceleration (CHIMERA) to investigate the long-term neuropathological and cognitive functional consequences of rmTBI. Adult C57BL/6 male mice were subjected to CHIMERA for 3 consecutive days 24 h apart. Functional outcomes were assessed by the beam walk and Morris water maze tests. Neuropathology was evaluated by immunostaining of glial fibrillary acidic protein (GFAP), amyloid precursor protein (APP), and ionizing calcium-binding adaptor molecule-1 (Iba-1), and by quantitative reverse transcription polymerase chain reaction (qRT-PCR) or Western blotting of GFAP, Iba-1, and tumor necrosis factor (TNF)-α. Repeated CHIMERA (rCHIMERA) resulted in motor deficits at 3 days, and in learning and memory impairments that were sustained up to 6 months post injury. GFAP and TNF-α gene expression was increased within a week, whereas astrogliosis and microgliosis were induced starting from day 1 up to 6.5 months after rCHIMERA with upregulated GFAP and Iba-1 protein levels. rCHIMERA also induced APP deposition from day 1 to day 7, but this diminished by 1 month. In conclusion, rCHIMERA produces long-lasting cognitive impairments with astrogliosis and microgliosis in mice, suggesting that rCHIMERA can be a useful animal model to study the long-term complications, as well as the cellular and molecular mechanisms, of human rmTBI.
authors.affiliation: 1 Laboratory of Molecular Signaling, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health , Rockville, Maryland.|2 Center for Neuroscience and Regenerative Medicine at the Uniformed Services University of Health Sciences , Bethesda, Maryland.
authors.forename: Huazhen
authors.initials: H
authors.lastname: Chen
authors.affiliation: 1 Laboratory of Molecular Signaling, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health , Rockville, Maryland.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Desai
authors.affiliation: 1 Laboratory of Molecular Signaling, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health , Rockville, Maryland.
authors.forename: Hee-Yong
authors.initials: HY
authors.lastname: Kim
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001924:Brain Concussion / Q000150:complications / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D003072:Cognition Disorders / Q000209:etiology / Q000503:physiopathology*; D004195:Disease Models, Animal; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000209:etiology / Q000378:metabolism*; D007249:Inflammation / Q000209:etiology / Q000378:metabolism*; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism; D009069:Movement Disorders / Q000209:etiology / Q000503:physiopathology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C491049:Aif1 protein, mouse; D016564:Amyloid beta-Protein Precursor; D002135:Calcium-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; D014409:Tumor Necrosis Factor-alpha; C528900:glial fibrillary astrocytic protein, mouse
keywords: CHIMERA; learning and memory; neuroinflammation; rmTBI