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Abrogation of atypical neurogenesis and vascular-derived EphA4 prevents repeated mild TBI-induced learning and memory impairments

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dc.contributor.authorGreer, Kishaen
dc.contributor.authorGudenschwager-Basso, Erwin K.en
dc.contributor.authorKelly, Colinen
dc.contributor.authorCash, Alisonen
dc.contributor.authorKowalski, Elizabeth A.en
dc.contributor.authorCerna, Stevenen
dc.contributor.authorOcampo, Collin Tanchancoen
dc.contributor.authorWang, Xiaen
dc.contributor.authorTheus, Michelle H.en
dc.contributor.departmentBiomedical Sciences and Pathobiologyen
dc.date.accessioned2021-02-08T15:46:23Zen
dc.date.available2021-02-08T15:46:23Zen
dc.date.issued2020-09-21en
dc.description.abstractBrain injury resulting from repeated mild traumatic insult is associated with cognitive dysfunction and other chronic co-morbidities. The current study tested the effects of aberrant neurogenesis in a mouse model of repeated mild traumatic brain injury (rmTBI). Using Barnes Maze analysis, we found a significant reduction in spatial learning and memory at 24 days post-rmTBI compared to repeated sham (rSham) injury. Cell fate analysis showed a greater number of BrdU-labeled cells which co-expressed Prox-1 in the DG of rmTBI-injured mice which coincided with enhanced cFos expression for neuronal activity. We then selectively ablated dividing neural progenitor cells using a 7-day continuous infusion of Ara-C prior to rSham or rmTBI. This resulted in attenuation of cFos and BrdU-labeled cell changes and prevented associated learning and memory deficits. We further showed this phenotype was ameliorated in EphA4f.(/f)/Tie2-Cre knockout compared to EphA4f.(/f) wild type mice, which coincided with altered mRNA transcript levels of MCP-1, Cx43 and TGF beta. These findings demonstrate that cognitive decline is associated with an increased presence of immature neurons and gene expression changes in the DG following rmTBI. Our data also suggests that vascular EphA4-mediated neurogenic remodeling adversely affects learning and memory behavior in response to repeated insult.en
dc.description.notesThis work was supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health, R01NS096281 (MHT) and Diversity Supplement to R01NS092681 (KMG). We thank Dr. Gregorio Valdez for the FGF2 primers. We recognize The Center for Engineered Health, The Institute for Critical Technology and Science (JFA award, MHT) and the Initiative for Maximizing Student Development (IMSD) for support (KMG).en
dc.description.sponsorshipNational Institute of Neurological Disorders and Stroke of the National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Neurological Disorders & Stroke (NINDS) [R01NS096281, R01NS092681]; Center for Engineered Health; Institute for Critical Technology and Science (JFA award); Initiative for Maximizing Student Development (IMSD)en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1038/s41598-020-72380-1en
dc.identifier.issn2045-2322en
dc.identifier.issue1en
dc.identifier.other15374en
dc.identifier.pmid32958852en
dc.identifier.urihttp://hdl.handle.net/10919/102300en
dc.identifier.volume10en
dc.language.isoenen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.titleAbrogation of atypical neurogenesis and vascular-derived EphA4 prevents repeated mild TBI-induced learning and memory impairmentsen
dc.title.serialScientific Reportsen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.dcmitypeStillImageen

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