Author:
Greer Kisha,Basso Erwin Kristobal Gudenschwager,Kelly Colin,Cash Alison,Kowalski Elizabeth,Cerna Steven,Ocampo Collin Tanchanco,Wang Xia,Theus Michelle H.
Abstract
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 TGFβ. 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.
Funder
National Institutes of Health
Publisher
Springer Science and Business Media LLC
Reference68 articles.
1. Taylor, C. A., Bell, J. M., Breiding, M. J. & Xu, L. Traumatic brain injury-related emergency department visits, hospitalizations, and deaths: United States, 2007 and 2013. MMWR Surveill. Summ. 66(9), 1–16 (2017).
2. Mez, J., Solomon, T. M., Daneshvar, D. H., Stein, T. D. & McKee, A. C. Pathologically confirmed chronic traumatic encephalopathy in a 25-year-old former college football player. JAMA Neurol. 73(3), 353–355 (2016).
3. Antonius, D. et al. Behavioral health symptoms associated with chronic traumatic encephalopathy: a critical review of the literature and recommendations for treatment and research. J. Neuropsychiatry Clin. Neurosci. 26(4), 313–322 (2014).
4. Turner, R. C. et al. Repetitive traumatic brain injury and development of chronic traumatic encephalopathy: a potential role for biomarkers in diagnosis, prognosis, and treatment?. Front. Neurol. 3, 186 (2012).
5. Daneshvar, D. H. et al. Long-term consequences: effects on normal development profile after concussion. Phys. Med. Rehabil. Clin. N. Am. 22(4), 683–700 (2011).
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