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Mild traumatic brain injury induces transient, sequential increases in proliferation, neurogenesis, and cell survival: a time course study in the male mouse dentate gyrus

LR Clark, S Yun, NK Acquah, PL Kumar, HE Metheny, RCC Paixao, AS Cohen, AJ Eisch
doi: https://doi.org/10.1101/2020.10.07.330118
LR Clark
1Department of Anesthesiology and Critical Care Medicine, The Children’s Hospital of Philadelphia (CHOP) Research Institute, Philadelphia, PA USA 19104
2Mahoney Institute for Neuroscience, Perelman School of Medicine, Philadelphia, PA USA 19104
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S Yun
1Department of Anesthesiology and Critical Care Medicine, The Children’s Hospital of Philadelphia (CHOP) Research Institute, Philadelphia, PA USA 19104
2Mahoney Institute for Neuroscience, Perelman School of Medicine, Philadelphia, PA USA 19104
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NK Acquah
1Department of Anesthesiology and Critical Care Medicine, The Children’s Hospital of Philadelphia (CHOP) Research Institute, Philadelphia, PA USA 19104
3Biological Basis of Behavior Program, University of Pennsylvania, Philadelphia, PA USA 19104
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PL Kumar
1Department of Anesthesiology and Critical Care Medicine, The Children’s Hospital of Philadelphia (CHOP) Research Institute, Philadelphia, PA USA 19104
4Biomechanical Engineering, University of Pennsylvania, Philadelphia, PA USA 19104
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HE Metheny
1Department of Anesthesiology and Critical Care Medicine, The Children’s Hospital of Philadelphia (CHOP) Research Institute, Philadelphia, PA USA 19104
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RCC Paixao
1Department of Anesthesiology and Critical Care Medicine, The Children’s Hospital of Philadelphia (CHOP) Research Institute, Philadelphia, PA USA 19104
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AS Cohen
1Department of Anesthesiology and Critical Care Medicine, The Children’s Hospital of Philadelphia (CHOP) Research Institute, Philadelphia, PA USA 19104
2Mahoney Institute for Neuroscience, Perelman School of Medicine, Philadelphia, PA USA 19104
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AJ Eisch
1Department of Anesthesiology and Critical Care Medicine, The Children’s Hospital of Philadelphia (CHOP) Research Institute, Philadelphia, PA USA 19104
2Mahoney Institute for Neuroscience, Perelman School of Medicine, Philadelphia, PA USA 19104
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  • For correspondence: eisch@upenn.edu
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Abstract

Mild traumatic brain injuries (mTBIs) are prevalent worldwide. mTBIs can impair hippocampal-based functions such as memory and cause network hyperexcitability of the dentate gyrus (DG), a key entry point to hippocampal circuitry. One candidate for mediating mTBI-induced hippocampal cognitive and physiological dysfunction is injury-induced changes in DG neurogenesis, a process that mediates spatial/contextual memory. There are conflicting results on how TBI impacts DG neurogenesis; this is not surprising given that both the neurogenesis process and the post-injury period are dynamic, and that neurogenesis quantification varies widely in the literature. Even within the minority of TBI studies focusing specifically on mild injuries, there is disagreement about if and how mTBI changes DG neurogenesis. Here we utilized a clinically-relevant rodent model of mTBI (lateral fluid percussion injury, LFPI), gold-standard neurogenesis markers and quantification approaches, and three time points post-injury to generate a comprehensive picture of how mTBI affects adult hippocampal DG neurogenesis. Male C57BL/6J mice (6-8 weeks old) received either sham surgery or mTBI via LFPI. Proliferating cells, neuroblasts/immature neurons, and surviving cells were quantified via stereology in DG subregions (subgranular zone [SGZ], outer granule cell layer [GCL], molecular layer, and hilus) at short-term (3 days post-injury, dpi), intermediate (7 dpi), and long-term (31 dpi) time points. The data suggest this model of mTBI induces transient, sequential increases in ipsilateral SGZ/GCL proliferating cells, immature neurons, and surviving cells which are indicative of mTBI-induced neurogenesis. In contrast to these ipsilateral hemisphere findings, measures in the contralateral hemisphere show no increase in neurogenesis indices in the key neurogenic DG subregions. Our work in this mTBI model is in line with the large fraction of literature that reports increased DG neurogenesis in other and more severe models of TBI. As our DG neurogenesis data in this mTBI model provide temporal, subregional, and neurogenesis-stage resolution, these data are important to consider in regard to the functional importance of TBI-induced neurogenesis and future work assessing the potential of replacing and/or repairing DG neurons in the brain after TBI.

Competing Interest Statement

The authors have declared no competing interest.

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Posted October 08, 2020.
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Mild traumatic brain injury induces transient, sequential increases in proliferation, neurogenesis, and cell survival: a time course study in the male mouse dentate gyrus
LR Clark, S Yun, NK Acquah, PL Kumar, HE Metheny, RCC Paixao, AS Cohen, AJ Eisch
bioRxiv 2020.10.07.330118; doi: https://doi.org/10.1101/2020.10.07.330118
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Mild traumatic brain injury induces transient, sequential increases in proliferation, neurogenesis, and cell survival: a time course study in the male mouse dentate gyrus
LR Clark, S Yun, NK Acquah, PL Kumar, HE Metheny, RCC Paixao, AS Cohen, AJ Eisch
bioRxiv 2020.10.07.330118; doi: https://doi.org/10.1101/2020.10.07.330118

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