TY - JOUR
T1 - Mild Traumatic Brain Injury Induces Transient, Sequential Increases in Proliferation, Neuroblasts/Immature Neurons, and Cell Survival
T2 - A Time Course Study in the Male Mouse Dentate Gyrus
AU - Clark, Lyles R.
AU - Yun, Sanghee
AU - Acquah, Nana K.
AU - Kumar, Priya L.
AU - Metheny, Hannah E.
AU - Paixao, Rikley C.C.
AU - Cohen, Akivas S.
AU - Eisch, Amelia J.
N1 - Funding Information:
We thank Giulia Zanni and Kait Folweiler for helpful discussion about initial experiment design and Danielle Barber for discussions about the role of microglia in the reported results. We also thank Ryan Reynolds for his initial graphic design that inspired Figures 1D?F. Funding. Funding for this work was provided by grants to AC (R37HD059288) and AE (DA023555, NNX15AE09G, 80NSSC17K0060, MH117628, and NS007413, PI: MB Robinson). LC was supported by NIH T32-GM07517 (PI: JI Gold). SY was supported by Penn?s McCabe Pilot Award, a Penn Undergraduate Research Foundation Award, and a NARSAD Young Investigator Award from the Brain and Behavior Research Foundation. NA was supported by Penn?s Center for Undergraduate Research and Fellowships (CURF) program. PK was supported by Penn?s Undergraduate Research Mentoring Program (PURM). RP was supported by CHOP Research Institute Summer Scholars Program (CRISSP).
Publisher Copyright:
© Copyright © 2021 Clark, Yun, Acquah, Kumar, Metheny, Paixao, Cohen and Eisch.
PY - 2021/1/7
Y1 - 2021/1/7
N2 - 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 the process of DG neurogenesis. There are conflicting results on how TBI impacts the process of DG neurogenesis; this is not surprising given that both the neurogenesis process and the post-injury period are dynamic, and that the quantification of neurogenesis 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 the process of DG neurogenesis. Here we utilized a clinically relevant rodent model of mTBI (lateral fluid percussion injury, LFPI), gold-standard markers and quantification of the neurogenesis process, 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 [oGCL], molecular layer, and hilus) at short-term (3 days post-injury, dpi), intermediate (7 dpi), and long-term (31 dpi) time points. The data show this model of mTBI induces transient, sequential increases in ipsilateral SGZ/GCL proliferating cells, neuroblasts/immature neurons, and surviving cells which is suggestive of mTBI-induced neurogenesis. In contrast to these ipsilateral hemisphere findings, measures in the contralateral hemisphere were not increased in key neurogenic DG subregions after LFPI. Our work in this mTBI model is in line with most literature on other and more severe models of TBI in showing TBI stimulates the process of DG neurogenesis. However, as our DG data in mTBI provide temporal, subregional, and neurogenesis-stage resolution, these data are important to consider in regard to the functional importance of TBI-induction of the neurogenesis process and future work assessing the potential of replacing and/or repairing DG neurons in the brain after TBI.
AB - 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 the process of DG neurogenesis. There are conflicting results on how TBI impacts the process of DG neurogenesis; this is not surprising given that both the neurogenesis process and the post-injury period are dynamic, and that the quantification of neurogenesis 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 the process of DG neurogenesis. Here we utilized a clinically relevant rodent model of mTBI (lateral fluid percussion injury, LFPI), gold-standard markers and quantification of the neurogenesis process, 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 [oGCL], molecular layer, and hilus) at short-term (3 days post-injury, dpi), intermediate (7 dpi), and long-term (31 dpi) time points. The data show this model of mTBI induces transient, sequential increases in ipsilateral SGZ/GCL proliferating cells, neuroblasts/immature neurons, and surviving cells which is suggestive of mTBI-induced neurogenesis. In contrast to these ipsilateral hemisphere findings, measures in the contralateral hemisphere were not increased in key neurogenic DG subregions after LFPI. Our work in this mTBI model is in line with most literature on other and more severe models of TBI in showing TBI stimulates the process of DG neurogenesis. However, as our DG data in mTBI provide temporal, subregional, and neurogenesis-stage resolution, these data are important to consider in regard to the functional importance of TBI-induction of the neurogenesis process and future work assessing the potential of replacing and/or repairing DG neurons in the brain after TBI.
KW - LFPI
KW - TBI
KW - dentate gyrus
KW - neurogenesis
KW - proliferation
UR - http://www.scopus.com/inward/record.url?scp=85099727766&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85099727766&partnerID=8YFLogxK
U2 - 10.3389/fnins.2020.612749
DO - 10.3389/fnins.2020.612749
M3 - Article
C2 - 33488351
AN - SCOPUS:85099727766
SN - 1662-4548
VL - 14
JO - Frontiers in Neuroscience
JF - Frontiers in Neuroscience
M1 - 612749
ER -