Mild Traumatic Brain Injury Induces Transient, Sequential Increases in Proliferation, Neuroblasts/Immature Neurons, and Cell Survival: A Time Course Study in the Male Mouse Dentate Gyrus.

Lyles R Clark,Sanghee Yun,Amelia J Eisch,Hannah E Metheny,Nana K Acquah,Priya L Kumar,Akivas S Cohen,Rikley C C Paixao

doi:10.3389/fnins.2020.612749

Lyles R Clark, Sanghee Yun + Show 6 more

Open Access

https://doi.org/10.3389/fnins.2020.612749

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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 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.

Highlights

Traumatic brain injury (TBI) is a leading cause of death and disability in the United States, affecting ∼2.8 million new people annually (Report to Congress on Mild Traumatic Brain Injury in the United States, 2003; Taylor et al, 2017)
Given that new neuron replacement has been suggested as a potential treatment for TBI-induced cognitive dysfunction (Blaiss et al, 2011; Sun et al, 2015; Aertker et al, 2016; Sun, 2016), and the prevalence of mild TBIs (mTBIs) in humans, it is surprising that only two rodent studies have examined injuryinduced effects on the process of dentate gyrus (DG) neurogenesis after mTBI caused by lateral fluid percussion injury (LFPI)
In the preclinical TBI literature - even within the minority of studies focused on mild injuries - there is disagreement about if and how mTBI changes the process of DG neurogenesis

Summary

INTRODUCTION

Traumatic brain injury (TBI) is a leading cause of death and disability in the United States, affecting ∼2.8 million new people annually (Report to Congress on Mild Traumatic Brain Injury in the United States, 2003; Taylor et al, 2017). Given that new neuron replacement has been suggested as a potential treatment for TBI-induced cognitive dysfunction (Blaiss et al, 2011; Sun et al, 2015; Aertker et al, 2016; Sun, 2016), and the prevalence of mTBI in humans, it is surprising that only two rodent studies have examined injuryinduced effects on the process of DG neurogenesis after mTBI caused by LFPI. We find the ipsilateral DG neurogenic regions of LFPI mice have more proliferation 3 dpi, more neuroblasts/immature neurons 7 dpi, and more new cell survival 31 dpi relative to these regions in Sham mice These results suggest this model of mTBI produces a transient increase of DG neurogenesis in canonical DG neurogenic regions, consistent with the increased neurogenesis seen after other and more severe models of TBI. We discuss this and other interpretations of our DG data, and consider the implications for the temporal, subregional, and neurogenesis-stage resolution data provided here for the first time in a mouse model of mTBI

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