Abstract
Neural stem cells in the adult brain possess the ability to remain quiescent until needed in tissue homeostasis or repair. It was previously shown that traumatic brain injury (TBI) stimulated neural stem cell (NSC) proliferation in the adult hippocampus, indicating an innate repair mechanism, but it is unknown how TBI promotes NSC proliferation. In the present study, we observed dramatic activation of mammalian target of rapamycin complex 1 (mTORC1) in the hippocampus of mice with TBI from controlled cortical impact (CCI). The peak of mTORC1 activation in the hippocampal subgranular zone, where NSCs reside, is 24–48 h after trauma, correlating with the peak of TBI-enhanced NSC proliferation. By use of a Nestin-GFP transgenic mouse, in which GFP is ectopically expressed in the NSCs, we found that TBI activated mTORC1 in NSCs. With 5-bromo-2′-deoxyuridine labeling, we observed that TBI increased mTORC1 activation in proliferating NSCs. Furthermore, administration of rapamycin abolished TBI-promoted NSC proliferation. Taken together, these data indicate that mTORC1 activation is required for NSC proliferation postinjury, and thus might serve as a therapeutic target for interventions to augment neurogenesis for brain repair after TBI.
- mammalian target of rapamycin
- neural stem/progenitor cells
- proliferation
- quiescence
- traumatic brain injury
Footnotes
The authors declare no conflict of interest.
Contribution Statement: X.W., collection and/or assembly of data, data analysis and interpretation, and manuscript writing; P.S., collection and/or assembly of data; X.G., collection and/or assembly of data, data analysis and interpretation. J.C., conception and design, financial support, data analysis and interpretation, manuscript writing, and final approval of manuscript.
This work was supported by funding from the Indiana Spinal Cord and Brain Injury Research Grants, the Ralph W. and Grace M. Showalter Research Award, and Indiana University Biological Research Grant.
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