Neural stem cells in the adult brain possess the ability to remain quiescent until needed in tissue homeostasis or repair. It is previously shown that traumatic brain injury (TBI) stimulated neural stem cells (NSCs) proliferation in the adult hippocampus, indicating an innate repair mechanism. It is unknown how TBI promotes NSCs proliferation. In the present study, we observed dramatic activation of mammalian target of rapamycin complex 1 (mTORC1) in the hippocampus of mice that received TBI by a controlled cortical impact (CCI) model. The peak of mTORC1 activation in the hippocampal subgranular zone, where the NSCs reside, is 24 h to 48 h post-trauma, correlating with the peak of TBI-enhanced NSC proliferation. We took advantage of a Nestin-GFP transgenic mouse, in which GFP is ectopically expressed in the NSCs, and found that TBI activated mTORC1 in the NSCs. With the combination of 5-bromo-2'-deoxyuridine (BrdU) 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 post-injury, thus might serve as a therapeutic target for interventions to augment neurogenesis for brain repair following TBI.
Significance Statement: Traumatic brain injury induced cell death compromises learning and memory functions in survivors by disconnecting neurocircuitries in the hippocampus, requesting an urgent need for repair strategy. Innate repair machinery driven by endogenous neural stem cells (NSC) responds to injury while retains a gap to full recovery. Elusive mechanism of injury induced NSC activation further impedes possible interventions for augmenting the intrinsic restoration. Our present study demonstrates that mTORC1 signal is activated in NSCs post-trauma, and further inhibition on mTORC1 pathway diminished effect of injury on NSC proliferation. Together, our result suggests that mTORC1 activation mediates TBI-enhanced NSC proliferation, thus provides a potential therapeutic target for modulation on NSC activity post-injury for clinical relevance.
The authors declare no conflict of interest.
Contribution Statement: XW: Collection and/or assembly of data, Data analysis and interpretation, and Manuscript writing; PS: Collection and/or assembly of data; XG: Collection and/or assembly of data, data analysis and interpretation. JC: 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 & Brain Injury Research Grants, the Ralph W. and Grace M. Showalter Research Award, and Indiana University Biological Research Grant.