Traumatic Brain Injury Stimulates Neural Stem Cell Proliferation via Mammalian Target of Rapamycin Signaling Pathway Activation.
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.
Spinal Cord and Brain Injury Research Group, Indiana University, Indianapolis, IN 46202; Stark Neuroscience Research Institute, Indiana University, Indianapolis, IN 46202; Department of Neurological Surgery, Indiana University, Indianapolis, IN 46202.
Xiaoting
0000-0002-5712-3103
X
Wang
Spinal Cord and Brain Injury Research Group, Indiana University, Indianapolis, IN 46202; Stark Neuroscience Research Institute, Indiana University, Indianapolis, IN 46202; Department of Neurological Surgery, Indiana University, Indianapolis, IN 46202.
Pich
P
Seekaew
Spinal Cord and Brain Injury Research Group, Indiana University, Indianapolis, IN 46202; Stark Neuroscience Research Institute, Indiana University, Indianapolis, IN 46202; Department of Neurological Surgery, Indiana University, Indianapolis, IN 46202.
Xiang
0000-0001-7483-0048
X
Gao
Spinal Cord and Brain Injury Research Group, Indiana University, Indianapolis, IN 46202; Stark Neuroscience Research Institute, Indiana University, Indianapolis, IN 46202; Department of Neurological Surgery, Indiana University, Indianapolis, IN 46202.
Jinhui
J
Chen
D000818:Animals; D000070642:Brain Injuries, Traumatic / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D064231:Nestin / Q000235:genetics / Q000378:metabolism; D058953:Neural Stem Cells / Q000378:metabolism* / Q000473:pathology; D055495:Neurogenesis / Q000502:physiology*; D055153:Stem Cell Niche / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D046912:Multiprotein Complexes; C577485:Nes protein, mouse; D064231:Nestin; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
mammalian target of rapamycin; neural stem/progenitor cells; proliferation; quiescence; traumatic brain injury