Although stroke occurs mainly in the aged population, most animal studies investigating both stroke and neurogenesis are conducted on young-adult brains. Hence, better understanding of how neural stem/progenitor cells (NSCs) are regulated after stroke in the aged brain seems essential. In the past funding period, we study the roles of aging in neurogenesis after stroke. The goal of our research in the next funding period is to focus on the mechanisms underlying regulation of stroke-induced neurogenesis by aging. Specifically, we will explore the role of the Notch pathway in neurogenesis during aging. Previous studies show that Notch signaling pathway plays critical roles during maintenance, proliferation, and differentiation of NSCs in developing brain. Recent evidence shows that Notch1 signaling is conserved in the regulation of adult neurogenesis. Our pilot studies show that Notch1 and its downstream targets are expressed in SVZ cells, and that the number of BrdU-positive (proliferating) cells in the normal adult SVZ is significantly altered after inhibiting or activating the Notch1 pathway. In addition, we find that Notch1 signaling in the SVZ is activated after stroke and that stroke-induced cell proliferation in the SVZ can be blocked by inhibiting the Notch1 pathway in young-adult brain. These results led to our hypothesis that Notch1 signaling is essential for neurogenesis to occur in the adult brain and that changes in Notch1 signaling activity may contribute, directly or indirectly, to the aged-dependent decline in neurogenesis, including that following stroke. To test this hypothesis, we propose to: (1) to examine the temporal profiles of Notch1 signaling molecule expression in the SVZ in response to aging, and to characterize the phenotypes of SVZ cells expressing Notch1 pathway molecules in the young-adult vs. aged rat brain;(2) to investigate the effect of altering the Notch1 pathway on cell proliferation and other signaling pathways in the SVZ of young-adult and aged rat brain in vivo;(3) to examine Notch1 pathway activity in the SVZ of the young-adult and aged rat brain after stroke;(4) to assess the effect of forced activation or blockade of the Notch1 pathway on neurogenesis in SVZ of young-adult and aged rat brain after stroke in vivo. The long-term goal of the proposed experiments is, by studying the mechanisms that regulate stroke- induced neurogenesis in aged brain, to achieve better understanding of the fundamental principles that govern neurogenesis in normal aging and age-related neurological diseases like stroke.

Public Health Relevance

The proposed experiments is, by studying the mechanisms that regulate stroke-induced neurogenesis in aged brain, to achieve better understanding of the fundamental principles that govern neurogenesis in normal aging and age-related neurological diseases like stroke. PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page Continuation Format Page

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Wise, Bradley C
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of North Texas
Other Domestic Higher Education
Fort Worth
United States
Zip Code
Xie, Luokun; Choudhury, Gourav Roy; Winters, Ali et al. (2015) Cerebral regulatory T cells restrain microglia/macrophage-mediated inflammatory responses via IL-10. Eur J Immunol 45:180-91
Tang, Yaohui; Wang, Jixian; Lin, Xiaojie et al. (2014) Neural stem cell protects aged rat brain from ischemia-reperfusion injury through neurogenesis and angiogenesis. J Cereb Blood Flow Metab 34:1138-47
Xie, Luokun; Sun, Fen; Wang, Jixian et al. (2014) mTOR signaling inhibition modulates macrophage/microglia-mediated neuroinflammation and secondary injury via regulatory T cells after focal ischemia. J Immunol 192:6009-19
Huang, Lijie; Wu, Zhe-Bao; Zhuge, Qichuan et al. (2014) Glial scar formation occurs in the human brain after ischemic stroke. Int J Med Sci 11:344-8
Ruan, Linhui; Lau, Benson Wui-Man; Wang, Jixian et al. (2014) Neurogenesis in neurological and psychiatric diseases and brain injury: from bench to bedside. Prog Neurobiol 115:116-37
Sun, Yong-Xin; Ji, Xunming; Mao, Xiaoou et al. (2014) Differential activation of mTOR complex 1 signaling in human brain with mild to severe Alzheimer's disease. J Alzheimers Dis 38:437-44
Wang, Liu-Qing; Lin, Zhen-Zhen; Zhang, Hong-Xia et al. (2014) Timing and dose regimens of marrow mesenchymal stem cell transplantation affect the outcomes and neuroinflammatory response after ischemic stroke. CNS Neurosci Ther 20:317-26
Sun, Fen; Mao, XiaoOu; Xie, Lin et al. (2013) Notch1 signaling modulates neuronal progenitor activity in the subventricular zone in response to aging and focal ischemia. Aging Cell 12:978-87
Tang, Huidong; Mao, XiaoOu; Xie, Lin et al. (2013) Expression level of vascular endothelial growth factor in hippocampus is associated with cognitive impairment in patients with Alzheimer's disease. Neurobiol Aging 34:1412-5
Wang, Liuqing; Lin, Zhenzhen; Shao, Bei et al. (2013) Therapeutic applications of bone marrow-derived stem cells in ischemic stroke. Neurol Res 35:470-8

Showing the most recent 10 out of 52 publications