Aging and Neurogenesis

描述(申请人提供)：尽管中风主要发生在老年人群中，但大多数研究中风和神经发生的动物研究都是在年轻人的大脑上进行的。因此，更好地了解老年大脑中风后神经干细胞/祖细胞(NSCs)是如何调节的似乎是至关重要的。在过去的资助期间，我们研究了衰老在中风后神经发生中的作用。我们在下一个资助期的研究目标是关注衰老对中风诱导的神经发生的潜在调控机制。具体地说，我们将探索Notch通路在衰老过程中神经发生中的作用。以往的研究表明，Notch信号通路在发育过程中神经干细胞的维持、增殖和分化过程中起关键作用。最近的证据表明，Notch1信号在成人神经发生的调控中是保守的。我们的初步研究表明，Notch1及其下游靶点在SVZ细胞中表达，抑制或激活Notch1途径后，正常成人SVZ中BrdU阳性(增殖)细胞的数量显著改变。此外，我们发现卒中后SVZ中的Notch1信号被激活，而卒中诱导的SVZ中的细胞增殖可以通过抑制青年脑中的Notch1途径而被阻断。这些结果导致了我们的假设，即Notch1信号对成人大脑中发生的神经发生至关重要，并且Notch1信号活性的变化可能直接或间接地导致神经发生的年龄依赖性下降，包括随后的中风。为了验证这一假说，我们建议：(1)检测SVZ中Notch1信号分子表达随年龄增长的时间分布，并分析青年与老年大鼠脑内表达Notch1通路分子的SVZ细胞的表型；(2)研究Notch1通路改变对幼年和老年大鼠在体脑SVZ中细胞增殖和其他信号通路的影响；(3)检测卒中后青年和老年大鼠SVZ中Notch1通路的活性；(4)探讨强制激活或阻断Notch1通路对幼年和老年大鼠卒中后SVZ区神经发生的影响。拟议中的实验的长期目标是，通过研究老年大脑中中风诱导的神经发生的调控机制，更好地理解控制正常衰老和中风等与年龄相关的神经疾病的神经发生的基本原理。

DESCRIPTION (provided by applicant): 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.