Investigating human adult neurogenesis within the basal ganglia in response to ischemic stroke using the radiocarbon-based technique of retrospective birth dating of neural cells.

申请人获得了DFG津贴，并在初步研究中使用基于放射性碳的神经细胞追溯出生日期技术调查了成人神经发生的存在。作为一个关键发现，有证据表明成年人大脑海马齿状回内存在终身连续的神经发生，这是年龄依赖性的，每年高达2-6%（申请人是2013年发表在Cell上的这项研究的共同作者）。此外，作者是2014年发表在Nature Neuroscience上的一篇论文的第一作者，该论文研究了缺血性中风后的神经发生。作为一个关键发现，有证实性数据表明，健康的大脑皮层没有成年神经发生。在大脑皮层缺血性中风后，没有可检测到的诱导，因此也没有显著的神经发生。基于这一初步工作，目前的资助申请集中在相关的两个最相关的研究问题。首先，该项目将调查是否有人类成年神经发生在基底神经节内的缺血性中风。第二，申请人将研究海马内的连续神经发生是否在基底神经节或大脑皮层的缺血性中风时改变。据报道，啮齿动物实验性卒中后，基底神经节内以及同侧海马内的神经发生率均增加，以响应缺血性卒中。研究这些发现是否也适用于人类似乎具有根本的相关性。鉴于大量关于人类缺血性卒中急性期神经保护的阴性临床研究，（这些试验主要研究靶向药物对缺血级联反应的操纵的有益作用），拟议的研究项目旨在提供有关急性中风的生理和病理生理机制以及长期，可能影响功能恢复这将有助于了解缺血性卒中后神经发生是否发生和改变，如果是，神经发生是否具有功能相关性。所获得的结果可能具有临床意义，从而可以实现临床前研究到成功临床试验的有意义的转化。

The applicant had received a DFG-stipend and investigated the existence of adult human neurogenesis in preliminary studies using the Radiocarbon-based technique of retrospective birth dating of neural cells. As a key finding there was evidence of lifelong continuous neurogenesis within the dentate gyrus of the hippocampus in the adult human brain which was age-dependent and amounted up to 2-6% per year (the applicant was coauthor of this study published 2013 in Cell). Further, the author was first author of a paper published 2014 in Nature Neuroscience that investigated neurogenesis after ischemic stroke. As a key finding there was confirmatory data that with the healthy cerebral cortex there is no adult neurogenesis. After ischemic stroke of the cerebral cortex there is no detectable induction and thus also no significant neurogenesis. Based on this preliminary work the present grant application focusses on the related two most relevant research questions. First, the proposed project will investigate whether there is human adult neurogenesis within the basal ganglia in response to ischemic stroke. Second, the applicant will study whether the continuous neurogenesis within the hippocampus is altered upon ischemic stroke of the basal ganglia or the cerebral cortex. Both, an increased rate of neurogenesis within the basal ganglia as well as within the ipsilateral hippocampus in response to ischemic stroke has been reported in rodents after experimental stroke. It appears of fundamental relevance to study whether these finding also hold true in man. Given the bulk of negative clinical studies regarding neuroprotection in the acute phase of ischemic stroke in humans (those trials predominantly investigated beneficial effects of drugs targeting on manipulation of the ischemic cascade), the proposed research project aims to provide information on the physiological and pathophysiological mechanisms that act in acute stroke and also on the long-term, possibly affecting functional recovery. This will help to understand if neurogenesis occurs and is altered upon ischemic stroke and, if so, whether neurogenesis has a functional relevance. The obtained results may have clinical implications such that a meaningful translation of preclinical studies to successful clinical trials can be achieved.