Adult neurogenesis in the human central nervous system in response to stroke - an investigation using the novel methodology of retrospective radiocarbon-based birth dating of cells

与长期以来的观点相反，即使在成年期，人类中枢神经系统的某些区域，特别是海马体，也会不断地从神经干细胞中产生新的神经元。成人神经发生的这一发现提出了一种可能性，即休眠的神经干细胞可能也存在于成人大脑的许多其他区域，并在神经疾病和创伤，特别是中风的反应中被激活。最近，利用冷战时期地面核弹试验造成的急剧变化的14C含量，利用加速器质谱法测定细胞中DNA的年龄，开发出了一种以放射性碳为基础的回溯性细胞出生年代测定方法。在这里，我们建议应用这种新颖的方法来明确回答以下问题：(i)神经发生是否存在于健康成人大脑的其他区域，以及（ii）成人神经发生是否在神经创伤和疾病（特别是中风）的反应中被诱导。拟议调查的一个重要方面是将获得的成人神经发生数据与个体病例的临床病史联系起来，以确定成人神经发生是否有助于功能恢复。进一步建议通过分析人脑脊液中的膜囊泡来探索成体神经干细胞和其他具有神经前体电位的细胞的可能激活来补充这些研究，这是一种最近被申请人验证的新方法。该项目的最终目标是利用新颖和创新的方法，在医学感兴趣的情况下，建立人类中枢神经系统的生理和病理细胞更新图谱，从而为再生疗法的发展提供基础信息。

Contrary to a long-lasting belief, new neurons are continuously generated from neural stem cells even during adulthood in certain regions of the human central nervous sytem, notably the hippocampus. This discovery of adult neurogenesis raises the possibility that dormant neural stem cells may exist in many other regions of the adult human brain as well, and be activated in response to neural disease and trauma, in particular stroke. Recently, an ingenious method of retrospective radiocarbon-based birth dating of cells has been developed, which takes advantage of the drastically altered 14C levels due to above-ground nuclear bomb testing during the Cold War and allows the determination of the age of DNA in cells by accelerator mass spectrometry. Here, it is proposed to apply this novel methodology to unequivocally answer the questions (i) whether neurogenesis exists in other regions of the healthy adult human brain, and (ii) whether adult neurogenesis is induced in response to neurological trauma and disease, notably stroke. An important aspect of the proposed investigations will be to relate the data obtained on adult neurogenesis to the clinical history of the individual cases, in order to determine whether adult neurogenesis contributes to functional recovery. It is further proposed to complement these studies by exploring the possible activation of adult neural stem cells and other cells with neural precursor potential via analysis of membrane vesicles in human cerebrospinal fluid, a novel approach recently validated by the applicant. The ultimate goal of the project is to establish a map of cell renewal in physiology and pathology in the human central nervous system in situations of medical interest using novel and innovative methodology, thereby contributing basic information for the development of regenerative therapies.