KINETICS OF CELL PROLIFERATION IN THE STRIATUM

该研究计划的长期目标是描述 调节神经元生成的机制 纹状体(前脑基底节的一个组成部分) 正常发育或在病理条件下。这些目标将是 实现在三个阶段：个体发育变异的大小 细胞动力学参数(调节细胞过程的变量 世代)的纹状体祖细胞将被量化，并且变异 将与世代率和表型的变异有关 子代的多样性；基于这些数据，建立了一个体外模型 将发展纹状体细胞发生；使用该体外模型， 内因或外因影响纹状体的机制 在生理或病理条件下的细胞发生 特色化的。这些数据将对分析 特定基因的产物(如亨廷顿病基因)或 特定的生化物质(例如生长因子、神经递质或 神经肽)对纹状体发育的影响，特别是在转基因动物 适合于这种分析的模型出现了。方法，如 上述内容已被用于非神经系统的研究 取得了显著的成功，但在细胞生成方面的研究还不够 纹状体。 这一应用的实验将是三个阶段中的第一个阶段 如上所述。他们会估计纹状体的每一天 神经发生期，细胞动力学参数的平均值 神经节隆起中的祖细胞(纹状体的胚胎来源 细胞)；量化神经节细胞输出的速率 显赫，并决定了两个类别的产生时间 纹状体神经元。个体发育变异的价值 细胞动力学参数将与细胞生长速度的变化有关 产生的后代的细胞产量和表型多样性 相应的时期。这些数据将作为关键的基线 体外培养细胞生成模型的建立参数 纹状体。目前要使用的主要技术 实验将标记处于有丝分裂周期的细胞 溴脱氧尿嘧啶核苷和/或氚胸苷 神经节隆起或神经节体部组织切片中的细胞 用免疫细胞化学或放射自显影方法检测纹状体。数字和 不同发育时期标记细胞的空间分布 将被分析以估计细胞动力学参数和 蜂窝输出。这些技术将与 免疫细胞化学法测定纹状体的发生时间 含P物质或脑啡肽的神经元的神经元类型 在亨廷顿病中选择性耗尽。

The long term goals of the research program are to characterize the mechanisms which regulate the generation of neurons destined for the corpus striatum (a component of the basal ganglia of the forebrain) during normal development or under pathological conditions. Those goals will be achieved in three stages: ontogenetic variation in the magnitudes of cytokinetic parameters (variables which regulate the process of cell generation) of striatal progenitors will be quantified and the variation will be related to the variation in the rate of generation and phenotypic diversity of the progeny; based on those data, an in vitro model of striatal cytogenesis will be developed; and using that in vitro model, the mechanisms by which intrinsic or extrinsic factors influence striatal cytogenesis under physiological or pathological conditions will be characterized. The data will be critically important for analyzing the effects of products of specific genes (e.g. Huntington's disease gene) or specific biochemical substances (e.g. growth factors, neurotransmitters or neuropeptides) on striatal development especially if transgenic animal models suitable for such analyses become available. Approaches such as those described above have been employed in research on non-neural systems with remarkable success, but not in research on cell generation in the corpus striatum. Experiments of this application will be the first of the three stages mentioned above. They will estimate for every day of the striatal neurogenetic period, the average values of the cytokinetic parameters of progenitors in the ganglionic eminence (embryonic source of striatal cells) in mice; quantify the rate of cellular Output from the ganglionic eminence, and determine the time of generation of two categories of striatal neurons. The Ontogenetic variation in the values of the cytokinetic parameters will be related to the variation in the rate of cellular output and phenotypic diversity of the progeny generated at the corresponding periods. Those data will serve as critical, baseline parameters for developing the in vitro model of cell generation in the corpus striatum. The principal technique to be used in the present experiments will be labeling cells in -phase of the mitotic cycle with bromodeoxyuridine and/or tritiated thymidine and identifying the labeled cells in tissue sections from the ganglionic eminence or the corpus striatum by immunocytochemical or autoradiographic methods. The number and spatial distribution of labeled cells at different developmental periods will be analyzed to estimate the cytokinetic parameters and the rate of cellular output. Those techniques will be combined with immunocytochemistry to determine the time of generation of striatal neurons containing substance P or enkephalin, the neuronal types selectively depleted in Huntington's disease.