GLIA AND GLYCOCONJUGATES IN THE NEOSTRIATUM

在大脑发育过程中以及受伤后， 产生各种分子， 神经元和它们的过程。 最近，胶质和糖缀合物 （糖蛋白、糖脂和糖胺聚糖）边界具有 在大脑模式形成过程中被发现，而这些结构 用警戒线隔离功能不同的神经元和它们的 神经突 在发育中的尾壳核（新纹状体）中， 边界围绕着新纹状体镶嵌体的不同隔室， 斑块和基质，最有可能用于分离生长过程 细胞在两个不同的隔间在一个关键时期， 他们的形成。 以下建议将测试以下方面的可能作用： 星形胶质细胞和糖复合物在正常和异常发育 黑质纹状体回路是大脑中一个重要的临床区域 在目标1中，星形胶质细胞出现和消失的时间过程- 衍生的细胞外基质（ECM）分子将在本研究中测定。 电路. 具体目标2将集中在潜在的再现， 黑质纹状体回路内不同病变后的边界 在发育过程中和成年期， 与腱生蛋白敲除小鼠的研究相比， 关于特定ECM边界可能功能的补充数据 分子对神经炎生长的影响 第三组实验将利用 两个体外生物测定，以影响某些边界的功能 细胞边界相互作用过程中的分子 黑质纹状体回路，以及在受损的成人回路中， 导致另一种类型的神经胶质/糖缀合物的出现 边界-星形胶质细胞疤痕。 这些研究将在 正常以及腱生蛋白缺陷的动物， (e.g. DSD-1）现在可以在黑质纹状体中进行研究和操作。 电路，例如，一直缺乏腱生蛋白 在第4章中， 星形胶质细胞和ECM在神经退行性疾病中的潜在作用 影响人类基底神经节的神经系统将在广泛的 收集了亨廷顿氏病、帕金森氏病和其他疾病及其控制 允许边界元素的彻底相关的标本， 在这些患者中，黑质纹状体回路中发生的神经元丢失与 疾病 总之，这里提出的研究将建立功能性的 星形胶质细胞和相关的，发育调节的 分子在发育过程中形成正常的基础电路， 也许它们如何对神经元和可能的神经突产生不利影响 创伤性损伤或慢性疾病后的再生。 正常 发展和受伤的黑质纹状体回路适合研究 神经胶质/糖缀合物边界元件的功能。 神经胶质和 糖复合物可能在脑型中起重要作用 形成，但细胞和分子相互作用的重演 在正常发育过程中可能发生的变化可能会产生有害影响 在受损的、成熟的神经细胞中， 个脑袋

During brain development and again following injury, glial cells produce a variety of molecules that affect the positioning and growth of neurons and their processes. Recently, glial and glycoconjugate (glycoproteins, glycolipids, and glycosaminoglycans) boundaries have been discovered during brain pattern formation, and these structures cordon off developing groups of functionally distinct neurons and their neurites. In the developing caudate-putamen (neostriatum), these boundaries surround different compartments of a neostriatal mosaic, the patch and matrix, and most likely serve to separate growing processes of cells in the two different compartments during a critical period of their formation. The following proposal will test possible roles for astrocytes and glycoconjugates during normal and abnormal development of a clinically important area of the brain, the nigrostriatal circuit. In Aim 1, the time course of appearance and disappearance of astrocyte- derived extracellular matrix (ECM) molecules will be determined in this circuit. Specific Aim 2 will focus on the potential reappearance of boundaries following different lesions within the nigrostriatal circuit during development and in the adult, and antibody perturbation experiments versus studies on a tenascin-knockout mouse will provide complementary data on possible functions of particular ECM boundary molecules on neuritic growth. A third set of experiments will exploit two in vitro bioassays to affect the functions of certain boundary molecules during cell-boundary interactions in the developing nigrostriatal circuit, as well as in the lesioned adult circuit that results in the appearance of another type of glial/glycoconjugate boundary - the astroglial scar. These studies will be performed in normal as well as tenascin-deficient animals where other ECM molecules (e.g. DSD-1) can now be studied and manipulated in a nigrostriatal circuit that, e.g., has always lacked tenascin. In Specific 4, the potential roles of astrocytes and ECM in neurodegenerative diseases that affect the human basal ganglia will be explored in an extensive collection of Huntington's, Parkinson's, and other disease and control specimens that allow a thorough correlation of boundary elements in relation to neuronal loss that occurs in nigrostriatal circuit in these diseases. In all, the studies proposed here will establish functional roles for astrocytes and associated, developmentally-regulated molecules in shaping normal basal circuitry during development, and perhaps how they adversely affect neurons and possible neurite regeneration following traumatic injury or chronic disease. The normal developing and injured nigrostriatal circuit is amenable to studies of functions of glial/glycoconjugate boundary elements. Glia and glycoconjugates may play important roles during brain pattern formation, but the recapitulation of cell and molecular interactions that might occur during normal development may have deleterious effects on neuron survival and neuritic regrowth in the compromised, mature brain.