NEUROTROPHIN CONTROL OF THALAMOCORTICAL DEVELOPMENT

初级躯体感觉(SMI)皮层中头面部外周(啮齿类动物的胡须图案)的有序表征的正常发展需要外周输入。虽然很明显，大脑皮层之间的竞争格局的形成。因此，竞争性相互作用可能不是基于电活动，而是基于对中枢神经系统产生的一种促进生长的物质(S)的获取。在这里，我们建议评估神经营养因子，通常存在于这些地区，对丘脑皮质传入(TCA)的发展的作用。基于对发育中的视觉系统(Cabelli et al.，1995)和三叉神经初级传入(Project 1)的观察，我们假设TCA在发育的关键时期竞争获得有限的特定神经营养因子的供应，并且神经营养因子在发育关键时期的时空分布，以及神经营养因子的空间和时间分布是丘脑皮质结构和功能的重要决定因素。具体地说，NT-3将产生轴突树枝，BDNF将产生轴突延长。增加NT-3和BDNF的传递将使用三种佐证方法，包括浸渍Elvax植入(实验1a)、转基因过表达(实验1b)和移植含有旨在有条件地过表达每种神经营养因子的转基因的神经诱导ES细胞(实验2)。在实验1和实验2中，因变量使用神经生物素和DII死后顺行标记来评估TCA的形态指标，包括单纤维和总产量分析。实验2将评估含有过量表达神经营养因子的转基因的神经ES细胞的整合和分化。实验3将比较皮质桶状结构与实验1和实验2中观察到的单个TCA的形态和地形变化。核心A将对TCA和第四层神经元进行标记，并对ES细胞上的TCA突触进行立体超微结构分析。核心B将产生四环素调控的NT-3/BDNF转基因小鼠。核心C将对TCA形态和皮质C共聚焦显微镜进行量化，并在核心C中使用体视学方法进行量化。这些研究将为移植的ES细胞提供洞察力，这些研究将与使用移植来恢复失去的功能的治疗策略相关，单个非区域定位的神经前体是否能够整合到正常的SMI皮质躯体组织中，以及是否存在关键敏感期。

Normal development of ordered representations of the craniofacial periphery (whisker pattern in rodents) in the primary somatosensory (SmI) cortex requires peripheral input. Although it is clear that competition between cortical pattern formation. Thus, competitive interactions may not be based upon electrical events, but rather, access to a growth-promoting substance(s) that (are) produce in the central nervous system. Here, we propose to evaluate the actions of neurotrophins, normally present in these areas, upon the development of thalamocortical afferents (TCAs). Based upon observations in the developing visual system (Cabelli et al., 1995) and trigeminal primary afferents (Project 1), we hypothesize that TCAs compete for access to a limited supply of particular neurotrophins during critical periods of development, and that the spatial and temporal distribution of neurotrophins during critical periods of development, and that the spatial and temporal distribution of neurotrophins is an important determinant of thalamocortical structure and function. Specifically, NT-3 will produce axon arborization and BDNF will produce axon elongation. Augmented delivery of NT-3 and BDNF will be accomplished using three corroborative approaches that include impregnated Elvax implants (Experiment 1a), transgenic over- expression (Experiment 1b), and transplantation of neural induced ES cells containing transgenes designed to conditionally over-express each neurotrophin (Experiment 2). In Experiments 1 & 2, the dependent variable assess TCA morphologic indices including single fiber and total production analysis using neurobiotin and DiI post-mortem anterograde labeling. Experiment 2 will assess integration and differentiation of neural ES cells containing transgenes to over-express the neurotrophins. Experiment 3 will compare cortical barrel patterns to individual TCA morphologic and topographic changes observed in Experiments 1 & 2. Core A will perform labeling of TCAs and layer IV neurons and stereologic ultrastructural analysis of TCA synapses upon ES cells. Core B will produce the tetracycline regulated NT-3/BDNF transgenic mice. Core C will quantify TCA morphology and cortical C confocal microscope and quantified using stereologic methods in Core C. These studies will provide insights with transplanted ES cells will be relevant to therapeutic strategies using transplantation to restore function lost whether individual non-regionally committed neural precursors are capable of being integrated into the normal somatotopic organization of the SmI cortex and if a critical-sensitive period exists.