NEUROTROPHIN CONTROL OF THALAMOCORTICAL DEVELOPMENT

神经营养因子对丘脑皮质发育的控制

• 批准号: 6584617
• 负责人: JOHN W MCDONALD
• 金额: $ 7.7万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6584617
• 关键词: afferent nerve; axon; cell cell interaction; dendrites; developmental neurobiology; genetically modified animals; histology; laboratory mouse; nervous system transplantation; neurogenesis; neurotrophic factors; stem cell transplantation; thalamocortical tract; vibrissae

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.

正常发展的有序表示颅面周边（胡须模式在啮齿动物）在初级躯体感觉（SmI）皮层需要外围输入。虽然很明显，竞争之间的皮层模式的形成。因此，竞争性相互作用可能不是基于电事件，而是基于获得在中枢神经系统中产生的生长促进物质。在这里，我们建议评估行动的神经营养因子，通常存在于这些领域，丘脑皮层传入（TCAs）的发展。基于对发育中的视觉系统的观察（Cabelli等人，1995）和三叉神经初级传入（项目1），我们假设TCA在发育的关键时期竞争获得特定神经营养因子的有限供应，并且神经营养因子在发育的关键时期的空间和时间分布，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。具体而言，NT-3将产生轴突树枝状化，BDNF将产生轴突伸长。将使用三种确证方法来实现NT-3和脑源性神经营养因子的增强递送，包括浸渍的Elvax植入物（实验1a）、转基因过表达（实验1b）以及移植含有旨在条件性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2中，因变量评估TCA形态学指标，包括使用神经生物素和DiI死后顺行标记的单纤维和总产量分析。实验2将评估含有过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将比较皮质桶图案与实验1和2中观察到的个体TCA形态和地形变化。核心A将进行TCA和IV层神经元的标记以及ES细胞上TCA突触的体视学超微结构分析。Core B将产生四环素调控的NT-3/BDNF转基因小鼠。核心C将量化TCA形态学和皮质C共聚焦显微镜，并在核心C中使用体视学方法进行量化。这些研究将提供与移植的ES细胞相关的治疗策略，使用移植来恢复功能丧失，无论个体非区域性神经前体是否能够整合到SmI皮质的正常躯体组织中，以及是否存在关键敏感期。