ROLE OF GROWTH FACTORS IN BRAIN DEVELOPMENT

经典的神经营养因子理论认为， 存活因子对神经元的影响。然而，我们发现， 支持细胞也可以是这些分子的来源。当前项目 使用基底前脑内侧隔（BF）作为一个关键的模型，以探讨 局部神经元-星形胶质细胞-神经元调节环支持 发育过程中特定脑区的存活和功能， 成熟 对培养的BF神经元和星形胶质细胞的初步研究是 拟议工作的基础。我们发现单个BF神经信号 差异调节BF星形胶质细胞的基因表达， 神经营养因子、NGF、BDNF和NT 3。反过来，这些神经营养因子， 差异影响BF神经元存活、神经突延伸和 功能，并在相关研究中，调节突触传递， 星形胶质细胞形态探讨神经元-星形胶质细胞-神经元在脑缺血中的作用 我们将1）检查星形胶质细胞的发育， BF神经元，2）通过神经信号定义星形胶质细胞的调节，3） 评估神经营养因子的自分泌调节，4）比较星形胶质细胞 从胚胎第17天衍生到出生后第1天衍生的细胞， 成年人定义阶段特异性星形胶质细胞功能，和5）定义 在文化中确定的机制的生理后果， 描述上述神经信号和营养因子的作用 对E17、P1和成年BF的影响。 这些研究旨在探索局部神经元-星形胶质细胞-神经元 在发展和成熟的高炉调整。理解本 调节将为优化生存和功能提供见解 阿尔茨海默病患者退化的脑区。

The classic neurotrophin theory holds that distant targets provide survival factors to innervating neurons. However, we have found that local support cells may also be sources of these molecules. The current project uses the basal-forebrain medial septum (BF) as a critical model to explore the proposal that local neuron-astrocyte-neuron regulatory loops support survival and function of specific brain regions during development and maturity. Preliminary studies examining cultured BF neurons and astrocytes are the basis for the proposed work. We found that individual BF neural signals differentially regulate BF astrocytic gene expression of the neurotrophins, NGF, BDNF and NT3. These neurotrophins, in turn, differentially influence BF neuron survival, neurite extension and function, and, in related studies, regulate synaptic transmission and astrocyte morphology. To investigate the role of neuron-astrocyte-neuron regulatory loops we will 1) examine astrocyte development in the absence of BF neurons, 2) define regulation of astrocytes by neural signals, 3) evaluate autocrine regulation by neurotrophines, 4) compare astrocytes derived from embryonic day 17 to cells derived from postnatal day 1 and adults to define stage-specific astrocyte function, and 5) define physiologic consequences of mechanisms identified in culture by delineating the effects of the aforementioned neural signals and trophins on E17, P1 and adult BF in vivo. These studies are designed to explore local neuron-astrocyte-neuron regulation in the developing and mature BF. An understanding of this regulation will provide insights for optimization of survival and function of BF, a region that degenerates in Alzheimer's disease.