NEUROTRANSMITTER REGULATION OF NFG IN THE CNS

本建议的目标将侧重于具体的参与， 调节神经生长因子基因的神经递质系统 在中枢神经系统（CNS）中的表达。 描述的研究 旨在验证神经递质谷氨酸 通过N-甲基-d-天冬氨酸（NMDA）受体激活，和去甲肾上腺素 (NE)参与了神经生长因子基因表达的调节。 这些 选择神经递质系统的原因有很多。两 已知这些神经递质系统在突触中起作用， 可塑性 此外，还有电生理学，神经解剖学， 和药理学数据支持这两个相互作用 神经递质系统 我们将分别关注每个系统， 然后提出这两种神经递质系统 在海马结构和皮层中相互作用， NGF mRNA。 可以推测，这两种基因的激活 神经递质系统可能最终影响功能（存活 和可塑性）的神经生长因子反应性胆碱能基底前脑神经元 通过激活NGF的表达。 然而，在这个时候，我们将 将我们的努力集中在NGF基因表达上， 未来的目标将是测试NE和谷氨酸的后果， （NMDA）诱导的NGF对胆碱能功能的影响。 中的研究 这一建议有助于进一步了解 神经生长因子在中枢神经系统，以及参与的潜在过程， 与阿尔茨海默病相关的神经变性。 有证据 胆碱能去甲肾上腺素能和谷氨酸的功能改变 阿尔茨海默病患者的神经递质系统。 因为基底前脑胆碱能神经元被认为是 敏感的神经生长因子的神经营养特性，研究调节 这种神经营养因子的NE和谷氨酸可能是关键， 了解一些神经退行性过程与 老年痴呆症 我们将使用原位杂交组织化学 和核糖核酸酶保护试验来研究神经递质诱导的 体外（组织切片）和体内NGF mRNA水平的变化。 这些 两种技术将用于定量和定位 海马结构和皮层神经生长因子基因表达的变化。 在提案的早期阶段，我们将使用组织切片， 海马和皮质组织，以研究特定条件 （神经递质剂量，时间过程，受体药理学，次要 信使等）了解神经递质调节的必要条件 NGF基因的表达。 一旦这些条件建立，我们将 然后转移到体内研究，以定位NGFmRNA表达， 对神经递质的挑战做出反应的细胞。 最后我们 建议研究这些生理作用（和相互作用） 两种神经递质在体内使用充分研究的范例， 分别刺激每种神经递质的内源性作用， 并联

The goals of this proposal will focus on the involvement of specific neurotransmitter systems in regulating nerve growth factor (NGF) gene expression in the central nervous system (CNS). The studies described are designed to test the hypothesis that the neurotransmitters glutamate, via N-methyl-d-aspartate (NMDA) receptor activation, and norepinephrine (NE) are involved in the regulation of NGF gene expression. These neurotransmitter systems were chosen for a number of reasons. Both of these neurotransmitter systems are known to play a role in synaptic plasticity. In addition, there is electrophysiological, neuroanatomical, and pharmacological data supporting the interaction of these two neurotransmitter systems. We will focus on each system separately and then formulate the hypothesis that these two neurotransmitter systems interact in the hippocampal formation and cortex to regulate levels of NGF mRNA. It could be postulated that the activation of these two neurotransmitter systems may ultimately influence the function (survival and plasticity) of NGF responsive cholinergic basal forebrain neurons through activation of NGF expression. However, at this time we will focus our efforts on NGF gene expression, with the understanding that future goals will be to test the consequence of NE and glutamate (NMDA)-induced changes in NGF on cholinergic function. The studies in this proposal are relevant for further understanding of the actions of NGF in the CNS, as well as potential processes involved in neurodegeneration associated with Alzheimer's disease. There is evidence for altered function in the cholinergic, noradrenergic, and glutamate neurotransmitter systems in patients suffering from Alzheimer's disease. Because the basal forebrain cholinergic neurons are thought to be sensitive to the neurotrophic properties of NGF, studying the regulation of this neurotrophic factor by NE and glutamate may be critical in understanding some of the neurodegenerative processes associated with Alzheimer's disease. We will use in situ hybridization histochemistry and a ribonuclease protection assay to study neurotransmitter-induced changes in NGF mRNA levels in vitro (tissue slices) and in vivo. These two techniques will be utilized for quantification and localization of changes in NGF gene expression in the hippocampal formation and cortex. In the early phases of the proposal, we will use tissue slices of hippocampal and cortical tissue to investigate the specific conditions (neurotransmitter dose, time course, receptor pharmacology, secondary messengers, etc.) necessary for understanding neurotransmitter regulation of NGF gene expression. Once these conditions are established, we will then move to in vivo studies in order to localize NGF mRNA expressing cells that are responding to neurotransmitter challenge. Finally, we propose to study the physiological actions (and interactions) of these two neurotransmitters in vivo using well-studied paradigms designed to stimulate the endogenous actions of each neurotransmitter separately and in parallel.