NGF REGULATION AND THE AGED BRAIN

NGF 调节与老年大脑

• 批准号: 3745501
• 负责人: CHRISTINE GALL
• 金额: --
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3745501
• 关键词: Alzheimer's disease; NMDA receptors; RNase protection assay; aging; antidromic impulse; behavior disorders; brain mapping; cholinergic receptors; dentate gyrus; electrophysiology; electrostimulus; experimental brain lesion; gene expression; gene induction /repression; generalized seizures; genetic transcription; granule cell; growth factor receptors; hippocampus; immunocytochemistry; in situ hybridization; laboratory rat; messenger RNA; neocortex; neurophysiology; neurotrophic factors; prosencephalon; space perception; synapses; tissue /cell culture

Nerve growth factor produced by forebrain neurons is thought to provide essential trophic support for the cholinergic neurons of basal forebrain which degenerate in behaviorally impaired aged rats and in diseases of cognitive impairment. This has stimulated interest in understanding the regulation of NGF expression in brain and attempts to augment NGF availability in aged brain. The recent collaborative studies of GAll and Isackson have demonstrated that, in addition to localization in hippocampus and cortex, neurons containing NGF mRNA are distributed within basal forebrain fields containing cholinergic neurons. In addition, seizure activity has been found to stimulate a dramatic increase in NGF mRNA content of dentate gyrus granule cells and neurons of olfactory- and neocortex. The goals of the 5 studies proposed here are to further evaluate the mechanisms by which physiological activity regulates NGF expression in young adult brain and to determine if there are differences in the cellular localization and "reactivity" of NGF expression in aged brain which correlate with the degree of behavioral impairment. Throughout the proposed work in situ hybridization and S1 nuclease protection techniques will be used to localize and quantify mRNA levels. Exp. 1 will utilize acute electrical stimulation to determine if the activity dependent stimulation of NGF expression is dependent upon synaptic mechanisms; specifically, if orthodromic, as opposed to antidromic, activation and NMDA receptor mechanisms; specifically, if orthodromic, as opposed to antidromic, activation and NMDA receptor mechanisms are required. Exp. 2 will determine if NGF mRNA expression becomes refractory to further stimulation in the wake of seizure-induced increases in this mRNA species. Exp. 3 will examine whether the seizure-stimulation of increased hippocampal NGF synthesis leads to changes in the biosynthetic activities of basal forebrain neurons; specifically, amyloid precursor protein mRNA, NGF receptor mRNA< and choline acetyltransferase (ChAT) immunoreactivity will be evaluated. In Exp. 4 in situ hybridization and immunohistochemical techniques will be used to determine if there are changes in the neuronal localization and abundance of mRNAs for NGF and NGF receptor that correspond with the degree of behavioral impairment and the apparent viability of basal forebrain cholinergic neurons in aged rat brain. Finally, in Exp. 5 acute electrical stimulation techniques will be used to determine if the response of NGF mRNA expression to physiological activation differs in old and aged (impaired and non-impaired) rats as compared to young adults. The proposed studies should further resolve the relationship of NGF trophic support to degenerative processes in the aged brain and begin to explore the feasibility of using physiological stimulation of NGF as a therapeutic strategy for maintaining viability of cholinergic forebrain neurons.

前脑神经元产生的神经生长因子被认为提供 基础前脑的胆碱能神经元的必要营养支持 在行为受损的老年大鼠和 认知障碍。 这激发了人们对理解的兴趣 调节大脑中NGF表达的调节，并尝试增加NGF 老年大脑的可用性。 Gall和 伊萨克森（Isackson）证明，除了海马中的本地化外 皮质，含有NGF mRNA的神经元分布在基础内 含有胆碱能神经元的前脑场。 另外，癫痫发作 已经发现活性刺激NGF mRNA的急剧增加 嗅觉和嗅觉和神经元的含量 - 嗅觉和神经元 新皮层。 这里提出的5项研究的目标是进一步 评估生理活性调节NGF的机制 年轻大脑的表达并确定是否存在差异 在老年人中NGF表达的细胞定位和“反应性”中 与行为障碍程度相关的大脑。 自始至终 拟议的原位杂交和S1核酸酶保护 技术将用于定位和量化mRNA水平。 经验。 1将 利用急性电刺激来确定活动是否取决于 NGF表达的刺激取决于突触机制。 具体而言，如果正质，与抗胶质性，激活和NMDA相反 受体机制；具体而言，如果正质，而不是 需要抗体，激活和NMDA受体机制。 经验。 2 将确定NGF mRNA表达是否变得难治性 在癫痫发作引起的这种mRNA物种的增加之后，刺激。 经验。 3将检查癫痫发作是否增加 海马NGF合成导致生物合成活动的变化 基底前脑神经元；具体而言，淀粉样蛋白前体蛋白mRNA， NGF受体mRNA <和胆碱乙酰转移酶（CHAT）免疫反应性 将进行评估。 在Exp。 4原位杂交和免疫组织化学 技术将用于确定神经元是否有变化 NGF和NGF受体的MRNA定位和丰度 与行为障碍的程度相对应 老化大鼠大脑中基底前脑胆碱能神经元的生存能力。 最后，在Exp中。 5急性电刺激技术将用于 确定NGF mRNA表达对生理的反应是否 激活在老年和老化（受损和不受影响的）大鼠中有所不同 与年轻人相比。 拟议的研究应进一步解决 NGF营养支持与年龄的退化过程的关系 大脑并开始探索使用生理的可行性 刺激NGF作为维持生存能力的治疗策略 胆碱能的前脑神经元。