NGF AND CHOLINERGIC FUNCTION IN ADULT AND AGING BRAIN

成人和衰老大脑中的 NGF 和胆碱能功能

• 批准号: 2051892
• 负责人: HYLAN C MOISES
• 金额: $ 17.42万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-09-29 至 1996-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2051892
• 关键词: Alzheimer's disease; acetylcholine; aging; amygdala; animal old age; brain metabolism; choline; choline acetyltransferase; cholinergic receptors; electrophysiology; electrostimulus; immunocytochemistry; laboratory rat; membrane potentials; muscarine; muscarinic receptor; nervous system regeneration; neural plasticity; neural transmission; neurons; neurotrophic factors; prosencephalon; pyramidal cells; synapses; voltage /patch clamp

The primary goal of this research is to characterize the effects of administration of exogenous nerve growth factor (NGF) on cholinergic neurotransmission and synaptic function within the projection systems of basal forebrain cholinergic neurons (BFCN) in both normal adult and aged mammalian brain. This understanding is being sought to determine whether treatment with NGF might prove effective in maintaining and/or restoring the functional integrity of forebrain cholinergic projections in individuals suffering from age-related neurodegenerative disorders, particularly Alzheimer's disease (AD). The work is predicated on prior knowledge that NGF stimulates the expression of a host of cholinergic neuronal traits in forebrain areas in rodents -- a major objective is to determine the functional significance that such effects might have on neurotransmission between BFCN and their postsynaptic target cells. To accomplish this, current-clamp and single electrode voltage-clamp techniques will be used to intracellularly record cholinergic effects produced by stimulation of forebrain inputs from nucleus basalis magnocellularis (NBM) to pyrmaidal neurons in basolateral amygdala (BLA) in rat brain slice preparations. NGF-related changes in forebrain cholinergic neurotransmission will be assessed by comparing the ability of NBM stimulation to elicit a cholinergic slow depolarization and its underlying synaptic current and to inhibit several intrinsic membrane potassium conductances in BLA neurons in slices from control and NGF-treated rats. The responses of control and NGF-treated neurons to bath application of cholinergic agonists will be compared to address the possibility that treatment with the neurotrophic factor might induce changes in postsynaptic cholinergic sensitivity. In addition, we will measure the activity of choline acetyltransferase (ChAT) and high affinity choline uptake in tissue samples taken from many of the same preparations in which recordings will be obtained to determine whether any NGF-related changes in NBM-mediated synaptic action within the BLA can be linked to alterations in presynaptic mechanisms that regulate acetylcholine (ACh) synthesis and/or release. Additional comparisons will be made of the release of 3H-ACh evoked by electrical field stimulation in slices of amygdala prepared from control and NGF-treated rats to directly ascertain whether treatment with NGF results in a facilitated release of transmitter from terminals of NBM cholinergic neurons. These investigations will be carried out in brain slices taken from young adult animals and in preparations obtained from aged rats at different stages of senescence. Overall, the proposed research is designed to provide a comprehensive picture of the ability of exogenous NGF to maintain central cholinergic transmission under conditions of cholinergic neurodegeneration that are associated with the aging process and which approximate the neuropathological profile found in patients with AD.

这项研究的主要目的是表征 胆碱能的外源性神经生长因子（NGF）给药 神经传递和突触功能在投影系统中 正常成人和老年人的基础前脑胆碱能神经元（BFCN） 哺乳动物的大脑。 正在寻求这种理解来确定是否 NGF治疗可能有效地维护和/或恢复 前脑胆碱能预测的功能完整性 患有与年龄有关的神经退行性疾病的人， 特别是阿尔茨海默氏病（AD）。 这项工作是基于先验的 NGF刺激胆碱能的表达的知识 啮齿动物前脑区域中的神经元特征 - 一个主要目标是 确定这种影响可能对的功能意义 BFCN及其突触后靶细胞之间的神经传递。 到 完成此操作，电流钳和单电极电压钳 技术将用于细胞内记录胆碱能效应 通过刺激基底核的前脑输入产生 巨细胞（NBM）到基底外侧杏仁核（BLA）中的倍毛神经元（BLA） 老鼠脑切片制剂。 NGF相关的前脑胆碱能的变化 神经传递将通过比较NBM的能力来评估 刺激引起胆碱能缓慢的去极化及其基础 突触电流并抑制几种固有的膜钾 来自对照和NGF处理的大鼠切片中BLA神经元的电导。 控制和NGF处理的神经元对沐浴应用的反应 将比较胆碱能激动剂，以解决 用神经营养因子的治疗可能引起突触后的变化 胆碱能灵敏度。 此外，我们将测量 胆碱乙酰转移酶（聊天）和组织中高亲和胆碱摄取 从许多相同的准备工作中取出的样本 获得以确定NBM介导的任何与NGF相关的变化是否 BLA内的突触作用可以与突触前的变化有关 调节乙酰胆碱（ACH）合成和/或释放的机制。 还将对3H-ACH的发布进行其他比较。 由对照制备的杏仁核切片中的电场刺激 和NGF处理的大鼠直接确定是否使用NGF治疗 导致从NBM端子促进发射机的释放 胆碱能神经元。 这些调查将在大脑中进行 从年轻动物和从制剂中获得的切片 老年大鼠在衰老的不同阶段。 总体而言，提议 研究旨在提供有关能力的全面图景 外源性NGF在条件下维持中央胆碱能传播 与衰老过程相关的胆碱能神经退行性变化 以及哪个近似于患者的神经病理学特征 广告。