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: 3122586
• 负责人: HYLAN C MOISES
• 金额: $ 15.28万
• 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/3122586
• 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.

这项研究的主要目标是表征 外源性神经生长因子（NGF）对胆碱能的影响 投射系统内的神经传递和突触功能 正常成人和老年人的基底前脑胆碱能神经元（BFCN） 哺乳动物的大脑。 正在寻求这种理解以确定是否 NGF 治疗可能会有效维持和/或恢复 前脑胆碱能投射的功能完整性 患有与年龄相关的神经退行性疾病的个体， 特别是阿尔茨海默病（AD）。 这项工作是基于先前 NGF 刺激大量胆碱能细胞表达的知识 啮齿动物前脑区域的神经元特征——一个主要目标是 确定这些影响可能产生的功能意义 BFCN 与其突触后靶细胞之间的神经传递。 到 实现这一点，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 由基底核刺激前脑输入产生 巨细胞神经元 (NBM) 到基底外侧杏仁核 (BLA) 的锥体神经元 大鼠脑切片制剂。 NGF 相关的前脑胆碱能变化 通过比较 NBM 的能力来评估神经传递 刺激引起胆碱能缓慢去极化及其潜在的 突触电流并抑制几种内在膜钾 对照和 NGF 处理的大鼠切片中 BLA 神经元的电导。 对照和 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以下可能性： 神经营养因子治疗可能会引起突触后的变化 胆碱能敏感性。 此外，我们还将测量 胆碱乙酰转移酶 (ChAT) 和组织中高亲和力胆碱摄取 从许多相同的制剂中采集的样本，其中的录音将 以确定 NBM 介导的 NGF 相关变化是否存在 BLA 内的突触活动可能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。 将对 3H-ACh 的释放进行额外的比较 对对照制备的杏仁核切片进行电场刺激 和 NGF 治疗的大鼠直接确定是否接受 NGF 治疗 导致发射机从 NBM 终端的释放变得容易 胆碱能神经元。 这些研究将在大脑中进行 取自年轻成年动物的切片和从以下来源获得的制剂 处于不同衰老阶段的老年大鼠。 总体而言，建议 研究旨在提供对能力的全面了解 外源性 NGF 在一定条件下维持中枢胆碱能传递 与衰老过程相关的胆碱能神经变性 以及在患有以下疾病的患者中发现的近似神经病理学特征 广告。