AFFERENT REGULATION OF BASAL FOREBRAIN CHOLINERGIC SYSTEM

基底前脑胆碱能系统的传入调节

• 批准号: 3760987
• 负责人: LASZLO ZABORSZKY
• 金额: --
• 依托单位: UNIVERSITY OF VIRGINIA
• 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/3760987
• 关键词: acetylcholine; afferent nerve; brain mapping; brain stem; choline acetyltransferase; dopamine receptor; electron microscopy; gamma aminobutyrate; glutamate decarboxylase; immunocytochemistry; interneurons; laboratory rat; light microscopy; muscarinic receptor; neuroanatomy; neurons; neuropeptide Y; prosencephalon; serotonin receptor; somatostatin; tissue /cell culture

Multiple dementing illnesses share the common neuropathological substrate of loss in the basal forebrain of large neurons, many of which are cholinergic. Hypotheses about the mechanism of cholinergic cell loss in Alzheimer's disease, and related disorders must include the observation that monoaminergic cell groups which project to the basal forebrain also suffer moderate to marked loss. A recently developed idea is that cholinergic cell loss in AD and related disorders is not primary, but results from degeneration mediated by transneuronal pathways. The overall goal of this project to acquire anatomical and functional neurochemical data in support of this idea by obtaining a systematic and detailed understanding of how the basal forebrain cholinergic system is modulated by monoaminergic afferents. In order to achieve this goal, specific attempts will be made to assess whether projections from different brainstem serotoninergic and dopaminergic cell groups terminate on cholinergic forebrain neurons. As a logical extension of these experiments we will identify the sources of monoaminergic (noradrenergic, dopaminergic and serotonergic) afferents to local GABAergic and peptidergic (NPY and somatostatin) neurons which are connected to cholinergic neurons. These studies will be aided by using in vivo anterograde (PHA-L) and in vitro (Lucifer Yellow) tracer techniques, immunocytochemical methods and the Golgi technique in various combinations at both the light and EM level, supplemented by 3-D reconstruction of cholinergic neurons and their putative terminals. We will also characterize how the disruption of monoaminergic afferent systems affects expression of mRNAs for neurotransmitter enzymes (ChAT, GAD), neuropeptides (NPY, somatostatin) and receptors (5-HT[1C], D2 and M2) in basal forebrain neurons. Finally, we will test the hypothesis whether the decrease of ChAT activity after monoaminergic deprivation is mediated through the forebrain GABAergic system by monitoring forebrain GABAergic activity and cortical acetylcholine release. Defining the precise anatomy and regulatory mechanisms in specific basal forebrain circuits will be essential in our understanding of the deficiencies in the information processing in these systems in disease states. Moreover our study may provide additional clues to the pathophysiology of cognitive disorders as to whether neuronal metabolism and/or degeneration in this brain region is due at least in part to anterograde transneuronal mechanisms.

多种痴呆症有着共同的神经病理学基础 大神经元的基底前脑的损失，其中许多是 胆碱能 关于胆碱能细胞丢失机制的假说 阿尔茨海默病及相关疾病必须包括观察 投射到基底前脑的单胺能细胞群也 遭受中度至显着损失。 一个最近发展起来的想法是， AD和相关疾病中胆碱能细胞的丢失不是原发性的， 由跨神经元通路介导的变性引起。 该项目的总体目标是获得解剖和功能 神经化学数据支持这一想法，通过获得一个系统的， 详细了解基底前脑胆碱能系统是如何 由单胺能传入神经调节。 为了实现这一目标， 将作出具体的努力，以评估预测是否从 不同的脑干肾上腺素能和多巴胺能细胞群终止于 对胆碱能前脑神经元的影响 作为这些的逻辑延伸， 实验中我们将鉴定单胺能（去甲肾上腺素能， 多巴胺能和多巴胺能）传入局部GABA能， 肽能（NPY和生长抑素）神经元连接到 胆碱能神经元 这些研究将通过使用体内 顺行（PHA-L）和体外（荧光黄）示踪技术， 免疫细胞化学方法和高尔基体技术在各种 在光和EM水平的组合，辅以3-D 胆碱能神经元及其假定终末的重建。 我们还将描述单胺能传入神经的中断 系统影响神经递质酶的mRNA表达（ChAT， GAD）、神经肽（NPY、生长抑素）和受体（5-HT[1C]、D2和 M2）。 最后，我们将测试假设 单胺能剥夺后ChAT活性的降低是否 通过监测前脑GABA能系统介导 GABA能活性和皮质乙酰胆碱释放。 明确特定基底细胞的精确解剖结构和调控机制 前脑回路对于我们理解 疾病中这些系统的信息处理缺陷 states. 此外，我们的研究可能会提供更多的线索， 认知障碍的病理生理学， 和/或退化至少部分是由于 顺行跨神经元机制