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.

多种痴呆疾病共享常见的神经病理底物 大神经元的基础前脑损失，其中许多是 胆碱能。 关于胆碱能细胞损失机制的假设 阿尔茨海默氏病和相关疾病必须包括观察 那个向基础前脑投射的单胺能细胞组也 遭受中等至明显的损失。 一个最近发展的想法是 AD和相关疾病中的胆碱能细胞损失不是主要的，而是 由跨神经元途径介导的变性结果。 该项目获得解剖和功能的总体目标 神经化学数据通过获得系统和 详细了解基础前脑胆碱能系统的方式 由单胺能传入调节。 为了实现这一目标， 将进行具体尝试来评估是否预测 不同的脑干5-羟色胺能和多巴胺能细胞组终止 在胆碱能的前脑神经元上。 作为这些的逻辑扩展 实验我们将确定单胺能的来源（去甲肾上腺素能， 多巴胺能和血清素能）与局部Gabaergic和 连接到的肽基（NPY和生长抑素）神经元 胆碱能神经元。 这些研究将通过使用体内帮助 顺行（PHA-L）和体外（路西法黄）示踪技术， 免疫细胞化学方法和多种高尔基技术 在光和EM水平上的组合，由3-D补充 重建胆碱能神经元及其假定的终端。 我们还将表征单胺能传入的破坏 系统会影响神经递质酶的mRNA表达（聊天， GAD），神经肽（NPY，生长抑素）和受体（5-HT [1C]，D2和 M2）在基础前脑神经元中。 最后，我们将检验假设 单胺能剥夺后的聊天活动减少是 通过监测前脑通过前脑GABA能系统介导 GABA能活性和皮质乙酰胆碱释放。 定义特定基础的精确解剖结构和调节机制 前脑电路对于我们对 这些系统中信息处理的缺陷 国家。 此外，我们的研究可能会为 关于神经元代谢的认知障碍的病理生理学 和/或该大脑区域的变性至少部分是由于 顺行跨神经元机制。