AFFERENT REGULATION OF BASAL FOREBRAIN CHOLINERGIC SYSTEM

多种痴呆疾病具有共同的神经病理基础 大神经元的基底前脑的损失，其中许多是 胆碱能。胆碱能细胞丢失机制的假说 阿尔茨海默病和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 遭受中等到显著的损失。最近发展出的一个想法是 阿尔茨海默病和相关疾病的胆碱能细胞丢失不是主要的，但 由跨神经元通路介导的退行性变所致。 这个项目的总体目标是获得解剖和功能 支持这一观点的神经化学数据通过获得系统和 详细了解基底前脑胆碱能系统是如何 受单胺能传入的调节。为了实现这一目标， 将进行具体尝试，以评估来自 不同的脑干5-羟色胺和多巴胺能细胞群终止 胆碱能前脑神经元。作为这些功能的逻辑扩展 实验我们将确定单胺能(去甲肾上腺素， 多巴胺能和5-羟色胺能)传入局部GABA能和 与神经肽Y和生长抑素相关的肽能神经元 胆碱能神经元。这些研究将通过在体内使用来辅助 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不同疾病中的应用 光和EM水平的组合，辅之以3-D 胆碱能神经元及其推测的终末的重建。 我们还将描述单胺能传入的中断 系统影响神经递质酶(ChAT， GAD)、神经肽(NPY、生长抑素)和受体(5-羟色胺[1C]、D2和 M2)。最后，我们将检验这一假设 单胺类剥夺后ChAT活性降低是否 通过监测前脑介导的前脑GABA能系统 GABA能活性和皮质乙酰胆碱释放。 在特定的基础上确定精确的解剖和调节机制 前脑回路将是我们理解 疾病中这些系统中信息处理的缺陷 各州。此外，我们的研究可能会提供更多线索 认知障碍的病理生理学关于神经元代谢是否 和/或这一大脑区域的退化至少部分是由于 顺行跨神经元机制。

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.