CENTRAL CHOLINERGIC PATHWAYS

这是一个项目的竞争性续订申请，该项目侧重于 大脑胆碱能神经支配的系统水平组织 猴子和人脑的大脑皮层。这项研究中提出的实验 调查具有直接的影响，可以理解 记忆和觉醒的神经化学底物，其发病机制 阿尔茨海默病和正常衰老的认知潜能。 我们将继续研究大脑皮层的区域差异 人脑新皮质胆碱能神经支配的比较 胆碱能神经元的细胞化学特征及其皮质投射 模式。 我们最近的研究表明，人类大脑包含一个巨大的网络， 皮质内富含乙酰胆碱酯酶(AChE)的胆碱能神经元 有着不同寻常的，或许是独一无二的人类发展概况。这个 这些神经元的富含AChE的染色模式直到 儿童期中后期，在成年期早期形成， 在非痴呆患者的晚期衰老过程中保持显著的稳定性 个人。同源神经元在其他动物中并不明显 物种。这些神经元可能为发育提供了解剖学基础。 以及成年期的可塑性，甚至在健康的老年时期。 这些富含AChE的新皮质神经元似乎在阿尔茨海默病中耗尽 疾病，并可能导致患者认知障碍的发生 在这种情况下。虽然这些神经元代表大脑皮层的子集 胆碱能感受性细胞，有理由认为它们强烈 AChE活性也与一系列非胆碱能机制有关 范围从蛋白质分解到神经可塑性。 这项提案的一个重点是阐明细胞化学签名和 这些神经元的发育调节及其在脑损伤过程中的命运 阿尔茨海默氏症。在一个特殊的认知评估样本中， 我们将确定非精神错乱的老年受试者的认知表现 与这些神经元的密度和 皮质胆碱能传入神经元的密度。 将采用的方法包括酶组织化学， 免疫细胞化学、原位杂交、电子显微镜 组织化学和轴突追踪(辣根过氧化物酶和 荧光示踪剂)。

This is a competitive renewal application for a project that focuses on the systems-level organization of cholinergic innervation in the cerebral cortex of the monkey and human brain. The experiments proposed in this investigation have immediate implications for understanding the neurochemical substrate of memory and arousal, the pathogenesis of Alzheimer's disease and the cognitive potential of normal aging. We will continue to investigate the regional variations of cortical cholinergic innervation in the human cerebral neocortex, the comparative cytochemical signature of cholinergic neurons and their cortical projection patterns. Our recent studies showed that the human brain contains a vast network of acetylcholinesterases (AChE)-rich intra-cortical cholinoceptive neurons with an unusual and perhaps uniquely human developmental profile. The AChE-rich staining pattern of these neurons is not detectable until mid-to-late childhood, becomes established during early adulthood and maintains a remarkable stability into advanced senescence in non-demented individuals. Homologous neurons are not conspicuous in other animals species. These neurons may provide an anatomical substrate for development and plasticity during adulthood and perhaps even during healthy old age. These AChE-rich neocortical neurons appear to be depleted in Alzheimer's disease and may contribute to the genesis of cognitive deficits in patients with this condition. While these neurons represent a subset of cortical cholinoceptive cells, there are reasons for suggesting that their intense AChE activity is also associated with a host of non-cholinergic mechanisms that range from proteolysis to neural plasticity. One focus of this proposal aims to elucidate the cytochemical signature and developmental regulation of these neurons and their fate in the course of Alzheimer's disease. In a special sample of cognitively evaluated, non-demented senescent subjects we will determine if cognitive performance in old age is correlated with the density of these neurons and with the density of cortical cholinergic afferents. The methods to be employed include enzyme histochemistry, immunocytochemistry, in situ hybridization, electron microscopic histochemistry and axonal tracing (with horseradish peroxidase and fluorescent tracers) in the monkey brain.