CENTRAL CHOLINERGIC PATHWAYS

这是一个项目的竞争性续期申请，重点是 脑内胆碱能神经支配的系统水平组织 猴子和人类大脑的皮层。 在此提出的实验 调查对理解 记忆和觉醒的神经化学基质， 阿尔茨海默病和正常衰老的认知潜力。 我们将继续研究皮层神经元的区域性变化， 人大脑新皮层胆碱能神经支配的比较研究 胆碱能神经元及其皮质投射的细胞化学特征 模式. 我们最近的研究表明，人类大脑包含一个巨大的网络， 富含乙酰胆碱酯酶的皮质内胆碱能神经元 具有不寻常的，也许是人类独有的发育特征 的 这些神经元的富含AChE的染色模式是不可检测的，直到 在童年中期到晚期，在成年早期形成， 在非痴呆患者中， 个体 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解剖学基础 和可塑性，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被耗尽 疾病，并可能导致患者认知缺陷的发生 在这种情况下。 虽然这些神经元代表了大脑皮层 胆碱能细胞，有理由表明，他们的强烈， 乙酰胆碱酯酶活性也与许多非胆碱能机制有关 从蛋白水解到神经可塑性。 该提案的一个焦点旨在阐明细胞化学特征， 这些神经元的发育调节及其在发育过程中的命运 老年痴呆症 在一个特殊的认知评估样本中， 我们将确定非痴呆衰老受试者的认知表现 与这些神经元的密度以及 皮质胆碱能传入神经密度。 所采用的方法包括酶组织化学， 免疫细胞化学，原位杂交，电镜 组织化学和轴突示踪（用辣根过氧化物酶和 荧光示踪剂）在猴脑中。

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.