Synaptic transmission in human ES cell-derived neurons: A potential cell replacement-model in the CNS.

大脑老化或头部损伤往往会导致相当程度的认知障碍。特别是，大脑颞叶神经元的丧失，如周围和内嗅觉皮质，被认为是阿尔茨海默病最早的神经病理变化之一。例如，受异常蛋白质碎片(淀粉样蛋白)和纤维(神经原纤维缠结)影响最早和最严重的区域--周围和内嗅觉皮质的萎缩，与阿尔茨海默病的严重程度相关。这些神经病变在成熟的中枢神经系统中不能自我修复。因此，神经元替代或保护可能是治疗中枢神经系统(CNS)神经变性或神经元死亡的一种潜在方法。因此，如何在损伤和/或退行性疾病后修复中枢神经系统是目前神经科学研究的主要问题之一。最近，胚胎干细胞(ES)来源于胚泡内细胞团，可以自我更新或分化为成熟生物体中的任何细胞类型。自我更新或分化的选择取决于干细胞的微环境。动物模型研究表明，多能神经干细胞或祖细胞在体外可以分化为神经元或神经胶质细胞。因此，这项拟议的研究将旨在建立中枢神经系统细胞替代的体外模型。这项研究将测试植入的ES细胞是否能够功能整合到周围皮质的宿主神经元回路中。视皮层位于感觉处理层级的顶端，与视觉识别记忆有关。再认记忆需要对先前发生的事情作出判断。例如，要在街上认出一个人，你可能会回忆起他们的信息，比如他们的名字或你们以前在哪里见过面。正常情况下，辨别什么是新奇的、什么是熟悉的或最近发生的事情是一项毫不费力的任务。对先前事件的判断，如识别记忆过程，对人类日常生活很重要。然而，识别记忆丧失是健忘症和早期阿尔茨海默病的主要症状。利用干细胞生物学和体外电生理学，这项研究将1.表征人类ES细胞来源神经元的兴奋性和抑制性突触传递；2.研究ES细胞来源神经元与宿主神经元回路形成突触的能力。这项拟议的研究将为中枢神经系统中丢失或受损的神经元建立一个简单的细胞替换模型，这可能最终增强我们对神经退行性疾病可用的治疗方法的理解。

Brain aging or head injury often leads to substantial levels of cognitive disability. In particular, loss of neurons in the temporal lobe of the brain, such as perirhinal and entorhinal cortices, is thought to be one of the earliest neuropathlogical changes in Alzheimer's disease. For example, atrophy of perirhinal and entorhinal cortices, the areas affected earliest and most severely by the abnormal protein fragments (amyloid) and fibers (neurofibrillary tangles), is correlated with the severity of Alzheimer's disease. These neuropathological changes cannot repair themselves in mature central nervous system. Therefore, neuronal replacement or protection may be a potential therapy for neurodegeneration or neuronal death in the central nervous system (CNS). Strategies by which the CNS can be repaired following injury and/or degenerative disorder is, therefore, one of the major concerns in neuroscience at the present time. Recently, embryonic stem (ES) cells, derived from the inner cell mass of the blastocyst, can either self-renew or differentiate into any of the cell types found in the mature organism. The choice of self-renewal or differentiation is dependent on the micro-environment of the stem cell. Animal model studies have demonstrated that multipotent neuronal stem cells or progenitor cells can differentiate to neurons or glia in vitro. Thus, the proposed study will aim to establish an in-vitro model for cell replacement in the CNS. The study will test whether implanted ES cells are capable of functional integration into host neuronal circuitry in the perirhinal cortex. The perirhinal cortex is at the top of the sensory processing hierarchy, and involves visual recognition memory. Recognition memory requires judgement concerning prior occurrence. For example, to recognise a person in the street you might recollect information about them such as their name or where you previously met. Normally, the ability to discriminate what is novel, what is familiar or what has occurred recently is an effortless task. Judgements of prior occurrence, such as the recognition memory process, are important for everyday human life. However, loss of recognition memory is a major symptom of amnesia and early Alzheimer's disease. Using stem-cell biology and in-vitro electrophysiology, the proposed study will 1. characterize excitatory and inhibitory synaptic transmission in human ES cell derived neurons; 2. investigate the ability of ES cell-derived neurons to form synapses with host neuronal circuitry. The proposed study will establish a simple model for the cell replacement of lost or damaged neurons in the CNS, which may eventually enhance our understanding of the treatment methods available in neuro-degenerative disorders.