Optical Studies of Single Hippocampal Synapses

超出所提供的空间。人类大脑包含超过10^10个神经元，由超过10^13个突触连接成一个令人敬畏的网络，构成神经计算和认知功能的基础。人们普遍认为，突触是认知及其功能障碍的重要方面的基础。例如，依赖经验的可塑性，如记忆，可能表现在单个突触的属性中。为了支持这些认知功能，单个突触被认为是自主运作的，并且具有异质性。因此，揭示突触功能的基本方面需要对单个突触进行研究。然而，突触是大脑中最小的功能单位（尺寸约为1微米），仅包含少数给定类型的信号转导分子，并且单个突触的功能测定仍然具有挑战性。因此，突触功能和可塑性的基本方面仍然存在争议。这项建议的目标是探索突触功能和可塑性的基本方面，使用最近开发的光学技术的基础上2-光子[Ca 2 +]成像在脊柱。这些技术具有检测啮齿动物脑片中海马皮层突触处的单个Ca 2+渗透通道和受体的开放的灵敏度。可以测量由突触激活的NMDA-R介导的[Ca 2 +]积累的事实允许确定在突触传递期间打开的NMDA-R的数量和突触处的受体的数量。这个问题对突触传递中的噪声源和突触传递的动态范围具有重要影响。NMDA-R激活也可用于检测谷氨酸在细胞外空间中的扩散。因此有可能确定单个突触是否是独立的，或者在一个突触释放的谷氨酸是否溢出以激活邻近突触的受体。这个问题对神经网络的记忆能力和突触可塑性机制有重要影响。最后，成像的NMDA-R激活可以用来开发一种方法的光学量子分析在单个突触，允许直接测试的uni-囊泡假说和解剖的短期突触可塑性的机制。我们希望最终对单个突触的功能和可塑性有一个核心的描述。性能现场=

EXCEED THE SPACE PROVIDED. The human brain contains >10^10 neurons connected by > 10^13 synapses into an awesome network that underlies neural computation and cognitive function. It is widely believed that synapses form the substrate of important aspects of cognition and its dysfunctions. For example, experience-dependent plasticity, such as memory, may express itself in the properties of individual synapses. To support these cognitive functions individual synapses are thought to function autonomously and have heterogeneous properties. Unraveling basic aspects of synaptic function therefore demands the study of individual synapses. However, synapses are the smallest functional units of the brain (size ~ 1 micrometer), containing only a handful of signal transduction molecules of a given type, and functional assays for single synapses have remained challenging. As a consequence, fundamental aspects of synaptic function and plasticity have remained controversial. The goal of this proposal is to explore fundamental aspects of synaptic function and plasticity using recently developed optical techniques based on 2-photon [Ca2+] imaging in spines. These techniques have the sensitivity to detect the opening of single Ca2+ permeable channels and receptors at hippocampal cortical synapses in rodent brain slices. The fact that [Ca2+] accumulations mediated by synaptically activated NMDA-Rs can be measured allows the determination of the number of NMDA-Rs opened during synaptic transmission and the number of receptors at synapses. This issue has important consequences for the sources of noise in synaptic transmission and the dynamic range of synaptic transmission. NMDA-R activation can also be used to detect the spread of glutamate in the extracellular space. Hence it is possible to determine if individual synapses are independent or if glutamate released at one synapse spills over to activate receptors at neighboring synapses. This issue has important consequences for the memory capacity of neural networks and the mechanisms of synaptic plasticity. Finally, imaging of NMDA-R activation can be used to develop a method of optical quantal analysis at single synapses, allowing a direct test of the uni--vesicular hypothesis and a dissection of the mechanisms of short-term synaptic plasticity. We hope to end up with a core description of the function and plasticity of single synapses. PERFORMANCE SITE ========================================Section End===========================================