Timing of Neurotransmitter Release

总结 BRAIN计划和欧洲人脑项目的挑战是确定 人类大脑中数十亿的神经元和数万亿的突触将自己组织成神经回路， 使大脑功能。然而，神经回路的解剖组织不足以理解 信息处理，因为众所周知，作用于突触外的神经调质可以 通过招募或拒绝特定回路的参与来重新配置神经激活模式 件.动态地改变神经激活的空间模式在神经系统中可能是特别重要的。 小脑皮层，浦肯野细胞（PC）激活的精确时空模式对于大脑皮层的活动至关重要。 电机控制的复杂传感器集成功能。浦肯野细胞激活的模式由 橄榄小脑攀爬纤维（CF）与单个PC形成强大的一对一突触。 CF在突触后PC中产生复杂的尖峰，以及PC简单尖峰的暂停。然而，CF可以 还通过激活抑制性中间神经元来控制邻近PC的兴奋性。令人惊讶的是， CF-中间神经元信号传导在缺乏解剖学定义的突触的情况下通过溢出传递发生。 结构.这项计划的目的是确定CFs的谷氨酸溢出如何影响小脑 在单细胞、小微电路和小脑隔室水平上的电路功能。我们假设 CF溢出在各个层次上组织神经活动的时空模式，扩大影响 目标PC之外的CF。我们将使用各种电生理，成像和转基因技术， 测试CF谷氨酸溢出在小脑空间组织中作用的预测方法 电路活动成功完成拟议的目标有可能大大改变目前的 CFs在小脑功能中的作用。这一建议的概念新奇源于 证明快速突触外谷氨酸信号传导不需要形态学定义的突触 并提供了一种机制来介导由空间接近度调节的神经激活模式 而不是突触连接。所提出的实验的意义得到了几个体内实验的支持。 观察表明，这种非常规的传播模式从CF有助于时间- PC活动的空间模式对小脑功能至关重要。小脑功能障碍会导致 许多涉及运动控制的人类疾病，包括一个近40种疾病的家族， 脊髓小脑共济失调。小脑也参与执行功能，空间学习和记忆， 以及最近与精神分裂症和自闭症有关。更完整 因此，对小脑回路信息处理的理解将有利于广泛的基础和临床研究。 领域的

Summary The challenge of the BRAIN Initiative and the European Human Brain Project is to determine how the billions of neurons and trillions of synapses in the human brain organize themselves into neural circuits that enable brain function. Yet the anatomical organization of neural circuits is not sufficient to understand information processing, since it is well known that neuromodulators that act outside of synapses can reconfigure patterns of neural activation by recruiting or rejecting the involvement of specific circuit components. Dynamically changing the spatial pattern of neural activation may be particularly important in the cerebellar cortex, where the precise spatial-temporal patterns of Purkinje cell (PC) activation are critical for the complex sensory-integration function of motor control. The pattern of Purkinje cell activation is controlled by olivocerebellar climbing fibers (CFs) that form powerful one-to-one glutamatergic synapses with single PCs. CFs generate a complex spike in postsynaptic PCs as well as a pause in PC simple spiking. However, CFs can also control the excitability of neighboring PCs through the activation of inhibitory interneurons. Surprisingly, CF-interneuron signaling occurs via spillover transmission in the absence of anatomically defined synaptic structures. The goal of this proposal is to determine how glutamate spillover from CFs influences cerebellar circuit function at the level of single cells, small microcircuits and cerebellar compartments. We hypothesize that CF spillover organizes the temporal-spatial pattern of neural activity at each level to expand the influence of CFs beyond the targeted PC. We will use a variety of electrophysiological, imaging and transgenic approaches to test predictions about the role of CF glutamate spillover in the spatial organization of cerebellar circuit activity. Successful completion of the proposed Aims has the potential to dramatically shift the current view of the role of CFs in cerebellar function. The conceptual novelty of this proposal stems from the demonstration that fast extrasynaptic glutamate signaling does not require morphologically-defined synapses and provides a mechanism to mediate patterned of neural activation that is regulated by spatial proximity rather than synaptic connectivity. The significance of the proposed experiments is supported by several in vivo observations suggesting that this unconventional mode of transmission from CFs contributes to the temporal- spatial pattern of PC activity in a manner that is critical for cerebellar function. Cerebellar dysfunction can lead to many human diseases involving motor control, including a family of nearly 40 conditions known as the spinocerebellar ataxias.The cerebellum is also involved in executive functions, spatial learning and memory, and emotion as well as more recently being associated with schizophrenia and autism. A more complete understanding of cerebellar circuit information processing will thus benefit a wide range of basic and clinical fields.