Timing of Neurotransmitter Release

摘要 大脑倡议和欧洲人类大脑项目的挑战是确定 人脑中的数十亿个神经元和数万亿个突触将自己组织成神经回路， 启用大脑功能。然而，神经回路的解剖学组织还不足以理解 信息处理，因为众所周知，作用于突触外的神经调节剂可以 通过重新招募或拒绝特定回路的参与来重新配置神经激活模式 组件。动态改变神经激活的空间模式在 小脑皮质，在那里精确的浦肯野细胞(PC)激活的时空模式对于 运动控制的复杂感觉整合功能。浦肯野细胞的激活模式受 橄榄小脑攀升纤维(CFs)与单个PC形成强大的一对一谷氨酸能突触。 CFS在突触后PC中产生复杂的尖峰，在PC中产生暂停，简单的尖峰。但是，CFS可以 也通过激活抑制性中间神经元来控制相邻PC的兴奋性。令人惊讶的是， 在没有解剖学定义的突触的情况下，cf-神经元间信号通过溢出传递发生 结构。这项提议的目标是确定CFS产生的谷氨酸溢出如何影响小脑 电路在单细胞、小微电路和小脑室的水平上起作用。我们假设 Cf溢出效应组织了每个级别的神经活动的时空模式，以扩大影响 目标PC之外的CFS的数量。我们将使用各种电生理、成像和转基因技术 关于Cf谷氨酸溢出在小脑空间组织中作用的预测的检验方法 电路活动。成功完成拟议的目标有可能极大地改变目前的 关于CFS在小脑功能中作用的观点。这项提议的概念新颖性源于 证明快速突触外谷氨酸信号不需要形态定义的突触 并提供了一种机制来调节由空间邻近性调节的神经激活模式 而不是突触连接。提出的实验的意义得到了几个活体实验的支持 观察表明，这种来自CFS的非常规传播方式有助于时间- PC活动的空间模式对小脑功能至关重要。小脑功能障碍可导致 许多涉及运动控制的人类疾病，包括一个近40人的家庭，称为 脊髓小脑性共济失调。小脑还参与执行功能、空间学习和记忆， 以及最近与精神分裂症和自闭症有关的因素。一个更完整的 因此，对小脑回路信息处理的了解将有助于广泛的基础和临床研究 菲尔兹。

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.