Timing of Neurotransmitter Release

神经递质释放的时机

• 批准号: 8759425
• 负责人: Jacques Wadiche
• 金额: $ 32.16万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8759425
• 关键词: Address; Autistic Disorder; Brain; Cells; Cerebellar Diseases; Cerebellar cortex structure; Cerebellum; Clinical; Communication; Complex; Data; Diffusion; Disinhibition; Educational process of instructing; Emotions; European; Family; Fiber; Glutamate Receptor; Glutamate Transporter; Glutamates; Goals; Golgi Apparatus; Human; Image; In Vitro; Interneurons; Knowledge; Lead; Learning; Location; Maps; Measures; Mediating; Memory; Molecular; Motor; Movement; Neuromodulator; Neurons; Output; Pattern; Population; Purkinje Cells; Recruitment Activity; Reporting; Role; Schizophrenia; Sensory; Shapes; Signal Transduction; Spinocerebellar Ataxias; Structure; Structure of molecular layer of cerebellar cortex; Synapses; Synaptic Cleft; Testing; Time; Transgenic Organisms; base; executive function; feeding; human disease; in vivo; information processing; insight; motor control; motor impairment; nerve supply; neural circuit; neural patterning; neurotransmitter release; postsynaptic; receptor; relating to nervous system; research study; sensory integration; stem; transmission process

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.

概括 大脑倡议和欧洲人类大脑项目的挑战是确定 人脑中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，神经回路的解剖组织不足以理解 信息处理，因为众所周知，在突触之外行动的神经调节剂可以 通过招募或拒绝特定电路的参与，神经激活的重新配置模式 成分。动态改变神经激活的空间模式可能在 小脑皮层，其中Purkinje细胞（PC）激活的精确时空模式对 运动控制的复杂感觉融合函数。 Purkinje细胞激活的模式由 橄榄球攀爬纤维（CFS）与单个PC形成强大的一对一谷氨酸突触突触。 CFS在突触后PC中产生复杂的尖峰，以及PC简单尖峰的暂停。但是，CFS可以 还通过激活抑制性神经元的激活来控制相邻PC的兴奋性。出奇， CF interneuron信号传导在没有解剖学突触的情况下通过溢出传播发生 结构。该提案的目的是确定CFS的谷氨酸溢出如何影响小脑 电路功能在单细胞，小微电路和小脑室的水平上。我们假设 CF溢出组织在每个层面上组织神经活动的时间空间模式以扩大影响 超越目标PC的CF。我们将使用各种电生理，成像和转基因 测试有关CF谷氨酸溢出在小脑空间组织中的作用预测的方法 电路活动。成功完成拟议的目标有可能显着转移电流 CFS在小脑功能中的作用的视图。该提议的概念新颖性源于 证明快速突触外谷氨酸信号传导不需要形态定义的突触 并提供了一种介导由空间接近调节的神经激活图案的机制 而不是突触连通性。拟议的实验的意义得到了几个体内的支持 观察结果表明，这种非常规的传输方式有助于时间 PC活性的空间模式以小脑功能至关重要的方式。小脑功能障碍可以引导 对于许多涉及运动控制的人类疾病，包括一个近40个条件的家族称为 小脑也参与执行功能，空间学习和记忆， 和情感以及最近与精神分裂症和自闭症有关的。更完整 因此，了解小脑电路信息处理将有益于广泛的基本和临床 字段。