Mechanisms and Functions of Synapses and Circuits

突触和电路的机制和功能

• 批准号: 9388386
• 负责人: WADE G REGEHR
• 金额: $ 92.2万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9388386
• 关键词: Adult; Behavior; Behavior Control; Behavioral; Calcium; Calcium Signaling; Cerebellar Diseases; Cerebellar cortex structure; Chemosensitization; Elements; Epilepsy; Feedback; Frequencies; Future; Goals; Grant; Kinetics; Knockout Mice; Mediating; Molecular Genetics; Neurons; Output; Parkinson Disease; Play; Probability; Protein Isoforms; Proteins; Purkinje Cells; Role; Schizophrenia; Social Behavior; Synapses; Synaptic plasticity; Testing; Time; Viral; brain dysfunction; cell type; in vivo; insight; knockout animal; millisecond; motor learning; nervous system disorder; neurotransmitter release; presynaptic; presynaptic neurons; protein kinase C beta; sensor; synaptic function; synaptotagmin VII; transmission process

Project Summary The ultimate goal of this grant is to determine how synapses and circuits function in vivo to control behaviors. One major focus is to clarify the mechanisms of short-term plasticity, and to understand the functional and behavioral role of short term plasticity at different synapses. Although synaptic plasticity plays a crucial role throughout the brain, and dysfunction has been implicated in numerous neurological disorders, the many interacting forms of plasticity remain poorly understood. We will focus on the hypothesis that specialized calcium sensors respond to presynaptic calcium signals to enhance neurotransmitter release. Our findings suggest that facilitation and posttetanic potentiation (PTP) use 2 different types of calcium sensors to enhance transmission on different time scales. Facilitation is a form of synaptic enhancement that lasts for hundreds of milliseconds. We have found that facilitation is mediated by synaptotagmin 7 (syt7), which is a calcium- sensitive isoform with slow kinetics. In preliminary studies we find that in syt7 knockout mice, facilitation is eliminated even though the initial probability of release and presynaptic calcium signals are unaltered. Viral expression of syt7 restores facilitation in syt7 knockout animals. These studies indicate that we have identified the long sought after calcium sensor for facilitation. Future studies will clarify the role of syt7 in facilitation in contributing to different behaviors. PTP is a form of synaptic enhancement lasting for tens of seconds following a period of high-frequency firing of presynaptic neurons. We have recently shown that PKCβ is a calcium sensor for PTP at the calyx of Held. We will continue to clarify the mechanism of PTP and ultimately plan to use molecular genetics to selectively eliminate PTP from specific synapses to determine the role of PTP in different behaviors. A second major focus is to clarify cerebellar circuitry and understand how different circuit elements contribute to cerebellar function, which regulates motor learning, sensorimotor integration and social behaviors. We have recently shown that all Purkinje cells (PCs) have collaterals that target many types of cells within the cerebellar cortex, even in adults. This indicates it is necessary to consider feedback from the output of PCs to the cerebellar cortex. We will determine if PCPC synapses promote synchronous activity also test the hypothesis that synaptically-connected PCs converge onto the same DCN neuron and regulate its firing. These studies will extend our understanding of cerebellar processing and will provide important insights into neurological disorders that arise from cerebellar dysfunction. We will also determine how specific regions of the cerebellar cortex regulate specific behaviors.

项目摘要 这项资助的最终目标是确定突触和回路在体内如何发挥作用来控制行为。 一个主要的焦点是阐明短期可塑性的机制，并理解功能和 短期可塑性在不同突触中的行为作用。尽管突触的可塑性起着至关重要的作用 在整个大脑中，功能障碍与许多神经疾病有关，许多 人们对塑性的相互作用形式仍知之甚少。我们将重点关注这样一个假设，即 钙传感器对突触前钙信号作出反应，以促进神经递质的释放。我们的发现 建议易化和强直后强化(PTP)使用两种不同类型的钙感受器来增强 在不同的时间尺度上传输。易化是突触增强的一种形式，持续数百年 毫秒。我们已经发现，促进作用是由突触素7(Syt7)介导的，Syt7是一种钙- 动力学较慢的敏感异构体。在初步研究中，我们发现在syt7基因敲除小鼠中，易化是 即使初始释放概率和突触前钙信号没有改变，也被消除了。病毒式传播 在syt7基因敲除动物中，syt7的表达恢复了易化性。这些研究表明，我们已经确定 长久以来被追捧的钙传感器。未来的研究将阐明syt7在促进 导致了不同的行为。PTP是突触增强的一种形式，持续数十秒 突触前神经元的高频放电阶段。我们最近发现pkcβ是一种钙。 用于PTP的传感器，在保持的花萼。我们将继续澄清PTP的机制，并最终计划 利用分子遗传学选择性地消除特定突触中的PTP，以确定PTP在 不同的行为。 第二个主要关注点是阐明小脑回路和了解不同回路元素是如何起作用的。 调节运动学习、感觉运动整合和社会行为的小脑功能。我们有 最近发现，所有的浦肯野细胞(PC)都有针对小脑内许多类型细胞的侧枝。 大脑皮层，即使是成年人。这表明有必要考虑从PC的输出到 小脑皮层。我们将确定PCPC突触是否促进同步活动也测试 假设突触连接的PC会聚到同一个DCN神经元上，并调节其放电。 这些研究将扩大我们对小脑加工的理解，并将为 由小脑功能障碍引起的神经性疾病。我们还将确定特定区域如何 小脑皮质调节特定的行为。