Mechanisms and Functions of Synapses and Circuits

突触和电路的机制和功能

• 批准号: 10307133
• 负责人: WADE G REGEHR
• 金额: $ 92.47万
• 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/10307133
• 关键词: Adult; Behavior; Behavior Control; Behavioral; Calcium; Calcium Signaling; Cerebellar Cortex; Cerebellar Diseases; 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 该赠款的最终目标是确定突触和电路如何在体内发挥作用以控制行为。 一个主要重点是阐明短期可塑性的机制，并了解功能和 短期可塑性在不同突触中的行为作用。尽管突触可塑性起着至关重要的作用 在整个大脑中，在许多神经系统疾病中隐含了功能障碍，许多 相互作用的可塑性形式仍然很少理解。我们将重点介绍专业的假设 钙传感器响应突触前钙信号，以增强神经递质释放。我们的发现 建议使用2种不同类型的钙传感器来增强促进和tetaniic增强（PTP） 在不同的时间尺度上传输。促进是一种突触增强的形式，可持续数百种 毫秒。我们发现，促进是由突触女7（SYT7）介导的，这是钙 - 敏感的同工型和缓慢的动力学。在初步研究中，我们发现在SYT7敲除小鼠中，设施是 即使释放的初始概率和突触前钙信号的最初概率没有改变，也消除了。病毒性的 SYT7的表达恢复了SYT7敲除动物中的设施。这些研究表明我们已经确定 钙传感器后的长时间气味。未来的研究将阐明SYT7在设施中的作用 促进不同的行为。 PTP是一种突触增强的形式，持续数十秒钟之后 突触前神经元的高频触发时期。我们最近表明PKCβ是钙 pTP的传感器在Held的花萼上。我们将继续阐明PTP的机制，并最终计划 使用分子遗传学选择性地从特定的突触中消除PTP，以确定PTP在 不同的行为。 第二个主要重点是阐明小脑电路并了解不同的电路元件如何贡献 为了调节运动学习，感觉运动整合和社会行为的小脑功能。我们有 最近表明，所有Purkinje细胞（PC）都有针对小脑中多种细胞的侧支 皮质，即使在成年人中。这表明有必要考虑从PC的输出到该的反馈 小脑皮质。我们将确定PCPC突触是否促进同步活动也测试 突触连接PC的假设会收敛到相同的DCN神经元并调节其发射。 这些研究将扩展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系统疾病。我们还将确定如何 小脑皮层调节特定行为。