The role of patterned spontaneous network activity in motor circuit activity

模式化自发网络活动在运动回路活动中的作用

• 批准号: 9741874
• 负责人: Arnaldo Carreira-Rosario
• 金额: $ 3.72万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2020-05-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9741874
• 关键词: Address; Affect; Behavior; Biological Assay; Brain; Cell physiology; Cognition; Collection; Computer Analysis; Cues; Development; Drosophila genus; Elements; Embryo; Event; Exhibits; Goals; Image; Individual; Injury; Interneurons; Invertebrates; Locomotion; Mammals; Mental disorders; Molecular; Motor; Motor Neurons; Nervous system structure; Neuraxis; Neurons; Neurophysiology - biologic function; Pattern; Periodicity; Population; Proxy; Reagent; Role; Spinal cord injury; Stroke; Synapses; Synaptic Membranes; System; Testing; Time; Transmission Electron Microscopy; Vertebrates; calcium indicator; cell type; connectome; design; hatching; insight; neural circuit; neuronal circuitry; optogenetics; regenerative therapy; synaptogenesis; time use; tool; virtual

The nervous system uses neural circuits to generate cognition and behavior. These circuits are often disrupted in spinal cord injury or stroke, and are aberrant in mental disorders. One way to treat these conditions is to re- grow or modify neural circuits. Thus, understanding how neural circuits are assembled may aid in the design of regenerative therapies, and brain stimulation therapies to treat mental disorders. During circuit assembly, nervous systems exhibit patterned spontaneous network activity (PaSNA). PaSNA is necessary to build a functional circuit in vertebrates and invertebrates, yet we know surprisingly little about the mechanisms involved. My strategy is to use Drosophila embryonic and larval locomotion as a system to uncover the underlying molecular and cellular mechanisms by which PaSNA promotes neural circuit assembly. The advent of new tools in Drosophila, such as optogenetic reagents, Gal4 lines to manipulate single neurons in the central nervous system (CNS), and a transmission electron microscopy connectome of the entire CNS make this a powerful system for studying neural circuits. Similar to vertebrates, premotor neurons are required for PaSNA. This raises the questions that this proposal addresses: Which specific interneuron populations generate PaSNA, do different interneurons have different patterns of activity, and how does interneuron PaSNA drive motor circuit development? With the use of Gal4 lines unique to our system and genetically encoded calcium indicators, I will identify the interneurons participating in PaSNA. I will use a characterized circuit required for larval locomotion together with optogenetic tools to identify the effect of PaSNA in establishing circuit connectivity and function. This proposal will reveal (1) the neuronal components that generate PaSNA during locomotor circuit assembly, (2) whether PaSNA is stochastic or stereotypic with the population of active neurons, (3) whether there is a correlation between neuronal identity and participation in PaSNA; (4) whether PaSNA is required for locomotor circuit establishment, and (5) whether PaSNA is required for locomotor circuit function. These represent critical advances that will provide insight into the formation and function of neural circuits in both Drosophila and mammals, where PaSNA is a conserved element of neural circuit formation.

神经系统使用神经回路来产生认知和行为。这些电路经常被中断 在脊髓损伤或中风中，在精神障碍中是异常的。治疗这些疾病的一种方法是重新- 生长或修改神经回路。因此，了解神经电路是如何组装的可能有助于设计 再生疗法和脑刺激疗法来治疗精神障碍。在电路组装期间， 神经系统表现出模式化的自发网络活动(PaSNA)。PaSNA是构建 脊椎动物和无脊椎动物的功能回路，但令人惊讶的是，我们对其机制知之甚少 牵涉其中。我的策略是利用果蝇胚胎和幼虫的运动作为一个系统来揭示 PaSNA促进神经回路组装的潜在分子和细胞机制。《降临》 在果蝇中的新工具，如光遗传试剂，Gal4线，以操纵中央的单个神经元 神经系统(CNS)，以及整个CNS的透射电子显微镜连接体，使这成为一种 研究神经回路的强大系统。与脊椎动物类似，PaSNA需要运动前神经元。 这就引出了这个提议所要解决的问题：哪些特定的中间神经元群体产生 PaSNA，不同的中间神经元是否有不同的活动模式，以及中间神经元PaSNA如何驱动 马达电路的发展？通过使用我们系统独有的Gal4线和遗传编码的钙 指标，我将确定参与PaSNA的中间神经元。我将使用所需的特征化电路 结合光遗传学工具鉴定PaSNA在建立环路中的作用 连接性和功能。这一提议将揭示(1)产生PaSNA的神经元成分 运动电路组件，(2)PaSNA是随机的还是与活跃的人群固定的 神经元，(3)神经元认同感与参与PaSNA是否相关；(4)是否 运动回路建立需要PaSNA，以及(5)运动是否需要PaSNA 电路功能。这些都是关键的进展，将为深入了解 果蝇和哺乳动物的神经回路，其中PaSNA是神经回路的保守元件 队形。