Structure and function of spontaneous network activity during circuit formation

项目摘要 在神经系统发育的末期，神经回路可塑性极强。小扰动 在这段时间内，会导致终生的电路和行为变化。毫不奇怪，越来越多的证据表明 几种神经发育障碍，包括自闭症谱系障碍和癫痫，起源于 晚期神经回路形成有缺陷。在这一后期阶段，神经回路的精细化发生了， 成熟行为的组成部分逐渐出现。当这种情况发生时，不依赖刺激的活动爆发 扫过神经元群。这种类型的活动称为自发网络活动(SNA)，它具有 是脊椎动物系统的特征，在脊椎动物系统中，它精炼神经连接以生成感觉地图和 建立本地电路。然而，令人惊讶的是，我们对SNA的分子机制知之甚少 它是如何启动的，它如何发挥作用，以及它最终如何支撑行为。这项建议确立了发展中的 果蝇幼虫运动系统作为遗传上易驯化的模型，具有丰富的早期知识 神经发育和回路功能，在那里这些问题可以被解决。我们结合了基因和 系统神经科学技术，以获得对SNA在晚期回路形成过程中的功能的新理解。这 提案有三个目标。(1)在运动回路中启动SNA的确切神经元尚不清楚。这个 这项提议的第一个目标是确定SNA启动神经元和它们的作用机制。揭开面纱 在神经和活动水平上启动SNA的机制是理解SNA如何 实施。(2)在启动后，SNA扩展并开始产生成熟到幼虫的运动输出 行为。这种活动模式是如何发展起来的？这项提议的第二个目的是揭示 SNA在种群水平和单个神经元的活动模式，并开始了解SNA的作用 关于成熟的行为。(3)产生SNA的分子机制在任何 有机体。第三个目标将确定启动和/或扩展SNA所必需的基因。我们会 关注与神经发育障碍相关的基因，耐人寻味的是 在国民账户体系窗口期间明确表示。总而言之，这个提议将揭示神经机制如何 SNA的启动，启动后SNA的结构和神经成分，以及SNA所需的基因。这些 研究将为神经发育中神经回路的形成或不能正确形成提供新的见解 精神错乱。

Project Summary Towards the end of nervous system development, neural circuits are extremely plastic. Small perturbations during this time can cause lifelong circuit and behavioral changes. Not surprisingly, mounting evidence suggests that several neurodevelopmental disorders, including autism spectrum disorder and epilepsy, have origins in defective late neural circuit formation. During this late stage, neural circuits refinement takes place, and components of the mature behavior gradually appear. As this occurs, stimulus-independent bursts of activity sweep through neuronal populations. This type of activity, known as spontaneous network activity (SNA), has been characterized in vertebrate systems where it refines neural connections to generate sensory maps and establish local circuits. However, we know surprisingly little about the molecular mechanisms by which SNA is initiated, how it functions, and how it ultimately underpins behavior. This proposal establishes the developing Drosophila larval locomotor system as a genetically tractable model, with a wealth of knowledge on early stages of neurodevelopment and circuit function, where these questions can be tackled. We combine genetic and systems neuroscience techniques to gain new understanding into SNA function during late circuit formation. This proposal has three goals. (1) The exact neurons that initiate SNA within locomotor circuits are not known. The first aim of this proposal is to identify the SNA initiator neurons and the mechanism by which they act. Uncovering the mechanism that initiates SNA at the neural and activity level is fundamental to understand how SNA is implemented. (2) After initiation, SNA expands and begins to produce motor outputs that mature into the larval behavior. How does this activity pattern develop? The second aim of this proposal is to reveal the structure of SNA at the population level and the pattern of activity in individual neurons, and begin to learn the effect of SNA on mature behavior. (3) The molecular mechanisms that produce SNA remain poorly understood in any organism. The third aim will identify genes that are necessary for the initiation and/or expansion of SNA. We will focus on genes that have been associated with neurodevelopmental disorders, which intriguingly are highly expressed specifically during the SNA window. In sum, this proposal will reveal the neural mechanisms for how SNA initiates, the structure and neural components of SNA after initiation, and genes required for SNA. These studies will provide new insight into how neural circuits form, or fail to form properly, in neurodevelopmental disorders.