Structure and function of spontaneous network activity during circuit formation

项目摘要 在神经系统发育的末期，神经回路具有极强的可塑性。小扰动 在这段时间内可能会导致终身电路和行为变化。毫不奇怪，越来越多的证据表明， 一些神经发育障碍，包括自闭症谱系障碍和癫痫， 有缺陷的晚期神经回路形成在这个晚期阶段，神经回路发生了改善， 成熟行为的成分逐渐显现。当这种情况发生时，与刺激无关的活动爆发 横扫神经元群体这种类型的活动，称为自发网络活动（SNA）， 在脊椎动物系统中，它的特点是改进神经连接以生成感觉地图， 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，它是如何运作的，以及它最终是如何支撑行为的。该提案确立了发展 果蝇幼虫运动系统作为一个遗传学上易于处理的模型，在早期阶段有丰富的知识 神经发育和电路功能的研究，这些问题都可以在这里得到解决。我们将联合收割机基因和 系统神经科学技术，以获得新的理解SNA功能在后期电路形成。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。的 该建议的第一个目的是识别SNA起始神经元和它们的作用机制。揭开 在神经和活动水平上启动SNA的机制是理解SNA如何 切实贯彻(2)启动后，SNA扩展并开始产生成熟为幼虫的运动输出 行为这种活动模式是如何形成的？本建议的第二个目的是揭示 SNA在群体水平上和单个神经元的活动模式，并开始学习SNA的效果 成熟的行为。(3)产生SNA的分子机制在任何领域都仍然知之甚少。 有机体第三个目标是鉴定SNA起始和/或扩展所必需的基因。我们将 重点关注与神经发育障碍相关的基因，有趣的是，这些基因高度 特别是在SNA窗口期间。总之，这项建议将揭示神经机制， SNA的起始，起始后SNA的结构和神经成分，以及SNA所需的基因。这些 研究将提供新的见解，神经回路如何形成，或未能正确形成，在神经发育， 紊乱

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.