Neuromodulatory control of collective circuit dynamics in C. elegans

许多动物的行为被组织成长期持续的状态，也许最引人注目的是在睡眠/清醒状态 和情绪状态的区别然而，让动物能够 初始化、维持和终止这些状态是未知。生物胺和神经肽神经调节剂 对于行为状态的产生至关重要，但对神经调节剂如何起作用的机械理解 在电路上产生稳定的电路范围内的神经活动模式一直缺乏，主要是由于 哺乳动物回路中神经调节的复杂性。我们选择使用C来解决这个问题。优雅， 一种神经系统由302个神经元组成的线虫，有一个完全明确的线路图。我们之前 特征C. elegans运动模式，并表明，喂养动物之间的两个稳定的过渡 唤醒状态漫游和居住我们描述了产生漫游和居住的神经回路 他发现，两种相反的神经调节剂，血清素和神经肽PDF，作用于一个定义的 神经回路产生这种双稳态行为：血清素对回路的作用稳定了居住状态， PDF稳定漫游状态。既然我们已经定义了一个神经调节回路， 行为状态，我们准备解决有关神经回路功能的几个基本问题， organization.在这里，我们建议通过研究如何具体的神经回路持续性解剖机制， 神经调质重新配置神经回路，以稳定回路范围的活动模式， 行为状态解决这个问题需要对动物的神经活动进行全回路测量 在国家之间自由转换。因此，我们已经开发出一种新的成像技术， 同时监测自由运动的C神经回路中每个神经元的活动。优雅的动物。通过组合 这种成像技术与遗传/光遗传学操纵和新的分析/建模方法，我们将 说明了一种新的多学科方法，可用于剖析集体神经元 动态在电路中出现。首先，我们将首先确定电路范围的活动模式，这些模式定义了不同的 行为状态（目标1）。第二，我们将扰乱这个系统，以检查神经调节剂如何作用于特定的神经元。 神经元在电路中产生这些稳定的电路范围内的活动模式（目的2）。最后，我们将确定 神经调节回路的活动如何被环境的变化所改变， 记录进入这个回路的感觉神经元，我们将开发一个网络模型，描述如何 将嘈杂的感觉输入转换为双稳态行为状态输出（Aim 3）。这些研究将提供 神经调节剂如何协调活动中的整个回路变化以影响 行为通过提供神经调节的特定位点、全回路动力学和 紧急行为，这些研究将产生一个可推广的模型，电路功能，将承担研究 睡眠/清醒状态、情绪状态和认知状态。

Many animal behaviors are organized into long-lasting states, perhaps most strikingly in the sleep/wake and emotional states that mammals display. However, the fundamental mechanisms that allow animals to initiate, maintain and terminate these states are unknown. Biogenic amine and neuropeptide neuromodulators are critical for the generation of behavioral states, but a mechanistic understanding of how neuromodulators act on circuits to generate stable circuit-wide patterns of neural activity has been lacking, largely due to the complexity of neuromodulation in mammalian circuits. We have chosen to tackle this problem using C. elegans, a nematode whose nervous system consists of 302 neurons with a fully defined wiring diagram. We previously characterized C. elegans movement patterns and showed that feeding animals transition between two stable arousal states, roaming and dwelling. We characterized the neural circuit that generates roaming and dwelling states, and found that two opposing neuromodulators, serotonin and the neuropeptide PDF, act on a defined neural circuit to generate this bi-stable behavior: serotonin action on the circuit stabilizes dwelling states, while PDF stabilizes roaming states. Now that we have defined a neuromodulatory circuit that generates persistent behavioral states, we are poised to resolve several fundamental questions about neural circuit function and organization. Here, we propose to dissect mechanisms of neural circuit persistence by examining how specific neuromodulators reconfigure neural circuits to stabilize circuit-wide activity patterns that give rise to long-lasting behavioral states. Resolving this question requires whole-circuit measurements of neural activity as animals freely transition between states. Thus, we have already developed a new imaging technology that allows us to simultaneously monitor the activity of every neuron in a circuit in freely-moving C. elegans animals. By combining this imaging technology with genetic/optogenetic manipulations and new analysis/modeling methods, we will illustrate a new multi-disciplinary approach that can be used to dissect the mechanisms by which collective neural dynamics arise in a circuit. First, we will first identify the circuit-wide patterns of activity that define different behavioral states (Aim 1). Second, we will perturb this system to examine how neuromodulators act on specific neurons in the circuit to generate these stable circuit-wide patterns of activity (Aim 2). Finally, we will determine how activity in this neuromodulatory circuit is altered by changes in the environment and, after simultaneously recording the sensory neurons that feed into this circuit, we will develop a network model that describes how noisy sensory inputs are transformed into a bi-stable behavioral state output (Aim 3). These studies will provide new mechanistic insights into how neuromodulators orchestrate whole-circuit changes in activity to influence behavior. By providing quantitative links between specific sites of neuromodulation, whole-circuit dynamics, and emergent behaviors, these studies will yield a generalizable model for circuit function that will bear on studies of sleep/wake states, emotional states, and cognitive states.