CAREER: Dissecting Neural Mechanisms of Behavioral State Control in C. elegans

许多动物的行为被组织成持久的状态，也许最引人注目的是哺乳动物的三种主要唤醒状态：清醒、非快速眼动睡眠和快速眼动睡眠。尽管行为状态在动物王国中普遍存在，但人们对动物启动、维持和终止这些状态的基本机制知之甚少。为了解决这个问题，研究人员在一种简单的动物模型——秀丽隐杆线虫中研究了行为状态产生的大脑机制。具体来说，他们研究了相互作用的神经元群（或神经回路）如何促进行为状态的产生。秀丽隐杆线虫对这些研究来说是一个有吸引力的系统，因为它的神经系统只有302个神经元。此外，这些神经元之间的联系是已知的。因此，神经回路功能的基本原理可以在这种动物中迅速发现，然后应用于更复杂的动物。该研究计划的具体目标是：(1)全面表征秀丽隐杆线虫的行为状态，(2)研究行为状态下神经元群如何相互作用，以及(3)使用新的光学方法来表征行为状态下的全脑活动。这些研究将对动物如何产生行为状态产生新的见解，并对人类福祉，公共政策等产生影响。本研究计划与教育计划相结合，以发展本科实验课程为中心，让学生学习并应用现代神经科学方法来研究神经回路。课程材料将免费提供给其他教育工作者。要全面了解神经回路的功能，需要对多个层面的分析有详细的了解：从单个神经元中的分子事件到大规模的神经活动模式，再到紧急动物行为。本研究项目在长期行为状态的神经调节控制的背景下，将这些分析范围联系起来。尽管几乎所有的动物都表现出持久的行为状态，但人们对动物产生这些状态的神经机制知之甚少。该项目的目标是剖析线虫简单神经系统中的这些机制，将神经调节剂释放的特定位点与大规模活动模式和行为联系起来。目标1：首先，一个新的成像平台将被用来确定秀丽隐杆线虫的行为如何随着时间的推移而共同变化，因为动物在行为状态之间切换。目标2：有针对性的机制实验将用于检查特定的神经调节剂如何允许运动前回路之间的状态依赖耦合，以协调动物切换状态时的行为。目的3：最后，全脑钙成像方法将用于检查行为状态下的全脑活动模式。这些研究将揭示允许动物协调和组织其行为的基本神经机制。本研究计划与教育计划相辅相成，教育计划以发展一门新的本科实验课程为中心，让学生学习并应用现代神经科学技术来解剖神经回路功能。本课程强调使用不同的实验方法来探索神经回路的功能。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Many animal behaviors are organized into long-lasting states, perhaps most strikingly in the three main arousal states in mammals: wakefulness, non-REM (rapid eye movement) sleep, and REM sleep. Although behavioral states are pervasive throughout the animal kingdom, the fundamental mechanisms that allow animals to initiate, maintain and terminate these states are poorly understood. To address this problem, the researchers examine the brain mechanisms that underlie behavioral state generation in a simple animal model, the roundworm C. elegans. Specifically, they examine how groups of interacting neurons --or neural circuits-- contribute to the generation of behavioral states. C. elegans is an attractive system for these studies because its nervous system consists of just 302 neurons. Moreover, the connections between these neurons are already known. Thus, fundamental principles of neural circuit function can be rapidly discovered in this animal and then applied to more complex animals. The specific goals of the research plan are to (1) fully characterize behavioral states in C. elegans, (2) examine how groups of neurons interact during behavioral states, and (3) use new optical approaches to characterize brain-wide activity during behavioral states. These studies will yield new insights into how animals generate behavioral states, with implications for human well-being, public policy, and more. This research plan is integrated with an educational plan centered on developing an undergraduate laboratory course where students learn and apply modern neuroscience methods to study neural circuits. The course materials will be made freely available to other educators.A full understanding of neural circuit function requires detailed knowledge across many scales of analysis: from molecular events in single neurons to large-scale patterns of neural activity to emergent animal behaviors. This research project bridges these scales of analysis in the context of neuromodulatory control of long-lasting behavioral states. Although almost all animals display long-lasting behavioral states, the neural mechanisms that allow animals to generate these states are poorly understood. The goal of this project is to dissect these mechanisms in the simple nervous system of the nematode C. elegans, linking specific sites of neuromodulator release to large-scale activity patterns and behavior. Aim 1: First, a novel imaging platform will be used to determine how all C. elegans behaviors co-vary over time as animals switch between behavioral states. Aim 2: Targeted mechanistic experiments will then be used to examine how specific neuromodulators allow for state-dependent coupling between premotor circuits to coordinate behaviors as animals switch states. Aim 3: Finally, a whole-brain calcium imaging approach will be used to examine brain-wide activity patterns during behavioral states. These studies will reveal fundamental neural mechanisms that allow animals to coordinate and structure their behaviors. This research plan is complemented by an educational plan, which is centered on the development of a new undergraduate laboratory course in which students learn and apply modern neuroscience techniques to dissect neural circuit function. The course has an emphasis on the use of diverse experimental approaches to probe neural circuit function.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.