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

职业：剖析线虫行为状态控制的神经机制

• 批准号: 1845663
• 负责人: Steven Flavell
• 金额: $ 76.2万
• 依托单位: Massachusetts Institute of Technology
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1845663&HistoricalAwards=false
• 关键词: CAREER; Dissecting; Neural; Mechanisms; Behavioral

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.

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哺乳动物的三种主要唤醒状态：觉醒，非快速眼动（快速眼动）睡眠和快速眼动睡眠。虽然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，研究人员在一个简单的动物模型中研究了行为状态产生的大脑机制。优雅的具体来说，他们研究了相互作用的神经元组-或神经回路-如何有助于行为状态的产生。C.对于这些研究来说，秀丽线虫是一个有吸引力的系统，因为它的神经系统仅由302个神经元组成。此外，这些神经元之间的连接也是已知的。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。研究计划的具体目标是：（1）充分表征C。elegans，（2）研究神经元群在行为状态下如何相互作用，以及（3）使用新的光学方法来表征行为状态下的全脑活动。这些研究将为动物如何产生行为状态提供新的见解，并对人类福祉，公共政策等产生影响。该研究计划与以开发本科实验室课程为中心的教育计划相结合，学生在该课程中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者。对神经回路功能的全面理解需要跨许多尺度分析的详细知识：从单个神经元中的分子事件到神经活动的大规模模式再到动物行为的涌现。本研究项目在神经调节控制长期行为状态的背景下桥接这些分析尺度。尽管几乎所有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。本计画的目标是在线虫C. elegans，将神经调质释放的特定位点与大规模活动模式和行为联系起来。目的1：首先，一种新的成像平台将被用来确定所有的C.当动物在行为状态之间切换时，秀丽线虫的行为随着时间的推移而变化。目标二：有针对性的机械实验，然后将被用来检查特定的神经调节剂如何允许状态依赖性的耦合之间的前运动电路，以协调行为的动物切换状态。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。这些研究将揭示基本的神经机制，使动物能够协调和组织他们的行为。该研究计划由教育计划补充，该计划以开发新的本科实验室课程为中心，学生学习并应用现代神经科学技术来解剖神经回路功能。该课程强调使用多种实验方法来探索神经回路功能。该奖项反映了NSF的法定使命，并且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。

项目成果

Schrödinger Dynamics and Berry Phase of Undulatory Locomotion

薛定谔动力学和波动运动的贝里相

• DOI: 10.1103/physrevlett.130.258402
• 发表时间: 2023
• 期刊: Physical Review Letters
• 影响因子: 8.6
• 作者: Cohen, Alexander E.;Hastewell, Alasdair D.;Pradhan, Sreeparna;Flavell, Steven W.;Dunkel, Jörn
• 通讯作者: Dunkel, Jörn

The emergence and influence of internal states.

• DOI: 10.1016/j.neuron.2022.04.030
• 发表时间: 2022-08-17
• 期刊: NEURON
• 影响因子: 16.2
• 作者: Flavell, Steven W.;Gogolla, Nadine;Lovett-Barron, Matthew;Zelikowsky, Moriel
• 通讯作者: Zelikowsky, Moriel

Behavioral States.

• DOI: 10.1534/genetics.120.303539
• 发表时间: 2020-10
• 期刊: Genetics
• 影响因子: 3.3
• 作者: Flavell SW;Raizen DM;You YJ
• 通讯作者: You YJ

Whole-organism behavioral profiling reveals a role for dopamine in state-dependent motor program coupling in C. elegans

• DOI: 10.7554/elife.57093
• 发表时间: 2020-06-08
• 期刊: ELIFE
• 影响因子: 7.7
• 作者: Cermak, Nathan;Yu, Stephanie K.;Flavell, Steven W.
• 通讯作者: Flavell, Steven W.

A single neuron in C. elegans orchestrates multiple motor outputs through parallel modes of transmission.

线虫中的单个神经元通过并行传输模式协调多个运动输出。

• DOI: 10.1016/j.cub.2023.08.088
• 发表时间: 2023
• 期刊: Current biology : CB
• 作者: Huang,Yung-Chi;Luo,Jinyue;Huang,Wenjia;Baker,CaseyM;Gomes,MatthewA;Meng,Bohan;Byrne,AlexandraB;Flavell,StevenW
• 通讯作者: Flavell,StevenW