Dissecting the functional organization of the serotonergic system in C. elegans

剖析线虫血清素系统的功能组织

基本信息

批准号：
10725038
负责人：
Steven Willem Flavell
金额：
$ 1.94万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-19 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10725038
关键词：
Action Potentials Afferent Neurons Animal Behavior Animal Feed Animals Architecture Aversive Stimulus Behavior Behavior Control Behavioral Biological Models Brain Brain imaging CRISPR/Cas technology Caenorhabditis elegans Calcium Cells Circadian Rhythms Complex Cues Data Desire for food Drosophila genus Enteral Enzymes Equilibrium Food Genes Genetic Goals Human Image Immobilization Ingestion Invertebrates Kinetics Label Link Locomotion Mammals Maps Measures Mediating Membrane Membrane Transport Proteins Monitor Mutation Nervous System Neurons Neurosciences Optics Orthologous Gene Output Pattern Pharmaceutical Preparations Publishing Satiation Sensory Serotonergic System Serotonin Signal Transduction Site Source Stimulus Synapses System Technology Work behavioral response cell type connectome egg feeding genetic approach imaging approach in vivo mind control neural neural circuit optogenetics raphe nuclei receptor receptor expression receptor function response serotonin receptor squid axon tool

项目摘要

The serotonergic system impacts a wide range of human behaviors and is a common target of psychiatric drugs. In mammals, neural circuits that receive serotonergic inputs are composed of diverse cell types, each of which expresses a subset of 14 distinct serotonin (5-HT) receptors. The impact of 5-HT release on circuit function involves the coordinated activation of many receptor types in distinct neurons. However, we do not yet understand the fundamental principles by which 5-HT acts at many sites within a circuit to coherently alter circuit function. Here, we propose to resolve this question in C. elegans. The C. elegans nervous system is particularly attractive for whole-circuit questions in neuroscience because it consists of exactly 302 neurons, every neuron can be identified in every animal, the synaptic connections between these neurons (the “connectome”) have been fully defined, and excellent genetic tools can be used to manipulate single cells in this well-defined system. Moreover, this animal’s transparency allows us to use cutting-edge imaging approaches – including whole-brain calcium imaging – to monitor neural activity in freely-behaving animals. Importantly, 5-HT signaling is well- conserved from C. elegans to mammals: C. elegans orthologs of human genes encode for 5-HT synthesis enzymes (TPH), vesicular and membrane transporters (VMAT, SERT), 5-HT receptors (5-HT1, 5-HT2, etc) and more. Thus, studies of this animal should reveal general principles of 5-HT function that can be subsequently applied to more complex animals. The studies in this proposal build off recently published work from my lab and new preliminary data. In a recent study, we found that food ingestion by C. elegans activates a specific 5-HTergic neuron, called NSM, whose release of 5-HT drives slow locomotion while animals feed. We also showed that this neuron’s dynamical response to food ingestion controls locomotion dynamics: different patterns of 5-HT release drive different locomotion changes. In new preliminary data, we have systematically examined how patterned 5-HT release impacts locomotion, begun mapping out the 5-HT receptors that mediate these effects, and developed an approach to monitor 5-HT-induced changes in whole-brain activity. In the current proposal, we will use this well-constrained experimental paradigm and these cutting-edge imaging approaches to probe the functional architecture of the 5-HT system and examine how 5-HT receptors interact to control brain function. Specifically, we will first map out the 5-HT receptors and circuits that mediate behavioral responses to different patterns of 5-HT release (Aim 1). In a second aim, we will use new calcium imaging approaches to determine how different patterns of 5-HT release engage different 5-HT receptor types to alter whole-brain activity (Aim 2). Finally, we will also examine how aversive cues that antagonize 5-HT signaling modulate the function of serotonergic circuits, allowing animals to balance aversive and appetitive inputs (Aim 3). These studies will reveal how patterned 5-HT release engages specific 5-HT receptor types to impact brain function, yielding a new framework for 5-HT circuit organization and function.

血清素能系统会影响广泛的人类行为，是精神病的常见目标毒品。在哺乳动物中，接受血清能输入的神经回路由潜水细胞类型组成，每一种表达14个不同的5-羟色胺（5-HT）受体的子集。 5-HT释放对电路函数的影响涉及不同神经元中许多受体类型的协调激活。但是，我们还没有了解5-HT在电路中的许多站点进行作用以相干改变电路的基本原理功能。在这里，我们建议在秀丽隐杆线虫中解决这个问题。秀丽隐杆线虫神经系统尤其是神经科学中的全部电路问题有吸引力，因为它完全由302个神经元组成可以在每种动物中识别，这些神经元之间的突触连接（“连接”）具有被充分定义，可以使用出色的遗传工具来操纵这个定义明确的系统中的单个细胞。此外，这种动物的透明度使我们能够使用尖端的成像方法 - 包括全脑钙成像 - 监测自由行为动物的神经元活性。重要的是，5-HT信号是很好的从秀丽隐杆线虫到哺乳动物的保守：人类基因的秀丽隐杆线虫编码为5-HT合成酶（TPH），囊泡和膜转运蛋白（VMAT，SERT），5-HT接收器（5-HT1、5-HT2等）和更多的。这是对该动物的研究应揭示5-HT功能的一般原理，随后可以应用于更复杂的动物。该提案中的研究源于我实验室的最近发表的工作，新的初步数据。在最近的一项研究中，我们发现秀丽隐杆线虫摄入的食物摄入会激活特定的5次矫正神经元称为NSM，他的5-HT释放在动物进食时驱动缓慢的运动。我们还表明这种神经元对食物摄入的动态反应控制了运动动力学：5-HT的不同模式释放驱动器不同的运动变化。在新的初步数据中，我们系统地检查了图案化的5-HT释放会影响运动，开始绘制介导这些效果的5-HT接收器，并开发了一种监测5-HT诱导的全脑活动变化的方法。在当前的提议中我们将使用这种受约束的实验范式和这些尖端的成像方法来证明 5-HT系统的功能架构并检查了5-HT接收器如何相互作用以控制大脑功能。具体来说，我们将首先绘制出媒体行为对不同的媒体响应的5-HT接收器和电路 5-HT释放的模式（AIM 1）。在第二个目标中，我们将使用新的钙成像方法来确定 5-HT释放的不同模式如何吸引不同的5-HT受体类型来改变全脑活动（AIM 2）。最后，我们还将研究如何厌恶5-HT信号传导的厌恶提示调节血清素能圈，使动物能够平衡厌恶和食欲的输入（AIM 3）。这些研究将揭示图案化的5-HT释放如何与特定的5-HT接收器类型相关，以影响大脑功能，从而产生新的功能 5-HT电路组织和功能的框架。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

Dynamic functional connectivity in the static connectome of Caenorhabditis elegans.

DOI：
10.1016/j.conb.2021.12.002
发表时间：
2022-04
期刊：
Current opinion in neurobiology
影响因子：
5.7
作者：
通讯作者：

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
影响因子：
0
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

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

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：
10.1101/2023.04.02.532814
发表时间：
2023
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Huang,Yung-Chi;Luo,Jinyue;Huang,Wenjia;Baker,CaseyM;Gomes,MatthewA;Byrne,AlexandraB;Flavell,StevenW
通讯作者：
Flavell,StevenW