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:10542483
- 负责人:
- 金额:$ 5.83万
- 依托单位:
- 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 2024-01-31
- 项目状态:已结题
- 来源:
- 关键词:Animal FeedAnimalsArchitectureBehaviorBiological ModelsBrainCaenorhabditis elegansCalciumCellsComplexCuesDataDesire for foodEnzymesEquilibriumFoodGenesGeneticHumanImageIngestionLocomotionMammalsMapsMediatingMembrane Transport ProteinsMonitorNervous system structureNeuronsNeurosciencesOrthologous GenePatternPharmaceutical PreparationsPublishingSerotonergic SystemSerotoninSignal TransductionSiteSynapsesSystemWorkbehavioral responsecell typeconnectomeimaging approachin vivomind controlneural circuitreceptorrelating to nervous systemresponseserotonin receptortool
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.
血清素能系统影响广泛的人类行为,是精神病学的共同目标
药物。在哺乳动物中,接收血清素输入的神经回路由不同的细胞类型组成,每种细胞类型
它表达 14 种不同血清素 (5-HT) 受体的子集。 5-HT释放对电路功能的影响
涉及不同神经元中许多受体类型的协调激活。然而,我们还没有
了解 5-HT 在电路内多个部位发挥作用以连贯地改变电路的基本原理
功能。在这里,我们建议在线虫中解决这个问题。秀丽隐杆线虫的神经系统特别
对于神经科学中的全电路问题很有吸引力,因为它由 302 个神经元组成,每个神经元
可以在每只动物中识别出,这些神经元之间的突触连接(“连接组”)具有
已经完全定义,并且可以使用优秀的遗传工具来操纵这个定义明确的系统中的单细胞。
此外,这种动物的透明度使我们能够使用最先进的成像方法——包括全脑成像
钙成像——监测自由行为动物的神经活动。重要的是,5-HT 信号传导非常好——
从线虫到哺乳动物保守:编码 5-HT 合成的人类基因的线虫直系同源物
酶 (TPH)、囊泡和膜转运蛋白 (VMAT、SERT)、5-HT 受体(5-HT1、5-HT2 等)和
更多的。因此,对该动物的研究应该揭示 5-HT 功能的一般原理,随后可以对其进行研究。
应用于更复杂的动物。本提案中的研究以我的实验室最近发表的工作为基础
新的初步数据。在最近的一项研究中,我们发现线虫摄入食物会激活特定的 5-HTergic
神经元,称为 NSM,在动物进食时释放 5-HT 驱动缓慢运动。我们还表明
该神经元对食物摄入的动态反应控制着运动动力学:5-HT 的不同模式
释放驱动不同的运动变化。在新的初步数据中,我们系统地研究了如何
模式化 5-HT 释放影响运动,开始绘制介导这些影响的 5-HT 受体,
并开发了一种监测 5-HT 诱导的全脑活动变化的方法。在目前的提案中,
我们将使用这种严格约束的实验范式和这些尖端的成像方法来探索
5-HT 系统的功能架构,并检查 5-HT 受体如何相互作用来控制大脑功能。
具体来说,我们将首先绘制出介导对不同行为反应的 5-HT 受体和电路。
5-HT 释放模式(目标 1)。第二个目标是,我们将使用新的钙成像方法来确定
不同的 5-HT 释放模式如何结合不同的 5-HT 受体类型来改变全脑活动(目标 2)。
最后,我们还将研究拮抗 5-HT 信号传导的厌恶信号如何调节
血清素能回路,使动物能够平衡厌恶和食欲输入(目标 3)。这些研究将揭示
模式化 5-HT 释放如何结合特定 5-HT 受体类型影响大脑功能,从而产生新的
5-HT 电路组织和功能的框架。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Steven Willem Flavell其他文献
Steven Willem Flavell的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Steven Willem Flavell', 18)}}的其他基金
Neural Mechanisms that Underlie Flexible Sensory Control of Behavioral States in C. elegans
线虫行为状态灵活感觉控制的神经机制
- 批准号:
10659880 - 财政年份:2023
- 资助金额:
$ 5.83万 - 项目类别:
Brain-wide representations of behavior during aversive internal states in C. elegans
线虫厌恶的内部状态下的全脑行为表征
- 批准号:
10638999 - 财政年份:2023
- 资助金额:
$ 5.83万 - 项目类别:
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
- 批准号:
10334517 - 财政年份:2020
- 资助金额:
$ 5.83万 - 项目类别:
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
- 批准号:
10725038 - 财政年份:2020
- 资助金额:
$ 5.83万 - 项目类别:
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
- 批准号:
10554333 - 财政年份:2020
- 资助金额:
$ 5.83万 - 项目类别:
Neuromodulatory control of collective circuit dynamics in C. elegans
线虫集体回路动力学的神经调节控制
- 批准号:
10207798 - 财政年份:2017
- 资助金额:
$ 5.83万 - 项目类别:
相似海外基金
The earliest exploration of land by animals: from trace fossils to numerical analyses
动物对陆地的最早探索:从痕迹化石到数值分析
- 批准号:
EP/Z000920/1 - 财政年份:2025
- 资助金额:
$ 5.83万 - 项目类别:
Fellowship
Animals and geopolitics in South Asian borderlands
南亚边境地区的动物和地缘政治
- 批准号:
FT230100276 - 财政年份:2024
- 资助金额:
$ 5.83万 - 项目类别:
ARC Future Fellowships
The function of the RNA methylome in animals
RNA甲基化组在动物中的功能
- 批准号:
MR/X024261/1 - 财政年份:2024
- 资助金额:
$ 5.83万 - 项目类别:
Fellowship
Ecological and phylogenomic insights into infectious diseases in animals
对动物传染病的生态学和系统发育学见解
- 批准号:
DE240100388 - 财政年份:2024
- 资助金额:
$ 5.83万 - 项目类别:
Discovery Early Career Researcher Award
Zootropolis: Multi-species archaeological, ecological and historical approaches to animals in Medieval urban Scotland
Zootropolis:苏格兰中世纪城市动物的多物种考古、生态和历史方法
- 批准号:
2889694 - 财政年份:2023
- 资助金额:
$ 5.83万 - 项目类别:
Studentship
Using novel modelling approaches to investigate the evolution of symmetry in early animals.
使用新颖的建模方法来研究早期动物的对称性进化。
- 批准号:
2842926 - 财政年份:2023
- 资助金额:
$ 5.83万 - 项目类别:
Studentship
Study of human late fetal lung tissue and 3D in vitro organoids to replace and reduce animals in lung developmental research
研究人类晚期胎儿肺组织和 3D 体外类器官在肺发育研究中替代和减少动物
- 批准号:
NC/X001644/1 - 财政年份:2023
- 资助金额:
$ 5.83万 - 项目类别:
Training Grant
RUI: Unilateral Lasing in Underwater Animals
RUI:水下动物的单侧激光攻击
- 批准号:
2337595 - 财政年份:2023
- 资助金额:
$ 5.83万 - 项目类别:
Continuing Grant
RUI:OSIB:The effects of high disease risk on uninfected animals
RUI:OSIB:高疾病风险对未感染动物的影响
- 批准号:
2232190 - 财政年份:2023
- 资助金额:
$ 5.83万 - 项目类别:
Continuing Grant
A method for identifying taxonomy of plants and animals in metagenomic samples
一种识别宏基因组样本中植物和动物分类的方法
- 批准号:
23K17514 - 财政年份:2023
- 资助金额:
$ 5.83万 - 项目类别:
Grant-in-Aid for Challenging Research (Exploratory)














{{item.name}}会员




