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.
5-羟色胺能系统影响广泛的人类行为,是精神病学研究的共同目标。
毒品。在哺乳动物中,接受5-羟色胺能输入的神经回路由不同类型的细胞组成,每种细胞类型
它表达14个不同的5-羟色胺(5-HT)受体的子集。5-羟色胺释放对电路功能的影响
涉及不同神经元中多种受体类型的协调激活。然而,我们还没有
了解5-羟色胺在电路中的多个位置一致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。线虫的神经系统特别是
对神经科学中的全电路问题很有吸引力,因为它正好由302个神经元组成,每个神经元
在每种动物中都可以识别,这些神经元之间的突触连接(“连接体”)有
已经被完全定义,在这个定义明确的系统中,可以使用优秀的遗传工具来操纵单个细胞。
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--用于监测行为自由的动物的神经活动。重要的是,5-HT信号是很好的-
从线虫到哺乳动物的保守:线虫人类基因的同源基因编码5-羟色胺合成
酶(TPH)、囊膜转运蛋白(VMAT、SERT)、5-羟色胺受体(5-HT1、5-HT2等)和
更多。因此,对这种动物的研究应该揭示5-羟色胺功能的一般原理,以便后续研究
适用于更复杂的动物。这项建议中的研究建立在我的实验室最近发表的工作基础上,
新的初步数据。在最近的一项研究中,我们发现线虫摄取食物会激活一种特定的5-羟色胺
神经元,被称为NSM,它的5-羟色胺的释放驱动动物进食时的缓慢运动。我们还展示了
这种神经元对食物摄取的动态反应控制着运动动力学:不同的5-羟色胺模式
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
模式化的5-羟色胺释放影响运动,开始绘制出介导这些影响的5-羟色胺受体,
并开发了一种方法来监测5-羟色胺诱导的全脑活动的变化。在目前的提案中,
我们将使用这个受限的实验范例和这些尖端的成像方法来探测
5-羟色胺系统的功能结构,并研究5-羟色胺受体如何相互作用来控制大脑功能。
具体地说,我们将首先绘制出5-羟色胺受体和回路,这些受体和回路调节不同的行为反应
5-羟色胺释放模式(目标1)。在第二个目标中,我们将使用新的钙成像方法来确定
不同的5-羟色胺释放模式如何使不同的5-羟色胺受体类型参与改变整个大脑的活动(目标2)。
最后,我们还将研究拮抗5-羟色胺信号的厌恶线索如何调节
5-羟色胺能回路,允许动物平衡厌恶和欲望的输入(目标3)。这些研究将揭示
模式化的5-羟色胺释放如何与特定的5-羟色胺受体类型结合影响大脑功能,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




