Discovery and characterization of brain-wide neuromodulatory circuits regulating arousal
调节唤醒的全脑神经调节回路的发现和表征
基本信息
- 批准号:9452485
- 负责人:
- 金额:$ 12.09万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-09-15 至 2019-08-31
- 项目状态:已结题
- 来源:
- 关键词:AblationAcetylcholineAnatomyAnimal ModelAnxietyArousalAttention deficit hyperactivity disorderAutopsyBehaviorBehavioralBrainBrain MappingBrain imagingCatalogsCellsCognitiveDataDimensionsEmotionalFishesFunctional ImagingFunctional disorderFutureGoalsGrantHeadHeart RateImageImmunohistochemistryIndividualInvestigationLinkMammalsMapsMeasuresMediatingMental DepressionMental disordersMentorsMethodsMolecularNational Institute of Mental HealthNeuromodulatorNeuronsOpticsPeptidesPerformancePhasePhenotypePopulationPrimatesProcessReaction TimeResearchResearch Domain CriteriaResearch PersonnelResolutionRoleSchizophreniaSensoryShapesSourceSpeedSurveysSystemTechniquesTestingTissuesTrainingTransgenic OrganismsUniversitiesVertebratesWorkZebrafishaddictionbasal forebrainbehavior influencecareer developmentcell typecholinergiccognitive functioncommon symptomcomputerized toolsexhaustionexperimental studyinnovationinsightlocus ceruleus structuremonoamineneurochemistryneuroregulationnew therapeutic targetnoradrenergicnoveloptogeneticsreceptorrelating to nervous systemresponseskillssymptom treatmenttechnique developmenttool
项目摘要
Project Summary/Abstract
The internal state of arousal can dramatically influence behavior, from sensory processing to cognitive and
emotional function. Disrupted arousal is a symptom common to several psychiatric disorders, including
depression, anxiety, addiction, attention deficit hyperactivity disorder, and schizophrenia. Arousal can change
over multiple timescales, including rapid fluctuations that optimize performance during cognitive functions.
Slower forms of arousal are linked to the activity of multiple neuromodulatory cell types, including those
releasing monoamines, acetylcholine, and numerous peptides; conversely, rapid arousal has been primarily
attributed to the noradrenergic locus coeruleus. Neuromodulators are challenging to investigate in behaving
mammals, because they are small, deep, spatially dispersed, and molecularly diverse; consequently, a
comprehensive survey of neuromodulatory systems underlying rapid arousal has not been conducted. I propose
to overcome these obstacles by developing and applying tools to study neuromodulation and arousal in larval
zebrafish. These vertebrates share conserved neuromodulatory systems with mammals, yet are small and
transparent, so the neuromodulatory cell types underlying fast-timescale arousal can be exhaustively mapped at
the scale of the whole brain using cellular-resolution functional imaging. I hypothesize that multiple
neuromodulatory systems act in parallel to implement fast-timescale arousal. The goal of this proposal is to
identify and characterize the neuromodulatory systems implementing the internal state of arousal, and
determine how these systems shape global neural dynamics. In preliminary efforts, I developed a novel
whole-brain cellular-resolution tissue registration method for aligning the same neurons from live activity
recordings with postmortem immunohistochemical identification of multiple neuromodulatory cell types. In the
K99 mentored phase, I will use this method to catalogue the neuromodulatory cell types correlated with trial-to-
trial fluctuations in arousal, measured by sensorimotor reaction times. My preliminary data have revealed
multiple noradrenergic, cholinergic, serotonergic, dopaminergic, and peptidergic populations correlated with
arousal. I will subsequently map the functional connectivity of these arousal-correlated populations by
combining brain-wide imaging with optogenetics in transgenic fish, through training with my mentor Dr. Karl
Deisseroth and co-mentor Dr. Philippe Mourrain. In the R00 independent phase, I will apply these skills to
determine the causal impact of arousal-correlated neuromodulatory cell types on brain-wide dynamics and the
behavioral expression of arousal. Comprehensive training with Dr. Deisseroth and Dr. Mourrain at Stanford
University will provide me with the skills required to pursue research related to arousal and other internal states
as an independent investigator. These efforts will lead to insights into a class of arousal dysfunction symptoms
common to a diverse array of psychiatric disorders.
项目总结/摘要
唤醒的内部状态可以极大地影响行为,从感觉处理到认知和
情感功能觉醒中断是几种精神疾病的共同症状,包括
抑郁、焦虑、成瘾、注意力缺陷多动障碍和精神分裂症。觉醒可以改变
在多个时间尺度上,包括快速波动,优化认知功能期间的表现。
较慢的唤醒形式与多种神经调节细胞类型的活动有关,包括那些
释放单胺,乙酰胆碱和许多肽;相反,快速唤醒主要是
归因于去甲肾上腺素能蓝斑。神经调质在行为研究中具有挑战性
哺乳动物,因为它们小,深,空间分散,分子多样性;因此,
尚未对快速唤醒背后的神经调节系统进行全面调查。我提议
通过开发和应用工具来研究幼虫的神经调节和唤醒,
斑马鱼这些脊椎动物与哺乳动物共享保守的神经调节系统,但体积小,
透明的,因此快速时间尺度唤醒背后的神经调节细胞类型可以被详尽地映射在
整个大脑的尺度使用细胞分辨率功能成像。我假设多个
神经调节系统并行作用以实现快速时间尺度的唤醒。本提案的目的是
识别和表征实现唤醒的内部状态的神经调节系统,以及
确定这些系统如何塑造全局神经动力学。在初步的努力中,我写了一本小说,
用于从活体活动中对准相同神经元的全脑细胞分辨率组织配准方法
多种神经调节细胞类型的死后免疫组织化学鉴定记录。在
K99指导阶段,我将使用这种方法来分类与试验相关的神经调节细胞类型。
通过感觉运动反应时间测量的唤醒波动。我的初步数据显示
多个去甲肾上腺素能、胆碱能、多巴胺能、多巴胺能和肽能群体与
兴奋随后,我将绘制这些觉醒相关人群的功能连接图,
通过我的导师卡尔博士的培训,
Deisseroth和共同导师Philippe Escherrain博士。在R 00独立阶段,我将运用这些技能,
确定觉醒相关的神经调节细胞类型对全脑动力学的因果影响,
唤醒的行为表现在斯坦福大学接受Deisseroth博士和Dr.
大学将为我提供所需的技能,以从事与唤醒和其他内部状态有关的研究
作为一名独立调查员这些努力将导致深入了解一类唤醒功能障碍症状
常见于各种精神疾病
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)
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Matthew Lovett-Barron其他文献
Matthew Lovett-Barron的其他文献
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{{ truncateString('Matthew Lovett-Barron', 18)}}的其他基金
Functional maturation of neural circuits for biological motion perception and social engagement
生物运动感知和社会参与的神经回路的功能成熟
- 批准号:
10687450 - 财政年份:2023
- 资助金额:
$ 12.09万 - 项目类别:
Discovery and characterization of brain-wide neuromodulatory circuits regulating arousal
调节唤醒的全脑神经调节回路的发现和表征
- 批准号:
10405479 - 财政年份:2020
- 资助金额:
$ 12.09万 - 项目类别:
Discovery and characterization of brain-wide neuromodulatory circuits regulating arousal
调节唤醒的全脑神经调节回路的发现和表征
- 批准号:
10164909 - 财政年份:2020
- 资助金额:
$ 12.09万 - 项目类别:
Discovery and characterization of brain-wide neuromodulatory circuits regulating arousal
调节唤醒的全脑神经调节回路的发现和表征
- 批准号:
10210247 - 财政年份:2020
- 资助金额:
$ 12.09万 - 项目类别:
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