Molecular and genetic dissection of brain circuits controlling fever
控制发烧的脑回路的分子和遗传解剖
基本信息
- 批准号:10373051
- 负责人:
- 金额:$ 39.2万
- 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:2020-04-01 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AblationAdipose tissueAffectAnimalsAreaAtlasesAttenuatedAwarenessBehaviorBehavioralBloodBody TemperatureBrainCellsCollaborationsDataDesire for foodDiagnosisDinoprostoneDissectionDorsalExhibitsFeverFluorescent in Situ HybridizationFutureGene ExpressionGenerationsGenesGeneticGoalsHumanHypothalamic structureImmediate-Early GenesImmuneImmune responseImmune signalingImmunologic FactorsIn SituInfectionInflammatoryInjectionsLethargiesLibrariesLipopolysaccharidesMedialMediatingMethodsMiddle HypothalamusModelingMolecularMolecular GeneticsMusNervous system structureNeural PathwaysNeurogliaNeuronsPatientsPhysiologic ThermoregulationPhysiologicalPhysiologyPlayPopulationPreoptic AreasProstaglandin ReceptorProstaglandinsProteinsRoleStereotypingSymptomsSynapsesTemperatureTestingThermogenesisUniversitiesViralacute infectionadaptive immune responseassociated symptomattenuationbehavioral responsecell typecytokineexperimental studyfightinggenetic approachgenetic informationgenetic technologyimaging modalityinhibitorinsightneural circuitneuronal circuitrynovelnovel strategiesnovel therapeutic interventionparacrineparaventricular nucleuspathogenpromoterresponsesingle-cell RNA sequencingtherapeutic developmenttooltreatment strategy
项目摘要
PROJECT SUMMARY ABSTRACT
During an infection, animals exhibit adaptive changes in behavior and physiology aimed at increasing survival.
Although many causes of acute infection exist, a similar set of stereotyped symptoms occur, which includes
increased body temperature or fever, decreased appetite and increased lethargy. Both warm- and cold-blooded
animals generate a fever in response infection suggesting that fever circuits are hard-wired and highly
conserved, yet exactly how the nervous system alters body temperature and associated behavior in response to
infection remains unknown. We have identified a population of neurons in the preoptic area of the hypothalamus
that are highly activated following administration of inflammatory lipopolysaccharides (LPS). Due to the close
proximity between the organum vasculosum of the laminae terminalis (OVLT), where inflammatory cytokines
enter the brain to affect nearby cells, and neurons of the preotpic area regulating normal body temperature, and
our preliminary data, we propose that these newly identified LPS-sensitive neurons control fever initiation during
an immune response. We will use chemogenetic activation and cell ablation approaches to demonstrate that this
population plays a role in increasing body temperature and in affecting other fever-associated behaviors upon
LPS injection. Further, we have recently developed new approaches for molecular characterization of genetically
defined cell populations in situ using single-cell RNA sequencing (scRNA-seq) and multiplex, error-robust,
fluorescent in situ hybridization (MERFISH) to generate a spatially-resolved and functionally-aware atlas of the
preoptic area. We will apply a similar strategy to characterize fever-inducing neurons as well as surrounding non-
neuronal cell types that are likely to play a role in fever generation through paracrine mechanisms. Finally, we
propose to use viral-mediated tracing and functional tools to determine the direct and indirect circuit mechanisms
by which LPS-sensitive neurons and their targets exert control over body temperature and fever-related
behaviors. Our data will lead to a molecular and functional characterization of LPS-sensitive neurons in the
preoptic area and to a better understanding of how inflammatory sickness symptoms, such as fever and related
behavioral changes, are regulated in the brain. These efforts have direct implications for understanding the
mechanisms underlying human sickness, and may inform new therapeutic strategies for the treatment of fever
and associated symptoms.
项目摘要
在感染期间,动物表现出适应性的行为和生理变化,旨在提高生存率。
虽然存在许多急性感染的原因,但会出现一系列类似的定型症状,其中包括
体温升高或发烧,食欲下降,嗜睡增加。无论是温血还是冷血
动物对感染的反应是发烧,这表明发烧回路是硬连线的,
保守的,但确切地说,神经系统如何改变体温和相关的行为,以回应
我们在下丘脑视前区发现了一群神经元,
在给予炎性脂多糖(LPS)后高度活化。
终板血管器(OVLT)之间的接近,其中炎性细胞因子
进入大脑影响附近的细胞,以及调节正常体温的视前区神经元,
根据我们的初步数据,我们认为这些新发现的LPS敏感神经元控制发热的发生,
免疫反应。我们将使用化学遗传激活和细胞消融方法来证明这一点,
人群在增加体温和影响其他发热相关行为方面发挥作用,
此外,我们最近已经开发了用于遗传修饰的分子表征的新方法。
使用单细胞RNA测序(scRNA-DNA测序)和多重的,错误排除稳健的,
荧光原位杂交(MERFISH),以产生一个空间分辨和功能识别的图谱,
我们将应用类似的策略来表征发热诱导神经元以及周围的非发热诱导神经元。
神经元细胞类型,可能通过旁分泌机制在发热中发挥作用。最后,我们
建议使用病毒介导的追踪和功能工具来确定直接和间接回路机制
LPS敏感神经元及其靶细胞通过该通路控制体温和发热相关的
我们的数据将导致LPS敏感神经元的分子和功能特征,
为了更好地了解视前区和炎症性疾病的症状,如发烧和相关
行为的变化,是在大脑中调节。这些努力有直接的影响,
人类疾病的潜在机制,并可能为治疗发热提供新的治疗策略
和相关症状。
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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Catherine Dulac其他文献
Catherine Dulac的其他文献
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Odor trail tracking: a new paradigm to unveil algorithms and neural circuits underlying active sensation and continuous decision making
气味踪迹追踪:揭示主动感觉和持续决策背后的算法和神经回路的新范例
- 批准号:
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- 资助金额:
$ 39.2万 - 项目类别:
Systems-Level and in Situ Transcriptomics Deconstruction of Neural Circuits Underlying Sensorimotor Transformation in an Innate Behavior
先天行为中感觉运动转化的神经回路的系统级和原位转录组学解构
- 批准号:
10709855 - 财政年份:2020
- 资助金额:
$ 39.2万 - 项目类别:
Molecular and genetic dissection of brain circuits controlling fever
控制发烧的脑回路的分子和遗传解剖
- 批准号:
10589104 - 财政年份:2020
- 资助金额:
$ 39.2万 - 项目类别:
Center for Integrated Multi-modal and Multi-scale Nucleome Research
综合多模式和多尺度核组研究中心
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- 资助金额:
$ 39.2万 - 项目类别:
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综合多模式和多尺度核组研究中心
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10269034 - 财政年份:2020
- 资助金额:
$ 39.2万 - 项目类别:
Center for Integrated Multi-modal and Multi-scale Nucleome Research
综合多模式和多尺度核组研究中心
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10458025 - 财政年份:2020
- 资助金额:
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Microcircuits underlying murine parental behavior
小鼠父母行为背后的微电路
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10461107 - 财政年份:2015
- 资助金额:
$ 39.2万 - 项目类别:
Microcircuits underlying murine parental behavior
小鼠父母行为背后的微电路
- 批准号:
10227959 - 财政年份:2015
- 资助金额:
$ 39.2万 - 项目类别:
Microcircuits underlying murine parental behavior
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