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.
项目摘要和摘要:
在病毒感染期间,动物将在其行为和生理方面表现出适应性的变化,旨在提高动物的存活率。
虽然急性呼吸道感染的原因很多,但也会出现一系列类似的刻板印象的症状,其中包括。
体温升高,或发烧,食欲下降,嗜睡加剧。既有暖血,也有冷血。
动物在对感染的反应中会产生一种新的发热反应,这表明它们的发热回路是硬连接的,并且高度活跃。
保守,但尚未确切说明神经系统如何改变身体温度和与之相关的行为,以应对疾病。
感染原因尚不清楚。我们还没有发现在下丘脑的视前核区有大量的神经元。
在注射了炎症性脂多糖(LPS)后,这些细胞被高度激活。由于接近尾声,这些细胞被激活。
终板中央(OVLT)的细胞器和血管之间的距离很近,在那里有炎性和细胞因子。
进入大脑皮层,影响邻近脑区的神经细胞、神经细胞和神经细胞,调节机体正常的体温、体温和血压。
根据我们的初步数据,如果我们建议在这些新发现的内毒素敏感神经元中控制发烧和启动过程。
一种新的免疫反应。我们将不会使用化学发生激活技术和细胞消融技术来证明这一点。
人口数量在增加人体体温和影响其他与发热相关的行为方面发挥着重要作用。
此外,我们最近还开发了一些新的技术方法,用于基因突变的分子生物学表征。
使用单细胞DNA测序技术(scRNA-seq)和多路复接技术,原位检测已定义的细胞和群体,具有较强的鲁棒性。
荧光原位杂交技术(MerFish)能够产生一个空间分辨的图像和一个功能感知的图像图谱。
视前区。我们将继续应用一种类似的检查策略,以更好地描述导致发热的神经细胞以及周围非神经元的特征。
神经细胞的类型,他们很可能通过旁分泌调节机制在发热的发生中发挥重要作用。最后,我们。
建议更多地使用病毒介导的病毒追踪技术和功能强大的病毒工具来确定直接病毒和间接病毒的传播机制。
通过这种方式,对内毒素敏感的神经元和他们的免疫靶点可以对身体温度和发烧相关的疾病施加更多的控制。
行为。我们的研究数据将导致我们在未来建立一个新的分子生物学和对内毒素敏感的神经细胞的功能鉴定模型。
为了更好地了解炎症性眼病是如何引起症状的,如发烧和与此相关的疾病,我们需要更好地了解视前区。
行为的改变在大脑中是不受调控的。这些努力可能会对我们理解大脑产生直接的影响。
人类疾病、疾病和疾病的潜在机制可能会为新的治疗策略提供信息,以帮助寻找新的发烧治疗方案。
以及与之相关的症状。
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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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:
10524245 - 财政年份:2022
- 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:
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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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Microcircuits underlying murine parental behavior
小鼠父母行为背后的微电路
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Microcircuits underlying murine parental behavior
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Microcircuits underlying murine parental behavior
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Microcircuits underlying murine parental behavior
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