Behavioral state-dependent microglia Ca2+ dynamics
行为状态依赖性小胶质细胞 Ca2 动力学
基本信息
- 批准号:10593572
- 负责人:
- 金额:$ 23.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-01-01 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAffectAnesthesia proceduresAnimalsAreaArousalAstrocytesAttentionBehaviorBehavioralBrainCell physiologyCellsCephalicChronicCytoskeletonDataDeteriorationDevelopmentEndocytosisEventFoundationsFutureGene DeletionHeadImageImmuneImmune systemImpaired cognitionImpairmentIndividualInflammatoryInvestigationIon ChannelIon Channel GatingIschemiaKineticsLengthLinkLocomotionMacrophageMechanicsMembraneMembrane ProteinsMicrogliaMolecularMonitorMotorMusNeurodegenerative DisordersNeuronsOperative Surgical ProceduresPathologicPhagocytesPhagocytosisPharmacologyPhotic StimulationPopulationPotassiumProceduresProcessPurinoceptorRegulationReportingResidual stateSignal TransductionSignaling MoleculeSliceSourceSpeedSynapsesTestingTherapeuticTherapeutic InterventionTransgenic MiceTranslatingTraumaTreesVisualWorkantagonistattenuationawakeblood pressure controlbrain cellcell motilitycognitive performanceconditional knockoutcytokinedensityexperienceexperimental studyextracellulargenetic manipulationinterestnervous system disorderneuroinflammationneuropsychiatric disordernovelpharmacologicrational designreceptorresponseselective expressionsensory inputtargeted treatmenttreadmilltwo photon microscopyvigilancevisual processingvoltage
项目摘要
We propose to investigate a novel form of microglia Ca2+ signal that we have discovered in awake behaving
mice. It is the first microglia Ca2+ signal identified so far that represents a direct response to active, vigilant
behavior and neuronal activity within short latency (<10 seconds). Due to the complexity of experimental
procedures and the paucity of available data very little is known about microglia Ca2+ dynamics in awake
behaving mice. This is in striking contrast to the expected importance of Ca2+ signaling for microglia function.
From work on cultured microglia it is known that basic cellular processes such as cytoskeletal rearrangements,
which are a prerequisite for cell motility and phagocytosis, as well as most mechanisms underlying the secretion
of signaling molecules such as cytokines depend on intracellular fluctuations of Ca2+. Microglia express
numerous membrane proteins to potentially translate extracellular signals into intracellular Ca2+ elevations.
Among these are purinergic receptors, immune system-related receptors as well as ion channels. Specifically,
microglia express L-type Ca2+ channels (LTCCs). LTCCs have attracted special attention because antagonists
of this class of ion channels, traditionally applied to control blood pressure, have demonstrated therapeutic
potential for limiting neuroinflammation and cognitive impairments accompanying neurodegenerative diseases.
The contribution of microglia LTCCs to this therapeutic potential is not yet well established and it is not clear
when these ion channels become normally activated. For this proposal we will employ two-photon microscopy
on transgenic mice with microglia-specific expression of the genetically-encoded Ca2+ indicator GCaMP6f. The
mice will be head-fixed on a motorized linear treadmill for precise control over speed and duration of enforced
locomotion events in addition to the monitoring of voluntary locomotion events. Locomotion represents a reliable
means to induce moderate arousal, a behavioral state of heightened vigilance. To avoid a bias by the
experimental conditions the studies will include imaging of microglia through chronic cranial windows several
weeks following surgery as well as acute surgery experiments for topical pharmacology. Our preliminary
pharmacological experiments suggest that locomotion-induced microglia Ca2+ elevations depend on LTCCs. In
Aim 1 we will conduct a systematic characterization of the newly discovered locomotion-induced microglia Ca2+
elevations. We will investigate the kinetic constraints of the responses and test whether V1 microglia Ca2+
responses are affected by visual stimulation. In Aim 2 we will combine microglia-selective gene deletion and
pharmacological experiments to determine which LTCC subtype predominantly contributes to the responses.
Upon successful completion of the proposed experiments we will have established a rigorous foundation for
rational design of future studies aimed at unraveling the consequences of vigilance-dependent microglia Ca2+
responses for circuit activity and behavior. These findings may then open new avenues for microglia-centered
therapeutic interventions in neurodegenerative and neuropsychiatric diseases.
我们建议研究一种新的形式的小胶质细胞钙信号,我们已经发现在清醒的行为
小鼠这是迄今为止发现的第一个小胶质细胞Ca 2+信号,它代表了对活跃、警惕的
短潜伏期(<10秒)内的行为和神经元活动。由于实验的复杂性,
程序和缺乏可用的数据很少知道小胶质细胞Ca 2+动态清醒
行为老鼠这与Ca 2+信号对小胶质细胞功能的预期重要性形成鲜明对比。
从对培养的小胶质细胞的研究可知,基本的细胞过程如细胞骨架重排,
这是细胞运动和吞噬作用的先决条件,以及分泌的大多数机制
细胞因子等信号分子的活性依赖于细胞内Ca ~(2+)的波动。小胶质细胞表达
许多膜蛋白可能将细胞外信号翻译成细胞内Ca 2+升高。
其中包括嘌呤能受体、免疫系统相关受体以及离子通道。具体地说,
小胶质细胞表达L型钙通道(LTCCs)。LTCC引起了特别的关注,因为拮抗剂
传统上用于控制血压的这类离子通道中,
限制伴随神经退行性疾病的神经炎症和认知障碍的潜力。
小胶质细胞LTCC对这种治疗潜力的贡献尚未得到很好的确定,
当这些离子通道被正常激活时。对于这个建议,我们将采用双光子显微镜
在转基因小鼠与小胶质细胞特异性表达的遗传编码的Ca 2+指标GCaMP 6 f。的
将小鼠头部固定在电动线性跑步机上,以精确控制强制运动的速度和持续时间。
运动事件,除了监测自愿运动事件。运动是一种可靠的
意味着诱导中度觉醒,一种高度警惕的行为状态。为了避免偏见,
实验条件研究将包括通过慢性颅窗对小胶质细胞进行成像,
手术后数周以及局部药理学的急性手术实验。我们的初步
药理学实验表明运动诱导的小胶质细胞Ca 2+升高依赖于LTCC。在
目的1我们将对新发现的运动诱导的小胶质细胞Ca 2+进行系统的表征
海拔我们将研究反应的动力学约束,并测试V1小胶质细胞Ca 2 +
反应受到视觉刺激的影响。在目标2中,我们将结合联合收割机小胶质细胞选择性基因缺失和
药理学实验以确定哪种LTCC亚型主要有助于响应。
在成功完成拟议的实验后,我们将为以下方面奠定坚实的基础:
未来研究的合理设计旨在揭示警惕依赖性小胶质细胞Ca 2+的后果
电路活动和行为的响应。这些发现可能为以小胶质细胞为中心的
神经退行性疾病和神经精神疾病的治疗干预。
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 }}
Martin Paukert其他文献
Martin Paukert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('Martin Paukert', 18)}}的其他基金
Ethanol and brain state-dependent neural signaling
乙醇和大脑状态依赖性神经信号传导
- 批准号:
10190737 - 财政年份:2017
- 资助金额:
$ 23.25万 - 项目类别:
The Role of Astroglia in Brain State-Dependent Neural Activity
星形胶质细胞在大脑状态依赖性神经活动中的作用
- 批准号:
10153884 - 财政年份:2017
- 资助金额:
$ 23.25万 - 项目类别:
The Role of Astroglia in Brain State-Dependent Neural Activity
星形胶质细胞在大脑状态依赖性神经活动中的作用
- 批准号:
9918456 - 财政年份:2017
- 资助金额:
$ 23.25万 - 项目类别:
Effect of ethanol on Bergmann glia Ca2+ dynamics during motor behavior
乙醇对运动行为过程中伯格曼胶质细胞 Ca2 动力学的影响
- 批准号:
8490613 - 财政年份:2013
- 资助金额:
$ 23.25万 - 项目类别:
Effect of ethanol on Bergmann glia Ca2+ dynamics during motor behavior
乙醇对运动行为过程中伯格曼胶质细胞 Ca2 动力学的影响
- 批准号:
8837394 - 财政年份:2013
- 资助金额:
$ 23.25万 - 项目类别:
相似海外基金
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 23.25万 - 项目类别:
Standard Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 23.25万 - 项目类别:
Standard Grant
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 23.25万 - 项目类别:
Training Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 23.25万 - 项目类别:
Fellowship
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 23.25万 - 项目类别:
Research Grant
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 23.25万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 23.25万 - 项目类别:
Studentship
ERI: Developing a Trust-supporting Design Framework with Affect for Human-AI Collaboration
ERI:开发一个支持信任的设计框架,影响人类与人工智能的协作
- 批准号:
2301846 - 财政年份:2023
- 资助金额:
$ 23.25万 - 项目类别:
Standard Grant
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 23.25万 - 项目类别:
Operating Grants
How motor impairments due to neurodegenerative diseases affect masticatory movements
神经退行性疾病引起的运动障碍如何影响咀嚼运动
- 批准号:
23K16076 - 财政年份:2023
- 资助金额:
$ 23.25万 - 项目类别:
Grant-in-Aid for Early-Career Scientists