Neurophysiology and plasticity of cardiorespiratory circuits to hypoxia
神经生理学和心肺回路对缺氧的可塑性
基本信息
- 批准号:9301644
- 负责人:
- 金额:$ 49.3万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-07-01 至 2020-02-29
- 项目状态:已结题
- 来源:
- 关键词:Action PotentialsAcuteAdenosineAstrocytesBrain Hypoxia-IschemiaBreathingBuffersCalciumCarotid BodyCellsChronicClinicalCommunicationCouplingDevelopmentDiseaseEquilibriumEventExcitatory Amino AcidsFeedbackGABA transporterGlutamate TransporterGlutamatesGoalsGoldGray unit of radiation doseHomeostasisHypoxiaImageLeadMediatingModelingMolecular BiologyNerveNeuraxisNeurobiologyNeurogliaNeuronsNeurotransmittersNucleus solitariusObstructive Sleep ApneaPhysiologicalPhysiologyPlasticizersPresynaptic TerminalsReflex actionResearchRespirationRespiratory SystemRoleSensoryShapesSignal TransductionSynapsesSynaptic CleftSynaptic ReceptorsSynaptic TransmissionSynaptic plasticitySystemTestingTherapeuticVisceralexcitotoxicitygamma-Aminobutyric Acidin vivointegration siteneuronal cell bodyneuronal circuitryneurophysiologyneuroregulationneurotransmissionneurotransmitter releaseneurotransmitter uptakeoptogeneticspostsynapticpostsynaptic neuronspresynapticpreventpublic health relevancereceptorrelating to nervous systemrespiratoryresponsesensory inputsynaptic functionuptake
项目摘要
DESCRIPTION (provided by applicant): The nucleus tractus solitarii (nTS) is the first central termination and integration site for sensory reflexes, including the carotid body chemoreflex that is augmented during chronic intermittent hypoxia (CIH) and obstructive sleep apnea (OSA). The glutamatergic synapse between the primary afferent and second-order nTS neuron is highly modifiable, expressing multiple forms of synaptic plasticity and enhanced by CIH. This nTS synapse is closely associated with astrocytes (glia) that actively contribute to synaptic and neuronal activity and plasticity through the release of gliotransmitters and by uptake of neurotransmitter from the synaptic cleft. The interaction among glia, presynaptic terminals and postsynaptic neurons is referred to as the "tripartite synapse". Several gliotransmitters have been identified, including glutamate and ATP. Astrocytes in the nTS release glutamate in response to afferent sensory input to modify neuronal activity. Uptake of afferent and network released glutamate and GABA by their respective transporters is critical for shaping and synchronizing activity, and preventing excitotoxicity. Glia modify synaptic transmission in response to acute hypoxia, and prolonged hypoxia alter the expression and/or function of components of the tripartite synapse, and likely glia-neural communication. The role of astrocytes, gliotransmitters and their role in neurotransmitter uptake in synaptic plasticity in normoxia, let alone its enhancement in CIH, is unknown. Moreover, how astrocyte-mediated effects on synaptic plasticity augment cardiorespiratory reflexes is unknown. Our central hypothesis is glial transporters basally restrain synaptic activity, but increased activation of astrocytes within the tripartite synapse enhances synaptic and neuronal function to augment the cardiorespiratory system. CIH enhances nTS neurotransmission and hypoxic cardiorespiratory responses due to elevated astrocyte activity and excitatory GT release, and altered balance of Glu and GABA uptake. Aim 1 will define the magnitude by which nTS (a) neuronal and synaptic function, and their plasticity, are modulated by astrocytes and influenced by gliotransmitters, (b)
astrocytes are activated by neuronal activity, (c) tripartite synapses modulate respiration, sympathetic nerve activity and their coupling, and (d) excitability is augmented in CIH due to astrocyte activation. Aim 2 will determine the magnitude by which astrocyte Glu or GABA transporters (a) influence nTS neuronal function, (b) activate synaptic and extra-synaptic receptors, (c) regulate cardiorespiratory function, and (d) are altered by or contribute to CIH-induced augmentation of nTS neurotransmission. This study presents an integrative approach to exploring important basic and clinical questions, including the recording of neurons and astrocytes, imaging, molecular biology, optogenetics, DREADD manipulation and in vivo physiology. Understanding the circuits, and their glia-neural- interactions, involved in cardiorespiratory diseases will advance our understanding of its development and potentially lead to its treatment.
描述(由申请人提供):孤束核(nTS)是感觉反射的第一个中枢终止和整合位点,包括在慢性间歇性缺氧(CIH)和阻塞性睡眠呼吸暂停(OSA)期间增强的颈动脉体化学反射。初级传入神经元和二级 nTS 神经元之间的突触是高度可修改的,表达多种形式的突触可塑性,并通过CIH。这种 nTS 突触与星形胶质细胞(神经胶质细胞)密切相关,星形胶质细胞通过释放胶质递质和从突触间隙摄取神经递质,积极促进突触和神经元的活动和可塑性。神经胶质细胞、突触前末梢和突触后神经元之间的相互作用被称为 CIH。已鉴定出几种胶质递质,包括 nTS 中的谷氨酸和 ATP。响应传入感觉输入而释放谷氨酸,以改变神经元活动。各自的转运蛋白摄取传入和网络释放的谷氨酸和 GABA 对于形成和同步活动以及防止神经胶质细胞响应急性缺氧和长期缺氧而改变突触传递至关重要。缺氧改变三方突触成分的表达和/或功能,并可能改变星形胶质细胞、神经胶质递质及其作用。正常氧条件下神经递质摄取在突触可塑性中的作用尚不清楚,更不用说其在 CIH 中的增强。此外,星形胶质细胞介导的突触可塑性如何增强心肺反射尚不清楚,我们的中心假设是神经胶质转运蛋白基本上抑制突触活动,但增加了激活。三方突触内的星形胶质细胞增强突触和神经元功能,增强心肺系统,增强 nTS 神经传递和由于星形胶质细胞活性升高和兴奋性 GT 释放以及 Glu 和 GABA 摄取平衡改变而引起的缺氧心肺反应,目标 1 将定义 nTS (a) 神经元和突触功能及其可塑性受星形胶质细胞调节和影响的程度。神经胶质递质,(b)
星形胶质细胞被神经元活动激活,(c) 三方突触调节呼吸、交感神经活动及其耦合,(d) 由于星形胶质细胞激活,CIH 中的兴奋性增强。目标 2 将确定星形胶质细胞 Glu 或 GABA 转运蛋白的大小( a) 影响 nTS 神经元功能,(b) 激活突触和突触外受体,(c) 调节心肺功能,以及 (d) 被改变或有助于 CIH 诱导的 nTS 神经传递增强 这项研究提出了一种探索重要的基础和临床问题的综合方法,包括神经元和星形胶质细胞的记录、成像、分子生物学、光遗传学、DREADD 操作和理解电路。以及它们与心肺疾病有关的神经胶质-神经相互作用,将增进我们对其发展的理解,并有可能导致其治疗。
项目成果
期刊论文数量(0)
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David Douglas Kline其他文献
David Douglas Kline的其他文献
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{{ truncateString('David Douglas Kline', 18)}}的其他基金
GABA signaling in the nTS and cardiorespiratory responses to hypoxia
nTS 中的 GABA 信号传导和缺氧心肺反应
- 批准号:
10558915 - 财政年份:2023
- 资助金额:
$ 49.3万 - 项目类别:
Adaptation of Brainstem Circuits to Chronic Hypoxia
脑干回路对慢性缺氧的适应
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7464155 - 财政年份:2008
- 资助金额:
$ 49.3万 - 项目类别:
Adaptation of Brainstem Circuits to Chronic Hypoxia
脑干回路对慢性缺氧的适应
- 批准号:
7612033 - 财政年份:2008
- 资助金额:
$ 49.3万 - 项目类别:
Adaptation of Brainstem Circuits to Chronic Hypoxia
脑干回路对慢性缺氧的适应
- 批准号:
7612033 - 财政年份:2008
- 资助金额:
$ 49.3万 - 项目类别:
Adaptation of Brainstem Circuits to Chronic Hypoxia
脑干回路对慢性缺氧的适应
- 批准号:
8238323 - 财政年份:2008
- 资助金额:
$ 49.3万 - 项目类别:
Adaptation of Brainstem Circuits to Chronic Hypoxia
脑干回路对慢性缺氧的适应
- 批准号:
7789544 - 财政年份:2008
- 资助金额:
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