Synaptic Circuitry in Stroke

中风中的突触回路

基本信息

批准号：
9269265
负责人：
SERGEI A KIROV
金额：
$ 33.25万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-15 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9269265
关键词：
Acute Acute Brain Injuries Adult American Heart Association Astrocytes Axon Blood capillaries Blood flow Brain Brain Edema Brain Injuries Cations Cell membrane Chlorides Clinical Clinical Data Clinical Research Contusions Cortical Contusions Coupled Dendrites Dendritic Spines Development Edema Electron Microscopy Electrophysiology (science)Energy Supply Equilibrium Etiology Event Excision Extracellular Space Failure Floods Functional disorder Future Genetic Models Glutamates Heart Diseases Image Impairment Injury Ion Channel Ions Ischemic Penumbra Laser Scanning Microscopy Lasers Maintenance Mechanics Membrane Metabolic Metabolism Modeling Molecular Molecular Conformation Monitor Mus Na(+)-K(+)-Exchanging ATPase Neuronal Injury Neurons Optics Pathogenicity Pathologic Pathway interactions Patients Permeability Pharmacology Physiological Process Recovery Recurrence Reporting Risk Route Signal Transduction Stress Stretching Stroke Structure Swelling Synapses Testing Time Tissues Trauma patient Traumatic Brain Injury Update Vertebral column Water Work base brain cell brain tissue cell injury cytotoxic deprivation design extracellular hippocampal pyramidal neuron in vivo injured innovation insight mouse model nervous system disorder neural circuit neuron loss neuronal cell body novel public health relevance statistics synaptogenesis therapy design tool two-photon water channel

Acute Acute Brain Injuries Adult American Heart Association Astrocytes Axon Blood capillaries Blood flow Brain Brain Edema Brain Injuries Cations Cell membrane Chlorides Clinical Clinical Data Clinical Research Contusions Cortical Contusions Coupled Dendrites Dendritic Spines Development Edema Electron Microscopy Electrophysiology (science)Energy Supply Equilibrium Etiology Event Excision Extracellular Space Failure Floods Functional disorder Future Genetic Models Glutamates Heart Diseases Image Impairment Injury Ion Channel Ions Ischemic Penumbra Laser Scanning Microscopy Lasers Maintenance Mechanics Membrane Metabolic Metabolism Modeling Molecular Molecular Conformation Monitor Mus Na(+)-K(+)-Exchanging ATPase Neuronal Injury Neurons Optics Pathogenicity Pathologic Pathway interactions Patients Permeability Pharmacology Physiological Process Recovery Recurrence Reporting Risk Route Signal Transduction Stress Stretching Stroke Structure Swelling Synapses Testing Time Tissues Trauma patient Traumatic Brain Injury Update Vertebral column Water Work base brain cell brain tissue cell injury cytotoxic deprivation design extracellular hippocampal pyramidal neuron in vivo injured innovation insight mouse model nervous system disorder neural circuit neuron loss neuronal cell body novel public health relevance statistics synaptogenesis therapy design tool two-photon water channel

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项目摘要

DESCRIPTION (provided by applicant): Spreading depolarizations (SDs) are waves of sustained near-complete neuronal and glial depolarization that actively propagate a collapse of ion gradients through the brain with associated dramatic neuronal and glial swelling that entails cytotoxic edema. Recovery of ion gradients depends on the sufficient sodium pump activity which is energy-dependent. In stroke and trauma patients SDs are thought to exacerbate tissue damage in the at-risk cortical territory supporting the view that SD may be an important mechanistic endpoint in clinical studies. SD-induced neuronal damage involves a plasma membrane conformational change including soma swelling and terminal dendritic beading with spine loss which signifies acute damage to synaptic circuitry. In the ischemic core, where energy deprivation is maintained, dendrites remain terminally injured by SD. In contrast, we have shown that in the penumbra SDs result in rapid dendritic beading which is reversible, but signals leading to neuronal death could be initiated during this time. Hence, dendritic beading is the hallmark of neuronal injury. Once the energy demands for recovery of penumbral dendrites are no longer met by the diminishing blood flow, SD terminally injures dendrites and spines are lost indicating acute damage to synaptic circuitry and core expansion. SD-induced cytotoxic edema contributes to stroke injury. Mammalian pyramidal neurons lack functional aquaporins, thus the molecular pathways by which they accumulate osmotically obligated water and rapidly swell during SD is unknown. Bulk water influx could occur through large-pore pannexin channels opened by SD. Neuronal cation-chloride cotransporters may also be responsible for water accumulation as well as recovery and this will be studied in aim 1. We have shown that persistent astroglial swelling is initiated and exacerbated during SD in brain tissue with moderate to severe energy deficits, likely disrupting astroglial maintenance of homeostatic function and thus their ability to support neurons. Astroglial failure should advance the damage of neighboring neurons contributing to SD-induced expansion of the injury and it will be examined in aim 2. Astrocytes are part of the synaptic circuitry tightly coupled with neurons combining with axons and dendrites to form the tripartite synapse. SD-induced injury at the level of single synapses will be investigated in aim 3 with quantitative serial section electron microscopy. The specific aims are: 1) To examine possible routes of rapid water entry during SD-induced dendritic beading. 2) To test the hypothesis that SD-inflicted dendritic injury is aggravated in tissue with selectively impaired glial metabolism. 3) To test the hypothesis that SD is the mechanism implicated in rapid synapses disruption and loss. We will combine in vivo 2-photon laser scanning microscopy of fluorescent neurons, astrocytes and blood flow in adult mouse sensorimotor cortex with other sophisticated in vivo approaches such as laser speckle and functional intrinsic optical signal imaging while simultaneously monitoring occurrence of SD with electrophysiology. The results will bring new insight to the development and recovery from acute cellular injury in stroke.

描述（由申请人提供）：扩散去极化（SDS）是持续几乎完全完整的神经元和神经胶质去极化的波，它们通过大脑通过大脑积极传播离子梯度的崩溃，并与急剧的神经元和神经胶质肿胀，这些神经元和神经胶质肿胀所带来的，这些神经元和神经胶质肿胀，所产生的细胞毒性湿气。离子梯度的恢复取决于能量依赖的足够钠泵活性。在中风和创伤中，患者被认为会加剧高危皮质区域的组织损伤，这支持SD可能是临床研究中的重要机械终点。 SD诱导的神经元损伤涉及质膜构象变化，包括SOMA肿胀和末端树突状珠脊柱损失，这表明对突触电路的急性损害。在维持能量剥夺的缺血核心中，树突仍由SD终止伤害。相比之下，我们已经表明，在PENUMBRA SD中会导致快速的树突串珠，这是可逆的，但是在此期间可能会启动导致神经元死亡的信号。因此，树突珠是神经元损伤的标志。一旦无法通过减少的血流来满足半月形树突的恢复能量，SD终止损害树突和棘突，这表明突触电路和核心膨胀的急性损害。 SD诱导的细胞毒性水肿有助于中风损伤。哺乳动物锥体神经元缺乏功能性水通道蛋白，因此它们在SD期间积累渗透压的水和迅速膨胀的分子途径是未知的。大量的水流可能通过SD打开的大型泛毒素通道发生。神经元阳离子 - 氯化物的共转运蛋白也可能负责水的积累和恢复，这将在AIM 1中进行研究。我们已经表明，在SD中，在SD中启动并加剧了中度至严重能量缺陷的SD期间的持续性，并加剧了其能力中等的能力和支持Neurons Neurons的稳态维持能力。星形胶质失败应提高导致SD引起的损伤扩张的相邻神经元的损害，并将在AIM 2中进行检查。星形胶质细胞是突触电路的一部分，与轴突和树突结合形成三级突触的神经元与神经元紧密耦合。 SD诱导的单个突触水平上的损伤将在AIM 3中使用定量串行部分电子显微镜进行研究。具体目的是：1）检查在SD引起的树突状珠子期间可能的快速进水途径。 2）检验以下假设，即在有选择性损害的神经胶质代谢的组织中，SD造成的树突损伤会加剧。 3）检验假设，即SD是与快速突触中的破坏和损失有关的机制。我们将在成年小鼠感觉运动型皮层中的荧光神经元，星形胶质细胞和血流的体内2-光子激光扫描显微镜与其他复杂的体内方法，例如激光斑点和功能性光学信号成像，同时监测SD与Electrophysylysiolys的SD同时监测。结果将为中风中急性细胞损伤的发展和恢复带来新的见解。