Nervous System Development and Plasticity

神经系统发育和可塑性

基本信息

批准号：
10684572
负责人：
RICHARD DOUGLAS FIELDS
金额：
$ 126.63万
依托单位：
EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10684572
关键词：
2019-nCoV Action Potentials Adolescence Adult Anxiety Disorders Area Astrocytes Atomic Force Microscopy Autoimmune Diseases Axon Binding Biochemical Birth Brain Brain Hypoxia-Ischemia Brain region COVID-19 Cell Culture Techniques Cells Cerebral Palsy Child Development Childhood Chromatin Structure Coculture Techniques Code Cognition Communication Confocal Microscopy Coronavirus Coronavirus Infections Coupling Decision Making Demyelinating Diseases Development Developmental Delay Disorders Diabetic Neuropathies Disease Dyslexia Electric Stimulation Exposure to Foundations Gene Expression Regulation Gene Proteins Genes Glutamates Goals Health Human Development Impairment Impulsivity Infection prevention Injury Intervention Laboratories Language Development Learning Life Life Experience Mediating Medical Memory Mental disorders Molecular Monitor Multiple Sclerosis Myelin Myelin Sheath National Institute of Child Health and Human Development Nervous System Nervous System Physiology Neuroglia Neuronal Plasticity Neurons Neurophysiology - biologic function Neurotransmitters Oligodendroglia Pattern Peripheral Nervous System Pesticides Prefrontal Cortex Process Protease Inhibitor Ranvier&apos s Nodes Recovery Research Schwann Cells Second Pregnancy Trimester Signal Transduction Signaling Molecule Social Interaction Speed Structure Synaptic Transmission Synaptic plasticity Thick Thinness Thrombin Time Toxic Environmental Substances brain cell cell type executive function experience fetal gene network healthy pregnancy improved in vivo interest myelination nerve injury nervous system development neural neural circuit neural network neural patterning neurodevelopment neurofascin neuropsychiatry neurotransmitter release novel novel strategies oligodendrocyte myelination optogenetics postnatal postnatal development spasticity transcriptome sequencing treadmill vesicular release white matter damage

2019-nCoV Action Potentials Adolescence Adult Anxiety Disorders Area Astrocytes Atomic Force Microscopy Autoimmune Diseases Axon Binding Biochemical Birth Brain Brain Hypoxia-Ischemia Brain region COVID-19 Cell Culture Techniques Cells Cerebral Palsy Child Development Childhood Chromatin Structure Coculture Techniques Code Cognition Communication Confocal Microscopy Coronavirus Coronavirus Infections Coupling Decision Making Demyelinating Diseases Development Developmental Delay Disorders Diabetic Neuropathies Disease Dyslexia Electric Stimulation Exposure to Foundations Gene Expression Regulation Gene Proteins Genes Glutamates Goals Health Human Development Impairment Impulsivity Infection prevention Injury Intervention Laboratories Language Development Learning Life Life Experience Mediating Medical Memory Mental disorders Molecular Monitor Multiple Sclerosis Myelin Myelin Sheath National Institute of Child Health and Human Development Nervous System Nervous System Physiology Neuroglia Neuronal Plasticity Neurons Neurophysiology - biologic function Neurotransmitters Oligodendroglia Pattern Peripheral Nervous System Pesticides Prefrontal Cortex Process Protease Inhibitor Ranvier&apos s Nodes Recovery Research Schwann Cells Second Pregnancy Trimester Signal Transduction Signaling Molecule Social Interaction Speed Structure Synaptic Transmission Synaptic plasticity Thick Thinness Thrombin Time Toxic Environmental Substances brain cell cell type executive function experience fetal gene network healthy pregnancy improved in vivo interest myelination nerve injury nervous system development neural neural circuit neural network neural patterning neurodevelopment neurofascin neuropsychiatry neurotransmitter release novel novel strategies oligodendrocyte myelination optogenetics postnatal postnatal development spasticity transcriptome sequencing treadmill vesicular release white matter damage

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项目摘要

Our long-standing interest is in neural plasticity, but we are especially interested in the involvement of glial cells in nervous system development, learning & cognition. Glia are brain cells that do not fire electrical impulses, but they communicate by releasing neurotransmitters. This enables glia to monitor & regulate nervous system function. Myelinating glia (oligodendrocytes in the brain & Schwann cells in the body) form the electrical insulation on axons that greatly speeds impulse conduction velocity. Damage to myelin in multiple sclerosis, cerebral palsy, & other demyelinating disorders, causes severe nervous system impairment. Our research shows that myelination of axons is regulated by impulse activity. This suggests a new form of nervous system plasticity & cellular mechanism of learning that would be particularly important in child development, because myelination proceeds through childhood & adolescence. Early life experience, both adverse & enriching, influences development of the brain in ways that can persist into adulthood. Rather than directly modifying synaptic transmission, activity-dependent myelination alters the speed & timing of information transmitted between relay points in neural networks. The arrival time of neural impulses at relay points in neural networks is of fundamental importance in neural coding, information integration & synaptic plasticity, & in the coupling of brainwave oscillations. We have identified several molecular mechanisms for activity-dependent myelination & shown that electrically active axons are preferentially myelinated. The laboratory has four areas of current research interest 1. Determining how neurons & glia interact, communicate, & cooperate functionally. A major emphasis is in understanding how myelin is involved in learning, cognition, child development, & psychiatric disorders. We are determining how glia sense neural impulse activity & investigating the functional & developmental consequences. 2. We are also investigating how myelination in the peripheral nervous system (PNS) is influenced by neural impulse activity. Far less is known about PNS myelination, but normal child development & recovery from nerve injury & disease require appropriate myelination. 3. Functional experience influences nervous system development & plasticity by guiding appropriate changes in specific proteins & genes that regulate neural network formation & function. We are determining how different patterns of neural impulses regulate specific genes controlling development & plasticity of the nervous system. 4. We are developing a novel nanocellulose material that can be used to capture and inactivate coronavirus to prevent infection. Our research goals advance 4 of the 6 NICHD research themes: 1. Understanding Early Human Development, 2. Setting the Foundation for a Healthy Pregnancy & Lifelong Wellness, 3. Identifying Sensitive Time Periods to Optimize Health Interventions, & 4. Improving Health During the Transition from Adolescence to Adulthood, and pursuing a novel approach to preventing infection by coronavirus, including SARS-Cov2. Myelin Plasticity Myelination is an essential part of brain development that begins in the second trimester & continues through adolescence, but myelination of some brain regions is not completed until the early twenties. The last part of the brain to complete myelination is the prefrontal cortex, the brain region responsible for impulse control & other executive functions. Environmental and other influences on myelination of the prefrontal cortex during adolescences contribute to neuropsychiatric concerns, including social interactions, decision making, anxiety disorders, & impulsivity. Many pediatric disorders, including cerebral palsy, dyslexia, language development, spasticity, & developmental delay are associated with disorders of myelin, in addition to well recognized demyelinating disorders, such as multiple sclerosis. Our research shows that the neurotransmitter glutamate released from vesicles along axons initiates myelin formation. This signaling promotes myelination of electrically active axons to regulate neural development & function according to environmental experience. We also find that other signaling molecules released from axons, notably ATP, regulate development of myelinating glia. This nonsynaptic communication could mediate various activity-dependent interactions between axons & nervous system cells in normal conditions, development, & disease. Myelin Remodeling Our most recent research reveals that the structure of fully-formed myelin can change to adjust conduction velocity to optimize neural circuit function. Previously, it was assumed that myelin could not be altered, except by damage, but our research finds that myelin thickness & the node of Ranvier can be remodeled by a treadmilling process in which the outer layer of myelin wrapping is removed to thin the myelin sheath & slow conduction velocity, & new myelin is added beneath the overlaying layers to thicken the sheath. We find that glial cells called astrocytes, regulate the detachment of this outer layer of myelin from the axon by secreting molecules (thrombin protease inhibitors), that inhibit severing of the molecules that attach myelin to the axon (neurofascin 155). White Matter Damage Myelin damage is associated with many medical conditions, including hypoxia/ischemia during birth leading to cerebral palsy, exposure to environmental toxins such as pesticides, autoimmune disorders such as multiple sclerosis, & other conditions. We are investigating the possible involvement of myelin disruption in these contexts. PNS Myelination Myelin is formed in the PNS by Schwann cells, which are a different type of cells from oligodendrocytes which form myelin in the CNS. Far less is known about Schwann cell myelination, but normal development & many disorders are the result of disruption of PNS myelin, including diabetic neuropathy, Gillian Barre disease, & recovery from all nerve injury which results in damage to myelin. We are applying our findings on activity-dependent myelination by oligodendrocytes to determine if similar mechanisms regulate PNS myelination. Activity-Dependent Gene Regulation Using optogenetic stimulation in vivo & electrical stimulation in co-cultures, together with microarray and RNA sequencing, we are determining how gene networks & chromatin structure in neurons & glia are regulated by the pattern of neural impulse firing. Our studies show that specific patterns of action potentials regulate expression of thousands of genes in neurons and glia. COVID-19 We are developing a novel nanocellulose material that binds and inactivates coronavirus to prevent infection. The research involves cell culture, atomic force and confocal microscopy, and biochemical studies.

我们长期以来对神经可塑性的兴趣，但我们对神经胶质细胞参与神经系统发育，学习和认知特别感兴趣。神经胶质是不会发射电脉冲的脑细胞，但它们通过释放神经递质进行通信。这使Glia可以监测和调节神经系统功能。骨髓胶质神经胶质（体内脑和schwann细胞中的少突胶质细胞）形成了轴突上的电绝缘材料，从而极大地加速了脉冲传导速度。多发性硬化症，脑瘫和其他脱髓鞘疾病的损害会导致严重的神经系统损害。我们的研究表明，轴突的髓鞘形成受脉冲活性的调节。这表明了一种新的神经系统可塑性和细胞学习机制的新形式，在儿童发育中尤其重要，因为髓鞘化是通过儿童和青春期进行的。早期的生活经验，无论是不利还是丰富，都以能够持续成年的方式影响大脑的发展。与其直接修改突触传播，不如活动依赖性髓鞘变化，改变了神经网络中继电器点之间传递的信息的速度和时间。神经冲动在神经网络中接力点的到达时间在神经编码，信息整合和突触可塑性以及脑波振荡的耦合中至关重要。我们已经确定了几种用于活性依赖性髓鞘形成的分子机制，并表明电活性轴突优先是骨髓。实验室有四个目前的研究兴趣领域 1。确定神经元和神经胶质如何相互作用，交流和合作。一个主要的重点是理解髓磷脂如何参与学习，认知，儿童发展和精神疾病。我们正在确定神经胶质如何感知神经冲动活动并研究功能和发育后果。 2。我们还正在研究周围神经系统（PN）中的髓鞘形成如何受神经脉冲活性的影响。对PNS髓鞘形成知之甚少，但是神经损伤和疾病的正常儿童发育和恢复需要适当的髓鞘化。 3。功能经验通过指导调节神经网络形成和功能的特定蛋白质和基因的适当变化来影响神经系统的发展和可塑性。我们正在确定神经脉冲的不同模式如何调节控制神经系统发育和可塑性的特定基因。 4。我们正在开发一种新型的纳米纤维素材料，可用于捕获和灭活冠状病毒以防止感染。我们的研究目标提高了6个NICHD研究主题中的4个：1。了解早期人类发展，2。为健康的怀孕和终身健康奠定基础，3。确定敏感的时间段以优化健康干预措施，＆4。在从青春期过渡期间改善健康状况，从青春期过渡到成年，并追求coronavirus，包括Sars-Cov2（包括Sars-Cov2）的新颖方法。髓鞘可塑性髓鞘形成是大脑发育的重要组成部分，始于第二个孕期，一直延续到青春期，但是某些大脑区域的髓鞘形成直到二十多岁才能完成。完成髓鞘化的大脑的最后一部分是前额叶皮层，这是负责冲动控制和其他执行功能的大脑区域。在青少年期间，环境和其他对前额叶皮层的髓鞘形成的影响促成了神经精神上的关注，包括社交互动，决策，焦虑症和冲动性。许多小儿疾病，包括脑瘫，阅读障碍，语言发育，痉挛和发育延迟都与髓磷脂的疾病有关，此外还与众所周知的脱髓鞘疾病（例如多发性硬化症）有关。我们的研究表明，沿轴突从囊泡释放的神经递质谷氨酸会引发髓磷脂形成。该信号传导促进电活动轴突的髓鞘形成，以根据环境经验调节神经发育和功能。我们还发现，从轴突（尤其是ATP）释放的其他信号分子调节髓质神经胶质的发育。这种非突触通信可以在正常情况，发育和疾病中介导轴突和神经系统细胞之间的各种活动依赖性相互作用。髓鞘重塑我们最近的研究表明，完全成型的髓磷脂的结构可以改变以调节传导速度以优化神经回路功能。以前，假设除了受到损害外，不能改变髓鞘蛋白，但是我们的研究发现，可以通过一个踏板的过程来重塑髓磷脂的厚度和兰维尔节点，在该过程中，将髓磷脂包裹的外层移除以将髓磷脂的外层稀薄以将髓磷脂护套和缓慢的传导效率和新髓磷脂添加到覆盖层，以使其在覆盖层覆盖。我们发现神经胶质细胞称为星形胶质细胞，通过分泌分子（凝血酶蛋白酶抑制剂）来调节髓磷脂外层与轴突的脱落，从而抑制将髓磷脂附着在轴突上的分子切断（Neurofascin 155）。白质损坏髓磷脂损伤与许多医疗疾病有关，包括出生过程中缺氧/缺血，导致脑瘫，暴露于环境毒素，例如农药，自身免疫性疾病，例如多发性硬化症和其他疾病。我们正在研究这些情况下髓磷脂破坏的可能参与。 PNS髓鞘髓磷脂是由Schwann细胞在PNS中形成的，Schwann细胞是与CNS中形成髓磷脂的少突胶质细胞不同类型的细胞。关于施旺氏细胞髓鞘的了解鲜为人知，但是正常发育和许多疾病是PNS髓磷脂的破坏的结果，包括糖尿病神经病，吉利安·巴雷疾病以及从所有神经损伤中恢复，从而损害了髓磷脂。我们正在应用少突胶质细胞活性依赖性髓鞘形成的发现，以确定相似的机制是否调节PNS髓鞘化。活性依赖性基因调节我们在共培养的体内和电刺激中使用光遗传学刺激以及微阵列和RNA测序，我们正在确定神经元和神经元中的基因网络和染色质结构如何受神经脉冲触发的模式调节。我们的研究表明，特定的作用电位模式调节了神经元和神经胶质中数千种基因的表达。新冠肺炎我们正在开发一种新型的纳米纤维素材料，该纳米纤维素材料结合并灭活冠状病毒以防止感染。该研究涉及细胞培养，原子力和共聚焦显微镜以及生化研究。