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

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感兴趣，但我们对神经胶质细胞在神经系统发育、学习和认知中的参与特别感兴趣。神经胶质细胞是不发射电脉冲的脑细胞，但它们通过释放神经递质进行交流。这使得神经胶质细胞能够监测和调节神经系统功能。髓鞘神经胶质细胞（大脑中的少突胶质细胞和体内的雪旺细胞）在轴突上形成电绝缘体，大大加快脉冲传导速度。多发性硬化症、脑瘫和其他脱髓鞘疾病中的髓鞘质损伤会导致严重的神经系统损伤。我们的研究表明，轴突的髓鞘形成受冲动活动的调节。这表明一种新形式的神经系统可塑性和细胞学习机制对于儿童发育特别重要，因为髓鞘形成贯穿儿童期和青春期。早期的生活经历，无论是不利的还是丰富的，都会以某种方式影响大脑的发育，这种影响可以持续到成年。活动依赖性髓鞘形成不是直接改变突触传递，而是改变神经网络中中继点之间传输信息的速度和时间。神经脉冲到达神经网络中继点的时间对于神经编码、信息整合和突触可塑性以及脑电波振荡的耦合至关重要。我们已经确定了活性依赖性髓鞘形成的几种分子机制，并表明电活性轴突优先有髓鞘形成。该实验室目前有四个研究兴趣领域 1. 确定神经元和神经胶质细胞如何在功能上相互作用、沟通和合作。主要重点是了解髓磷脂如何参与学习、认知、儿童发育和精神疾病。我们正在确定神经胶质细胞如何感知神经冲动活动并研究其功能和发育后果。 2. 我们还在研究神经冲动活动如何影响周围神经系统（PNS）的髓鞘形成。人们对三七总皂苷髓鞘形成知之甚少，但正常的儿童发育以及神经损伤和疾病的恢复需要适当的髓鞘形成。 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育和可塑性。我们正在确定不同的神经冲动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纳米纤维素材料，可用于捕获和灭活冠状病毒以预防感染。我们的研究目标推进了 NICHD 6 个研究主题中的 4 个：1. 了解人类早期发育，2. 为健康怀孕和终身健康奠定基础，3. 确定敏感时间段以优化健康干预措施，4. 在怀孕期间改善健康从青春期过渡到成年期，并寻求预防冠状病毒（包括 SARS-Cov2）感染的新方法。髓磷脂可塑性髓鞘形成是大脑发育的重要组成部分，从妊娠中期开始并持续到青春期，但某些大脑区域的髓鞘形成直到二十岁出头才完成。大脑最后完成髓鞘形成的部分是前额叶皮层，该区域负责冲动控制和其他执行功能。青春期期间环境和其他对前额皮质髓鞘形成的影响会导致神经精神问题，包括社交互动、决策、焦虑症和冲动。除了众所周知的脱髓鞘疾病（如多发性硬化症）之外，许多儿科疾病，包括脑瘫、阅读障碍、语言发育、痉挛和发育迟缓都与髓鞘质疾病有关。我们的研究表明，沿着轴突的囊泡释放的神经递质谷氨酸启动髓磷脂的形成。这种信号传导促进电活性轴突的髓鞘形成，从而根据环境经验调节神经发育和功能。我们还发现从轴突释放的其他信号分子，特别是 ATP，调节髓鞘神经胶质细胞的发育。在正常条件、发育和疾病中，这种非突触通讯可以介导轴突和神经系统细胞之间各种依赖于活动的相互作用。髓磷脂重塑我们最新的研究表明，完全形成的髓磷脂的结构可以改变，以调整传导速度，从而优化神经回路功能。以前，人们认为髓磷脂不会被改变，除非受到损伤，但我们的研究发现，髓磷脂厚度和朗飞结可以通过跑步过程来重塑，其中髓磷脂包裹的外层被去除以减薄髓鞘＆传导速度慢，＆新的髓磷脂被添加到覆盖层下方以增厚鞘。我们发现，称为星形胶质细胞的神经胶质细胞通过分泌分子（凝血酶蛋白酶抑制剂）调节髓磷脂外层与轴突的分离，从而抑制将髓磷脂附着到轴突的分子（神经成束蛋白 155）的切断。白质损伤髓磷脂损伤与许多疾病有关，包括出生时缺氧/缺血导致脑瘫、接触杀虫剂等环境毒素、多发性硬化症等自身免疫性疾病和其他疾病。我们正在调查这些情况下髓鞘质破坏可能涉及的情况。三七总皂甙髓鞘化髓磷脂由雪旺细胞在三七总皂苷中形成，雪旺细胞是与中枢神经系统中形成髓磷脂的少突胶质细胞不同类型的细胞。人们对雪旺细胞髓鞘形成知之甚少，但正常发育和许多疾病是三七总皂苷髓鞘破坏的结果，包括糖尿病性神经病变、吉莉安·巴雷病以及导致髓鞘损害的所有神经损伤的恢复。我们正在应用我们对少突胶质细胞活动依赖性髓鞘形成的研究结果来确定类似的机制是否调节三七总皂甙髓鞘形成。活性依赖性基因调控利用体内光遗传学刺激和共培养中的电刺激，再加上微阵列和RNA测序，我们正在确定神经元和神经胶质细胞中的基因网络和染色质结构如何受到神经脉冲发射模式的调节。我们的研究表明，动作电位的特定模式调节神经元和神经胶质细胞中数千个基因的表达。新冠肺炎我们正在开发一种新型纳米纤维素材料，可以结合并灭活冠状病毒以预防感染。该研究涉及细胞培养、原子力和共焦显微镜以及生化研究。