Nervous System Development and Plasticity

神经系统发育和可塑性

• 批准号: 8736826
• 负责人: RICHARD DOUGLAS FIELDS
• 金额: $ 82.48万
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 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/8736826
• 关键词: 3' Untranslated Regions; Action Potentials; Adolescence; Alzheimer' s Disease; Anions; Area; Axon; Binding Sites; Bioinformatics; Biological; Brain; Brain Part; Brain region; Calcium; Cells; Child Development; Childhood; Cholesterol; Cognition; Cognitive; Collaborations; Communication; Complex; Confocal Microscopy; Demyelinating Diseases; Dendritic Spines; Development; Disease; Distal; Event; Fetal Development; Fire - disasters; Gap Junctions; Gene Expression; Genes; Genetic Translation; Glutamate Receptor; Glutamates; High Frequency Oscillation; Hippocampus (Brain); Huntington Disease; Image; Injury; Italy; L-Type Calcium Channels; Laboratories; Learning; Life; Long-Term Depression; Maintenance; Measures; Mediating; Membrane; Memory; Mental disorders; Messenger RNA; MicroRNAs; Microscopic; Molecular; Monitor; Multiple Sclerosis; Myelin; Myelin Basic Proteins; Myelin Sheath; Nerve Fibers; Nervous System Physiology; Nervous system structure; Neuroglia; Neurons; Neurophysiology - biologic function; Oligodendroglia; Optics; Phosphotransferases; Photons; Process; Proteins; Receptor Activation; Recovery; Regulation; Research; Rest; Schwann Cells; Short-Term Memory; Signal Pathway; Signal Transduction; Signaling Molecule; Slice; Slow-Wave Sleep; Specificity; Staging; Stem cells; Structure; Surface; Swelling; Synapses; Synaptic Transmission; Synaptic plasticity; Time; Vesicle; Weight; base; brain cell; density; experience; fetal; improved functioning; interest; long term memory; mRNA Stability; myelination; nervous system development; nervous system disorder; neural patterning; neurodevelopment; neuronal cell body; neurotransmitter release; novel; postnatal; postsynaptic; postsynaptic density protein; presynaptic; receptor; relating to nervous system; remyelination; response; synaptic depression; synaptogenesis; white matter

Research in the Section on Nervous System Development and Plasticity, is concerned with understanding the molecular and cellular mechanisms by which functional activity in the brain regulates development of the nervous system during late stages of fetal development and postnatally. Cellular Mechanisms of Learning While we continue our long-standing research interest in synaptic plasticity, our laboratory is actively exploring new mechanisms of nervous system plasticity during learning that extend beyond the neuron doctrine. This includes neurons firing antidromically, and the release of neurotransmitters along axons. We are particularly interested in the involvement of glial cells in learning and cognition. Glia are brain cells that do not fire electrical impulses, but they communicate by releasing neurotransmitters. This enables glia to monitor and regulate synaptic transmission. Our research showing that myelination of axons by glia (oligodendrocytes and Schwann cells) is regulated by impulse activity, suggests a new form of nervous system plasticity and learning that would be particularly important in child development, because myelination proceeds through childhood and adolescence. The mechanisms we have identified suggest that environmental experience would alter myelin formation in an activity-dependent manner, thereby improving function based on experience. The laboratory has three broad areas of interest: 1. Determining how different patterns of neural impulses regulate specific genes controlling development and plasticity of the nervous system. This includes effects of impulse activity on neurons and glia and the molecular signaling pathways regulating gene expression in these cells in response to neural impulses. 2. Investigating how neurons and non-neuronal cells (glia) interact, communicate, and cooperate functionally. A major emphasis of this current research is in understanding how myelin (white matter in the brain) is involved in learning, cognition, child development, and psychiatric disorders. This research is exploring how glia sense neural impulse activity at synapses and non-synaptic regions, and the functional and developmental consequences of activity-dependent regulation of neurons and glia. 3. Determining the molecular mechanisms converting short-term memory into long-term memory, and in particular, how gene expression necessary for long-term memory is controlled. Cellular, molecular, and electrophysiological studies on synaptic plasticity (LTP) in hippocampal brain slice are used. Myelin Plasticity Myelin, the multilayered membrane of insulation wrapped around nerve fibers by glial cells (oligodendrocytes), is essential for nervous system function, increasing conduction velocity by at least 50 times. Myelination is an essential part of brain development. The processes controlling myelination of appropriate axons are not well understood. Myelination begins in late fetal life and continues through childhood and adolescence, but myelination of some brain regions is not completed until the early twenties. Our research shows that release of the neurotransmitter glutamate from vesicles along axons promotes the initial events in myelin induction. This includes stimulating the formation of cholesterol-rich signaling domains between oligodendrocytes and axons, and increasing the local synthesis of the major protein in the myelin sheath, myelin basic protein, through Fyn kinase dependent signaling. This axon-oligodendrocyte signaling would promote myelination of electrically active axons to regulate neural development and function according to environmental experience. The findings are also relevant to demyelinating disorders, such as multiple sclerosis, and remyelination after axon injury. We also find that other signaling molecules released from axons, notably ATP, act to stimulate differentiation of oligodendrocytes with increases myelination. In collaboration with colleagues in Italy, found that a new membrane receptor on oligodendrocyte progenitor cells, GPR-17, regulates oligodendrocyte differentiation. The release of neurotransmitters and other signaling molecules outside synapses has broad biological implications, particularly with regard to communication between axons and glia. We have identified a mechanism for nonsynaptic, nonvesicular release of the neurotransmitter ATP from axons through volume-activated anion channels (VAACs) that are activated by microscopic axon swelling during action potential firing. These studies combined imaging single photons to measure ATP release, together with imaging intrinsic optical signals, intracellular calcium, time-lapse video, and confocal microscopy. Microscopic axon swelling accompanying electrical depolarization of axons activates VAACs to release ATP. This nonvesicular, nonsynaptic communication could mediate various activity-dependent interactions between axons and nervous system cells in normal conditions, development, and disease. Synaptic Plasticity Learning and other cognitive tasks require integrating new experiences into context. Coherent high-frequency oscillations of electrical activity in CA1 hippocampal neurons (sharp-wave ripple complexes, SPW-Rs) functionally couple neurons into transient ensembles. This is thought to contribute to the formation of a schema, which is the combination of multimodal aspects of an experience in proper temporal sequence to form a coherent memory. These oscillations occur during slow-wave sleep or at rest. Neurons that participate in SPW-Rs are distinguished from adjacent nonparticipating neurons by firing action potentials that are initiated ectopically in the distal region of axons and propagate antidromically to the cell body. We find that facilitation of spontaneous SPW-Rs in hippocampal slices and electrical antidromic stimulation of axons evokes a cell-wide, long-lasting synaptic depression, which we term AP-LTD (action potential-induced long-term depression). This new form of synaptic plasticity is not dependent upon synaptic input or glutamate receptor activation, but rather requires L-type calcium channel activation and functional gap junctions. Rescaling synaptic weights through this mechanism of plasticity in subsets of neurons firing antidromically during SPW-Rs would contribute to memory consolidation by sharpening specificity of subsequent synaptic input and promoting incorporation of novel information. Homeostatic mechanisms are required to control formation and maintenance of synaptic connections to maintain the general level of neural impulse activity within normal limits. How genes controlling these processes are coordinately regulated during homeostatic synaptic plasticity is unknown. Micro RNAs (miRNAs) exert regulatory control over mRNA stability and translation and they may contribute to local activity-dependent posttranscriptional control of synapse associated mRNAs. Using a bioinformatics screen to identify sequence motifs enriched in the 3'UTR of mRNAs that are rapidly destabilized after increasing impulse activity in hippocample neurons in culture, we identified a developmentally and activity-regulated miRNA (miR485) and found that it controls dendritic spine number and synapse formation in an activity dependent homeostatic manner. Many plasticity associated genes contain predicted miR-485 binding sites including the presynaptic protein SV2A. We found that miR-485 decreases SV2A abundance and negatively regulates dendritic spine density, postsynaptic density protein (PSD-95) clustering, surface expression of GluR2 and postsynaptic currents. These findings show that miRNAs participate in homeostatic synaptic plasticity with possible implications in neurological disorders such as Huntington and Alzheimer's disease, where miR-485 is dysregulated.

神经系统发育和可塑性部分的研究涉及了解大脑功能活动在胎儿发育后期和出生后调节神经系统发育的分子和细胞机制。 学习的细胞机制 在我们继续对突触可塑性进行长期研究的同时，我们的实验室正在积极探索学习过程中神经系统可塑性的新机制，超越神经元学说。 这包括神经元的逆向放电以及神经递质沿轴突的释放。 我们对神经胶质细胞参与学习和认知特别感兴趣。 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突触传递。 我们的研究表明，神经胶质细胞（少突胶质细胞和雪旺细胞）对轴突的髓鞘形成受冲动活动的调节，这表明神经系统可塑性和学习的新形式对儿童发育特别重要，因为髓鞘形成贯穿儿童期和青春期。 我们已经确定的机制表明，环境经验会以活动依赖性方式改变髓磷脂的形成，从而根据经验改善功能。 该实验室有三个广泛的兴趣领域： 1. 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。这包括脉冲活动对神经元和神经胶质细胞的影响，以及调节这些细胞中响应神经脉冲的基因表达的分子信号传导途径。 2. 研究神经元和非神经元细胞（神经胶质细胞）如何相互作用、沟通和功能合作。当前研究的重点是了解髓磷脂（大脑中的白质）如何参与学习、认知、儿童发育和精神疾病。这项研究正在探索神经胶质细胞如何感知突触和非突触区域的神经冲动活动，以及神经元和神经胶质细胞的活动依赖性调节的功能和发育后果。 3.确定将短期记忆转化为长期记忆的分子机制，特别是如何控制长期记忆所需的基因表达。使用对海马脑切片突触可塑性 (LTP) 的细胞、分子和电生理学研究。 髓磷脂可塑性 髓磷脂是神经胶质细胞（少突胶质细胞）包裹在神经纤维周围的多层绝缘膜，对于神经系统功能至关重要，可将传导速度提高至少 50 倍。髓鞘形成是大脑发育的重要组成部分。控制适当轴突髓鞘形成的过程尚不清楚。髓鞘形成从胎儿晚期开始，一直持续到童年和青春期，但某些大脑区域的髓鞘形成直到二十出头才完成。我们的研究表明，沿着轴突的囊泡释放神经递质谷氨酸可促进髓磷脂诱导的初始事件。这包括刺激少突胶质细胞和轴突之间富含胆固醇的信号传导域的形成，并通过 Fyn 激酶依赖性信号传导增加髓鞘中主要蛋白质（髓鞘碱性蛋白）的局部合成。这种轴突-少突胶质细胞信号传导将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。这些发现还与脱髓鞘疾病有关，例如多发性硬化症和轴突损伤后的髓鞘再生。 我们还发现从轴突释放的其他信号分子，特别是 ATP，可以刺激少突胶质细胞的分化，增加髓鞘形成。与意大利同事合作，发现少突胶质细胞祖细胞上的一种新膜受体 GPR-17 可调节少突胶质细胞分化。 神经递质和其他信号分子在突触外的释放具有广泛的生物学意义，特别是在轴突和神经胶质细胞之间的通讯方面。我们已经确定了一种通过体积激活阴离子通道（VAAC）从轴突非突触、非囊泡释放神经递质 ATP 的机制，该通道在动作电位放电过程中被微观轴突肿胀激活。这些研究结合了单光子成像来测量 ATP 释放，以及内在光学信号、细胞内钙、延时视频和共焦显微镜成像。伴随轴突电去极化的微观轴突肿胀激活 VAAC 释放 ATP。在正常条件、发育和疾病中，这种非囊泡、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。 突触可塑性 学习和其他认知任务需要将新体验融入到情境中。 CA1 海马神经元电活动的相干高频振荡（尖波波纹复合体，SPW-R）在功能上将神经元耦合成瞬态集合。 这被认为有助于图式的形成，图式是按适当的时间顺序组合体验的多模态方面以形成连贯的记忆。 这些振荡发生在慢波睡眠或休息时。 参与 SPW-R 的神经元通过激发动作电位与相邻的非参与神经元区分开来，动作电位在轴突远端区域异位启动并逆向传播到细胞体。 我们发现海马切片中自发的 SPW-R 的促进和轴突的逆向电刺激会引起细胞范围内的持久突触抑制，我们将其称为 AP-LTD（动作电位诱导的长期抑制）。 这种新形式的突触可塑性不依赖于突触输入或谷氨酸受体激活，而是需要 L 型钙通道激活和功能性间隙连接。 通过这种在 SPW-R 期间逆向放电的神经元亚群的可塑性机制来重新调整突触权重，将有助于通过增强后续突触输入的特异性并促进新信息的整合来巩固记忆。 需要稳态机制来控制突触连接的形成和维持，以将神经冲动活动的一般水平维持在正常范围内。控制这些过程的基因如何在稳态突触可塑性过程中协调调节尚不清楚。微小 RNA (miRNA) 对 mRNA 稳定性和翻译发挥调节控制作用，它们可能有助于突触相关 mRNA 的局部活性依赖性转录后控制。使用生物信息学筛选来识别富含 mRNA 3'UTR 的序列基序，这些基序在培养的海马神经元中脉冲活性增加后迅速不稳定，我们鉴定了一种发育和活性调节的 miRNA (miR485)，并发现它控制树突棘数量和突触形成以活动依赖的稳态方式。许多可塑性相关基因含有预测的 miR-485 结合位点，包括突触前蛋白 SV2A。我们发现 miR-485 降低 SV2A 丰度并对树突棘密度、突触后密度蛋白 (PSD-95) 聚类、GluR2 表面表达和突触后电流产生负调节。这些发现表明，miRNA 参与稳态突触可塑性，可能对亨廷顿病和阿尔茨海默病等神经系统疾病（其中 miR-485 失调）有影响。