Nervous System Development and Plasticity

神经系统发育和可塑性

基本信息

批准号：
7968534
负责人：
RICHARD DOUGLAS FIELDS
金额：
$ 106.13万
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/7968534
关键词：
Achievement Action Potentials Adenosine Affect Area Astrocytes Axon Brain Cell Adhesion Molecules Cell model Cells Child Development Cognition Communication Development Disease Fetal Development Gene Expression Genes Genetic Transcription Hippocampus (Brain)Injury Investigation Learning Life Memory Mental disorders Modeling Molecular Myelin Nervous System Physiology Nervous system structure Neuroglia Neuromuscular Junction Neurons Oligodendroglia Process Recovery Regulation Research Schwann Cells Short-Term Memory Signal Pathway Signal Transduction Slice Staging Structure Synapses Synaptic Potentials Synaptic Vesicles Synaptic plasticity Work cytokine fetal leukemia inhibitory factor long term memory myelination nervous system development neural patterning neurotransmitter release postnatal relating to nervous system response synaptogenesis white matter

项目摘要

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 early postnatal life. This work has three main areas of emphasis: 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 emphesis 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. Major recent achievements include showing that myelination is regulated by electrical activity. We have identified three general mechanisms for activity-dependent myelination: (1) regulation of cell adhesion molecules on axons affecting myelination; (2) release of ATP and adenosine from axons regulating development and myelination by Schwann cells and oligodendrocytes; (3) release the cytokine leukemia inhibitory factor (LIF) from astrocytes in response to ATP liberated by axons firing action potentials. LIF then stimulates myelination by mature oligodendrocytes. New researach has identified how neurotransmitters are released from axons firing action potentials without synaptic vesicles, and identified a microRNA that regulates synaptic development in a homeostatic manner according to functional activity. Other achievements include identifying changes in gene expression associated with conversion of e-LTP to l-LTP, a cellular model for conversion of short-term to long term memory. We have explored the intracellular signaling pathways involved in this model of synaptic plasticity and shown the importance of action potentials (in contrast to synaptic potentials) in activating gene transcription necessary for long-term changes in synaptic strength. We have shown that gene expression in neurons is regulated by specific patterns of neural impulses, and identified the intracellular signaling mechanisms regulating gene expression by the pattern of neural impulse firing. We have identified and explored several different modes of activity-dependent interactions between neurons and glia, including how myelination in the PNS and CNS is regulated by axonal firing. The axon-glial signals regulating gene transcription in astrocytes, oligodendrocytes, and Schwann cells in response to impulse activity are being identified. Our work shows that purinergic signaling (via ATP and adenosine release from axons) is a major mechanism of activity-dependent communication between axons and glia, but several other modes of activity-dependent neuron-glia communication have also been identified and are under investigation. The relevance of this neuron-glial communication to synaptogenesis and synapse elimination were shown in hippocampal cultures, and the involvement of ATP release in stabilization and elimination of neuromuscular junctions has been shown.

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早期调节神经系统发育的分子和细胞机制。这项工作有三个主要重点领域： 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。当前这项研究的一个主要重点是了解髓磷脂（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。最近的主要成就包括表明髓鞘形成受电活动调节。我们已经确定了活性依赖性髓鞘形成的三种一般机制：（1）影响髓鞘形成的轴突上细胞粘附分子的调节； (2)轴突释放ATP和腺苷，调节雪旺细胞和少突胶质细胞的发育和髓鞘形成； (3) 星形胶质细胞响应轴突放电动作电位释放的 ATP，释放细胞因子白血病抑制因子 (LIF)。然后，LIF 刺激成熟少突胶质细胞的髓鞘形成。新研究确定了神经递质如何在没有突触小泡的情况下从轴突发射动作电位中释放出来，并确定了一种根据功能活动以稳态方式调节突触发育的 microRNA。其他成就包括识别与 e-LTP 向 l-LTP 转换相关的基因表达变化，l-LTP 是一种将短期记忆转换为长期记忆的细胞模型。我们探索了这种突触可塑性模型中涉及的细胞内信号传导途径，并证明了动作电位（与突触电位相反）在激活突触强度长期变化所需的基因转录中的重要性。我们已经证明神经元中的基因表达受到特定的神经脉冲模式的调节，并确定了通过神经脉冲发射模式调节基因表达的细胞内信号传导机制。我们已经确定并探索了神经元和神经胶质细胞之间活动依赖性相互作用的几种不同模式，包括三七总皂甙和中枢神经系统中的髓鞘形成如何受到轴突放电的调节。星形胶质细胞、少突胶质细胞和雪旺细胞响应脉冲活动调节基因转录的轴突神经胶质信号正在被识别。我们的工作表明，嘌呤能信号传导（通过轴突释放 ATP 和腺苷）是轴突和神经胶质细胞之间活动依赖性通讯的主要机制，但其他几种活动依赖性神经元-神经胶质细胞通讯模式也已被识别并正在研究中。海马培养物中显示了这种神经元-胶质细胞通讯与突触发生和突触消除的相关性，并且 ATP 释放参与了神经肌肉接头的稳定和消除。