Sensory-motor processing in a developing nervous system

发育中的神经系统的感觉运动处理

• 批准号: 9133477
• 负责人: Mark Alkema
• 金额: $ 56.75万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9133477
• 关键词: Achievement; Adaptive Behaviors; Adolescent; Adult; Animal Behavior; Animals; Area; Axon; Behavior; Behavioral; Biological Models; Biology; Birth; Brain; Caenorhabditis elegans; Calcium; Cells; Chemicals; Computer Assisted; Dendrites; Destinations; Development; Electron Microscopy; Feedback; Functional Imaging; Genetic; Goals; Growth; Health; Image Analysis; Invertebrates; Larva; Lead; Life; Maps; Mediating; Modeling; Motor; Motor Neurons; Motor output; Nematoda; Nervous system structure; Neuromuscular Junction; Neurons; Neurotransmitters; Optics; Pathway interactions; Pattern; Physiological; Process; Property; Resolution; Sensory; Shapes; Site; Staging; Structural Models; Structure; Synapses; Technology; Testing; Therapeutic; Time; Touch sensation; Transplantation; Update; brain repair; developmental plasticity; flexibility; genetic approach; hatching; in vivo; mature animal; motor control; nervous system development; neural circuit; neurogenetics; neurophysiology; newborn neuron; optogenetics; progenitor; relating to nervous system; response; sensory feedback; sensory input

 DESCRIPTION (provided by applicant): The goal of this project is to understand how newly born neurons integrate into existing neural circuits and change sensorimotor responses from juvenile to adult. Throughout development, the nervous system undergoes drastic changes in neuron number, neural connectivity, and neurotransmitter properties. From sensory periphery to neuromuscular junctions, circuits expand as new cellular components, differentiated from progenitors, update sensorimotor responses and adapt to changing body plans at each new life stage. A full understanding of the interplay between anatomical, functional, and behavioral changes across development, requires dynamic and structural models of complete neural circuits at different stages. To construct these models, we need to identify and perform physiological analysis of all circuit components. Because circuit function is flexible and heavily modulated by sensory feedback, we need to perform these studies in vivo in behaving animals where key sensorimotor feedback loops are intact. The nematode C. elegans is a particularly suitable model to unravel the interplay between the developing sensorimotor circuits, and the altering behavioral patterns. The genetic accessibility, known adult neural connectivity, and optical transparency of C. elegans provides an exceptional opportunity to fully dissect relationships between overall animal behaviors and the reshaping of neural circuits by the integration and rewiring of new neurons and synapses. Some C. elegans mechanosensory neurons and many motor neurons are born postembryonically, and incorporated the existing circuit during the larval development to the adult sensorimotor circuit. The adult escape response mediated by touch is one of the few behaviors where we know the complete descending pathway, from sensory input to motor output. We found that the C. elegans escape response changes during development. We hypothesize that changes in neural connectivity and integration of sub-motor circuits are required for the compound motor sequence that comprises the adult escape response. To test this hypothesis, we will use: 1) high-throughput serial-section electron microscopy and computer-aided image analysis to precisely map the C. elegans wiring diagram for escape response at each developmental stage, from juvenile larvae to adulthood; 2) quantitative behavioral analysis and optical neurophysiology, to determine the functional contribution of each circuit component to the escape response across development; and 3) optogenetic and genetic perturbation in freely behaving animals, to pinpoint the causative neural connectivities that underlie the execution, transition and developmental changes of the escape motor sequence. Our studies will unravel how neurons integrate into existing circuits with unparalleled resolution, and how new connections shape behavior throughout development. This studies not only are central to our understanding of neural circuit development, and but also has potential biomedical relevance. Cell replacement is viewed as a promising strategy for brain repair, but transplanted neurons often fail to properly integrate into pre-existing circuits. Understanding on how a complete and functioning circuit continuously integrates new components to generate adaptive behavior is critical for advancing an area of basic biology with great translational significance.

 描述（由适用提供）：该项目的目的是了解新出生的神经元如何整合到现有神经元中，并改变从少年到成人的感觉运动反应。通过发育，神经系统发生神经元数，神经连接性和神经递质特性的急剧变化。从感觉外围设备到神经肌肉连接，电路随着新的细胞成分的扩展，与祖细胞区别开来，更新感觉运动反应并适应每个新生活阶段的身体计划。对整个开发的解剖学，功能和行为变化之间的相互作用的全面了解需要在不同阶段的完全中性电路的动态和结构模型。要构建这些模型，我们需要确定和执行所有电路组件的物理分析。由于电路函数是灵活的，并且通过感觉反馈进行了严格的调节，因此我们需要在体内进行这些研究，以在关键的感觉运动反馈回路完好无损的行为动物中进行。线虫C.秀丽隐杆线虫是一个特别合适的模型，用于揭示发育中的感觉运动电路与改变行为模式之间的相互作用。秀丽隐杆线虫的遗传可及性，已知的成年神经连通性和光学透明度为通过新神经元和突触的整合和重新布线的整合和重塑神经元之间完全剖析了整体动物行为之间的关系提供了极大的机会。一些秀丽隐杆线虫机理感知神经元和许多运动神经元在术后出生，并在幼虫发育过程中将现有电路纳入了成人感觉运动电路。触摸介导的成人逃生响应是我们知道从感觉输入到电动机输出的少数几个行为之一。我们发现秀丽隐杆线虫在开发过程中逃脱了反应。我们假设神经元连通性的变化和包括成人逃生反应的复合运动序列需要亚运动电路的整合。为了检验这一假设，我们将使用：1）高通量串行部分电子显微镜和计算机辅助图像分析以精确映射秀丽隐杆线虫接线图，以在每个发育阶段，从少年幼虫到成年期在每个发育阶段进行逃生响应； 2）定量行为分析和光学神经生理学，以确定每个电路成分对整个发育过程中逃逸响应的功能贡献； 3）自由行为动物的光遗传学和遗传扰动，以查明逃脱运动序列的执行，过渡和发育变化的关键神经元。我们的研究将揭示神经元如何通过无与伦比的分辨率整合到现有电路中，以及新的连接如何影响整个发展的行为。这项研究不仅是我们对神经元电路发展的理解的核心，而且还具有潜在的生物医学相关性。细胞更换被视为脑修复的承诺策略，但是移植的神经元通常无法正确整合到 预先存在的电路。了解完整和运行的电路如何继续整合新组件以产生适应性行为对于推进具有巨大转化意义的基本生物学领域至关重要。