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（由申请人提供）：该项目的目标是了解新生神经元如何融入现有的神经回路并改变从青少年到成人的感觉运动反应，神经系统在神经元数量、神经连接和神经元发育过程中经历了巨大的变化。神经递质特性。从感觉外周到神经肌肉接头，回路随着新的细胞成分而扩展，与祖细胞不同，更新感觉运动反应并适应每个新生命阶段不断变化的身体计划。发育过程中解剖、功能和行为变化之间的相互作用，需要不同阶段的完整神经回路的动态和结构模型，为了构建这些模型，我们需要识别所有回​​路组件并进行生理分析，因为回路功能是灵活的。在很大程度上受到感觉反馈的调节，我们需要在关键感觉运动反馈回路完整的动物体内进行这些研究。线虫是一个特别适合揭示发育中的感觉运动回路和神经元之间相互作用的模型。线虫的遗传可及性、已知的成体神经连接性和光学透明度为充分剖析动物整体行为与新神经元和突触的整合和重新连接之间的关系提供了绝佳的机会。秀丽隐杆线虫的机械感觉神经元和许多运动神经元是在胚胎后出生的，并在幼虫发育过程中将现有的回路整合到成虫的感觉运动回路中，由触摸介导的成虫逃避反应是其中之一。我们知道从感觉输入到运动输出的完整下降路径的少数行为，我们发现线虫在发育过程中逃避反应发生变化，我们发现该化合物需要神经连接和子运动回路整合的变化。为了检验这一假设，我们将使用：1）高通量连续切片电子显微镜和计算机辅助图像分析来精确绘制每个发育阶段的逃避反应的线虫接线图。 ，来自少年幼虫到成年；2) 行为分析和光学神经生理学，以确定每个定量回路成分对整个发育过程中的逃避反应的功能贡献；3) 自由行为动物的光遗传学和遗传扰动，以确定导致神经连接的原因。我们的研究将揭示神经元如何以无与伦比的分辨率整合到现有的回路中，以及新的连接如何在整个发育过程中塑造行为。细胞替代被认为是一种有前途的大脑修复策略，但移植的神经元往往无法正确整合到神经回路发育中。 了解完整且功能正常的电路如何集成新组件以产生适应性行为对于推进具有重大转化意义的基础生物学领域至关重要。