Sensory-motor processing in a developing nervous system

 描述（由申请人提供）：该项目的目标是了解新生神经元如何整合到现有的神经回路中，并改变从青少年到成年的感觉运动反应。在整个发育过程中，神经系统在神经元数量、神经连接和神经递质特性方面经历了剧烈的变化。从感觉外周到神经肌肉接头，电路扩展为新的细胞成分，从祖细胞分化，更新感觉运动反应，并适应每个新的生命阶段不断变化的身体计划。要全面了解发育过程中解剖学、功能和行为变化之间的相互作用，需要完整神经回路在不同阶段的动态和结构模型。为了构建这些模型，我们需要识别和执行所有电路组件的生理分析。由于回路功能是灵活的，并且受到感觉反馈的严重调制，我们需要在关键感觉运动反馈回路完整的行为动物体内进行这些研究。 线虫C. elegans是一个特别适合的模型，以解开发展中的感觉运动回路和改变行为模式之间的相互作用。遗传可及性，已知的成人神经连接，和C。线虫提供了一个特殊的机会，充分剖析动物整体行为与新神经元和突触的整合和重新布线重塑神经回路之间的关系。 一些C。线虫的机械感觉神经元和许多运动神经元是胚后出生的，并将幼虫发育期间的现有回路并入成体感觉运动回路。由触摸介导的成人逃避反应是我们知道从感觉输入到运动输出的完整下行通路的少数行为之一。我们发现C. elegans逃避反应在发育过程中的变化。我们假设，在神经连接和整合的子电机电路的变化所需的复合电机序列，包括成人逃避反应。 为了验证这一假设，我们将使用：用途：1）高通量连续切片电子显微镜和计算机辅助图像分析，以精确定位C。elegans的逃避反应的接线图在每个发育阶段，从幼虫到成年：2）定量行为分析和光学神经生理学，以确定每个电路组件的功能贡献的逃避反应在整个发展;以及3）在自由行为的动物中的光遗传学和遗传扰动，以精确定位执行的基础的因果神经连接，逃避运动序列的过渡和发展变化。 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电路中，以及新的连接如何在整个发育过程中塑造行为。这项研究不仅对我们理解神经回路的发展至关重要，而且具有潜在的生物医学意义。细胞替代被认为是一种有前途的脑修复策略，但移植的神经元往往不能正确地整合到大脑中。 预先存在的电路。了解一个完整的功能电路如何不断整合新的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。

 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.