Reorganization of a Dopamine-Sensitive Locomotor Neural Network

多巴胺敏感运动神经网络的重组

• 批准号: 1454904
• 负责人: Karen Mesce
• 金额: $ 51万
• 依托单位: University of Minnesota-Twin Cities
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1454904&HistoricalAwards=false
• 关键词: Reorganization; Dopamine; Sensitive; Locomotor; Neural

Almost all living organisms need to move for their survival, and that locomotion is often rhythmic and highly coordinated across an animal's legs, wings, fins, or other body parts. How such coordination is orchestrated is not well understood, but the consequences of losing nerve cells that are vital for locomotion, for example, during a spinal cord injury, are strikingly clear. This project examines how the nervous system can be retuned after a significant perturbation or injury to regain its former ability to generate rhythmic patterns of locomotion. Such reorganization addresses an emerging and highly significant problem in the neurosciences -that of understanding the cellular mechanisms of homeostatic plasticity. Essentially, this plasticity enables a system to go back to its set point or regain its original operational status after a perturbation. Currently, very little is known about locomotor-related homeostatic mechanisms. To understand such events, at the level of individual neurons, this project will use a combination of cellular, molecular and behavioral methods to study how a recovering nervous system achieves its transformation. The scientific team has chosen to study the medicinal leech as a model of locomotor control and homeostatic plasticity because of its experimental accessibility and well-studied locomotor circuits. Its central pattern generators (CPGs) for crawling behavior have been shown to be regulated by dopamine, a universal modulator of motor activity in most animals; each of these CPGs is located within each and every segmental ganglion comprising the nerve cord. The compelling aspect of this project is discovering how the crawl CPGs become retuned or reconfigured so that all timing events are fully restored without the physical reconnection of cephalic inputs. Three hypotheses will be tested: 1) proprioceptive inputs from the body wall substitute for brain-specific timing events; 2) the CPG in the ganglion immediately below the site of nerve cord injury takes the lead in initiating and directing the metachronal crawl waves in the caudal direction; 3) changes in gene expression patterns in the lead CPG provide for a lower crawl-activation threshold to DA and/or proprioceptive inputs. Experimental methods will include electrophysiology, immunocytochemistry, confocal imaging, behavioral video-capture, computational neuroscience, and cutting-edge single-cell quantitative PCR. This project's outcomes have potential to impact disparate fields outside of the biological sciences, including physics, math, computer science and engineering. The planned development of a leech transcriptome will also propel the medicinal leech model into the era of genomics. The project will support the training of female and minority participants, several leech-based laboratory teaching modules, and community outreach projects involving a leech Critter-Cam for middle school students.

几乎所有的生物体都需要移动来生存，而这种运动通常是有节奏的，并且在动物的腿，翅膀，鳍或其他身体部位之间高度协调。 这种协调是如何协调的还不清楚，但失去对运动至关重要的神经细胞的后果，例如，在脊髓损伤期间，是非常清楚的。 这个项目研究了神经系统在受到严重干扰或损伤后如何重新调整，以恢复其以前产生运动节奏模式的能力。 这种重组解决了神经科学中一个新兴的和非常重要的问题-理解稳态可塑性的细胞机制。 从本质上讲，这种可塑性使系统能够在扰动后回到其设定点或恢复其原始操作状态。 目前，人们对运动相关的稳态机制知之甚少。 为了理解这些事件，在单个神经元的水平上，该项目将使用细胞，分子和行为方法的组合来研究恢复中的神经系统如何实现其转变。 科学小组选择研究药用水蛭作为运动控制和稳态可塑性的模型，因为它的实验可及性和良好的运动回路研究。其爬行行为的中央模式发生器（CPG）已被证明是由多巴胺调节的，多巴胺是大多数动物运动活动的普遍调节剂;这些CPG中的每一个都位于构成神经索的每个节段神经节内。 该项目的引人注目的方面是发现爬行CPG如何重新调整或重新配置，以便在没有头部输入的物理重新连接的情况下完全恢复所有计时事件。 将测试三个假设：1）来自体壁的本体感受输入替代脑特异性定时事件; 2）神经索损伤部位正下方的神经节中的CPG率先启动并引导尾侧方向的异时性爬行波; 3）前导CPG中基因表达模式的变化为DA和/或本体感受输入提供了较低的爬行激活阈值。 实验方法将包括电生理学，免疫细胞化学，共聚焦成像，行为视频捕捉，计算神经科学和尖端的单细胞定量PCR。该项目的成果有可能影响生物科学以外的不同领域，包括物理学，数学，计算机科学和工程。 水蛭转录组的计划开发也将推动药用水蛭模型进入基因组学时代。该项目将支持培训女性和少数民族参与者、几个以水蛭为基础的实验室教学模块以及涉及针对中学生的水蛭Critter-Cam的社区推广项目。