A Flexible Circuit Design that Restores Locomotion after Injury

可在受伤后恢复运动的柔性电路设计

• 批准号: 2317542
• 负责人: Karen Mesce
• 金额: $ 100万
• 依托单位: University of Minnesota-Twin Cities
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2317542&HistoricalAwards=false
• 关键词: Flexible; Circuit; Design; Restores; Locomotion

A huge barrier for restoring locomotion after injury in mammals, including humans, is that the descending brain inputs needed to initiate and regulate downstream spinal circuits are unable to regrow across the damaged spinal cord. Unfortunately, biologically ‘tricking’ neurons to reconnect with former targets has been met with limited success. Might there be another way of activating locomotor spinal circuitry below the site of injury? Our newest experiments in the medicinal leech indicate that the remodeling of the stretch-sensitive neurons, activated during the elongation and shortening phases of crawling behavior, are likely key to the understanding of how locomotor circuits are once again turned on and contribute to coordinated locomotion. Our work provides a rare and unique opportunity to explore how a novel sensory-based circuit design replaces a centrally-based governing system for the initiation and coordination of locomotion. Importantly, we can examine the cellular basis of this switch in the same individuals over time. This flexibility in design should have significant ramifications for the creation of locomoting robotic systems, especially those that are soft-bodied like the leech. Our research is highly interdisciplinary and will involve the use of innovative molecular and anatomical approaches to understanding neuronal plasticity; we also aim to include citizen-scientists and other volunteers around the globe in our research. The PI and Co-PI will continue to develop ways to support women, first-generation college students, and underrepresented scientists in their labs, and through the development of new inclusion and diversity initiatives through their respective scientific organizations.Our interdisciplinary team will explore how novel neural circuits, in the medicinal leech, emerge and orchestrate a recovery of locomotion after the nerve cord and brain become separated. When descending inputs from the brain neuron R3b-1 are removed, crawling is completely lost, yet surprisingly returns after about 2 weeks. Our goal is to study the underlying circuit design that accounts for this restored crawling. Key to crawl recovery are the proprioceptive stretch receptors (SRs) that pepper each body-wall segment. These proprioceptors, although not injured themselves, sprout new centrally-located (and intersegmental) output branches that are predicted to target crawl-related circuitry, especially in the ‘lead’ ganglion directly below the site of nerve cord injury. We will use electrophysiological recording, voltage-sensitive dye imaging, and electron microscopy to interrogate the role of the lead ganglion and SRs in establishing crawl recovery. To study changes in gene expression across neurons in the lead and adjacent ganglia, and in the SRs, we will use spatial transcriptomics, whereby genome-wide expression analysis will be mapped back to precise locations in specific ganglia and SR processes obtained from histological sections. Our methods and instrumentation, at our respective institutions, will allow for subcellular localization of mRNA molecules in somata, neuronal processes (intrinsic and extrinsic), and synaptic terminals.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

包括人类在内的哺乳动物在受伤后恢复运动的一个巨大障碍是，启动和调节下游脊髓回路所需的下行大脑输入无法在受损的脊髓上重新生长。不幸的是，通过生物学手段“诱骗”神经元与以前的目标重新连接的方法收效甚微。有没有其他方法可以激活损伤部位下方的运动脊髓回路？我们在药用水蛭上的最新实验表明，在爬行行为的延长和缩短阶段激活的拉伸敏感神经元的重塑，可能是理解运动电路如何再次启动并有助于协调运动的关键。我们的工作提供了一个难得而独特的机会来探索一种新颖的基于感官的电路设计如何取代基于中央的控制系统来启动和协调运动。重要的是，随着时间的推移，我们可以在相同的个体中研究这种转换的细胞基础。这种设计上的灵活性应该会对移动机器人系统的创建产生重大影响，特别是那些软体的机器人系统，如水蚤。我们的研究是高度跨学科的，将涉及使用创新的分子和解剖学方法来了解神经元的可塑性；我们的目标还包括全球各地的公民科学家和其他志愿者参与我们的研究。PI和Co-Pi将继续开发方法来支持其实验室中的女性、第一代大学生和代表性不足的科学家，并通过各自的科学组织开发新的包容性和多样性倡议。我们的跨学科团队将探索药用水蛭中新的神经回路如何出现，并在神经线和大脑分离后协调运动的恢复。当移除脑神经元R3b-1的下行输入时，爬行完全消失，但令人惊讶的是，大约两周后又恢复了。我们的目标是研究解释这种恢复的爬行的基本电路设计。爬行恢复的关键是本体感受器(SRS)，它分布在每个身体壁节上。这些本体感受器虽然本身没有损伤，但会萌发新的位于中央(和节段间)的输出分支，预计这些分支将以爬行相关回路为靶点，特别是在神经索损伤部位正下方的“主导”神经节。我们将使用电生理记录、电压敏感染料成像和电子显微镜来询问铅神经节和SRS在建立爬行恢复中的作用。为了研究前导神经节和邻近神经节以及SRS中神经元基因表达的变化，我们将使用空间转录切割技术，从而将全基因组表达分析映射到从组织切片获得的特定神经节和SR过程中的精确位置。我们的方法和仪器，在我们各自的机构，将允许在胞体、神经元突起(内部和外部)和突触终末的mRNA分子的亚细胞定位。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。