CRCNS: Rhythm generation in rodent spinal cord

CRCNS：啮齿动物脊髓节律的产生

• 批准号: 9114688
• 负责人: Kimberly J Dougherty
• 金额: $ 33.8万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9114688
• 关键词: Address; Affect; Arts; Behavior; Collaborations; Computer Simulation; Degenerative Disorder; Development; Doctor of Philosophy; Electrophysiology (science); Experimental Models; Felis catus; Female; Flexor; Frequencies; Future; Generations; Goals; Interneurons; Laboratories; Left; Link; Locomotion; Medical; Medical Students; Medicine; Methods; Modeling; Molecular Genetics; Motor; Neurons; Neurosciences; Pattern; Physiological; Postdoctoral Fellow; Property; Research; Research Infrastructure; Research Personnel; Rodent; Role; Rotation; Science; Scientist; Source; Speed; Spinal; Spinal Cord; Spinal cord injury; Students; Supervision; Technical Expertise; Underrepresented Groups; Universities; V1 neuron; Validation; Work; base; career; college; education research; graduate student; insight; minority student; motor control; neural circuit; programs; research study; restoration; simulation; skills; web site

 DESCRIPTION (provided by applicant): The overall goal of this collaborative project is to use state-of-art experimental studies of spinal neurons and neural circuits in combination with computational modeling to dissect the organization and operating mechanisms of the spinal locomotor CPG. The central issues addressed in this study include understanding the rhythm-generating mechanisms operating in the spinal cord as well as the organization of flexor-extensor interactions. We propose to (a) investigate recently identified spinal interneurons that are considered to belong to rhythm-generating circuits, (b) identify their connectivity pattern, an (c) determine the functional links between these neurons and other key components in the spinal locomotor CPG. The project brings together two female scientists with complementary expertise in experimental (Dr. Dougherty) and computational (Dr. Shevtsova) neuroscience. The project has the following three objectives: OBJECTIVE 1: Determine and investigate the cellular basis of rhythmic bursting in Shox2 neurons and their mutual interactions. Investigate potential differences between these neurons with flexor- vs. extensor-related activity. OBJECTIVE 2: Investigate inhibitory interactions between the flexor- and extensor-related rhythm-generating neurons and the role of genetically-identified V2b and V1 neurons in these interactions. OBJECTIVE 3: Investigate properties of neuronal and network organization leading to the frequency-dependent flexor-extensor asymmetry and study interactions between flexor-extensor and left-right coordinating networks The model will be progressively developed by continuous interaction with the experimental studies and will serve both as a testbed for working concepts on the organization of the rhythm generating circuits in the spinal cord and as a source of predictions for subsequent experimental validation. Intellectual Merit: This collaborative study will use state-of-art genetic, molecular and physiological methods in combination with computational modeling to address the most fundamental questions on the neuronal and network organization in the mammalian spinal circuits allowing them to generate rhythmic activity and perform flexor-extensor coordination at different speeds to control locomotion and other motor behaviors. The results of this study will provide valuable insights into general principles of CPG organization and CPG-based motor control. Broader Impacts of the Project: (a) Integrating research and education: The experimental approaches and computational models developed in this project will be included in the core Neuroengineering course for students of the multi-departmental Neuroengineering Program at Drexel and in the core Advanced Neuroscience course for medical students of the College of Medicine. The project will provide a platform for short-term rotation of graduate students allowing them to gain both experimental and computational modelling skills. 2 PhD students and one postdoc researcher will be supported by this project. (b) Underrepresented groups: Both PI (Dougherty) and Co-PI (Shevtsova) are female scientists. Dr. Dougherty is a young scientist at the beginning of her scientific carrier, and this project will help her to further develop her research at Drexel and establish her future career in science. Minority students will be encouraged by both PIs to do lab rotations under their supervision with the possibility to extend the rotation work to a thesis project. (c) Enhance infrastructure for research and education: Two laboratories with mostly non-overlapping technical expertise will collaborate during this project. This collaboration will allow for the combination of genetic, molecular, physiological, electrophysiological, and computational modeling approaches to study the locomotor neural circuits participating in locomotor rhythm generation. The simulation package NSM 3.0 and all models developed in this project will be made available to other research groups via a specially developed website at Drexel University. (d) Medical Impact: As demonstrated in rodents (Orsal et al. 2002; Tillakaratne et al. 2010) and cats (Rossignol and Frigon, 2011), activation of the spinal locomotor CPG leads to the restoration of locomotion after upper spinal cord injury. The proposed study will provide an important theoretical basis for the future development of new, effective methods for restoring locomotor function after spinal cord injury and various degenerative disorders affecting normal locomotion.

 描述（由应用程序提供）：该协作项目的总体目标是使用对脊髓神经元和神经元电路的最新实验研究，并结合计算建模，以剖析脊柱运动CPG的组织和操作机制。这项研究中解决的中心问题包括了解脊髓中运行的节奏生成机制以及屈肌相互作用的组织。我们建议（a）调查最近确定的脊柱中间神经元，这些脊柱中间神经元被认为属于节奏的回路，（b）确定其连通性模式，A（c）确定这些神经元与脊柱机动体CPG中其他关键成分之间的功能联系。 该项目将两名女科学家与实验（Dougherty博士）和计算（Shevtsova博士）神经科学专家汇集在一起​​。该项目具有以下三个目标： 目标1：确定和研究SHOX2神经元中节奏爆发的细胞基础及其相互作用。研究这些神经元之间具有屈肌与扩展相关活性的潜在差异。 目标2：研究屈肌和外部相关节奏神经元之间的抑制作用，以及遗传鉴定的V2B和V1神经元在这些相互作用中的作用。 目标3：研究神经元和网络组织的特性，导致频率依赖性屈伸器不对称和研究屈伸器与左右协调网络之间的相互作用 该模型将通过与实验研究的持续相互作用逐步开发，并将作为有关在脊髓中产生节奏产生电路的工作概念的测试床位，也将作为随后实验验证的预测来源。 智力优点：这项合作研究将使用最先进的遗传，分子和物理方法与计算建模相结合，以解决有关哺乳动物脊柱回路中关于神经元和网络组织的最基本问题，允许它们产生节奏活动并在不同的速度上进行弹性 - extensor配位以控制位置和其他运动行为。这项研究的结果将为CPG组织和基于CPG的运动控制的一般原则提供宝贵的见解。 该项目的更广泛影响：（a）整合研究和教育：该项目中开发的实验方法和计算模型将包括在Drexel的多部门神经工程计划的核心神经工程课程中，以及医学院医学院的核心神经科学课程。该项目将为研究生的短期轮换提供一个平台，使他们能够获得实验和计算建模技能。该项目将为2名博士学位学生和一名博士后研究员提供支持。 （b）代表性不足的群体：PI（Dougherty）和Co-Pi（Shevtsova）都是女科学家。 Dougherty博士是她科学运输公司开始时的年轻科学家，该项目将帮助她进一步发展Drexel的研究并确立她未来的科学职业。两个PI都会鼓励少数族裔学生在其监督下进行实验室轮换，并有可能将旋转工作扩展到论文项目。 （c）增强研究和教育的基础设施：两个具有非重叠技术专长的实验室将在此项目期间进行合作。这种合作将允许遗传，分子，物理，电生理和计算建模方法的结合，以研究参与运动节律产生的运动神经回路。仿真软件包NSM 3.0和该项目中开发的所有模型将通过Drexel University的特殊开发的网站提供给其他研究小组。 （d）医学影响：如啮齿动物（Orsal等，2002; Tillakaratne etal。2010）和猫（Rossignol和Frigon，2011年）所证明的那样，脊柱运动CPG的激活会导致上脊髓损伤后的运动恢复。拟议的研究将为未来开发新的有效方法来恢复脊髓损伤后的运动功能和影响正常运动的各种退化性疾病后，为恢复运动功能的未来发展提供重要的理论基础。