CRCNS: Rhythm generation in rodent spinal cord

 描述（由申请人提供）：该合作项目的总体目标是使用最先进的脊髓神经元和神经回路的实验研究结合计算建模来剖析脊髓运动CPG的组织和操作机制。在这项研究中解决的中心问题包括了解在脊髓中运作的节律产生机制以及屈伸肌相互作用的组织。我们建议（a）调查最近发现的被认为属于节律产生回路的脊髓中间神经元，（B）确定它们的连接模式，（c）确定这些神经元与脊髓运动CPG中其他关键成分之间的功能联系。 该项目汇集了两名在实验（Doughnut博士）和计算（Shevtsova博士）神经科学方面具有互补专长的女科学家。该项目有以下三个目标： 目的1：确定和研究Shox 2神经元节律性爆发的细胞基础及其相互作用。研究这些神经元与屈肌和伸肌相关活动之间的潜在差异。 目标二：研究屈肌和伸肌相关的节律产生神经元之间的抑制性相互作用，以及遗传鉴定的V2 b和V1神经元在这些相互作用中的作用。 目标3：研究导致频率依赖性屈伸肌不对称的神经元和网络组织的特性，并研究屈伸肌和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互动逐步开发，并将作为脊髓中节律产生回路组织的工作概念的试验平台，并作为后续实验验证的预测来源。 智力优势：这项合作研究将使用最先进的遗传，分子和生理学方法结合计算建模，以解决哺乳动物脊髓回路中神经元和网络组织的最基本问题，使它们能够产生有节奏的活动并以不同的速度进行屈伸肌协调，以控制运动和其他运动行为。这项研究的结果将提供有价值的见解CPG组织和CPG为基础的运动控制的一般原则。 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被纳入Drexel多部门神经工程计划学生的核心神经工程课程和医学院医学生的核心高级神经科学课程。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。本项目将资助2名博士生和1名博士后研究员。(b)代表性不足的群体：PI（Doughnut）和Co-PI（Shevtsova）都是女科学家。Doughnard博士是一位年轻的科学家，在她的科学载体的开始，这个项目将帮助她进一步发展她在德雷克塞尔的研究，并建立她未来的科学事业。少数民族学生将鼓励两个PI在他们的监督下做实验室轮换，并有可能将轮换工作扩展到论文项目。(c)加强研究和教育的基础设施：两个具有基本不重叠的技术专长的实验室将在本项目期间进行合作。这种合作将允许遗传，分子，生理，电生理和计算建模方法的组合，以研究参与运动节律生成的运动神经回路。模拟软件包NSM 3.0和在这个项目中开发的所有模型将提供给其他研究小组通过一个专门开发的网站在德雷克塞尔大学。(d)医疗影响：如啮齿动物（Orsal等人，2002; Tillakaratne等人，2010）和猫（Rossignol和Frigon，2011）所示，脊髓运动CPG的激活导致上脊髓损伤后运动恢复。这项研究将为今后开发新的、有效的方法恢复脊髓损伤和各种影响正常运动的退行性疾病后的运动功能提供重要的理论基础。

 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.