A new mechanistic and technological framework for uncovering the spinal cord neural systems important for functional recovery after injury

揭示脊髓神经系统对损伤后功能恢复至关重要的新机制和技术框架

• 批准号: 10876503
• 负责人: Victoria Eugenia Guadalupe Abraira
• 金额: $ 24.37万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10876503
• 关键词: 3-Dimensional; Anatomy; Artificial Intelligence; Award; Behavior; Behavioral; Behavioral Assay; Biological Markers; Complex; Data; Development Plans; Elements; Ensure; Foundations; Funding; Gait; Genetic; Goals; Grant; Growth and Development function; Injury; Institution; Interneurons; Intervention; Label; Laboratories; Leg; Link; Liquid substance; Locomotion; Mediating; Mentors; Mentorship; Mission; Modeling; Motor; Motor Neurons; Movement; Muscle; National Institute of Neurological Disorders and Stroke; Natural regeneration; Neurons; Output; Parvalbumins; Pattern; Performance; Play; Population; Positioning Attribute; Privatization; Probability; Process; Proprioceptor; Publishing; Records; Recovery; Recovery of Function; Rehabilitation therapy; Research; Rodent; Role; Secure; Sensorimotor functions; Sensory; Sensory Process; Shapes; Site; Spinal Cord; Spinal Cord Contusions; Spinal cord injury; Structure; Synapses; System; Tactile; Technology; Testing; Therapeutic Intervention; Three-Dimensional Imaging; Touch sensation; Training; United States National Institutes of Health; Visualization; behavior influence; behavioral outcome; career development; cell type; cutaneous sensory neurons; defined contribution; experimental study; genetic approach; improved; injury recovery; insight; kinematics; motor behavior; motor recovery; mouse genetics; neural; programs; response; success; synergism; tool

Project Summary and Abstract Interventions that increase plasticity and regeneration after spinal cord injury (SCI) are improving, but little is known about the neural systems that would be most effective to target such interventions. Sensory based rehabilitation suggests a strong link between cutaneous and proprioceptive sensory neuron activity and motor recovery. Previous experiments provide strong support for the intermediate zone (IZ) of the spinal cord (SC) as an important site mediating this recovery. However, few studies have assessed the role of specific IZ neurons in functional recovery. Key barriers to progress include lack of characterization of specific cell types within the IZ and a paucity of tools to visualize circuits and test their functions in motor performance and recovery following SCI. Our lab combines sophisticated mouse genetic approaches with sensitive motor movement tracking to understand how sensory information is encoded by the SC to influence behavior. Using this approach, we uncovered that intermediate zone (IZ) parvalbumin positive interneurons (PVs) are important for tactile motor responses and locomotion. We hypothesize that IZ-PVs process sensory information to activate specific muscle groups during locomotion and that they play a critical role in activity-based functional recovery following SCI. The ability to identify circuits important for functional recovery relies on how accurately we can quantify differences in behavioral outcomes. We are implementing an unsupervised approach using 3-D pose dynamics and artificial intelligence (AI) to characterize both sensitive behavioral biomarkers and uncover key spinal cord circuits important for the recovery process. Interventions that increase plasticity and regeneration are improving, and this project both identifies the neural systems and synaptic mechanisms that would be most effective to target such interventions and establishes an AI-based platform for fast, reliable and unbiased quantification of motor recovery in rodents. Thus, this project makes original and important contributions to the field of spinal cord research in ways that are specifically aligned with central missions of the NINDS. Moreover, our experimental scrutiny at both the neural and behavioral levels establishes a critical foundation for developing a leading research program and securing independent award funding studying the spinal cord circuits important for sensorimotor function and recovery following SCI. To this end, I have developed a thorough and pragmatic career development plan supported by a strong committee of mentors with extensive track records of laboratory and departmental level mentoring and distinguished portfolios of SCI-specific grant support from the NIH, DoD and private foundations. My career development activities will be focused on four aspects of my academic success. 1) Mentorship and guidance focused on laboratory management. 2) Development and growth of my independent research program and award funding, with a focus on SCI research gap-based training. 3) Navigating institutional responsibilities and fulfilling requirements for promotion and tenure. 4) Expanding my scientific network and profile.

项目概要和摘要 增加脊髓损伤（SCI）后可塑性和再生的干预措施正在改善，但效果甚微 了解最有效针对此类干预措施的神经系统。基于感官 康复表明皮肤和本体感觉神经元活动与运动之间存在密切联系 恢复。先前的实验为脊髓（SC）的中间区（IZ）提供了强有力的支持： 调解这一复苏的重要场所。然而，很少有研究评估特定 IZ 神经元的作用 在功能恢复中。进展的主要障碍包括缺乏对特定细胞类型的表征 IZ 和缺乏用于可视化电路并测试其运动性能和恢复功能的工具 继SCI。我们的实验室将复杂的小鼠遗传方法与敏感的运动运动相结合 跟踪以了解 SC 如何编码感官信息以影响行为。使用这个 方法，我们发现中间区（IZ）小白蛋白阳性中间神经元（PV）对于 触觉运动反应和运动。我们假设 IZ-PV 处理感官信息以激活 运动过程中的特定肌肉群，它们在基于活动的功能恢复中发挥着关键作用 继SCI。识别对功能恢复重要的电路的能力取决于我们的准确程度 量化行为结果的差异。我们正在实施一种使用 3-D 姿势的无监督方法 动力学和人工智能（AI）来表征敏感的行为生物标志物并揭示关键 脊髓回路对于恢复过程很重要。增加可塑性和再生的干预措施 正在改进，这个项目既确定了最重要的神经系统和突触机制 有效地针对此类干预措施，并建立一个基于人工智能的平台，以实现快速、可靠和公正的 啮齿动物运动恢复的量化。因此，该项目对 脊髓研究领域的研究方式与 NINDS 的中心任务特别一致。而且， 我们在神经和行为层面上的实验审查为 制定领先的研究计划并获得研究脊髓的独立奖励资金 对于 SCI 后的感觉运动功能和恢复很重要的电路。为此，我开发了一个 全面、务实的职业发展计划，由拥有广泛经验的强大导师委员会支持 跟踪实验室和部门级指导的记录以及 SCI 特定资助的杰出组合 来自 NIH、DoD 和私人基金会的支持。我的职业发展活动将集中在四个方面 我的学业成功的各个方面。 1）重点关注实验室管理的指导和指导。 2） 我的独立研究项目和奖励资金的发展和成长，重点是 SCI 基于差距的研究培训。 （三）落实机构职责，落实晋升要求 和任期。 4）扩大我的科学网络和形象。