The effects of activity on propriospinal neuron morphology and connectivity

活动对本体脊髓神经元形态和连接的影响

• 批准号: 10533795
• 负责人: Brandon Lee Brown
• 金额: $ 2.98万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10533795
• 关键词: Anatomy; Animal Housing; Animal Model; Animals; Area; Axon; Behavior; Behavioral; Behavioral Assay; Breathing; Cells; Central Nervous System; Cervical; Cervical spine; Chest; Clinical; Data; Dendrites; Dependovirus; Ensure; Enterobacteria phage P1 Cre recombinase; Forelimb; GTP-Binding Proteins; Gait; Genes; Genetic Transcription; Growth and Development function; Hindlimb; Human; Injections; Injury; Kentucky; Label; Lateral; Lentivirus; Limb structure; Locomotion; Locomotor Recovery; Mentors; Messenger RNA; Morphology; Motor; Muscle; Nervous System; Neuronal Plasticity; Neurons; Ontology; Outcome; Output; Pathology; Pathway interactions; Pattern; Periodicity; Physical activity; Positioning Attribute; Postdoctoral Fellow; Presynaptic Terminals; Productivity; Rabies; Rabies virus; Recording of previous events; Recovery of Function; Regulation; Rehabilitation therapy; Research; Rodent; Role; Sensory; Signal Transduction; Source; Specificity; Spinal; Spinal Ganglia; Spinal cord injury; Stereotyping; Synapses; System; Therapeutic Intervention; Training; Transcriptional Regulation; Vertebral column; Vertebrates; Viral; career; central pattern generator; improved; kinematics; neuronal excitability; neuroregulation; new therapeutic target; receptor; reconstruction; skills; transcriptome sequencing; white matter

Project Summary. The majority of human spinal cord injuries (SCI) are anatomically incomplete, potentially leaving propriospinal pathways, which may relay information past the injury epicenter, intact. Following SCI in rodents, descending motor tracts sprout and increasingly contact descending propriospinal neurons (DPNs), forming detour circuits to relay signals caudal to the injury. However, no studies have evaluated the potential for ascending PNs to form bottom-up detour circuits post-SCI. We previously found that silencing long ascending PNs (LAPNs), which directly connect the lumbar and cervical spinal enlargements, disrupted coordination at each limb girdle. Surprisingly, silencing this anatomically intact pathway post-SCI improved locomotor function. Thus, it is critical to evaluate LAPN plasticity, and determine how this plasticity might be refined by therapeutic interventions. To do so, LAPN somatic and dendritic morphology will be characterized using a dual-viral system to specifically label LAPNs. We will also use a multi-viral system with a highly modified rabies virus to identify the sources of direct synaptic input to LAPNs. Increased physical activity and rehabilitative training are known to improve locomotor function and anatomical outcomes post-SCI. To evaluate the impact of physical activity and rehabilitative training on LAPN plasticity and locomotor function post-SCI, we will alter activity levels by housing animals in tiny cages or in large cages to restrict or facilitate activity. Animals in large cages will also receive rehabilitative training, which mimics clinical rehabilitation. Further understanding SCI-induced neuroplasticity, and how physical activity and rehabilitative training impact this plasticity will further our understanding of SCI pathology and provide new therapeutic targets. Working closely with my mentors, we have developed a training plan that will broaden my scientific skills, facilitate independent scientific thought, and cultivate skills needed to be a productive postdoctoral fellow. The Kentucky Spinal Cord Injury Research Center provides clinical and scientific expertise in SCI and related fields, and has a history of successfully preparing trainees for current and next stages in their careers. Hypothesis. Pre-SCI we hypothesize that DPNs, reticulospinals, and sensory afferents will provide input to LAPNs. Post-SCI we anticipate 1) LAPN dendrite orientation change, 2) LAPNs will be increasingly contacted by sensory afferents to form bottom-up detour circuits, and 3) increased activity plus rehabilitative training post- SCI will improve locomotor function, impact dendrite reorganization, and refine detour circuits. Aim 1. Characterize the somatic and dendritic morphology of LAPNs, and identify the sources of direct synaptic input onto LAPNs. Aim 2. Evaluate the effects of activity and rehabilitative training on locomotor function, LAPN morphology, and the sources of direct synaptic inputs to LAPNs after T10 contusive spinal cord injury.

项目摘要。大多数人类脊髓损伤（SCI）在解剖学上是不完整的， 留下脊髓本体通路，它可以传递信息通过损伤中心，完好无损。在SCI之后， 在啮齿类动物中，下行运动束发芽并越来越多地接触下行固有脊髓神经元（DPN）， 形成迂回回路将信号传递到损伤的尾部。然而，没有研究评估了 用于上升PN以在SCI后形成自底向上的迂回电路。我们以前发现，长时间沉默 直接连接腰椎和颈椎扩大的上行PN（LAPN）被破坏， 每个肢带的协调性。令人惊讶的是，脊髓损伤后沉默这种解剖学上完整的通路， 运动功能因此，评估LAPN的可塑性，并确定这种可塑性如何可能是至关重要的。 通过治疗干预来改善。为此，将表征LAPN体细胞和树突状细胞形态 使用双病毒系统来特异性标记LAPN。我们还将使用一个多病毒系统， 修饰的狂犬病病毒，以确定直接突触输入LAPNs的来源。增加体育运动和 已知康复训练可改善SCI后的运动功能和解剖结果。评价 体力活动和康复训练对SCI后LAPN可塑性和运动功能的影响， 我们将通过将动物关在小笼子或大笼子中来限制或促进活动，从而改变活动水平。 大笼子里的动物也将接受康复训练，模拟临床康复。进一步 理解SCI诱导的神经可塑性，以及体力活动和康复训练如何影响这一点 可塑性将进一步加深我们对SCI病理的理解，并提供新的治疗靶点。密切合作 与我的导师，我们已经制定了一个培训计划，将扩大我的科学技能，促进独立 科学的思想，培养技能需要是一个富有成效的博士后研究员。肯塔基州脊髓 创伤研究中心提供SCI及相关领域的临床和科学专业知识， 成功地为受训人员的职业生涯的当前和下一个阶段做好准备。 假说.在SCI前，我们假设DPN、网状脊髓和感觉传入神经将提供输入， LAPN。SCI后，我们预计1）LAPN枝晶取向的变化，2）LAPN将越来越多地接触 通过感觉传入形成自下而上的迂回回路，和3）增加活动加上康复训练后， SCI将改善运动功能，影响树突重组，并改善迂回电路。 目标1。描述LAPNs的体细胞和树突状细胞的形态，并确定LAPNs的直接来源。 突触输入到LAPN上。 目标2.评价活动和康复训练对运动功能、LAPN形态学和 T10挫伤性脊髓损伤后LAPN的直接突触输入来源。