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: 10284936
• 负责人: Brandon Lee Brown
• 金额: $ 3.34万
• 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/10284936
• 关键词: Anatomy; Animal Housing; Animal Model; Animals; Area; Axon; Behavior; Behavioral; Behavioral Assay; Breathing; Cells; Cervical; 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 structure; Neuraxis; Neuronal Plasticity; Neurons; Ontology; Outcome; Output; Pathology; Pathway interactions; Pattern; Periodicity; Physical Rehabilitation; Physical activity; Positioning Attribute; Postdoctoral Fellow; Presynaptic Terminals; Rabies; Rabies virus; Recording of previous events; Recovery of Function; Regulation; Rehabilitation therapy; Research; Rodent; Role; Sensory; Signal Transduction; Source; Specificity; Spinal; Spinal Cord Contusions; Spinal Ganglia; Spinal cord injury; Synapses; System; Therapeutic Intervention; Training; Transcriptional Regulation; Vertebrates; Viral; base; 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.

项目总结。大多数人类脊髓损伤（SCI）是解剖学上不完整的，潜在的