Role of Intraspinal Plasticity in Autonomic Dysreflexia

椎管内可塑性在自主神经反射异常中的作用

基本信息

批准号：
7243358
负责人：
Alexander George Rabchevsky
金额：
$ 32.3万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-08-02 至 2009-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7243358
关键词：
Acute Adenoviruses Affect Afferent Neurons Amines Animal Model Animals Anxiety Appendix Architecture Attention Autonomic Dysfunction Autonomic Dysreflexia Axon Back Bladder Blood Pressure Blood flow Brain Brain-Derived Neurotrophic Factor C Fiber Calcitonin Gene-Related Peptide Cells Chest Cholera Toxin Chronic Colon Complication Data Development Distal Dorsal Equilibrium Event Fiber Fibroblast Growth Factor 2 Ganglia Gene Delivery Genus Cola Goals Green Fluorescent Proteins Growth Growth Factor Growth Factor Overexpression Growth Inhibitors Headache Hemorrhage High Blood Pressure Horseradish Hypertension Hypertensive Crisis Image Analysis Immunohistochemistry Incidence Individual Inferior Injection of therapeutic agent Injury Intestines Label Laboratories Lead Life Localized Location Measurement Mediating Mesentery Modeling Muscle Myxoid cyst Natural regeneration Nerve Growth Factors Neural Pathways Neurons Neurotrophin 3 Nociception Pathway interactions Patients Pattern Pelvis Peripheral Phase Physiologic Monitoring Physiological Play Population Process Protein Overexpression Quality of life Rattus Reflex action Research Role Sacral spinal cord structure Seizures Sensory Severities Shivering Signal Transduction Site Specific qualifier value Specificity Spinal Spinal Cord Spinal Ganglia Spinal Injections Spinal cord injury Spinal cord injury patients Stimulus Substance P Suid Herpesvirus 1 Sweat Sweating Synapses System Techniques Temperature Testing Thinking Thoracic spinal cord structure Time Tissue Harvesting Tracer Vasoconstrictor Agents Viscera Visceral Visceral Afferents Wheat Germ Agglutinins Work adenoviral-mediated base biotinylated dextran amine clinically relevant colorectal distension dorsal column dorsal horn fighting gene therapy glial cell-line derived neurotrophic factor improved in vivo inhibitor/antagonist injured innovation programs receptor research study response sensory stimulus spinal nerve posterior root spinal pathway spine bone structure

项目摘要

DESCRIPTION (provided by applicant): Autonomic dysreflexia is a potentially life-threatening complication of spinal cord injury (SCI) that is characterized by episodic hypertension (high blood pressure) due to sudden, massive discharge of the sympathetic neurons in the injured spinal cord. The sympathetic neurons enable the 'fight or flight' response of an individual (e.g. more blood flow to the muscles). The reason the sympathetic neurons are so sensitive is that descending inhibitory pathways from higher brain centers are interrupted as a result of the SCI. In spinal injured patients, autonomic dysreflexia is frequently triggered by distension of, or activity within pelvic viscera (bladder or bowel). Therefore, distension of the bladder or bowel sends a signal via sensory neurons to the sacral spinal cord (the lower back). From here, the signal is relayed to thoracic and lumbar sympathetic neurons (chest region of the cord) by relay neurons. Because there is no modulating influence from the higher brain, the action of the sympathetic neurons is unopposed. As a result, the sudden increase in their activity following visceral stimulation causes a sudden rise in blood pressure (up to 200 mmHg) that can cause potentially fatal brain or spinal hemorrhage, seizures, as well as severe headache, shivering, sweating and anxiety. Unfortunately, little is known about the anatomical or functional relationships between the visceral sensory neurons, the spinal relay neurons, and the sympathetic neurons. We propose to use a variety of histological and physiological techniques in a well-defined rat model of autonomic dysreflexia to discover the anatomical connections between these three types of neurons that are critical for the development of autonomic dysreflexia. It is currently not known how visceral sensory information entering the lumbosacral spinal cord is relayed to sympathetic preganglionic neurons in the intermediolateral cell column (IML) of the thoracolumbar cord. Since nociceptive afferent sprouting after SCI is NGF-dependent and is correlated with the incidence of autonomic dysreflexia, we have injected temperature sensitive adenoviruses (Adts) encoding nerve growth factor (NGFAdts) into thoracic, lumbar and sacral spinal cord to trigger sprouting to determine which regions are critical for eliciting autonomic dysreflexia. Overexpression of NGFAdts only in the T13/L1 and L6/S 1 segments produced significant increases in arterial blood pressure evoked by colorectal distension versus injured controls injected with GFPAdts. This suggests that following spinal transection, pelvic visceral information is relayed from its input site in the lumbosacral dorsal horn to the IML via unidentified projection pathways. This proposal has 4 goals. Firstly, we will use anterograde tracing of biotinylated dextran amine (BDA) from the L6/S 1 cord, and retrograde transsynaptic tracing of pseudorabies virus (PRV) from sympathetic pre-vertebral ganglia to identify the neural pathways that transmit visceral information from lumbosacral to thoracic cord after SCI. Secondly, since NGFAdts exacerbate dysreflexia, we will establish whether this correlates with increased pathway sprouting. Thirdly, since it is possible that NGF-independent afferents play a role in autonomic dysreflexia, we will inject Adts encoding other growth factors, FGF-2, NT-3, BDNF and GDNF, into multiple levels of the lumbosacral cord. We will also assess their direct influence on lumbar propriospinal neurons by injecting them in the distal thoracic cord. Finally, based on our recent evidence, we will inject chemorepulsive semaphorin3aAdts after injury into the lumbosacral spinal cord in an attempt to thwart early sprouting events and minimize dysreflexia, as well as establish whether chronic injections are capable of inducing retraction of established sprouts. This information will form the basis for developing potential treatments for this common and debilitating complication of SCI.

描述（由申请人提供）：自主神经反射异常是脊髓损伤（SCI）的一种潜在危及生命的并发症，其特征是由于受伤脊髓中交感神经元突然大量放电而导致的阵发性高血压（高血压）。交感神经元使个体能够做出“战斗或逃跑”反应（例如，更多的血液流向肌肉）。交感神经元如此敏感的原因是来自高级大脑中枢的下行抑制通路因脊髓损伤而被中断。在脊柱损伤的患者中，自主神经反射异常常常是由盆腔内脏（膀胱或肠）的扩张或活动引发的。因此，膀胱或肠的扩张会通过感觉神经元向骶脊髓（下背部）发送信号。从这里，信号通过中继神经元传递到胸交感神经元和腰交感神经元（脊髓的胸部区域）。由于没有来自高级大脑的调节影响，交感神经元的活动不受阻碍。因此，内脏刺激后活动量突然增加会导致血压突然升高（高达 200 毫米汞柱），从而可能导致致命的脑或脊髓出血、癫痫发作以及严重头痛、颤抖、出汗和焦虑。不幸的是，人们对内脏感觉神经元、脊髓中继神经元和交感神经元之间的解剖或功能关系知之甚少。我们建议在明确的自主神经反射异常大鼠模型中使用各种组织学和生理学技术，以发现这三种类型的神经元之间的解剖学联系，这些神经元对于自主神经反射异常的发展至关重要。目前尚不清楚进入腰骶段脊髓的内脏感觉信息如何传递至胸腰段中间外侧细胞柱（IML）中的交感神经节前神经元。由于 SCI 后伤害性传入出芽是 NGF 依赖性的，并且与自主神经反射异常的发生率相关，因此我们将编码神经生长因子 (NGFAdts) 的温度敏感腺病毒 (Adts) 注射到胸、腰和骶脊髓中以触发出芽，以确定哪些这些区域对于引发自主神经反射异常至关重要。与注射 GFPAdts 的受伤对照相比，NGFAdts 仅在 T13/L1 和 L6/S 1 节段中过度表达，导致结直肠扩张引起的动脉血压显着升高。这表明，脊柱横断后，骨盆内脏信息通过未识别的投射路径从腰骶背角的输入位点传递到 IML。该提案有 4 个目标。首先，我们将使用来自 L6/S 1 脊髓的生物素化葡聚糖胺 (BDA) 的顺行追踪，以及来自交感椎前神经节的伪狂犬病病毒 (PRV) 的逆行突触追踪，以确定将内脏信息从腰骶部传递到腰部的神经通路。 SCI 后的胸髓。其次，由于 NGFAdts 会加剧反射障碍，我们将确定这是否与通路萌芽增加相关。第三，由于不依赖NGF的传入神经可能在自主神经反射异常中发挥作用，因此我们将编码其他生长因子（FGF-2、NT-3、BDNF和GDNF）的Adts注射到腰骶索的多个水平。我们还将通过将它们注射到远端胸髓来评估它们对腰椎本体脊髓神经元的直接影响。最后，根据我们最近的证据，我们将在受伤后将化学脉冲信号蛋白3aAdts注射到腰骶脊髓中，试图阻止早期发芽事件并尽量减少反射障碍，并确定长期注射是否能够诱导已形成的发芽回缩。这些信息将为开发针对这种常见且使人衰弱的 SCI 并发症的潜在治疗方法奠定基础。