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

• 批准号: 7051961
• 负责人: Alexander George Rabchevsky
• 金额: $ 33.26万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 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/7051961
• 关键词: Adenoviridae; autonomic disorder; central neural pathway /tract; dextrans; disease /disorder model; fluorescence microscopy; gene therapy; immunocytochemistry; laboratory rat; nerve growth factors; nervous system disorder therapy; neural plasticity; neurogenic hypertension; neuronal guidance; spinal cord injury; suid alphaherpesvirus 1

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）：自主性反射症是一种潜在的威胁生命的脊髓损伤并发症（SCI），其特征是受伤受伤的脊髓中的交感神经元突然出现，突然出现了情节性高血压（高血压）。交感神经元可以实现个人的“战斗或飞行”反应（例如，流向肌肉的血液流动更多）。交感神经元之所以如此敏感的原因是，由于SCI而导致较高脑中心的降低抑制途径被中断。在脊柱受伤的患者中，自主神经反射症经常是由骨盆内脏（膀胱或肠）内的活性引发的。因此，膀胱或肠道的延伸通过感觉神经元将信号发送到脊髓（下背部）。从这里开始，信号通过继电器神经元传递到胸腔和腰部交感神经元（绳索的胸部区域）。由于没有较高大脑的调节影响，因此交感神经元的作用没有反应。结果，内脏刺激后其活性的突然增加会导致血压突然升高（高达200 mmHg），这会导致潜在的致命大脑或脊髓出血，癫痫发作，以及严重的头痛，发抖，出汗和焦虑。不幸的是，关于内脏感觉神经元，脊柱中继神经元和交感神经元之间的解剖学或功能关系知之甚少。我们建议在明确的自主性屈光疾病的大鼠模型中使用各种组织学和生理技术，以发现这三种类型的神经元之间的解剖联系，这些神经元对于自主性纵横运动症的发展至关重要。目前尚不清楚进入腰脊髓脊髓的内脏感官信息如何转移到胸骨托管中间中间细胞柱（IML）中的交感神经前神经元。由于SCI后的伤害性传入发芽与NGF相关，并且与自主性功能障碍的发生率相关，因此我们将编码神经生长因子（NGFADTS）的温度敏感腺病毒（ADTS）注入温度敏感的腺病毒（ADTS），以确定tor骨，腰部和sac中心自动化的区域。 NGFADT仅在T13/L1和L6/S 1段中的过表达在结直肠扩张与注入GFPADT的受伤对照中引起的动脉血压显着升高。这表明，脊柱横断后，通过未鉴定的投影途径，骨盆内脏信息从其腰椎角角的输入位点传递到IML。该提议有4个目标。 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.其次，由于NGFADTS加剧了Dysreflexia，我们将确定这是否与途径增加有关。第三，由于独立于NGF的传入可能在自主神经性障碍症中发挥作用，因此我们将注入编码其他生长因子FGF-2，NT-3，BDNF和GDNF的ADT，分为多个腰椎绳的水平。我们还将通过将它们注射到远端胸部线中来评估它们对腰椎前脊髓神经元的直接影响。最后，根据我们最近的证据，我们将在损伤后注入化学螺栓液含量，以试图挫败早期发芽事件并最大程度地减少肿瘤反射症，并确定慢性注射是否能够诱导已建立的芽菜恢复。这些信息将构成为这种常见和使人衰弱的SCI并发症开发潜在治疗的基础。