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: 6840756
• 负责人: Alexander George Rabchevsky
• 金额: $ 34.06万
• 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/6840756
• 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）：自主神经反射障碍是脊髓损伤（SCI）的一种潜在危及生命的并发症，其特征是由于受损脊髓中交感神经元的突然大量放电引起的发作性高血压（高血压）。交感神经元使个体的“战斗或逃跑”反应成为可能（例如，更多的血液流向肌肉）。交感神经元如此敏感的原因是，由于SCI，来自高级大脑中心的下行抑制通路被中断。在脊髓损伤患者中，自主神经反射异常通常由盆腔脏器（膀胱或肠）的扩张或活动触发。因此，膀胱或肠的扩张通过感觉神经元向骶脊髓（下背部）发送信号。从这里，信号被中继神经元中继到胸和腰交感神经元（脊髓的胸部区域）。因为没有来自高级大脑的调节影响，交感神经元的作用是不受阻碍的。因此，内脏刺激后他们的活动突然增加会导致血压突然升高（高达200 mmHg），这可能会导致致命的脑或脊髓出血，癫痫发作，以及严重的头痛，颤抖，出汗和焦虑。不幸的是，很少有人知道内脏感觉神经元，脊髓中继神经元和交感神经元之间的解剖或功能关系。我们建议使用各种组织学和生理学技术在一个明确的自主神经反射障碍大鼠模型，发现这三种类型的神经元，自主神经反射障碍的发展是至关重要的解剖连接。目前尚不清楚进入腰骶脊髓的内脏感觉信息是如何传递给胸腰段脊髓中间外侧细胞柱（IML）中的交感节前神经元的。由于脊髓损伤后伤害性传入芽生是神经生长因子依赖性的，并与自主神经反射障碍的发生率相关，我们注射了温度敏感性腺病毒（Adts）编码神经生长因子（NGFAdts）到胸，腰和骶脊髓触发芽生，以确定哪些区域是诱发自主神经反射障碍的关键。仅在T13/L1和L 6/S1节段中过表达NGFAdts与注射GFPAdts的损伤对照相比，结肠直肠扩张引起的动脉血压显著增加。这表明脊髓横断后，盆腔内脏信息从腰骶部背角的输入部位通过不明投射途径传递到IML。该提案有四个目标。首先，我们将利用生物素葡聚糖胺（BDA）在L 6/S1脊髓的顺行追踪和伪狂犬病病毒（PRV）在交感神经节前的逆行跨突触追踪来确定脊髓损伤后内脏信息从腰骶髓到胸髓的神经通路。其次，由于NGFAdts加剧反射障碍，我们将确定这是否与增加的通路发芽相关。第三，由于神经生长因子非依赖性传入神经可能在自主神经反射障碍中起作用，我们将编码其他生长因子，FGF-2，NT-3，BDNF和GDNF的Adts注射到腰骶髓的多个水平。我们还将通过将它们注射到远侧胸髓中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，我们将在损伤后将化学排斥性semaphorin 3aAdts注射到腰骶脊髓中，试图阻止早期发芽事件并最大限度地减少反射障碍，以及确定慢性注射是否能够诱导已建立的芽的退缩。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。