Celiac ganglia plasticity after spinal cord injury

脊髓损伤后腹腔神经节的可塑性

• 批准号: 10303883
• 负责人: Yaqing Li
• 金额: $ 43.03万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10303883
• 关键词: Abdomen; Adrenergic Agents; Adult; Anatomy; Autonomic Dysfunction; Autonomic Dysreflexia; Axon; Behavioral; Blood Pressure; Blood Volume; Celiac ganglion; Chest; Colon; Drug Delivery Systems; Electric Stimulation; Electrophysiology (science); Essential Hypertension; Fiber; Frequencies; Functional disorder; Ganglia; Ganglionectomy; Gastrointestinal tract structure; Glutamate Receptor; Hypertension; Hypertensive Crisis; Hypotension; Implant; Infusion procedures; Intestines; Investigation; Kidney; Lead; Lesion; Life; Liver; Measures; Modification; Morphology; Mus; Nerve; Neuronal Plasticity; Neurons; Nociception; Nociceptors; Organ; Output; Pain; Patients; Pattern; Peripheral; Pharmaceutical Preparations; Pharmacology; Physiological; Play; Presynaptic Terminals; Property; Pump; Role; Site; Source; Spinal; Spinal Cord; Spinal cord injury; Spinal cord injury patients; Splanchnic Nerves; Spleen; Synapses; Testing; Thoracic spinal cord structure; Vasoconstrictor Agents; Vasomotor; Visceral; Visceral Afferents; Whole-Cell Recordings; awake; behavioral outcome; colon distension; designer receptors exclusively activated by designer drugs; in vivo; motility disorder; mouse model; neuromechanism; optogenetics; peripheral blood vessel; programs; recruit; relating to nervous system; response; synaptogenesis; therapeutic target; vascular bed; vasoconstriction

Project Summary/Abstract Patients with spinal cord injury (SCI) above spinal level T6 commonly have reduced basal sympathetic tone due to the loss of supraspinal sympathetic drive. Hypotension is common, but it is the profound nociceptor induced uncontrolled hypertensive crisis termed autonomic dysreflexia (AD) that is potentially life-threatening. Studies on AD mechanisms mostly focus on spinal cord where sprouting nociceptive afferents are thought to lead to exaggerated sympathetic preganglionic output. Nevertheless, missing from most studies is consideration of sympathetic post-ganglionic neurons (SPNs), the final neural step for sympathetic vasoconstriction. Conventionally considered simple relays, SPNs can integrate input from multiple preganglionic sources and so may substantially amplify CNS preganglionic drive post-SCI. Moreover, in contrast to paravertebral SPNs, prevertebral SPNs also receive direct input from afferent collaterals ascending through visceral nerves toward spinal cord. This feature makes prevertebral SPNs a peripheral sympathetic integration center. Prevertebral celiac ganglionic neurons (CGNs) innervate abdominal vascular beds that comprise ~1/3 of total body blood volume. This suggests that hyperresponsive CGN vasoconstrictor drive may be prominent in generating the observed hypertension in AD. In preliminary CGN whole cell recordings from the isolated adult mouse celiac ganglia, we observed that high thoracic SCI (SCIHT) had increased intrinsic and increased capability of repetitive firing. We also observe the substantially increased number of nociceptive afferent (CGRP+) synapses, that could further enhance CGNs excitability during AD. Thus, our first aim will test the hypothesis that SCIHT leads to intrinsic and synaptic modifications that promote exaggerated CGN output. We will use electrophysiological, optogenetic, pharmacological and anatomical approaches to determine pathophysiological and morphological modifications of CGNs after SCIHT in adult mice. Our second aim will test the hypothesis that CGN activity is both necessary and sufficient to generate hypertensive responses seen in mice with colon distention-induced AD. We will use implantable mini-pumps to deliver local infusions to the celiac ganglia that selectively block CGN activity while recording blood pressure during distention- induced AD (tests necessity) or selectively recruit CGNs while measuring blood pressure changes (sufficiency). These studies are expected to have broad impact on the field of autonomic dysfunction after SCI. First, if observed mechanisms of celiac ganglia dysfunction are associated with the expression of AD, the celiac ganglia would be an important site for subsequent therapeutic targeting. Secondly, as celiac ganglia have impact on multiple visceral organs (gastrointestinal tract, spleen kidney, liver) the identification of CGN circuit dysfunction may also contribute to various dysfunction in innervated organs (e.g. SCI -induced intestinal dysmotility).

项目摘要/摘要 脊髓损伤的患者（SCI）高于脊柱T6的患者通常会降低基础交感神经。 脊柱上交感神经驱动器的丧失。低血压很常见，但它是深刻的伤害感受器引起的不受控制 高血压危机称为自主性逆转录病毒（AD），可能威胁生命。广告机制的研究 主要集中在脊髓上，人们认为发芽的伤害感受传入会导致夸张的同情 前产量输出。然而，大多数研究缺少的是考虑交感神经后神经元 （SPNS），同情血管收缩的最终神经步骤。常规考虑的简单继电器，SPN可以 整合了来自多个前神经原始源的输入，因此可能会大大扩大CNS前SCI前驱动驱动器。 此外，与副SPN相比，前脊椎SPN还收到了来自传入侧支的直接输入 通过内脏神经升到脊髓。此功能使椎骨SPNS成为外围交感神经 集成中心。脊椎神经节神经元（CGNS）支配腹部血管床，包括〜1/3 全身血液体积。这表明高反应性CGN血管收缩驱动器可能突出 在AD中产生观察到的高血压。在孤立的成年小鼠的初步CGN全细胞记录中 腹腔神经节，我们观察到高胸科SCI（SCIHT）的内在固有性和重复的能力增加 射击。我们还观察到年度伤害感（CGRP+）突触的数量大大增加，这可能会进一步 在AD期间增强CGN兴奋性。因此，我们的第一个目标将检验SCIHT导致内在和突触的假设 促进夸张的CGN输出的修改。我们将使用电生理，光遗传学，药理 以及确定SCIHT后CGN的病理生理和形态学修饰的解剖方法 成年小鼠。我们的第二个目标将检验以下假设，即CGN活动既需要又足以生成 在结肠扩张引起的AD的小鼠中看到的高血压反应。我们将使用可植入的迷你泵交付 局部注入腹腔神经节，在延伸期间记录血压时，该腹腔神经节有选择性地阻断了CGN活性 在测量血压变化（充分性）的同时，诱导的AD（测试必要性）或选择性地募集CGN。这些 在SCI后，研究对自主神经功能障碍领域有广泛的影响。首先，如果观察到的机制 腹腔神经节功能障碍与AD的表达相关，腹腔神经节将是重要的部位 随后的治疗靶向。其次，由于腹腔神经节对多个内脏器官产生影响（胃肠道 区域，脾肾脏，肝）CGN电路功能障碍的鉴定也可能导致各种功能障碍 神经支配的器官（例如Sci诱导的肠道运动障碍）。