Celiac ganglia plasticity after spinal cord injury

项目摘要/摘要 脊髓损伤(SCI)在脊柱T6节段以上的患者通常由于 失去了脊椎上的交感神经动力。低血压是常见的，但它是深层次的伤害性感受器诱发的失控 高血压危机被称为自主神经反射障碍(AD)，可能危及生命。阿尔茨海默病发病机制的研究 主要集中在脊髓，在那里萌发的伤害性传入被认为会导致夸大的交感 节前输出。然而，大多数研究忽略了对交感神经节后神经元的考虑。 (SPN)，交感血管收缩的最后神经步骤。通常被认为是简单的中继，SPN可以 整合来自多个节前来源输入，因此可显著放大脊髓损伤后的中枢神经系统节前驱动。 此外，与椎旁SPN不同，椎前SPN也接受来自传入络脉的直接输入 通过内脏神经上升到脊髓。这一特征使椎前SPN成为一种外周交感神经 整合中心。椎前腹神经节神经元(CGN)支配腹部血管床，约占1/3 占身体总血量的比例。这表明，高反应性CGN血管收缩驱动可能在 在AD中产生观察到的高血压。在分离的成年小鼠的CGN全细胞记录中 腹腔神经节，我们观察到上胸脊髓损伤(SCIHT)增加了固有的和增强的重复能力。 开火。我们还观察到伤害性传入(CGRP)突触数量的大幅增加，这可能会进一步 增强CGNS在AD期间的兴奋性。因此，我们的首要目标是检验SCIHT导致内源性和突触的假设 促进夸大CGN产出的修改。我们将使用电生理学、光遗传学、药理学 SCIHT后CGNS病理生理和形态改变的解剖学研究 成年小鼠。我们的第二个目标将测试CGN活动既必要又充分的假设 结肠扩张诱导的AD小鼠的高血压反应。我们将使用植入式微型泵来提供 局部灌流到腹神经节，选择性地阻断CGN的活动，同时记录扩张期间的血压- 诱发性AD(测试必要性)或选择性地招募CGN，同时测量血压变化(充分性)。这些 这些研究有望对脊髓损伤后自主神经功能障碍领域产生广泛影响。首先，如果观察到的机制 腹神经节功能障碍与AD的表达有关，腹神经节可能是AD发生的重要部位 随后的治疗靶向。其次，由于腹腔神经节对多脏器(胃肠)有影响 途径、脾、肾、肝)CGN回路功能障碍的识别也可能有助于 神经器官(如脊髓损伤引起的肠道运动障碍)。

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).