Recruitment principles and injury-induced plasticity in thoracic paravertebral sympathetic postganglionic neurons

胸椎旁交感节后神经元的募集原理和损伤诱导的可塑性

• 批准号: 9368086
• 负责人: SHAWN HOCHMAN
• 金额: $ 34.13万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9368086
• 关键词: Address; Adult; Amplifiers; Area; Autonomic Dysreflexia; Autonomic nervous system disorders; Axon; Binding Sites; Blood Vessels; Brain Stem; Cells; Cervical; Chest; Complex; Computer Simulation; Data Set; Databases; Dendrites; Drug effect disorder; Electrodes; Electrophysiology (science); Elements; Fatigue; Frequencies; Functional disorder; Ganglia; Hyperactive behavior; Hypertensive Crisis; In Vitro; Individual; Injury; Knowledge; Lead; Life; Measures; Mediating; Membrane; Modeling; Motor Neurons; Motor output; Mus; Neurons; Neurosciences; Nodal; Output; Participant; Pathway interactions; Pharmaceutical Preparations; Physiological; Plasticizers; Population; Preclinical Testing; Preparation; Property; Protocols documentation; Recruitment Activity; Role; Signal Transduction; Site; Spinal; Spinal cord injury; Study models; Sympathetic Ganglia; Synapses; System; Testing; Therapeutic; Thoracic spinal cord structure; Upper Extremity; Vasomotor; Ventral Roots; Whole-Cell Recordings; base; clinically relevant; clinically significant; drug discovery; experimental study; in vivo; light intensity; neuroregulation; patch clamp; pre-clinical; preclinical study; relating to nervous system; response; simulation; study population; translational study; voltage

Project Summary The present project explores a barely studied and poorly-understood area of vertebrate autonomic neuroscience: the recruitment properties of thoracic paravertebral sympathetic postganglionic neurons (tSPNs). The prominent role of thoracic paravertebral sympathetic chain ganglia is as the final neural control element regulating vasomotor tone. Given their strategic nodal site in autonomic signaling to body, any plasticity in tSPNs is likely to be of high significance. Unfortunately, tSPNs are largely inaccessible for in vivo study, so operational principles are inferred from studies in cervical and lumbar chain ganglia. Only 3 in vitro studies have revealed tSPN electrophysiological properties: none accurately measure cellular integrative properties or underlying recruitment principles due to electrode impalement injury. We undertook the first physiological studies on caudal thoracic chain ganglia in the adult mouse by developing an ex vivo preparation with intact segmental preganglionic and rostrocaudal interganglionic connections. We obtained the first whole- cell patch clamp recordings of tSPNs and observed fundamentally different integrative and firing properties are than previously observed. This reliable data set is a critical prerequisite to realistic computational simulation. We propose to interleave experimental testing with modeling to understand tSPN recruitment principles and their integrative properties. [SA1] We will test the hypothesis that tSPNs have heterogeneous synaptic, cellular, and network properties, and are active participants in input-output recruitment strategies. Higher thoracic spinal cord injuries (SCI) disrupt the brainstem pathways that regulate tSPN excitability via spinal preganglionic loops. Such disruption can lead to sudden life-threatening tSPN mediated hypertensive crises (autonomic dysreflexia). Whether paravertebral sympathetic chain ganglia dysfunction contributes to amplification in a vasomotor response is unknown. To fill this significant gap in knowledge, experimental studies will disclose plasticity in the cellular and synaptic organizational rules serving tSPN recruitment. [SA2] We will test the hypothesis that tSPNs increased their intrinsic excitability and convert from linear to non-linear gain amplifiers after SCI. Computational simulation will construct a database amenable to realistic modeling of recruitment principles of potential clinical relevance that could be transformative to the field. The relative simplicity of the organization makes discovery of principles through modeling more assured than in more complex systems. Realistic simulation of the neural bases of tSPN function and emergent dysfunction could catalyze predictive drug discovery-based high throughput simulations that normalize function for rapid preclinical testing. Significance: we aim to uncover the operational principles governing the final neural command pathways regulating vascular tone. As sympathetic hyperactivity is implicated in various autonomic disorders, a database amenable to realistic modeling studies will be of broad predictive use in preclinical and translational studies.

项目概要 本项目探索了脊椎动物自主神经的一个几乎没有研究和了解的领域 神经科学：胸椎旁交感神经节后神经元的募集特性 （tSPN）。胸椎旁交感链神经节的突出作用是作为最终的神经控制 调节血管舒缩张力的元素。鉴于其在向身体发出自主信号的战略节点位置，任何 tSPN 的可塑性可能具有重要意义。不幸的是，tSPN 在体内基本上无法获得 研究，因此操作原理是从颈椎和腰椎链神经节的研究中推断出来的。体外实验仅3例 研究揭示了 tSPN 电生理特性：无法准确测量细胞整合 由于电极刺穿损伤而导致的特性或基本招募原则。我们承担了第一个 通过开发离体制剂对成年小鼠尾胸链神经节进行生理研究 具有完整的节段前节前和头尾节间连接。我们得到了第一个完整的—— tSPN 的细胞膜片钳记录并观察到根本不同的整合和激发特性 比之前观察到的。这个可靠的数据集是现实计算模拟的关键先决条件。 我们建议将实验测试与建模相结合，以了解 tSPN 招募原则和 它们的综合属性。 [SA1] 我们将检验 tSPN 具有异质突触、细胞、 和网络属性，并且是投入产出招聘策略的积极参与者。 高级胸脊髓损伤 (SCI) 通过破坏调节 tSPN 兴奋性的脑干通路 脊髓节前环。这种干扰可能导致突然危及生命的 tSPN 介导的高血压 危机（自主神经反射障碍）。椎旁交感神经节功能障碍是否导致 血管舒缩反应的放大尚不清楚。为了填补这一知识上的重大空白，实验 研究将揭示服务 tSPN 募集的细胞和突触组织规则的可塑性。 [SA2] 我们将测试 tSPN 增加其内在兴奋性并从线性转换为非线性的假设 SCI后的增益放大器。计算模拟将构建一个适合现实建模的数据库 具有潜在临床相关性的招募原则可能会对该领域产生变革。亲戚 组织的简单性使得通过建模比其他方式更能确定原则的发现 复杂的系统。 tSPN 功能和紧急功能障碍的神经基础的真实模拟可以 催化基于预测性药物发现的高通量模拟，可快速标准化功能 临床前测试。 意义：我们的目标是揭示控制最终神经命令路径的操作原理 调节血管张力。由于交感神经过度活跃与各种自主神经紊乱有关，数据库 适合现实建模研究的模型将在临床前和转化研究中具有广泛的预测用途。