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

基本信息

批准号：
10208977
负责人：
SHAWN HOCHMAN
金额：
$ 34.13万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10208977
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 Models Computer Simulation Data Set Databases Dendrites Electrodes Electrophysiology (science)Elements Fatigue Frequencies Functional disorder Ganglia Hyperactivity 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 Population Preclinical Testing Preparation Property Protocols documentation 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 action drug discovery experimental study in vivo light intensity neuroregulation patch clamp pre-clinical preclinical study recruit relating to nervous system response simulation study population translational study voltage

项目摘要

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.

项目摘要本项目探索了一个脊椎动物自主神经的几乎没有研究且被遗忘的区域神经科学：胸部副脑交感神经后神经元的招募特性（TSPN）。胸椎副交感神经神经节的重要作用是最终的神经控制元素调节血管舒缩音。鉴于他们在自主信号向身体的战略性淋巴结位置，任何 TSPN中的可塑性可能具有很高的意义。不幸的是，TSPN在体内基本上是无法访问的研究，从宫颈和腰部链神经节的研究中推断出操作原理。只有3个体外研究揭示了TSPN电生理特性：无准确测量细胞整合性由于电极强化损伤而导致的性质或基本募集原则。我们第一个成年小鼠中有关尾胸链神经节的生理研究通过开发离体制备具有完整的节段前和尾mauthion的连接。我们获得了第一个完整细胞贴片夹TSPN的记录以及观察到的根本不同的整合性和发射特性是比以前观察到的。此可靠的数据集是实现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进行交流，以了解TSPN招聘原则和它们的集成特性。 [SA1]我们将检验以下假设：TSPN具有异质性突触，细胞，和网络属性，并且是投入输出招聘策略的积极参与者。较高的胸脊髓损伤（SCI）破坏了调节TSPN兴奋性的脑干途径脊柱前环路。这种破坏会导致突然威胁生命的TSPN介导的高血压危机（自主性逆转录病毒）。副交感神经神经节功能障碍是否有助于血管舒缩反应中的扩增尚不清楚。为了填补知识的显着空白，实验性研究将在服务于TSPN招聘的细胞和突触组织规则中披露可塑性。 [SA2] 我们将测试以下假设，即TSPN提高了它们的内在兴奋性并从线性转换为非线性 SCI后获得放大器。计算模拟将构建一个数据库，适合于现实的建模潜在临床相关性的招聘原则可能对该领域进行变革。亲戚组织的简单性通过建模比更多地确保了原理，从而发现原理复杂系统。对TSPN功能和新功能障碍的神经碱基的现实模拟可以催化基于预测药物发现的高吞吐量模拟，以使功能正常化以快速临床前测试。意义：我们旨在揭示有关最终神经命令途径的操作原则调节血管张力。由于各种自主性疾病涉及交感神经多动症，因此数据库适合现实的建模研究将在临床前和翻译研究中具有广泛的预测用途。