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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.

项目摘要目前的项目探索了脊椎动物自主神经的一个鲜为人知的领域。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。鉴于它们在自主神经中向身体发出信号的战略节点位置，任何 TSPN的可塑性可能具有很高的意义。不幸的是，tSPN在体内很大程度上是无法获得的因此，操作原理是从颈链和腰链神经节的研究中推断出来的。只有3个人在体外研究揭示了TSPN的电生理特性：没有一种能准确测量细胞的整合率由于电极穿透损伤而导致的特性或潜在的招募原则。我们承担了第一项任务成年小鼠尾胸链神经节体外制剂的生理学研究节段性节前和吻尾节间连接完整。我们得到了第一个完整的- 细胞膜片钳记录和观察到根本不同的整合和放电特性是比之前观察到的要多。这种可靠的数据集是进行真实计算模拟的关键前提。我们建议将实验测试与建模相结合，以了解TSPN的招聘原则和它们的综合性能。[SA1]我们将检验这样一种假设，即tSPN具有不同的突触、细胞和和网络属性，是投入产出征聘战略的积极参与者。高位胸段脊髓损伤(SCI)通过破坏调节TSPN兴奋性的脑干通路脊髓节前环路。这种干扰可导致突发性危及生命的TSPN介导性高血压。危机(自主神经反射障碍)。椎旁交感神经节功能障碍是否参与血管舒缩反应的放大作用尚不清楚。为了填补这一重大的知识空白，试验性的研究将揭示服务于TSPN招募的细胞和突触组织规则的可塑性。[SA2] 我们将检验这样一种假设，即tSPN增加了它们的内在兴奋性，并从线性转化为非线性 SCI后的增益放大器。计算模拟将构建一个服从于真实建模的数据库潜在临床相关性的招募原则，可能对该领域具有变革性。相对的组织的简单性使通过建模发现原则比在复杂的系统。真实模拟TSPN功能和急诊功能障碍的神经基础可以催化基于预测药物发现的高通量模拟，使快速功能正常化临床前测试。意义：我们的目标是揭示支配最终神经指挥路径的操作原理调节血管张力。由于交感神经过度活动与各种自主神经紊乱有关，一个数据库符合现实的建模研究将在临床前和转化性研究中具有广泛的预测性用途。