Physiology of Muscarinic Synapses in Sympathetic Ganglia

描述（由申请人提供）：交感神经节和副交感神经节是介导自主神经行为的组织中平滑肌、心肌和腺体的所有中央运动控制的最终共同途径。该项目的长期目标是确定自主神经节的神经结构如何使它们能够转化尖峰序列，阐明突触可塑性的分子和细胞机制如何塑造这一过程，并定义有助于行为的神经节整合原则。提出的工作将集中在交感神经节中的调节性毒蕈碱突触，重点是控制心血管功能的神经元子集。本项目将采用细胞神经生理学、计算模拟和神经解剖学方法对牛蛙交感神经节和大鼠颈上交感神经节两个模型系统进行研究。许多生理实验将使用动态钳法在活神经元上实现虚拟尼古丁突触，然后确定它们如何与代谢神经调节机制相互作用。该分析基于一个有效的假设，即椎旁交感神经节作为可变的突触活动放大器，其增益受尼古丁突触的强度和收敛以及用于调节尼古丁突触强度的神经调节机制的表达的调节。具体目的是：1)对比3种不同交感细胞类型中活动依赖性的毒蕈碱增益调节。2)测量量子噪声和突触前可塑性对突触增益的贡献。3)分析心律对神经节整合的调节。4)验证通过毒蕈碱受体、α -肾上腺素能受体和血管紧张素II受体传递的代谢信号为大鼠SCG神经节整合的表型特化提供了基础。通过本研究开发的概念将有助于对正常自主神经行为和人类病理生理的基本理解，特别是与晕厥、高血压和心力衰竭相关的变化。

DESCRIPTION (provided by applicant): Sympathetic and parasympathetic ganglia provide the final common pathway for ail central motor control of smooth muscle, cardiac muscle and glands in tissues that mediate autonomic behavior. The long-term goals of this project are to determine how the neural architecture of autonomic ganglia enables them to transform spike trains, to elucidate how molecular and cellular mechanisms of synaptic plasticity shape this process, and to define the principles of ganglionic integration that contribute to behavior. The proposed work will focus upon modulatory muscarinic synapses in sympathetic ganglia, with emphasis on the subset of neurons that control cardiovascular function. The project will employ cellular neurophysiology, computational simulations, and neuroanatomy methods in 2 model systems - bullfrog sympathetic ganglia and the rat superior cervical sympathetic ganglion. Many of the physiological experiments will use the dynamic clamp method to implement virtual nicotinic synapses on living neurons and then determine how they interact with metabotropic neuromodulatory mechanisms. The analysis is predicated upon a working hypothesis that paravertebral sympathetic ganglia behave as variable synaptic amplifiers of activity whose gain is regulated by the strength and convergence of nicotinic synapses and by the expression of neuromodulatory mechanisms that serve to adjust the strength of nicotinic synapses. The specific aims are: 1) To contrast activity-dependent muscarinic gain modulation in 3 different sympathetic cell types. 2) To measure the contributions of quantal noise and presynaptic plasticity to synaptic gain. 3) To analyze the regulation of ganglionic integration by cardiac rhythms. 4) To test the hypothesis that metabotropic signaling through muscarinic, alpha-adrenergic and angiotensin II receptors provides a basis for phenotypic specialization of ganglionic integration in the rat SCG. Concepts developed through this research will contribute to fundamental understanding of normal autonomic behavior and human pathophysiology, especially to changes associated with syncope, hypertension and heart failure.