Glial-Neural Interactions in Autonomic Control

描述（由申请人提供）：我们已经对蛋白酶激活受体[PAR]对胃功能的后脑调节的影响进行了初步研究。这项工作的起源是库欣70年前的观察，即颅内出血性脑损伤引起严重的厌食、恶心、胃郁积和伴随的溃疡。多年来，库欣溃疡被认为是由于颅内压升高对控制自主神经流出到肠道的延髓神经回路的影响，而对头部损伤患者的生理学研究表明，心室压和胃郁积程度之间没有相关性。脑干中“凝血酶受体”[蛋白酶激活受体- PAR]的发现使我们假设凝血酶对延髓背侧PAR的蛋白酶作用[表现为出血的功能]可能影响肠道自主控制的变化。在清醒的完整动物中进行的研究表明，第四脑室暴露于PAR 1激动剂肽SFLLRN [或凝血酶]可引起与全身性CCK相似的胃转运抑制; CCK是一种强效的胃转运抑制剂和抑制剂。我们初步尝试了解凝血酶和PAR激活作用背后的神经机制，揭示了一个惊人的可能性。也就是说，凝血酶作用的检测可能是孤束核[NST]内星形胶质细胞的主要功能。PAR激活导致的自主神经功能的变化可能是由于神经胶质与控制消化功能和摄食行为的脑干神经元的相互作用。更重要的是，神经胶质细胞神经通信在NST具有更广泛的意义，作为一个一般的化学感受机制，最终负责自主神经功能的显着调制的可能性。我们用活细胞钙成像方法的初步研究是第一次在脑干中观察到这种现象。我们将使用这种技术，沿着免疫组织化学，并在体内的神经生理学方法来测试的假设，PAR的行动，改变自主神经功能的结果是一个强大的神经胶质-神经相互作用的NST。这些结果将为进一步研究脑干自主神经和行为控制中的神经胶质-神经元相互作用提供基础。大脑检测营养物质、激素、细胞因子和其他化学刺激的方式还不清楚。历史上的假设是，中枢神经系统内的神经元进行检测。最近在细胞培养和切片制备方面的工作，结合我们的初步研究，表明神经胶质（而不是神经元）可能是许多化学刺激的主要检测器。此外，激活的神经胶质细胞然后与神经元通信，以诱导对化学刺激的适当反应。正确描述大脑如何检测局部和循环化学物质，将对我们理解健康和疾病中自主神经和行为功能的大脑调节产生重大影响。

DESCRIPTION (provided by applicant): We have conducted preliminary work on the impact of proteinase-activated receptors [PAR] on hindbrain regulation of gastric function. The genesis of this work was the 70 year-old observation by Cushing that bleeding intracranial head injury produced a profound anorexia, nausea, gastric stasis, and accompanying ulcer. While Cushing's ulcer was, for many years, attributed to the effects of increased intracranial pressure on medullary neural circuits that control autonomic outflow to the gut, physiological studies in head injury patients reveal that there is no correlation between ventricular pressure and the degree of gastric stasis. The discovery of "thrombin receptor" [proteinase activated receptor - PAR] in the brainstem led us to the hypothesis that proteinase action of thrombin [present as a function of bleeding] on PARs in the dorsal medulla could affect changes in autonomic control of the gut. Studies in intact, awake animals reveal that exposure of the 4th ventricle to the PAR1 agonist peptide SFLLRN [or thrombin] provokes a suppression of gastric transit similar to that seen with systemic CCK; a potent anorexic and inhibitor of gastric transit. Our preliminary attempts to understand the neural mechanisms behind the effects of thrombin and PAR activation have revealed a startling possibility. That is, the detection of thrombin action may be a primary function of astrocytes within the nucleus of the solitary tract [NST]. Changes in autonomic function that result from PAR activation could be due to glial interactions with brainstem neurons that control digestive functions and feeding behavior. Even more important is the possibility that glial-neural communication in the NST has wider significance as a general chemosensory mechanism ultimately responsible for significant modulation of autonomic functions. Our preliminary studies with live cell calcium imaging methods are the first to observe this phenomenon in the brainstem. We will use this technique, along with immunohistochemical, and in vivo neurophysiological methods to test the hypothesis that PAR action to change autonomic function is the result of a potent glial-neural interaction in the NST. These results will provide the basis for future studies of glial-neural interactions in brainstem autonomic and behavioral control. The way in which the brain detects nutrients, hormones, cytokines and other chemical stimuli is not well understood. The historical assumption has been that neurons within the CNS performed the detection. Recent work in cell culture and in slice preparations, in combination with our preliminary studies, suggests the possibility that glia (and not neurons) may be the principal detectors of many chemical stimuli. Furthermore, activated glia then communicate with neurons to induce the appropriate response to the chemical stimulus. A correct description of how the brain detects local and circulating chemical agents will have a significant impact on our understanding of brain regulation of autonomic and behavioral functions in health and disease.