Glial-Neural Interactions in Autonomic Control

描述（由申请人提供）：我们对蛋白酶激活受体（PAR）对胃功能后脑调节的影响进行了初步研究。这项工作的起源是70年前库欣的一项观察，即颅内出血的头部损伤会产生严重的厌食症、恶心、胃淤积和伴随的溃疡。多年来，库欣溃疡一直被认为是颅内压升高对髓质神经回路的影响，髓质神经回路控制着流向肠道的自主神经，但对头部损伤患者的生理学研究表明，脑室压与胃淤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]的发现使我们提出了这样的假设：凝血酶的蛋白酶作用[作为出血的功能存在]在髓质背侧的PAR上可能影响肠道自主控制的变化。在完整、清醒的动物中进行的研究表明，第4脑室暴露于PAR1激动剂肽SFLLRN[或凝血酶]会引起与全身性CCK相似的胃转运抑制；一种有效的厌食症和胃转运抑制剂。我们对凝血酶和PAR激活作用背后的神经机制的初步尝试揭示了一种惊人的可能性。也就是说，检测凝血酶的作用可能是孤立束核内星形胶质细胞的主要功能[NST]。PAR激活引起的自主神经功能的改变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，NST中的胶质-神经通讯作为一种普遍的化学感觉机制具有更广泛的意义，最终负责自主神经功能的重要调节。我们用活细胞钙成像方法进行的初步研究首次在脑干中观察到这种现象。我们将使用这种技术，以及免疫组织化学和体内神经生理学方法来测试PAR作用改变自主神经功能的假设，这是NST中强大的胶质-神经相互作用的结果。这些结果将为脑干自主和行为控制中神经胶质相互作用的进一步研究提供基础。大脑检测营养物质、激素、细胞因子和其他化学刺激的方式尚不清楚。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探测器。此外，被激活的胶质细胞随后与神经元交流，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的化学物质，将对我们理解大脑在健康和疾病中对自主神经和行为功能的调节产生重大影响。

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.