Glial-Neural Interactions in Autonomic Control

自主控制中的胶质神经相互作用

• 批准号: 7623523
• 负责人: Richard C. Rogers
• 金额: $ 32.16万
• 依托单位: LSU PENNINGTON BIOMEDICAL RESEARCH CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2013-08-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7623523
• 关键词: Affect; Afferent Neurons; Agonist; Animals; Anorexia; Area; Astrocytes; Behavior Control; Behavioral; Brain; Brain Stem; Calcium; Calcium Oscillations; Calcium Signaling; Cell Culture Techniques; Cells; Chemical Agents; Chemicals; Cholecystokinin; Communication; Complex; Craniocerebral Trauma; Detection; Disease; Dorsal; Excitatory Amino Acid Antagonists; F2R gene; Feeding behaviors; Figs - dietary; Future; Gastroparesis; Glutamates; Head; Health; Hemorrhage; Hormones; In Vitro; Indium; Intracranial Hypertension; Lasers; Lead; Life; Mediating; Methods; Nausea; Neuroglia; Neurons; Nucleus solitarius; Nutrient; PAR-1 Receptor; Patients; Peptide Hydrolases; Peptides; Physiologic intraventricular pressure; Physiological; Preparation; Proteinase-Activated Receptors; Reflex action; Regulation; Sensory; Signal Transduction; Slice; Stimulus; Stomach; Techniques; Testing; Thrombin; Thrombin Receptor; Ulcer; Visceral; Visceral Afferents; Work; awake; base; cell motility; computerized data processing; cytokine; detector; dorsal motor nucleus; extracellular; hindbrain; imaging modality; in vivo; inhibitor/antagonist; injured; neural circuit; neuromechanism; neurophysiology; relating to nervous system; response; thrombin receptor peptide (42-47); time use

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.

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工作。这项工作的起源是70岁的观察结果，即浮肿，颅内头部损伤会产生严重的厌食症，恶心，胃停滞和伴随的溃疡。尽管库欣的溃疡多年来一直归因于颅内压增加对髓质神经回路的影响，而胸腔神经回路控制了自主流向肠道的肠道损伤患者的生理研究表明，心脏损伤患者的生理研究表明心室压力与胃停滞的程度之间没有相关性。在脑干中发现“凝血酶受体” [蛋白酶激活的受体 - PAR]的发现，我们提出了这样一个假设，即凝血酶的蛋白酶作用[蛋白酶的作用[与出血的函数]在背髓质中的PARS上可能会影响肠道自主神经控制的变化。完整的清醒动物的研究表明，第四脑室暴露于PAR1激动剂肽sfllrn [或凝血酶]会引起对胃过渡的抑制，类似于系统性CCK。有效的厌食和胃转移抑制剂。我们的初步尝试了解凝血酶和PAR激活作用背后的神经机制已显示出令人震惊的可能性。也就是说，凝血酶作用的检测可能是孤立区核内星形胶质细胞的主要功能[NST]。由PAR激活导致的自主功能的变化可能是由于控制消化功能和喂养行为的脑干神经元的神经胶质相互作用。更重要的是，作为一般化学感应机制，NST中的神经神经通信具有更大的意义，最终负责自主功能的重大调节。我们使用活细胞钙成像方法的初步研究是第一个观察到这种现象的脑干中的研究。我们将使用该技术以及免疫组织化学和体内神经生理学方法来检验以下假设：改变自主功能的PAR作用是NST中有效的神经神经相互作用的结果。这些结果将为将来研究脑干自主神经和行为控制中的神经神经相互作用的研究提供基础。大脑检测营养，激素，细胞因子和其他化学刺激的方式尚不清楚。历史假设是中枢神经系统内的神经元进行了检测。细胞培养和切片制剂中的最新工作与我们的初步研究相结合表明，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，激活的神经胶质与神经元进行通信，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剂将对我们对健康和疾病中自主神经和行为功能的调节的理解产生重大影响。