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，即颅内出血损伤会导致严重的厌食、恶心、胃瘀滞和伴随的溃疡。多年来，库欣溃疡被归因于颅内压升高对控制自主神经流向肠道的髓质神经回路的影响，但对头部损伤患者的生理研究表明，心室压力与胃瘀滞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] 的发现使我们得出这样的假设：凝血酶的蛋白酶作用（作为出血的功能）对背髓质 PAR 的作用可能会影响肠道自主控制的变化。对完整、清醒动物的研究表明，将第四脑室暴露于 PAR1 激动剂肽 SFLLRN [或凝血酶] 会引起胃转运抑制，类似于全身性 CCK 所见的情况；一种有效的厌食剂和胃转运抑制剂。我们初步尝试了解凝血酶和 PAR 激活作用背后的神经机制，结果揭示了一种令人吃惊的可能性。也就是说，凝血酶作用的检测可能是孤束核内星形胶质细胞的主要功能[NST]。 PAR 激活导致的自主功能变化可能是由于神经胶质细胞与控制消化功能和进食行为的脑干神经元的相互作用所致。更重要的是，NST 中的胶质神经通讯作为一种最终负责自主神经功能显着调节的一般化学感应机制具有更广泛的意义。我们利用活细胞钙成像方法进行的初步研究是首次在脑干中观察到这种现象。我们将使用这项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：PAR 改变自主神经功能的作用是 NST 中有效的胶质神经相互作用的结果。这些结果将为未来脑干自主神经和行为控制中神经胶质-神经相互作用的研究提供基础。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。历史假设是中枢神经系统内的神经元执行检测。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，表明神经胶质细胞（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随后与神经元通讯，诱导对化学刺激的适当反应。对大脑如何检测局部和循环化学物质的正确描述将对我们对健康和疾病中自主神经和行为功能的大脑调节的理解产生重大影响。