The effects of glucose on central vagal brainstem circuits

葡萄糖对中枢迷走神经脑干回路的影响

• 批准号: 8133540
• 负责人: Kirsteen Nairn Browning
• 金额: $ 29.07万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8133540
• 关键词: Acute; Affect; Afferent Neurons; Attenuated; Biological Models; Blood; Blood Glucose; Brain Stem; Cachexia; Cell membrane; Data; Deglutition; Eating; Esophageal; Esophagus; Food; Gastrointestinal Hormones; Gastroparesis; Glucose; Homeostasis; Hormonal; In Vitro; Ingestion; Intestines; Laboratories; Lead; Measures; Mediating; Metabolic; Motor; Neurotransmitter Receptor; Nutrient; Obesity; Output; Pathway interactions; Pattern; Physiological; Protein Kinase C; Reflex action; Regulation; Relaxation; Sensory; Serotonin; Serotonin Receptors 5-HT-3; Site; Slice; Stomach; Synapses; Techniques; Testing; Time; Variant; Visceral; absorption; autonomic reflex; cell motility; extracellular; feeding; gastrointestinal; gastrointestinal function; immunocytochemistry; improved; in vivo; motility disorder; neural circuit; neurophysiology; pressure; public health relevance; receptor; receptor expression; response; trafficking

DESCRIPTION (provided by applicant): Vagal brainstem circuits are vitally important in the co-ordination of food ingestion, gastrointestinal (GI) functions and autonomic homeostasis. The receptive relaxation reflex is a classical, vagally-mediated reflex activated upon distension of the esophagus (during swallowing, for example) that induces gastric relaxation and suppression of motility, allowing the stomach to accept ingesta isobarically. At the same time, this reflex is used as the first step in regulation of nutrient absorption and homeostasis. By decreasing gastric tone and motility, the receptive relaxation reflex delays gastric emptying, slows the rate at which chyme is transported to the intestine and, by consequence, regulates the rate of nutrient absorption. Data collected in recent years by several laboratories, including our own, has suggested that many GI hormones released following meal ingestion exert dramatic control over vagally-mediated GI functions. Adaptive responses within autonomic neural circuits are essential to adjust to ever-changing physiological conditions, indeed some of the most dramatic physiological variations occur as a consequence of meal ingestion. Blood glucose levels oscillate throughout the day and increase dramatically following food intake; adaptive autonomic sensory and motor responses are necessary to stabilize these fluctuations and maintain homeostasis. Acute changes in blood glucose levels, even within the physiological range, exert profound vagally-mediated effects on gastric motility and emptying. These glucose-induced responses are extremely important in minimizing otherwise dramatic, potentially damaging, excursions in blood glucose levels. Short-term plasticity within homeostatic neural circuits allows autonomic reflexes to be modulated, by either exaggerating or attenuating the output response, or by transforming the response pattern or duration. Even transient modulation in the strength of key synapses within autonomic circuits has the potential to induce short-term plasticity. Disruption or untimely variations in these adaptive responses, however, may cause inappropriately exaggerated reflexes and possibly even induce pathophysiological results. Exacerbation of the normal physiological response to meal ingestion, for example, may induce a variety of pathological conditions, including, for example, functional gastric motility disorders, obesity or cachexia. The specific mechanisms by which glucose can reorganize vagally-mediated gastrointestinal visceral reflexes are not well understood. Preliminary data from our laboratories strongly suggest that the receptive relaxation reflex could provide an ideal model system in which we can test specific, mechanistic hypotheses. We will use a variety of techniques including in vivo neurogastroenterology, immunocytochemistry and in vitro neurophysiology to test the overarching hypothesis that glucose regulates vagally-mediated gastrointestinal reflexes via brainstem sites of action. In short, we propose that the vagally-mediated gastrointestinal reflexes, such as the receptive relaxation reflex, are under the direct control of brainstem glucose levels and that glucose regulates the expression of neurotransmitter receptors on selected subpopulations of gastrointestinal vagal sensory neurons via modulation of protein kinase C-dependent pathways. This proposal will generate data that will lead to an improved understanding of mechanisms regulating the modulation of vago-vagal reflexes and how changes in metabolic and hormonal parameters affect the brainstem plasticity of ingestive and gastrointestinal-related autonomic homeostatic circuits. PUBLIC HEALTH RELEVANCE: Vagal brainstem circuits are vitally important in the co-ordination of food ingestion, gastrointestinal (GI) functions and autonomic homeostasis. The receptive relaxation reflex is a classical, vagally-mediated reflex activated upon distension of the esophagus (during swallowing, for example) that induces gastric relaxation and suppression of motility, allowing the stomach to accept ingesta without increasing gastric pressure. At the same time, this reflex is used as the first step in regulation of nutrient absorption and homeostasis. By decreasing gastric tone and motility, the receptive relaxation reflex delays gastric emptying, slows the rate at which chyme is transported to the intestine and, by consequence, regulates the rate of nutrient absorption. Many GI hormones released following meal ingestion exert dramatic control over these vagally-mediated GI functions and such adaptive responses are essential to adjust to ever-changing physiological conditions. Disruption or untimely variations in these adaptive responses, however, may cause inappropriately exaggerated reflexes and possibly even induce pathophysiological results. Exacerbation of the normal physiological response to meal ingestion, for example, may induce a variety of pathological conditions, including, for example, functional gastric motility disorders, obesity or cachexia. The specific mechanisms by which glucose can reorganize vagally-mediated GI visceral reflexes are not well understood. Preliminary data from our laboratories strongly suggest that the receptive relaxation reflex could provide an ideal model system in which we can test specific, mechanistic hypotheses. We will use a variety of techniques including in vivo neurogastroenterology, immunocytochemistry and in vitro neurophysiology to test the overarching hypothesis that glucose regulates vagally-mediated gastrointestinal reflexes via brainstem sites of action. In short, we propose that the vagally-mediated GI reflexes, such as the receptive relaxation reflex, are under the direct control of brainstem glucose levels and that glucose regulates the expression of neurotransmitter receptors on selected subpopulations of gastrointestinal vagal sensory neurons via modulation of protein kinase C-dependent pathways. This proposal will generate data that will lead to an improved understanding of mechanisms regulating the modulation of vago-vagal reflexes and how changes in metabolic and hormonal parameters affect the brainstem plasticity of ingestive and GI-related autonomic homeostatic circuits.

描述（由申请人提供）：迷走神经脑干电路对食物摄入，胃肠道功能（GI）功能和自主稳态的协调至关重要。接受的松弛反射是一种经典的，模糊的介导的反射，在食管扩张（例如，在吞咽过程中）激活（例如），可诱导胃松弛和抑制运动性，从而使胃同样接受Ingesta。同时，这种反射被用作调节营养吸收和稳态的第一步。通过降低胃色调和运动能力，接受的松弛反射延迟了胃排空，减慢了将Chyme转运到肠道的速度，并因此调节了营养吸收的速度。 近年来，包括我们本人在内的几个实验室收集的数据表明，摄入进餐后释放的许多GI激素对模糊介导的GI功能产生了巨大的控制。自主神经回路内的自适应反应对于适应不断变化的生理状况至关重要，实际上，由于摄入饮食而发生了一些最戏剧性的生理变化。血糖水平全天振荡，食物摄入后急剧增加；自适应自主性感觉和运动反应是稳定这些波动并保持体内平衡的必要条件。血糖水平的急性变化，即使在生理范围内，对胃运动和排空的影响都具有深刻的模糊介导的影响。这些葡萄糖诱导的反应在最大程度地减少血糖水平的戏剧性，潜在破坏的偏移方面非常重要。 稳态神经回路内的短期可塑性可以通过夸大或衰减输出响应或转换响应模式或持续时间来调节自主反射。即使是在自主电路内关键突触强度的瞬时调制也有可能诱导短期可塑性。但是，这些适应性反应中的破坏或不合时宜的变化可能会导致不当夸张的反射，甚至可能引起病理生理结果。例如，对摄入饮食的正常生理反应加剧可能会引起多种病理状况，包括例如功能性胃运动障碍，肥胖或恶病虫病。 葡萄糖可以重组模糊介导的胃肠道内脏反射的特定机制尚不清楚。来自我们实验室的初步数据强烈表明，接受的松弛反射可以提供理想的模型系统，我们可以在其中测试特定的机械假设。我们将使用多种技术，包括体内神经胃肠病学，免疫细胞化学和体外神经生理学来测试葡萄糖通过作用部位调节葡萄糖调节葡萄糖的胃肠道反射的总体假设。简而言之，我们提出，隐式介导的胃肠道反射（例如接受弛豫反射）在脑干葡萄糖水平的直接控制下，葡萄糖通过蛋白酶Cinase Cypatelys的调节来调节神经递质受体的表达。 该提案将产生数据，从而提高对调节流失式反射调节的机制的理解，以及代谢和激素参数的变化如何影响摄入剂和胃肠道相关自主稳态的脑干可塑性。 公共卫生相关性：迷走神经脑干电路对食物摄入，胃肠道功能（GI）功能和自主稳态的协调至关重要。接受性弛豫反射是一种经典的，模糊的介导的反射，在食管扩张（例如，在吞咽过程中）激活，可诱导胃松弛和抑制运动性，从而使胃在不增加胃压的情况下接受Ingesta。同时，这种反射被用作调节营养吸收和稳态的第一步。通过降低胃色调和运动能力，接受的松弛反射延迟了胃排空，减慢了将Chyme转运到肠道的速度，并因此调节了营养吸收的速度。摄入后释放的许多胃肠道激素对这些模糊介导的GI功能产生了巨大的控制，这种适应性反应对于适应不断变化的生理状况至关重要。但是，这些适应性反应中的破坏或不合时宜的变化可能会导致不当夸张的反射，甚至可能引起病理生理结果。例如，对摄入饮食的正常生理反应加剧可能会引起多种病理状况，包括例如功能性胃运动障碍，肥胖或恶病虫病。 葡萄糖可以重组模糊介导的GI内脏反射的特定机制尚不清楚。来自我们实验室的初步数据强烈表明，接受的松弛反射可以提供理想的模型系统，我们可以在其中测试特定的机械假设。我们将使用多种技术，包括体内神经胃肠病学，免疫细胞化学和体外神经生理学来测试葡萄糖通过作用部位调节葡萄糖调节葡萄糖的胃肠道反射的总体假设。简而言之，我们提出，模糊介导的GI反射（例如接受弛豫反射）在脑干葡萄糖水平的直接控制下，葡萄糖通过蛋白酶激酶C依赖性蛋白激酶C依赖性蛋白质激酶C依赖性的胃肠道模糊感觉神经元所选亚群的神经递质受体的表达。该建议将生成数据，从而提高对调节流失式反射调节的机制的理解，以及代谢和激素参数的变化如何影响摄入剂和GI相关的自主性体内稳态电路的脑干可塑性。