The effects of glucose on central vagal brainstem circuits

描述（申请人提供）：迷走神经脑干回路在食物摄取、胃肠（GI）功能和自主体内平衡的协调中至关重要。接受性松弛反射是一种经典的迷走神经介导的反射，在食道扩张时（例如在吞咽时）被激活，引起胃松弛和抑制运动，使胃等压接受摄食。同时，这种反射被用作调节营养吸收和体内平衡的第一步。通过降低胃张力和胃运动，接受性松弛反射延迟胃排空，减慢食糜转运到肠道的速度，从而调节营养吸收的速度。近年来，包括我们自己的实验室在内的几个实验室收集的数据表明，进食后释放的许多GI激素对迷走神经介导的GI功能起着显著的控制作用。自主神经回路中的适应性反应对于适应不断变化的生理条件是必不可少的，事实上，一些最戏剧性的生理变化是由于食物摄入而发生的。血糖水平在一天中波动，并在食物摄入后急剧上升；自适应自主感觉和运动反应是稳定这些波动和维持体内平衡所必需的。血糖水平的急性变化，即使在生理范围内，也会对胃运动和排空产生深远的迷走神经介导的影响。这些葡萄糖诱导的反应对于最小化血糖水平的剧烈的、潜在的损害是极其重要的。内稳态神经回路的短期可塑性允许通过放大或减弱输出反应，或通过改变反应模式或持续时间来调节自主反射。即使是自主神经回路中关键突触强度的短暂调制，也有可能诱发短期可塑性。然而，这些适应性反应的中断或不合时宜的变化可能导致不适当的夸大反射，甚至可能诱发病理生理结果。例如，对膳食摄入的正常生理反应的加剧可能诱发多种病理状况，包括功能性胃运动障碍、肥胖或恶病质。葡萄糖重组迷走神经介导的胃肠道内脏反射的具体机制尚不清楚。我们实验室的初步数据有力地表明，接受性放松反射可以提供一个理想的模型系统，我们可以在其中测试特定的机制假设。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脑干作用部位调节迷走神经介导的胃肠道反射的总体假设。简而言之，我们提出迷走神经介导的胃肠道反射，如接受性松弛反射，是在脑干葡萄糖水平的直接控制下，葡萄糖通过调节蛋白激酶c依赖通路调节胃肠道迷走感觉神经元亚群上神经递质受体的表达。这一提议将产生的数据将导致对迷走神经反射调节机制的更好理解，以及代谢和激素参数的变化如何影响摄入和胃肠道相关自主稳态回路的脑干可塑性。

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.