Brainstem circuits controlling gastrointestinal function

项目总结 功能性胃肠动力障碍，包括功能性消化不良，是非常常见的，通常 慢性和致残，在初级保健和初级保健咨询中占很大比例的疾病 专科医生。这些疾病的病理生理学尚不完全清楚，但有几个 一系列证据表明连接肠道和中枢的迷走神经感觉-运动环受损 神经系统(CNS)和背部。内脏感觉信息通过迷走神经传入中枢 纤维，终止于脑干中的孤束核(NTS)。孤束核神经元 吸收这些感觉信息并投射到参与代谢动态平衡的综合中枢， 以及邻近的迷走神经背侧运动核，它提供节前迷走神经运动 输出，并最终协调胃肠迷走神经反射。 需要非凡程度的适应性可塑性来确保迷走神经调节的胃肠道功能 对各种内在和外在因素(口味、压力、食物、环境条件等)做出适当的反应， 但是，负责这种重塑的神经机制还没有被很好地理解。我们最近的数据显示 迷走神经脑干环路中的cAMP水平在其适应性可塑性中起着关键作用。而这些 适应性反应对于适应不断变化的生理条件、不良适应或 不及时的偏差可能是迷走神经介导的进食和/或应激诱导的功能恶化的背后原因 消化不良。事实上，我们的初步数据表明，与进食和压力相关的多肽可以诱导自由基。 迷走神经-迷走神经反射活动的改变。 我们将结合电生理(膜片钳记录)、体内功能(胃张力和运动 测量)和分子(单细胞RT-PCR)方法，目的是定义神经和细胞 迷走神经脑干回路可塑性的控制机制。我们最重要的假设是 迷走神经传入选择性激活不同代谢型谷氨酸受体 输入控制胃肠道脑干回路对应激和摄食相关激素的可塑性反应。 我们的主要假设是，抑制性脑干迷走神经回路通常是静止的。 这种休眠是由迷走神经传入纤维亚群中谷氨酸的低基础释放所决定的 与NTS神经元上Gi/O偶联的mGluRs相互作用。然而，在饭后，荷尔蒙或 增加cAMP水平的神经调节剂克服mGluR激活的抑制效应，诱导 感受器在离散的神经元回路上的运输，并决定适当的迷走神经运动输出。在生理上 条件，这些可塑性变化是必不可少的完成消化过程，然而，错乱或 不及时的偏差可能会产生病理生理后果，如迷走神经介导的进食和/或 应激性功能性消化不良。我们预计，本供资周期产生的成果将提供 开发新的治疗方法治疗这些疾病所需的背景信息 因应激或消化功能障碍而加重的功能性胃肠动力障碍。

Project summary Functional gastrointestinal (GI) motility disorders, including functional dyspepsia, are very common, often chronic and disabling, conditions that account for a large proportion of consultations with primary care and specialist physicians. The pathophysiology of these disorders remains incompletely understood, but several lines of evidence point toward impairment of the vagal sensory-motor loop connecting the gut to the central nervous system (CNS) and back. Visceral sensory information is conveyed to the CNS via vagal afferent nerve fibers, which terminate within the brainstem in the nucleus tractus solitarius (NTS). Neurons of the NTS assimilate this sensory information and project to integrative CNS centers involved in metabolic homeostasis, as well as to the adjacent dorsal motor nucleus of the vagus, which provides the preganglionic vagal motor output and, ultimately, coordinates GI vago-vagal reflexes. An extraordinary degree of adaptive plasticity is required to ensure that vagally-regulated GI functions respond properly to a variety of intrinsic and extrinsic (taste, stress, food, environmental conditions etc) factors, but the neural mechanisms responsible for this remodeling are not well understood. Our recent data indicate that the levels of cAMP in vagal brainstem circuits play a critical role in their adaptive plasticity. While these adaptive responses are essential to adjust to ever-changing physiological conditions, mal-adaptation or untimely deviations may lie behind the vagally-mediated exacerbation of meal- and/or stress-induced functional dyspepsia. Indeed, our preliminary data demonstrate that meal- and stress-related peptides induce radical modifications of vago-vagal reflex activities. We will combine electrophysiological (patch clamp recordings), in vivo functional (gastric tone and motility measurements) and molecular (single cell RT-PCR) approaches with the aim of defining the neural and cellular mechanisms controlling the plasticity of vagal brainstem circuits. Our overarching hypothesis is that selective activation of different groups of metabotropic glutamate receptors (mGluR) by vagal afferent inputs controls the plastic response of GI brainstem circuits to stress- and feeding-related hormones. Our overarching hypothesis predicts that inhibitory brainstem vago-vagal circuits are normally quiescent. This dormancy is determined by the low basal release of glutamate from subsets of vagal afferent fibers interacting with Gi/o-coupled mGluRs on NTS neurons. Following a meal, however, hormones or neuromodulators that increase cAMP levels overcome the dampening effects of mGluR activation, induce receptor trafficking on discrete neuronal circuits and dictate the appropriate vagal motor output. In physiological conditions, these plastic changes are essential to fulfill the digestive processes, however, derangements or untimely deviations may have pathophysiological consequences such as the vagally-mediated meal- and/or stress-induced functional dyspepsia. We anticipate that the results generated in this funding cycle will provide the background information necessary to develop novel therapeutic approaches to the treatment of those functional gastrointestinal motility disorders exacerbated by stress or digestive malfunctions.