Brainstem circuits controlling gastrointestinal function

描述（由申请人提供）：功能性胃肠道（GI）动力障碍，包括功能性消化不良，是非常常见的，通常是慢性和致残性疾病，占初级保健和专科医生咨询的很大比例。这些疾病的病理生理学仍不完全清楚，但有几条证据指向连接肠道和中枢神经系统（CNS）的迷走神经感觉-运动环路受损。内脏感觉信息通过迷走传入神经纤维传递到CNS，迷走传入神经纤维终止于脑干内的孤束核（NTS）中。NTS的神经元吸收这种感觉信息，并投射到参与代谢稳态的综合CNS中心，以及邻近的迷走神经背侧运动核，其提供节前迷走神经运动输出，并最终协调GI迷走神经-迷走神经反射。为了确保迷走神经调节的GI功能对各种内在和外在（味觉、压力、食物、环境条件等）因素做出适当的反应，需要非常程度的适应性可塑性，但负责这种重塑的神经机制尚未得到很好的理解。我们最近的数据表明，迷走神经脑干回路中的cAMP水平在其适应性可塑性中起着至关重要的作用。虽然这些适应性反应对于适应不断变化的生理条件是必不可少的，但适应不良或不合时宜的偏差可能是迷走神经介导的进餐和/或应激诱导的功能性消化不良恶化的原因。事实上，我们的初步数据表明，膳食和压力相关的肽诱导迷走神经-迷走神经反射活动的根本修改。我们将结合联合收割机电生理（膜片钳记录），在体内功能（胃张力和运动测量）和分子（单细胞RT-PCR）的方法，目的是确定控制迷走神经脑干回路可塑性的神经和细胞机制。我们的总体假设是，迷走神经传入输入的代谢型谷氨酸受体（mGluR）的不同群体的选择性激活控制胃肠道脑干回路的压力和喂养相关的激素的塑性反应。我们的总体假设预测，抑制性脑干迷走神经-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与NTS神经元上的Gi/o-偶联mGluRs相互作用的谷氨酸的低基础释放决定的。然而，餐后，增加cAMP水平的激素或神经调节剂克服了mGluR激活的抑制作用，诱导受体在离散神经元回路上的运输，并决定了适当的迷走神经运动输出。在生理条件下，这些可塑性变化对于完成消化过程是必不可少的，然而，紊乱或不合时宜的偏离可能具有病理生理学后果，例如迷走神经介导的进餐和/或应激诱导的功能性消化不良。我们预计，在这个资金周期产生的结果将提供必要的背景信息，开发新的治疗方法来治疗那些功能性胃肠动力障碍加剧的压力或消化功能障碍。公共卫生相关性：功能性胃肠动力障碍，包括功能性消化不良，是常见的，通常是慢性和致残性的，占初级保健和专科医生咨询的很大比例。这些疾病的病理生理学尚未完全了解，但有几条证据指向肠道和大脑之间的信息处理受损。在正常情况下，上胃肠道，即胃和小肠，通过感觉迷走神经将有关肠道状态的信息发送到特定的大脑区域。大脑解释这些信息，并通过迷走神经的运动部分将其反应发送回肠道。为了正确控制消化过程，这种肠-脑神经回路需要精确的适应机制。虽然这些适应性反应对于适应不断变化的生理条件是必不可少的，但适应不良或不合时宜的偏差可能具有病理生理学后果，例如，应激诱导的功能性胃肠动力障碍的恶化。在本研究中，我们将结合联合收割机最先进的生理和生化技术来研究应激和摄食相关激素对肠-脑界面神经过程的影响。我们预计，本提案所产生的信息将提供必要的背景开发新的治疗方法来治疗功能性胃肠动力障碍。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Functional gastrointestinal motility disorders, including functional dyspepsia, are 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 is not understood completely, but several lines of evidence point towards the impairment of information processing between the gut and the brain. Under normal conditions, the upper gastrointestinal tract, i.e. the stomach and the small intestine, sends information regarding the state of the gut to specific brain areas via the sensory vagus nerve. The brain interprets this information and sends its response back to the gut via the motor portion of the vagus nerve. In order to control digestive processes properly, this gut-brain neural circuit requires precise adaptive mechanisms. While these adaptive responses are essential to adjust to ever-changing physiological conditions, mal-adaptation or untimely deviations may have pathophysiological consequences such as, for example, exacerbation of stress-induced functional gastrointestinal motility disorders. In the present proposal we will combine state-of-the-art physiological and biochemical techniques to investigate the neural processes occurring at the gut-brain interface in response to stress and feeding-related hormones. We anticipate that the information generated by the present proposal will provide the background necessary to develop novel therapeutic approaches to the treatment of functional gastrointestinal motility disorders.