Brainstem circuits controlling gastrointestinal function

描述（由申请人提供）：功能性胃肠（GI）运动障碍，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仍不完全清楚，但一些证据表明，迷走神经感觉-运动回路的损伤连接肠道和中枢神经系统（CNS）和背部。内脏感觉信息通过迷走传入神经纤维传递到中枢神经系统，该神经纤维终止于脑干的孤束核（NTS）。NTS的神经元吸收这些感觉信息并投射到参与代谢稳态的综合中枢，以及邻近的迷走神经背运动核，后者提供神经节前迷走神经运动输出，最终协调GI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因素（味觉、压力、食物、环境条件等）做出适当的反应，需要一种特殊程度的适应性可塑性，但负责这种重塑的神经机制尚不清楚。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关键作用。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，但不适当的适应或不合时宜的偏差可能是迷走神经介导的膳食和/或应激诱导的功能性消化不良加剧的原因。事实上，我们的初步数据表明，饮食和应激相关肽诱导迷走神经反射活动的根本改变。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，目的是定义控制迷走脑干回路可塑性的神经和细胞机制。我们的主要假设是迷走神经传入输入选择性激活不同组的代谢性谷氨酸受体（mGluR），控制GI脑干回路对应激和摄食相关激素的可塑性反应。我们的首要假设预测，抑制性脑干迷走-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谷氨酸的低基底释放与NTS神经元上的Gi/o偶联mGluRs相互作用决定的。然而，饭后，增加cAMP水平的激素或神经调节剂克服mGluR激活的抑制作用，诱导离散神经元回路的受体运输，并指示适当的迷走神经运动输出。在生理条件下，这些可塑性变化是完成消化过程所必需的，然而，紊乱或不合时宜的偏差可能会产生病理生理后果，如迷走神经介导的膳食和/或应激诱导的功能性消化不良。我们预计在这个资助周期中产生的结果将为开发新的治疗方法提供必要的背景信息，以治疗那些因压力或消化功能障碍而加剧的功能性胃肠运动障碍。公共卫生相关性：功能性胃肠运动障碍，包括功能性消化不良，是常见的，通常是慢性和致残的，在初级保健和专科医生的咨询中占很大比例。这些疾病的病理生理学尚不完全清楚，但有几条线索表明肠道和大脑之间的信息处理受损。在正常情况下，上消化道，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大脑的特定区域。大脑解释这些信息，并将其反应通过迷走神经的运动部分传回肠道。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至关重要，但适应不良或不合时宜的偏差可能会产生病理生理后果，例如，应激诱导的功能性胃肠运动障碍加剧。在目前的建议中，我们将结合最先进的生理和生化技术来研究肠-脑界面发生的神经过程，以响应应激和喂食相关激素。我们预计，本提案产生的信息将为开发治疗功能性胃肠运动障碍的新治疗方法提供必要的背景。

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.