Functional Neural Circuits of Stomach-Brain Interoception

项目摘要 也许“内感”最显著的例子就是“直觉”。胃可以影响直觉、情绪和认知；大脑可以调节食物的摄取和消化。胃里有自己的肠道神经系统，也就是肠道中的“小脑”。它通过迷走神经直接连接到中枢神经系统。迷走神经为胃和脑之间的快速相互作用提供了双向传入和传出神经通路。胃-迷走神经-脑连接体是人类健康的核心，在功能障碍时具有重要的健康意义。然而，这个连接体还没有被绘制或详细描述。目前尚不清楚大脑在哪里以及如何监测和调节胃的电节律、机械收缩和营养处理方面的功能。迷走神经如何将感觉信息从胃传递到大脑，以及如何将运动控制从大脑传递到胃也不是很清楚。为了填补这些空白，这个项目的目的是描述大鼠胃-脑内感觉的中枢和外周神经回路。对于中心部分，我们将使用清醒动物的功能磁共振成像来绘制胃中央网络的图，并根据胃的电节律、机械收缩和营养处理来表征其活动和连通性。为了验证胃中枢网络，我们将使用伪狂犬病病毒和1型单纯疱疹病毒的神经解剖示踪。对于外周部分，我们将使用迷走神经和结状神经节电生理学来表征从胃到脑的传入信号和从大脑到胃的传出信号。为了阐明胃和脑之间的因果相互作用，我们将使用细胞类型特异性化学遗传学来扰乱胃中央网络并评估由此对胃的影响，并使用迷走神经切断术来扰乱迷走神经回路并评估由此对大脑的影响。该项目有4个具体目标，即绘制胃中枢网络图(目标1)，并描述与胃电生理(目标2)、运动(目标3)和营养摄取(目标4)有关的胃-脑相互感觉的中枢和外周神经回路。为了实现这些目标，我们组建了一个协作和跨学科的专家团队，在磁共振成像、胃肠病学、神经调节和电生理学方面拥有领先和互补的专业知识。该项目成功完成后，将把尖端技术整合到一个独特的平台上，全面评估胃-大脑相互感觉背后的中枢和外周功能神经回路。作为直接的结果，我们将在大鼠大脑中建立胃中枢网络，解开其功能角色，并阐明胃和大脑之间的因果关系，而不是相互关系。这些结果将为更好地理解胃-脑相互作用及其对精神疾病(如压力和焦虑)、神经疾病(如帕金森氏病)和胃病(如功能性消化不良)的深刻影响，以及脑和胃疾病的共同发生奠定机制和技术基础。

Project Summary Perhaps the most notable example of “interoception” is the “gut feeling”. The stomach can affect intuition, emotion and cognition; the brain can regulate food ingestion and digestion. The stomach contains its own enteric nervous system, or the “little brain” in the gut. It connects directly to the central nervous system via the vagus. The vagus nerves provide a bi-directional – afferent and efferent – neural pathway for rapid interactions between the stomach and the brain. The stomach-vagus-brain connectome is central to human health and has significant health implications at dysfunction. However, this connectome has not been mapped or characterized in detail. It is unclear where and how the brain monitors and regulates the function of the stomach in terms of its electrical rhythm, mechanical contraction, and nutrient handling. It is also not exactly clear how the vagus nerves relay sensory information from the stomach to the brain and convey motor control from the brain to the stomach. To fill these gaps, this project is aimed to characterize the central and peripheral neural circuits of stomach-brain interoception in rats. For the central component, we will use functional magnetic resonance imaging in awake animals to map the central gastric network and characterize its activity and connectivity with respect to gastric electrical rhythm, mechanical contraction, and nutrient handling. To verify the central gastric network, we will use neuroanatomical tracing with pseudorabies virus and herpes simplex virus type-1. For the peripheral component, we will use the vagus nerve and nodose ganglion electrophysiology to characterize the afferent signaling from the stomach to the brain and the efferent signaling from the brain to the stomach. To elucidate the causal interaction between the stomach and the brain, we will use cell-type specific chemogenetics to perturb the central gastric network and assess the resulting effect on the stomach and use vagotomy to perturb the vagal circuitry and assess the resulting effect on the brain. This project has 4 specific aims for mapping the central gastric network (Aim 1) and characterizing the central and peripheral neural circuits for stomach-brain interoception related to gastric electrophysiology (Aim 2), motility (Aim 3), and ingestion of nutrients (Aim 4). To accomplish these aims, we form a collaborative and interdisciplinary team of experts with leading and complementary expertise in magnetic resonance imaging, gastroenterology, neuromodulation and electrophysiology. Upon its successful completion, this project will have integrated cutting-edge technologies into a unique platform for comprehensive assessment of the central and peripheral functional neural circuits underlying stomach-brain interoception. As the immediate outcome, we will have established the central gastric network in the rat brain, disentangled its functional roles, and elucidated the causal, rather than correlational, interactions between the stomach and the brain. These outcomes will lay both mechanistic and technical foundations for better understanding of stomach-brain interoception and its profound implications to mental illnesses (e.g., stress and anxiety), neurological disorders (e.g., Parkinson’s diseases) and gastric disorders (e.g., functional dyspepsia), and the co-occurrence of both brain and gastric disorders.