Functional Neural Circuits of Stomach-Brain Interoception

项目摘要 也许“内感受”最著名的例子是“直觉”。胃可以影响直觉、情感和认知;大脑可以调节食物的摄取和消化。胃包含自己的肠神经系统，或肠道中的“小大脑”。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双向传入和传出神经通路。胃-迷走神经-脑连接体对人类健康至关重要，并且在功能障碍时具有显著的健康影响。然而，这个连接体还没有被详细地绘制或表征。目前还不清楚大脑在哪里以及如何监控和调节胃的电节律，机械收缩和营养处理功能。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，这一点也不清楚。为了填补这些空白，本项目旨在描述大鼠胃-脑内感受的中枢和外周神经回路。对于中枢部分，我们将使用清醒动物的功能性磁共振成像来绘制中枢胃网络，并表征其与胃电节律、机械收缩和营养处理相关的活动和连接。为了验证中央胃网络，我们将使用伪狂犬病病毒和单纯疱疹病毒1型神经解剖追踪。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脑到胃的传出信号。为了阐明胃和大脑之间的因果关系，我们将使用细胞类型特异性化学遗传学来扰乱胃中枢网络并评估对胃的影响，并使用迷走神经切断术来扰乱迷走神经回路并评估对大脑的影响。该项目有4个具体目标，即绘制中央胃网络（目标1），并表征与胃电生理学（目标2）、运动性（目标3）和营养摄入（目标4）相关的胃-脑内感受的中枢和外周神经回路。为了实现这些目标，我们组建了一支跨学科的专家团队，他们在磁共振成像、胃肠病学、神经调节和电生理学方面具有领先和互补的专业知识。成功完成后，该项目将把尖端技术整合到一个独特的平台中，用于全面评估胃-脑内感受的中枢和外周功能神经回路。作为直接结果，我们将在大鼠大脑中建立中央胃网络，解开其功能角色，并阐明胃和大脑之间的因果关系，而不是相关性。这些结果将为更好地理解胃-脑内感受及其对精神疾病的深远影响奠定机械和技术基础（例如，压力和焦虑），神经障碍（例如，帕金森病）和胃病（例如，功能性消化不良），以及脑和胃疾病的共同发生。

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.