Functional Neural Circuits of Stomach-Brain Interoception

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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.