Functional identification of vagal sensory neurons innervating the liver

支配肝脏的迷走神经感觉神经元的功能识别

基本信息

批准号：
10319267
负责人：
YOUNG-HWAN JO
金额：
$ 41.92万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10319267
关键词：
AVIL gene Adaptive Behaviors Afferent Neurons Anatomy Animals Appetite Stimulants Autonomic nervous system Behavior Behavioral Bipolar Disorder Blood Glucose Brain Brain Stem Calcitonin Gene-Related Peptide Cell Nucleus Cells Desire for food Diabetes Mellitus Dinoprostone Disease Dopamine Eating Behavior Emotions Feeding behaviors Feeling Food Foundations Future G-Protein-Coupled Receptors Gene Expression Genes Gluconeogenesis Glucose Health Hepatic Hormonal Hormones Human Hypothalamic structure Immune Individual Knowledge Kupffer Cells Liver Lung Mental Depression Mental disorders Mixed Function Oxygenases Molecular Moods Motivation Motor Neurons Mus Nerve Neural Pathways Neurons Neuropeptide Y Receptor Neuropeptides Neurotransmitters Nodose Ganglion Norepinephrine Nutrient Obesity Organ Pancreas Parasympathetic Nervous System Pathway interactions Peripheral Physiological Pilot Projects Play Population Purinoceptor Regulation Rewards Role Sensory Signal Transduction Sodium Channel Specificity Structure Structure of nucleus infundibularis hypothalami Subgroup Substance abuse problem Sympathetic Nervous System Synapses Techniques Transportation Vagus nerve structure Vasoactive Intestinal Peptide anatomical tracing awake base blood glucose regulation cell type cholinergic detection of nutrient dorsal motor nucleus experience experimental study falls feeding gamma-Aminobutyric Acid gastrointestinal system glucose metabolism glucose production glycogenolysis in vivo calcium imaging increased appetite inhibitory neuron interest loss of function neural circuit neurochemistry novel optogenetics parabrachial nucleus protachykinin psychologic purinoceptor P2Y1 receptor relating to nervous system sensory system single-cell RNA sequencing transcriptomics translational study

项目摘要

Proper integration and transportation of interoceptive signals from organs to the brain via the vagus nerve appear to be critical for psychological experiences ranging from a variety of feelings and emotions to motivations and adaptive behaviors. Individuals with psychological disorders, including depression and bipolar disorder experience changes in eating behavior in addition to low mood. It has been thought that loss or increase of appetite in individuals with psychological disorders and substance abuse disorders results from disruptions in central reward and interoceptive neurocircuits. This proposal will perform functional analysis using neural anatomical tracing combined with physiological and behavioral analysis of the vagal sensory neural circuit that senses and integrates interoceptive signals in the liver. Each vagal sensory neuron has a central brainstem terminal. A population of catecholaminergic cells in the nucleus tractus solitarius (NTS) receives input from liver-projecting vagal afferent neurons. These catecholaminergic neurons control glucoprivic feeding. Additionally, a subset of inhibitory neurons in the NTS regulate hepatic glucose production via preganglionic parasympathetic neurons. A subgroup of liver-projecting vagal sensory neurons can respond to changes in blood glucose and transmit this information to the neurons in the NTS. Intriguingly, a population of orexigenic neurons in the arcuate nucleus of the hypothalamus and a subgroup of appetite-suppressing neurons in the parabrachial nucleus receive synaptic inputs from catecholaminergic neurons in the NTS. These appetite-regulating neurons appear to project to the structures implicated in depression and emotion. Therefore, we propose that a liver-brain neural circuit is essential for ingestive behaviors and that this neural circuit also plays a vital role in brain functions, particularly psychological disorders, including depression and bipolar disorder. Studies in Aim 1 will determine the molecular and cellular identity of liver-projecting vagal sensory neurons. Experiments in Aim 2 will examine the functional consequences of the loss-of-function of a liver-brain neural circuit. Our proposal will have the potential to provide novel information on how nutrient and hormonal vagal afferent signals from the liver act on the CNS to drive appetitive and consummatory aspects of motivated feeding and reward behavior.

通过迷走神经从器官到大脑的内感受信号的正确整合和传输似乎对于从各种感觉和情绪到动机和适应性行为的心理体验至关重要。患有抑郁症和双相情感障碍等心理障碍的人除了情绪低落外，还会经历饮食行为的变化。人们认为，患有心理障碍和药物滥用障碍的个体食欲下降或增加是由于中枢奖励和内感受神经回路的破坏造成的。该提案将使用神经解剖追踪结合迷走神经感觉神经回路的生理和行为分析来进行功能分析，该迷走神经感觉神经回路感知并整合肝脏中的内感受信号。每个迷走神经感觉神经元都有一个中枢脑干末梢。孤束核 (NTS) 中的儿茶酚胺能细胞群接收来自肝脏投射迷走神经传入神经元的输入。这些儿茶酚胺能神经元控制糖缺乏喂养。此外，NTS 中的抑制性神经元子集通过节前副交感神经元调节肝葡萄糖的产生。肝脏投射迷走神经感觉神经元的一个亚群可以对血糖的变化做出反应，并将该信息传递给 NTS 中的神经元。有趣的是，下丘脑弓状核中的一群食欲抑制神经元和臂旁核中的一组食欲抑制神经元接收来自 NTS 中儿茶酚胺能神经元的突触输入。这些食欲调节神经元似乎投射到与抑郁和情绪有关的结构。因此，我们认为肝脑神经回路对于摄取行为至关重要，并且该神经回路在大脑功能中也发挥着至关重要的作用，特别是心理障碍，包括抑郁症和双相情感障碍。目标 1 的研究将确定肝脏投射迷走神经感觉神经元的分子和细胞特性。目标 2 中的实验将检查肝脑神经回路功能丧失的功能后果。我们的建议将有可能提供关于来自肝脏的营养和激素迷走神经传入信号如何作用于中枢神经系统以驱动主动进食和奖励行为的食欲和完成方面的新信息。