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

• 批准号: 10686107
• 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
• 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/10686107
• 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; Eating Behavior; Emotions; Feeding behaviors; Feeling; Foundations; Future; Gene Expression; Genes; Gluconeogenesis; Glucose; Health; Hepatic; Homeostasis; Hormonal; Hormones; Human; Hypothalamic structure; Immune; Individual; Knowledge; Kupffer Cells; LTB4R gene; Liver; Lung; Maps; 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; 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 output; glucose production; glycogenolysis; in vivo calcium imaging; increased appetite; inhibitory neuron; interest; liver ablation; loss of function; neural; neural circuit; neurochemistry; novel; optogenetics; parabrachial nucleus; protachykinin; psychologic; purinoceptor P2Y1; receptor; sensory system; single-cell RNA sequencing; transcriptome sequencing; translational study; transmission process

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.

从各种感觉和情绪到动机和适应行为的心理体验，适当的整合和通过迷走神经从器官到大脑的相互感觉信号的传输似乎是至关重要的。患有心理障碍的人，包括抑郁症和躁郁症，除了情绪低落外，还会在饮食行为上发生变化。人们认为，患有心理障碍和药物滥用障碍的个体的食欲丧失或增加是由于中枢奖赏和内感神经回路的中断造成的。这项提议将使用神经解剖追踪结合对迷走感觉神经回路的生理和行为分析来执行功能分析，迷走感觉神经回路感知并整合肝脏中的相互感觉信号。 每个迷走神经感觉神经元都有一个中央脑干终末。孤束核(NTS)中的一群儿茶酚胺能细胞接受来自肝脏投射的迷走神经传入神经元的输入。这些儿茶酚胺能神经元控制葡萄糖摄食。此外，NTS中的一部分抑制神经元通过节前副交感神经元调节肝脏葡萄糖的产生。投射肝脏的迷走感觉神经元的一个亚群可以对血糖的变化做出反应，并将信息传递给NTS中的神经元。有趣的是，下丘脑弓状核中的一群食欲性神经元和臂旁核中的一群食欲抑制神经元接受来自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中。因此，我们认为肝脏-大脑神经回路对摄食行为是必不可少的，并且该神经回路在大脑功能中也起着至关重要的作用，特别是心理障碍，包括抑郁症和双相情感障碍。 目标1的研究将确定投射肝脏的迷走感觉神经元的分子和细胞特性。目标2中的实验将检验肝脏-大脑神经回路功能丧失的功能后果。我们的提议将有可能提供新的信息，说明来自肝脏的营养和荷尔蒙迷走神经传入信号如何作用于中枢神经系统，以驱动动机进食和奖励行为的食欲和消耗性方面。