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Integration of Peripheral and Central Appetite Signals by Brainstem Neurons

脑干神经元整合外周和中枢食欲信号

基本信息

批准号：
8888987
负责人：
Suzanne M Appleyard
金额：
$ 33.98万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-15 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8888987
关键词：
Agonist Animals Area Behavioral Genetics Body Weight Brain Stem Brain region Cardiovascular Diseases Catecholamines Cholecystokinin Choline Comprehension Cues Desire for food Development Diabetes Mellitus Diet Disease Eating Electrophysiology (science)Fasting Fatty acid glycerol esters Feeding behaviors Fiber Funding Glucose Glutamates Goals HTR3A gene Health Hyperglycemia Intake Knowledge Lead Molecular Molecular Genetics Neurons Nicotine Nicotinic Agonists Nicotinic Receptors Nodose Ganglion Norepinephrine Nucleus solitarius Obesity Opioid Outcome Oxytocin Pathway interactions Peripheral Pharmaceutical Preparations Pharmacology Plastics Population Prevention approach Prevention strategy Public Health Regulation Research Satiation Serotonin Serotonin Receptors 5-HT-3 Signal Transduction Stomach Stroke Techniques Testing Therapeutic United States Visceral Afferents Work cholinergic expectation feeding ghrelin improved inhibitor/antagonist innovation interdisciplinary approach neuronal cell body novel obesity treatment postsynaptic presynaptic public health relevance receptor research study response

项目摘要

DESCRIPTION (provided by applicant): Obesity is a major health problem in the United States and a leading contributor to cardiovascular disease, diabetes mellitus and stroke. One region essential for appetite control is the nucleus of the solitary tract (NTS) in the brainstem. Visceral afferent fibers carrying satiety information terminate in the NTS and NTS neurons filter this information before relaying it on to other brain regions. Catecholamine neurons in the NTS (NTS-CA neurons) are one population critical for the control of food intake. In the previous funding period we showed that these neurons are 1) directly activated by vagal afferents, including gastric afferents; 2) activated by compounds that inhibit food intake, such as CCK, oxytocin and serotonin, and inhibited by factors that stimulate intake, such as ghrelin and opioids; and 3) that the activity of NTS-CA neurons is dependent on glutamate inputs, which can be increased by both serotonin (5-HT) through 5-HT3 receptors (Rs) and nicotine through nicotinic acetylcholine receptors (nAChRs). Serotonin and nicotine are two powerful inhibitors of food intake and adjusting the size of their effects could provide a sensitive way to adjust the strength of activation of a satiety pathway to adapt to energy needs. The central hypothesis of this proposal is that the expression of both 5-HT3Rs and nAChRs can be up and down regulated by different conditions to control glutamate release and alter the firing rate of NTS-CA neurons, resulting in the differential release of the transmitters, norepinephrine and glutamate. A multidisciplinary approach of electrophysiology, behavior and molecular genetics will be used to powerfully and comprehensively test the central hypothesis by pursuing the following specific aims. Aim 1. Establish how the response of NTS-CA neurons to serotonergic inputs is altered by changes in energy state, e.g. glucose concentration, fasting, obesity and diet. Aim 2. Establish how the response of NTS-CA neurons to cholinergic inputs is altered by changes in energy state, e.g. glucose concentration, fasting, obesity and high fat diet. Aim 3. Determine whether the feeding effects of serotonin and nicotine are plastic and whether they stimulate release of norepinephrine or glutamate from NTS-CA neurons. The expected outcomes of these experiments are that we will have a better understating of how different energy states alter activation of NTS neurons to control transmitter release and how this impacts feeding behaviors. These results are expected to positively impact the field by identifying how key mechanisms that control body weight are altered; knowledge that may eventually help lead to therapeutic strategies to alleviate the problems associated with obesity.