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

• 批准号: 9210080
• 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
• 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/9210080
• 关键词: Agonist; Animals; Area; Behavioral Genetics; Body Weight; Brain Stem; Brain region; Cardiovascular Diseases; Catecholamines; Cells; Cholecystokinin; Choline; Comprehension; Cues; Desire for food; Development; Diabetes Mellitus; Diet; Disease; Eating; Electrophysiology (science); Fasting; Feeding behaviors; Fiber; Funding; Glucose; Glutamates; Goals; HTR3A gene; Health; High Fat Diet; 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; Plasticizers; 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; cholinergic; expectation; experimental study; feeding; ghrelin; improved; inhibitor/antagonist; innovation; interdisciplinary approach; novel; obesity treatment; postsynaptic; presynaptic; public health relevance; receptor; response

 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.

 描述（由申请人提供）：肥胖是美国的一个主要健康问题，也是心血管疾病、糖尿病和中风的主要原因。控制食欲的一个重要区域是脑干中的孤束核（NTS）。携带饱腹感信息的内脏传入纤维终止于NTS，NTS神经元在将信息传递到其他大脑区域之前过滤这些信息。NTS中的儿茶酚胺神经元（NTS-CA神经元）是控制食物摄入的关键群体之一。在之前的资助期间，我们发现这些神经元1）直接被迷走神经传入激活，包括胃传入; 2）被抑制食物摄入的化合物激活，如CCK，催产素和血清素，并被刺激摄入的因素抑制，如ghrelin和阿片类药物; NTS-CA神经元的活性依赖于谷氨酸输入，其可通过5-HT 3受体（Rs）由5-羟色胺（5-HT）和通过烟碱乙酰胆碱受体（nAChRs）由烟碱增加。5-羟色胺和尼古丁是两种强大的食物摄入抑制剂，调节它们的作用大小可以提供一种敏感的方式来调节饱腹感通路的激活强度，以适应能量需求。该建议的中心假设是，5-HT 3R和nAChR的表达可以通过不同的条件进行上调和下调，以控制谷氨酸的释放并改变NTS-CA神经元的放电速率，从而导致递质去甲肾上腺素和谷氨酸的差异释放。一 电生理学、行为学和分子遗传学的多学科方法将被用来通过追求以下具体目标来有力地和全面地检验中心假设。目标1。确定NTS-CA神经元对多巴胺能输入的反应如何通过能量状态的变化而改变，例如葡萄糖浓度、禁食、肥胖和饮食。目标2.确定NTS-CA神经元对胆碱能输入的反应如何通过能量状态的变化而改变，例如葡萄糖浓度、禁食、肥胖和高脂肪饮食。目标3。确定5-羟色胺和尼古丁的摄食效应是否具有可塑性，以及它们是否刺激NTS-CA神经元释放去甲肾上腺素或谷氨酸。这些实验的预期结果是，我们将更好地理解不同的能量状态如何改变NTS神经元的激活以控制递质释放，以及这如何影响进食行为。这些结果预计将通过确定控制体重的关键机制如何改变而对该领域产生积极影响;这些知识最终可能有助于制定治疗策略，以缓解与肥胖相关的问题。