Integration of Peripheral and Central Appetite Signals by Brainstem Neurons

 描述(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诱因。控制食欲的一个重要区域是脑干的孤束核(NTS)。携带饱腹感信息的内脏传入纤维终止于NTS，NTS神经元过滤这些信息，然后将其传递到大脑的其他区域。NTS中的儿茶酚胺神经元(NTS-CA神经元)是控制食物摄入量的一个重要群体。在之前的资助期间，我们证明了这些神经元是：1)由迷走神经传入直接激活，包括胃传入；2)被抑制食物摄取的化合物激活，如CCK、催产素和5-羟色胺，并被刺激摄取的因素抑制，如Ghrelin和阿片；3)NTS-CA神经元的活动依赖于谷氨酸输入，谷氨酸输入可被5-羟色胺(5-HT)通过5-HT3受体(Rs)和尼古丁通过烟碱乙酰胆碱受体(NARs ChRs)所增强。5-羟色胺和尼古丁是食物摄取的两种强有力的抑制因子，调整它们的作用大小可以提供一种灵敏的方式来调节饱腹感途径的激活强度，以适应能量需求。这一假设的中心假设是，5-HT3Rs和nAChRs的表达可以在不同的条件下上调和下调，以控制谷氨酸的释放，改变NTS-CA神经元的放电频率，导致递质去甲肾上腺素和谷氨酸的差异释放。一个 将使用电生理学、行为学和分子遗传学的多学科方法，通过追求以下具体目标来有力地和全面地检验中心假说。目的1.建立NTS-CA神经元对5-羟色胺能输入的反应如何因能量状态的改变而改变，如葡萄糖浓度、空腹、肥胖和饮食。目的2.建立NTS-CA神经元对胆碱能输入的反应如何因能量状态的改变而改变，如葡萄糖浓度、空腹、肥胖和高脂饮食。目的3.确定5-羟色胺和尼古丁的摄食作用是否具有可塑性，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，以及这如何影响摄食行为。预计这些结果将通过确定控制体重的关键机制是如何改变的，从而对该领域产生积极影响；这些知识可能最终有助于制定治疗策略，以缓解与肥胖相关的问题。

 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.