INTERACTIONS OF LEPTIN AND CENTRAL SEROTONIN SYSTEMS

瘦素和中枢血清素系统的相互作用

• 批准号: 6392785
• 负责人: JOEL K. ELMQUIST
• 金额: $ 34.8万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-10 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6392785
• 关键词: body weight; central neural pathway /tract; corticotropin releasing factor; dorsal raphe nucleus; eating; fenfluramine; fos protein; hormone regulation /control mechanism; hypothalamus; immunocytochemistry; in situ hybridization; laboratory rat; leptin; messenger RNA; neuroanatomy; neuronal transport; neuropeptide Y; neuropharmacology; nutrition related tag; proopiomelanocortin; psychopharmacology; receptor expression; regulatory gene; serotonin; serotonin receptor

DESCRIPTION: (Adapted from the Investigator's Abstract) In the United States today aberrant food intake and body weight regulation is prevalent and is manifested by extremes that include obesity and anorexia nervosa. The central nervous system tightly regulates food intake and body weight. Central circuits which utilize serotonin (5HT) exert powerful behavioral effects to decrease body weight. However the mechanism(s) of action of serotonin in regulating feeding and body weight are not understood. Recent studies have established leptin as a fundamental in the regulation of energy balance and neuroendocrine function. Administration of both leptin and serotonergic agonists inhibit food intake. However, it is unknown if leptin and serotonin systems interact within the CNS. Our preliminary findings suggest that leptin engages serotonergic neurons in the dorsal raphe nucleus. We hypothesize that the action of serotonergic systems on feeding converge on leptin-regulated systems as a final common output mechanism and will test these ideas in our specific aims. We will also extend that knowledge to the human brain which will provide fundamental information regarding the mechanisms by which food intake is regulated aberrantly in obesity and in eating disorders such as anorexia nervosa. In this proposal, we outline experiments designed to characterize the neuroanatomic mechanisms by which leptin and serotonin systems interact to regulate food intake. First, we will identify and characterize the chemical identity of hypothalamic neurons that express 5-HT2C and 5-HT1B receptors as these receptors are thought to modulate food intake and body weight. We will use dual label in situ hybridization for 5-HT2C and 5-HT1B mRNA coupled with ISHH for neuropeptides known to regulate food intake. Next, using retrograde tracing and in situ hybridization of 5-HT2C and 5-HT1B receptor mRNA, we will determine if hypothalamic neurons that innervate key autonomic regulatory sites receive serotonergic innervation and express 5-HT1B and 2C receptor mRNA. Third, using retrograde tracing and in situ hybridization for immediate early genes we will determine the CNS sites innervated by leptin-responsive neurons in the dorsal raphe nucleus. Finally, using retrograde tracing and immunohistochemistry for Fos following fenfluramine administration, we will determine the chemical identity and CNS sites innervated by serotonin-activated neurons that regulate food intake.

描述：(改编自《调查者摘要》)在美国 今天，异常的食物摄入量和体重调节很普遍，而且 表现为极端的肥胖和神经性厌食症。中环 神经系统严格控制食物摄入量和体重。中央电路 其中利用5-羟色胺(5-羟色胺)发挥强大的行为效应来减少 体重。然而，5-羟色胺的调节机制(S) 喂食和体重是不被理解的。最近的研究证实了 瘦素在能量平衡和神经内分泌调节中的基础作用 功能。同时给予瘦素和5-羟色胺能激动剂会抑制食物 入口处。然而，瘦素和5-羟色胺系统是否在体内相互作用尚不清楚。 中枢神经系统。我们的初步发现表明，瘦素参与了5-羟色胺能 中缝背核内的神经元。我们假设...的行为 摄食的5-羟色胺能系统最终会聚在瘦素调节的系统上 共同的产出机制，并将在我们的具体目标中检验这些想法。我们会 还将这种知识扩展到人脑，这将为 关于调节食物摄入量的机制的信息 在肥胖和进食障碍如神经性厌食症中异常。在这 提案中，我们概述了设计用来描述神经解剖学特征的实验 瘦素和5-羟色胺系统相互作用调节食物的机制 入口处。首先，我们将鉴定和表征化学身份 表达5-HT2C和5-HT1B受体的下丘脑神经元 受体被认为可以调节食物摄入量和体重。我们将使用DUAL 5-HT2C和5-HT1B mRNA与ISHH的标记原位杂交 已知的调节食物摄入量的神经肽。接下来，使用逆行跟踪和 5-HT2C和5-HT1B受体mRNA的原位杂交，我们将确定 支配关键自主神经调节部位的下丘脑神经元 5-羟色胺能神经支配，表达5-HT1B和2C受体基因。第三，使用 我们将对即刻早期基因进行逆行追踪和原位杂交 确定背侧瘦素反应神经元支配中枢神经系统的部位 中缝核团。最后，采用逆行追踪和免疫组织化学的方法 在芬氟拉明给药后，我们将测定该化学物质 调节5-羟色胺激活神经元的身份和中枢神经系统部位 食物摄入量。