GENETIC APPROACHES TO SEROTONIN AND FEEDING BEHAVIOR

描述：（改编自研究者摘要）脑血清素系统 与正常摄食行为的调节和 进食障碍中观察到的进食失调。几行 有证据表明5-羟色胺5-HT 2C受体亚型 显著抑制食物摄入的肾上腺素能。符合 因此，缺乏功能性setotonin 5-HT 2C受体的小鼠显示出降低的 对通过血清素系统起作用的食欲抑制药物的敏感性。 此外，这些动物表现出进食行为的失调， 食物摄入量的慢性增加，晚发性（“中年”）肥胖， 2型糖尿病的易感性增加。这种肥胖症的几个特征 综合征让人联想到人类的常见症状。拟 5-HT 2C受体突变体提供了一种独特的遗传模型， 是由摄食行为的主要缺陷引起的，而不是直接影响 能量消耗的突变。除了验证这一假设外， 5-HT 2C受体调节摄食的神经机制将是 探讨了在目标1中，将进行摄食行为的详细研究， 测试假设5-HT 2C受体突变体补偿其 通过增加能量消耗而暴饮暴食， 因年龄原因未能维持该补偿。在目标3中， 5-羟色胺系统补偿5-HT 2C受体的机制 突变将被探索。将特别注意潜在的 5-HT 1B受体的补偿，包括摄食行为和 缺乏5-HT 2C和5-HT 1B的“双突变”小鼠的能量平衡 受体亚型目标4的研究将确定大脑区域和发射器 5-HT 2C受体可能通过这些系统调节进食。假设 目标4的结果产生的结果将在目标5中通过 5-HT 2C受体突变定位于 限制了大脑区域和细胞类型

DESCRIPTION: (Adapted from the Investigator's Abstract) Brain serotonin systems are strongly implicated in the regulation of normal feeding behavior and in the dysregulation of feeding observed in eating disorders. Several lines of evidence indicate that serotonin 5-HT2C receptor subtype contributes significantly to the serotonergic inhibition of food intake. Consistent with this, mice lacking functional setotonin 5-HT2C receptors display reduced sensitivity to appetite suppressant drugs that act through serotonin systems. In addition, these animals exhibit a dysregulation of feeding behavior leading to chronic elevations of food intake, late-onset ('middle-age") obesity and enhanced susceptibility to type 2 diabetes. Several features of this obesity syndrome are reminiscent of common forms of the human condition. It is proposed that 5-HT2C receptor mutants provide a unique genetic model in which obesity results from a primary defect in feeding behavior rather than a direct effect of the mutation on energy expenditure. In addition to testing this hypothesis, the neural mechanisms through which 5-HT2C receptors regulate feeding will be explored. In Aim 1, detailed studies of feeding behavior will be performed to test the hypothesis that 5-HT2C receptor mutants compensate for their overeating by increasing energy expenditure and that subsequent obesity results from an age dependent failure to maintain this compensation. In aim 3, mechanisms through which serotonin systems compensate for the 5-HT2C receptor mutation will be explored. Particular attention will be paid to potential compensation by the 5-HT1B receptor, including studies of feeding behavior and energy balance in "double-mutant" mice lacking both the 5-HT2C and 5-HT1B receptor subtypes. Studies of Aim 4 will identify brain regions and transmitter systems through which 5-HT2C receptors may regulate feeding. Hypotheses generated from the results of aim 4 will be tested in Aim 5 through the development of mice in which 5-HT2C receptor mutations are localized to restricted brain regions and cell types.