GENETIC APPROACHES TO SEROTONIN AND FEEDING BEHAVIOR

描述：(改编自《调查者摘要》)大脑5-羟色胺系统 与正常摄食行为的调节密切相关 进食失调在饮食失调中观察到的进食失调。几行 有证据表明，5-HT2C受体亚型对 显著抑制5-羟色胺能抑制食物摄取。与一致 这一点，缺乏功能性5-HT2C受体的小鼠显示减少 对通过5-羟色胺系统起作用的食欲抑制药物敏感。 此外，这些动物表现出摄食行为失调，导致 到慢性食物摄入量增加、晚发性(中年)肥胖和 增加了对2型糖尿病的易感性。这种肥胖的几个特征 综合症使人联想到人类疾病的常见形式。有建议说 5-HT2C受体突变提供了一种独特的遗传模型，在这种模型中 由进食行为的主要缺陷造成，而不是直接影响 能量消耗上的突变。除了检验这一假设外， 5-HT2C受体调节摄食的神经机制将是 探索过了。在目标1中，将对摄食行为进行详细研究，以 验证5-HT2C受体突变体补偿其 通过增加能量消耗而过量饮食以及随之而来的肥胖 由于年龄原因，未能维持这一补偿。在《目标3》中， 5-羟色胺系统补偿5-HT2C受体的机制 我们将探索突变。将特别关注潜在的 5-HT1B受体的补偿，包括对摄食行为和 缺乏5-HT2C和5-HT1B的“双突变”小鼠的能量平衡 受体亚型。AIM 4的研究将确定大脑区域和递质 5-HT2C受体调节摄食的系统。假设 根据目标4的结果生成的数据将在目标5中通过 5-HT2C受体突变定位于小鼠的发育 大脑区域和细胞类型受到限制。

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.