Modulation of feeding by dopamine and serotonin in Drosophila

描述(由申请者提供)：饲养规则是确保动物摄入的卡路里与其能量需求成比例的关键。调节进食的神经调节系统的失衡可能会导致肥胖和饮食失调，从而产生与健康相关的重大后果。这项提议的长期目标是增加对调节食物摄入的分子信号通路以及它们如何相互作用的理解，这对于设计合理的方法来控制肥胖和饮食失调至关重要。单胺类神经递质--多巴胺和5-羟色胺--则相反地调节进食。在哺乳动物中，多巴胺促进摄食，而5-羟色胺则抑制摄食。对这一提议的初步研究表明，多巴胺和5-羟色胺调节果蝇的摄食，并确定了促进摄食的多巴胺能神经元和抑制摄食的5-羟色胺能神经元。果蝇神经系统的相对简单为剖析多巴胺和5-羟色胺如何相反地调节摄食提供了一个易于处理的模型。目的1研究5-羟色胺能神经元的活动是否在外部味觉提示和内部生理状态下双向控制摄食行为。目标2将检验这一假设，即多巴胺和5-羟色胺在短时间内调节进食，以及在较长时间内根据内部生理状态调节进食。目标3将研究多巴胺和5-羟色胺是否是作用于相同或不同神经元以调节摄食的相反信号。所提出的分子遗传学、电生理和行为学方法将提供对多巴胺和5-羟色胺功能的全面分析，这在其他系统中是难以实现的。这些研究将为我们深入了解 单胺能神经递质系统对摄食进行控制，并将显著促进对摄食调节的理解，摄食调节是与人类健康和疾病相关的重要基础。

DESCRIPTION (provided by applicant): Feeding regulation is essential to ensure that animals consume calories in proportion to their energy requirements. An imbalance of neuromodulatory systems that regulate feeding may result in obesity and eating disorders, with significant health-related consequences. The long-term objective of this proposal is to increase understanding of the molecular signaling pathways that regulate food intake and how they interact, crucial for devising rational approaches toward controlling obesity and eating disorders. The monoaminergeric neurotransmitters, dopamine and serotonin, oppositely regulate feeding. In mammals, dopamine promotes feeding and serotonin inhibits it. Preliminary studies of this proposal showed that dopamine and serotonin regulate feeding in the fruit fly Drosophila melanogaster and identified the dopaminergic neurons that promote feeding and serotonergic neurons that inhibit feeding. The relative simplicity of the fruit fly nervous system provides a tractable model to dissect how dopamine and serotonin oppositely regulate feeding. Aim 1 will examine whether the activity of serotonergic neurons bidirectionally controls feeding behavior in response to external gustatory cues and internal physiological state. Aim 2 will test the hypothesis that dopamine and serotonin act over short timescales to regulate feeding during a meal as well as over longer timescales to adjust feeding based on internal physiological state. Aim 3 will examine whether dopamine and serotonin are opponent signals that act on the same or different neurons to modulate feeding. The proposed molecular genetic, electrophysiological and behavioral approaches will provide a comprehensive analysis of dopamine and serotonin function that is difficult to achieve in other systems. These studies will provide insight into how the monoaminergic neurotransmitter systems exercise control over feeding and will significantly advance understanding of feeding modulation, an essential foundation relevant for human health and disease.