Leptin Receptor Signaling and Function in Dopamine Neurons

描述(申请人提供)：肥胖在大多数工业化国家日益普遍，导致了严重的健康并发症，如心脏病和癌症。问题的根源在于，当我们面对过量食物时，我们无法控制食物的摄入量。动物模型，包括啮齿动物，也同样无法控制摄入量，当暴露在过量的丰富食物中时，会增加体重。重要的是要了解大脑的奖赏和动机回路是如何调节食物摄入量的，以及导致肥胖的功能障碍的本质。食物摄入量受到从身体传递到大脑的信号的影响，在识别瘦素激素等向大脑发出信号以调节食物摄入量的分子方面取得了相当大的进展。瘦素由体内的脂肪细胞分泌，用于将外周脂肪储存的状态传达给大脑。确定通过直接作用于瘦素受体来对瘦素做出反应的完整大脑回路是至关重要的。虽然目前的大多数研究都集中在下丘脑的瘦素受体功能上，但我们已经证明，瘦素直接向中脑的多巴胺神经元发出信号，以减少摄食行为。相反，多巴胺神经元中瘦素受体活性的降低会导致食物摄入量的增加。这些腹侧被盖区(VTA)多巴胺神经元被认为是动机行为的重要调节器，在药物成瘾的发展过程中发挥着特别重要的作用。在这项建议中，将使用生化和基因组技术来阐明VTA神经元中瘦素受体信号转导的机制。此外，还将探讨瘦素向VTA传递信号的神经回路和行为后果。对VTA中瘦素作用的表征将使我们更好地理解瘦素如何调节神经元，从而导致食物摄入量和一般动机行为的变化。此外，确定瘦素受体信号下游的分子通路也将阐明与VTA中的多巴胺神经元内其他关键信号通路的潜在相互作用。这些研究将对瘦素在大脑中的作用产生更全面的了解，并将有助于我们全面了解控制摄食行为的大脑回路。与公共卫生相关：在大多数工业化国家，肥胖症的流行日益普遍，导致了心脏病和癌症等严重的健康并发症。这一建议试图了解我们的身体通过荷尔蒙信号调节食物摄入量和进食动机的神经和分子机制。通过定义这些关键分子和神经机制，我们增加了对肥胖的理解，并确定了药物开发的可能靶点。

DESCRIPTION (provided by applicant): The increasing prevalence of obesity in most industrialized nations has contributed to significant health complications, such as heart disease and cancer. At the source of the problem is our inability to control food intake when presented with excess food. Animal models, including rodents, suffer from the same inability to control intake and will gain weight when exposed to rich food in excess. It is important to understand how reward and motivation circuits of the brain regulate food intake and the nature of the dysfunction that causes obesity. Food intake is influenced by signals that travel from the body to the brain and considerable progress has been made toward identifying molecules, such as the leptin hormone, that signal the brain to modulate food intake. Leptin is secreted from fat cells in the body and serves to communicate the state of peripheral fat stores to the brain. It is critical to define the complete brain circuits that respond to leptin via direct action on its receptor. While most current research has focused on leptin receptor function within the hypothalamus, we have demonstrated that leptin signals directly to dopamine neurons of the midbrain to reduce feeding behavior. Conversely, reduction in leptin receptor activity in dopamine neurons leads to increased food intake. These ventral tegmental area (VTA) dopamine neurons are known to be important modulators of motivated behavior and play a particularly important role in the development of drug addiction. In this proposal, biochemical and genomic techniques will be used to elucidate the mechanism of leptin receptor signaling in VTA neurons. In addition, the neural circuits and behavioral consequences of leptin signaling to the VTA will be explored. Characterization of leptin effects in the VTA will produce a better understanding of how leptin modulates neurons to result in changes in food intake and general motivated behavior. In addition, defining the molecular pathways downstream of leptin receptor signaling will also elucidate potential interactions with other critical signaling pathways within the dopamine neurons of the VTA. These studies will generate a more complete understanding of leptin action in the brain and will contribute to our overall understanding of brain circuits that control ingestive behavior. PUBLIC HEALTH RELEVANCE: The increasing prevalence of obesity in most industrialized nations has contributed to significant health complications, such as heart disease and cancer. This proposal seeks to understand the neural and molecular mechanisms by which our body, via hormonal signals, regulates our food intake and motivation to eat food. By defining these critical molecules and neural mechanisms, we increase our understanding of obesity and identify possibly targets for drug development.