BEHAVIORAL PHYSIOLOGY OF BODY WEIGHT REGULATION

饮食结构在人类肥胖的发展中起着重要作用。 在啮齿类动物中已经确定了饮食性肥胖的遗传倾向，肥胖个体表现出与瘦个体食物偏好的差异。 在啮齿动物模型中，饮食诱导的肥胖与候选肥胖信号胰岛素的外源性给药敏感性降低相关。 这表明，一些差异-代谢，神经化学，或两者-作为一个结果，吃一个非常可口，高能量的饮食是存在的，导致身体肥胖的生理调节的变化。中枢神经系统中脑边缘多巴胺（DA）神经元的激活涉及几类刺激（包括食物）的强化或奖励方面。 我们已经获得了初步的证据表明，胰岛素可以下调这些DA神经元的活动，无论是在突触水平和行为水平。 在这个建议中，我们追求的假设，这些神经元的活动改变与饮食性肥胖，并有一个损失的胰岛素诱导的下调DA神经元的活动。 为了验证这一假设，我们将评估表现在两个行为任务中，DA已牵连：舔率的甜和脂肪的解决方案，和条件性位置偏好（CPP）的范例;释放DA从中脑边缘DA神经元在体内微透析;和细胞机制改变DA释放，使用我们建立的方法。 所有研究均将使用正常体重和饮食性肥胖大鼠（远交系大鼠和近交系饮食诱导肥胖（DIO）/饮食性肥胖抵抗（DR）大鼠，其发生饮食性肥胖的倾向在基因型上不同），输注脑室内（IVT）溶媒或胰岛素。 总之，这些研究将评估候选肥胖信号与奖励相关的大脑通路相互作用的能力;以及可口的高能量饮食对中脑边缘DA神经元功能和调节的影响。

Diet composition plays a significant role in the development of human obesity. A genetic propensity towards dietary obesity has been identified in rodents, and obese individuals demonstrate differences in food preferences from lean individuals. In rodent models, dietary-induced obesity is associated with decreased sensitivity to exogenous administration of the candidate adiposity signal insulin. This suggests that some difference-metabolic, neurochemical, or both-as a consequence of eating a highly palatable, high energy diet is present, resulting in a change in the physiological regulation of body adiposity. Activation of the CNS mesolimbic dopamine (DA) neurons is implicated in the reinforcing or rewarding aspects of several classes of stimuli, including food. We have obtained preliminary evidence that insulin can downregulate the activity of these DA neurons, both at the level of the synapse and at the level of behavior. In this proposal, we pursue the hypothesis that activity of these neurons is altered in association with dietary obesity, and that there is a loss of insulin-induced downregulation of DA neuronal activity. To test this hypothesis, we will evaluate performance in two behavioral tasks in which DA has been implicated: lick rates of sweet and fat solutions, and the conditioned place preference (CPP) paradigm; release of DA from the mesolimbic DA neurons by in vivo microdialysis; and the cellular mechanisms underlying altered DA release, using our established methodologies. All studies will utilize normal weight and dietary obese rats (both outbred rats, and the inbred dietary-induced obese (DIO)/dietary obese-resistant (DR) rats, which are genotypically distinct in their propensity to develop dietary obesity), infused with intraventricular (IVT) vehicle or insulin. Together, these studies will evaluate the ability of a candidate adiposity signal to interact with brain pathways associated with reward; and the influence of palatable high energy diets on the function and regulation of the mesolimbic DA neurons.