BEHAVIORAL PHYSIOLOGY OF BODY WEIGHT REGULATION

饮食构成在人类肥胖的发生发展中起着重要作用。在啮齿动物中发现了饮食肥胖的遗传倾向，肥胖个体表现出与瘦个体不同的食物偏好。在啮齿动物模型中，饮食诱导的肥胖与对外部注射候选肥胖信号胰岛素的敏感性降低有关。这表明，由于食用非常可口的、高能量的饮食，存在一些不同--代谢、神经化学或两者都有--导致身体肥胖的生理调节发生变化。中枢神经系统中脑边缘多巴胺(DA)神经元的激活与包括食物在内的几类刺激的增强或奖励方面有关。我们已经获得了初步证据表明，胰岛素可以在突触水平和行为水平下调这些DA神经元的活动。在这个提议中，我们继续假设这些神经元的活动与饮食肥胖相关，并且存在胰岛素诱导的DA神经元活动下调的损失。为了验证这一假设，我们将评估与DA有关的两个行为任务的表现：甜味和脂肪溶液的舔速率，以及条件性位置偏爱(CPP)范式；体内微透析从中脑边缘DA神经元释放DA；以及使用我们建立的方法，改变DA释放的细胞机制。所有研究将利用正常体重和饮食肥胖大鼠(包括近交系大鼠和近交系饮食诱导肥胖(DIO)/饮食肥胖抵抗(DR)大鼠，它们患饮食性肥胖的倾向在基因上是不同的)，并注入脑室(IVT)载体或胰岛素。总之，这些研究将评估候选肥胖信号与与奖励相关的大脑通路相互作用的能力，以及美味的高能饮食对中脑边缘DA神经元的功能和调节的影响。

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.