BEHAVIORAL PHYSIOLOGY OF BODY WEIGHT REGULATION

描述(申请人提供)：目前美国肥胖症的流行被归因于过去20年来发生的环境变化。这方面最突出的是经济上现成的、美味的、高热量密度的食物。虽然许多研究都集中在胰岛素和瘦素等激素以及神经递质上，这些激素作用于下丘脑内侧，以调节卡路里的摄取，但很少有人关注中枢神经系统(CNS)回路的潜在调节，该回路调节食物的奖励或激励方面。这个回路包括中脑多巴胺神经元(DA)以及其他前脑区域，内侧下丘脑与这些区域有广泛的直接和间接联系。我们的实验室有证据表明，肥胖候选信号胰岛素和瘦素会降低在评估食物奖励和需要DA信号的行为任务中的表现。我们假设，胞体位于腹侧被盖区的中脑DA神经元是胰岛素和瘦素的直接靶点。在这项提议中，我们将通过研究直接注入VTA的胰岛素或瘦素对评估食物奖励/动机的不同方面的行为程序的影响，在大鼠身上验证这一假说：自由喂养的摄食任务、条件化的位置偏好和自我给药。我们将在这些任务中比较甜食和脂肪食物的奖励，以评估常量营养素的特异性。我们将胰岛素受体反义寡核苷酸直接注入VTA，以确定内源性胰岛素信号在调节食物奖励行为中的作用。由于VTA DA神经元表达胰岛素和瘦素受体，我们将测量胰岛素和瘦素对PI3激酶通路的刺激，作为在细胞水平上直接激活VTA的指标。类似的研究将在喂食定义的高脂肪饮食零食的大鼠身上进行，食物是我们最近开发的一种中枢神经系统胰岛素抵抗模型。我们将使用这个模型来测试VTA胰岛素和/或瘦素的行为和细胞活动是否会因高脂肪饮食摄入而减弱，即VTA胰岛素或瘦素抵抗的模型。总之，这些研究将评估肥胖信号对中枢神经系统奖赏回路和功能的潜在调节。这些研究的发现将有助于实现长期目标，即了解食物奖励价值的改变是否会导致(相对)暴饮暴食，这种暴饮暴食是与高度美味的食物的供应相关的，而不是与热量需求无关。

DESCRIPTION (provided by applicant): The current 'epidemic' of obesity in the United States has been ascribed to environmental changes that have occurred over the past two decades. Prominent in this is the ready economic availability of highly palatable, high caloric density foods. Although numerous studies have focused on hormones such as insulin and leptin, and neurotransmitters, which act at the medial hypothalamus to regulate calorie intake, little attention has focused on the potential regulation of central nervous system (CNS) circuitry which mediates the rewarding or motivating aspects of food. This circuitry includes the midbrain dopamine neurons (DA) as well as other forebrain areas with which the medial hypothalamus has extensive direct and indirect connections. Our lab has evidence that the candidate adiposity signals insulin and leptin decrease performance in behavioral tasks that assess food reward and that require DA signaling. We hypothesize that the midbrain DA neurons whose cell bodies are in the ventral tegmental area (VTA) serve as a direct target for insulin and leptin. In this proposal we will test this hypothesis in rats by studying the effects of insulin or leptin infused directly into the VTA on behavioral procedures that evaluate different aspects of food reward/motivation: a free-feeding ingestive task, the conditioned place preference, and self-administration. We will compare sweet vs. fat food reward in these tasks, to evaluate macronutrient specificity. We will infuse insulin receptor antisense oligonucleotides directly into the VTA to determine the role of endogenous insulin signaling in modulation of food reward behavior. Because VTA DA neurons express insulin and leptin receptors, we will measure insulin- and leptin-stimulation of the PI3 kinase pathway as an index of direct VTA activation at the cellular level. Comparable studies will be carried out in rats fed a defined high fat diet snack in addition to chow, a model of CNS insulin resistance that we have recently developed. We will use this model to test whether the behavioral and cellular actions of insulin and/or leptin at the VTA are blunted by high fat diet ingestion, i.e., a model of VTA insulin or leptin resistance. Together these studies will evaluate the potential regulation of reward circuitry and function in the CNS by adiposity signals. Findings from these studies will contribute to the long-term goal of learning whether altered food reward value contributes to the (relative) overeating which occurs in association with the availability of highly palatable foods, independent of caloric need.