Neurochemical mechanisms of bingeing on palatable foods

描述（由申请人提供）：肥胖目前对工业化国家的公众健康构成威胁，因此与NIMH的使命直接相关，即通过对大脑和行为的研究来减轻行为障碍的负担。这也与NIDDK利用基础科学研究影响公众健康的代谢和内分泌紊乱的使命有关。暴饮暴食美味食物是肥胖和其他饮食失调的一种行为特征，因此了解其行为背后的神经机制具有重要的临床意义。暴饮暴食可以诱发大脑的行为和改变，其效果类似于滥用药物；然而，人们对这种现象背后的神经化学或分子机制知之甚少。我的主要目标是学习和应用原位杂交、免疫组织化学、放射免疫测定和毛细管电泳技术，以识别和表征暴饮暴食和药物使用背后的一些常见神经机制。本研究将测量大脑中调节摄食行为和药物依赖的区域，即外侧下丘脑（LH）和伏隔核（NAc）中阿片和非阿片肽的表达以及氨基酸的释放。这些分析将作为对美味食物（脂肪与糖）的暴饮暴食与随意获取食物的比较进行。此外，将收集类固醇激素和脂质循环水平的测量，并将其与大脑中这些神经化学变化联系起来。我建议测试新的假设：1)LH中的阿片类物质和氨基酸与美味食物的大量营养素含量有关，独立于获取时间表，而在NAc中，它们与间歇性获取美味食物导致的暴饮暴食有关；2)这些脑区及其各自的功能通过LH中投射到NAc的非阿片类、促氧肽神经元群连接；3)循环中的类固醇和脂质，通过食用美味的高脂肪饮食而升高，调节LH和NAc的神经化学物质，从而促进暴饮暴食高脂肪食物的过程。这项研究将确定暴饮暴食与肥胖相关的一些神经和分子机制，这是一个重要的公共卫生问题。关于暴饮暴食高脂肪食物背后的大脑过程的信息将有助于开发减少这种行为并最终减少肥胖发生率的治疗方法。

DESCRIPTION (provided by applicant): Obesity currently poses a threat to public health in the industrialized nations and therefore is directly relevant to the mission of the NIMH to reduce the burden of behavioral disorders through research on the brain and behavior. It is also relevant to the mission of the NIDDK to study metabolic and endocrine disorders affecting public health using basic science. Binge eating of palatable foods is a behavioral characteristic of obesity and other eating disorders, making it of great clinical relevance and utmost importance to understand neural mechanisms underlying its behavior. Bingeing on palatable foods can induce behaviors and alterations in the brain that are similar to the effects of drugs of abuse; however, little is known about the neurochemical or molecular mechanisms underlying this phenomenon. The primary goal of this proposal is for me to learn and apply the techniques of in situ hybridization, immunohistochemistry, radioimmuno-assay and capillary electrophoresis to identify and characterize some common neural mechanisms underlying binge eating of palatable foods and drug use. This proposal will measure opioid and non-opioid peptide expression as well as amino acid release in areas of the brain that regulate both feeding behavior and drug dependence, namely, the lateral hypothalamus (LH) and nucleus accumbens (NAc). These analyses will be performed as a function of binge eating of palatable foods (fat vs. sugar) compared with ad libitum access to the food. In addition, measures of circulating levels of steroid hormones and lipids will be collected and related to these neurochemical changes in the brain. I propose to test the novel hypotheses that: 1) opioids and amino acids in the LH function in relation to the macronutrient content of a palatable food independent of access schedule, whereas in the NAc they function in relation to the binge eating resulting from intermittent access to a palatable food; 2) these brain regions and their respective functions are connected via a population of non-opioid, orexigenic peptide neurons in the LH that project to the NAc; 3) the circulating steroids and lipids, which are elevated by consumption of a palatable, high-fat diet, modulate the neurochemicals of the LH and NAc that contribute to the process of binge eating of fat- rich foods. This research will identify some neural and molecular mechanisms underlying binge eating associated with obesity, which is an important public health issue. Information about the processes in the brain underlying binge eating of fat-rich foods will be useful for developing treatments to reduce this behavior and ultimately the incidence of obesity.