Hippocampal inhibition and obesity

海马抑制与肥胖

• 批准号: 7300555
• 负责人: TERRY L DAVIDSON
• 金额: $ 16.02万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7300555
• 关键词: Accounting; Appetitive Behavior; Attention; Behavior; Behavioral; Biochemical; Body Weight; Brain; Brain region; Canned Foods; Cell Nucleus; Cholecystokinin; Consummatory Behavior; Consumption; Cues; Data; Dietary Factors; Dietary Fats; Disruption; Dorsal; Eating; Eating Behavior; Elevation; Energy Intake; Energy Metabolism; Equilibrium; Failure; Feeding behaviors; Food; Food Intake Regulation; General Population; Genetic; Hippocampus (Brain); Hormonal; Human; Hyperphagia; Hypothalamic structure; Incidence; Insulin; Intake; Laboratories; Lead; Learning; Learning Disorders; Leptin; Lesion; Link; Memory; Metabolic; Modeling; Neurohormones; Neuropeptides; Obesity; Operative Surgical Procedures; Output; Overweight; Pathology; Performance; Physiological; Play; Prefrontal Cortex; Process; Protein Synthesis Inhibition; Publishing; Rate; Rattus; Regulation; Reporting; Research; Research Personnel; Role; Signal Transduction; Structure; Structure of nucleus infundibularis hypothalami; System; Thinking; Weight Gain; Work; base; energy balance; interest; memory process; neurochemistry; novel; relating to nervous system; response; stem; sugar

At a simple behavioral level, food intake and body weight regulation depend on one's ability to balance the tendency to seek out and consume food with the ability to suppress or inhibit those responses. Accordingly, any factor that augments the tendency to engage in food seeking and eating or that interferes with the suppression of these behaviors could produce caloric intake at a level in excess of caloric need. The global objective of this project is to develop and evaluate a model that describes how failures in the ability to inhibit appetitive and ingestive behaviors might occur. Much research on the causes of overeating and excessive weight gain has been directed at identifying the brain regions where metabolic and hormonal signals that stimulate or suppress intake are detected and utilized. The hypothalamus has received the most attention by far as a substrate for the control of food intake and body weight regulation. Early interest in the hypothalamus stemmed from findings that dramatic elevations or reductions in eating and body weight could be produced by lesioning specific hypothalamic nuclei (124). More recently, many studies have identified the hypothalamus, especially the arcuate nucleus, as a target for neuropeptide signals that can produce marked changes in eating and body weight when manipulated experimentally (e.g., (79, 118). Since the mid-1960s, several thousand reports have been published investigating the potential role of various hypothalamic nuclei in the regulation of food intake and body weight. Unfortunately, clear links between the function of the hypothalamus and current alarming increases in the incidence of obesity in the general population (e.g., (45, 57) have not yet been identified. For example, relatively few cases of overweight or obesity in humans seem to involve hypothalamic pathologies or malfunctioning hypothalamic signaling systems. Thus, although, surgical, genetic, and pharmacological manipulations of the hypothalamus can have profound effects on energy regulation in laboratory settings, it is not clear that disruption in hypothalamic function can account for the reduced regulatory control that is occurring outside of the laboratory. Moreover, although eating can be stimulated or suppressed by experimentally manipulating the hypothalamus or the signals it detects, the mechanisms that convert hypothalamic outputs to specific decisions to eat or to refrain from eating remain largely unspecified. Common practice has been to describe the link between hypothalamic activity and eating behavior with nothing more than an arrow or a "+" or "-"in a diagram (e.g., (14, 137) This project will approach the problem of obesity from a different, and we think novel, perspective. We start with the idea that overweight and obesity stems from a failure or degradation of mechanisms that normally function to inhibit eating behavior. Unlike previous approaches, we will not focus directly on failures of physiological (e.g., neural, hormonal) inhibitory control mechanisms, but on disruptions of learned or environmental controls that help to regulate energy intake. Our view of overeating as a type of "learning disorder" leads us away from the hypothalamus as focal point for regulatory control, to the hippocampus, a brain structure that has long been regarded as an important substrate for learning and memory (43, 122) and which we think may be critically involved with a specific type of learning that could contribute much to the inhibition of food intake (30). With this new focus, the search for an environmental basis for obesity will now be directed toward factors that have been shown to alter hippocampal functioning. For example, increased incidence of overweight and obesity have been linked by some researchers to increased consumption of dietary fat and/or processed sugars (i.e., "junk" foods). We will pay special attention to these dietary factors because they have also been linked recently to altered biochemical and electrophysiological activity (91) in the rat hippocampus and to impaired performance on certain hippocampal-dependent learning tasks (53). One implication of these findings is that if consumption of inexpensive, highly palatable, high calorie foods can impair brain functions that help to inhibit caloric intake, it is conceivable that one consequence might be increased consumption of those foods¿ a type of "vicious" circle" that could lead to continued increases in obesity rates. Each of the following specific aims will assess important aspects of this model of the inhibitory control of energy intake.

在一个简单的行为水平上，食物摄入和体重调节取决于一个人平衡体重的能力。 倾向于寻找和消耗具有抑制或抑制这些反应的能力的食物。因此，委员会认为， 任何增加寻求食物和进食的倾向或干扰抑制的因素 这些行为中的一种可能会产生超过热量需求的热量摄入。全局目标 该项目的目的是开发和评估一个模型，该模型描述了抑制食欲的能力如何失败， 可能会发生摄食行为。 许多关于暴饮暴食和体重过度增加的原因的研究都是针对确定 大脑区域，其中刺激或抑制摄入的代谢和激素信号被检测和利用。 到目前为止，下丘脑作为控制食物摄入的底物受到了最多的关注， 体重调节。早期对下丘脑的兴趣源于发现， 通过损伤特定的下丘脑核团可以减少进食和体重（124）。更 近年来，许多研究发现下丘脑，尤其是弓状核，是神经肽的作用靶点 当实验操作时，可以产生饮食和体重显着变化的信号 (e.g., (79，118）。自20世纪60年代中期以来，已有数千份报告发表，调查了 各种下丘脑核团在调节食物摄入和体重中的作用。 不幸的是，下丘脑的功能与目前令人担忧的脑内 普通人群中肥胖症的发病率（例如，(45 57、还没有被发现。例如相对 人类超重或肥胖的少数病例似乎涉及下丘脑病变或功能障碍 下丘脑信号系统因此，虽然，外科手术，遗传学和药理学操作， 在实验室环境中，下丘脑可以对能量调节产生深远的影响，但目前尚不清楚这种干扰是否 在下丘脑功能可以解释减少的调节控制，是发生在外部的 实验室此外，尽管通过实验性地操纵胃， 下丘脑或它检测到的信号，将下丘脑输出转换为特定决定的机制 吃或不吃仍然在很大程度上不明确。通常的做法是描述 下丘脑活动和饮食行为，只不过是图中的箭头或“+”或“-” (e.g., (14，137） 这个项目将从一个不同的，我们认为新颖的角度来解决肥胖问题。我们 首先，超重和肥胖源于正常机制的失效或退化， 抑制进食行为的功能。与以前的方法不同，我们将不直接关注生理学上的失败， (e.g.,神经，激素）抑制控制机制，但对中断的学习或环境 有助于调节能量摄入的控制。我们认为暴饮暴食是一种“学习障碍”， 从作为调节控制的焦点的下丘脑到海马体，海马体是一种大脑结构， 长期以来一直被认为是学习和记忆的重要基质（43，122），我们认为这可能 批判性地参与一种特定类型的学习，这可能有助于抑制食物摄入 （30）.有了这个新的焦点，对肥胖的环境基础的研究现在将被导向因素 已经被证明可以改变海马体的功能。例如，超重的发生率增加， 一些研究人员认为肥胖与膳食脂肪和/或加工糖的消耗量增加有关 (i.e.,“垃圾”食品）。我们将特别注意这些饮食因素，因为它们也被 最近与大鼠海马中改变的生物化学和电生理活动以及受损的 在某些与夏令营相关的学习任务上的表现（53）。这些发现的一个含义是， 如果消费廉价、美味、高热量的食物会损害大脑功能， 抑制热量摄入，可以想象，一个后果可能是增加这些食物的消费。 这是一种可能导致肥胖率持续上升的“恶性循环”。以下各项具体 AIMS将评估这种能量摄入抑制控制模型的重要方面。