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.

在简单的行为层面上，食物摄入和体重调节取决于一个人平衡饮食的能力。 倾向于寻找和食用能够抑制或抑制这些反应的食物。 任何增加寻求食物和进食倾向或干扰抑制的因素 这些行为可能导致热量摄入超过全球目标。 该项目的目的是开发和评估一个模型，该模型描述抑制食欲的能力如何失败 并且可能会出现摄入行为。 关于暴饮暴食和体重过度增加的原因的许多研究都旨在确定 检测和利用刺激或抑制摄入的代谢和激素信号的大脑区域。 到目前为止，下丘脑作为控制食物摄入和营养的基质而受到最多的关注。 早期对下丘脑的兴趣源于体重急剧升高或体重调节的发现。 通过损害特定的下丘脑核团可以减少进食和体重（124）。 最近，许多研究已经确定下丘脑，尤其是弓状核，作为神经肽的靶点 通过实验操作可以产生饮食和体重显着变化的信号 （例如，(79, 118)。自 20 世纪 60 年代中期以来，已经发表了数千份报告来调查潜在的 下丘脑各个核团在调节食物摄入和体重中的作用。 不幸的是，下丘脑的功能与当前令人震惊的增加之间有明显的联系。 一般人群中肥胖的发生率（例如，(45, 57) 尚未确定。例如，相对 人类超重或肥胖的病例很少涉及下丘脑病变或功能障碍 因此，尽管如此，手术、遗传和药理学操作。 下丘脑可以对实验室环境中的能量调节产生深远的影响，但目前尚不清楚是否会受到干扰 下丘脑功能中的变化可以解释发生在下丘脑之外的调节控制的减少 此外，尽管可以通过实验操纵来刺激或抑制进食。 下丘脑或其检测到的信号，将下丘脑输出转化为特定决策的机制 吃或不吃在很大程度上仍然没有具体说明，通常的做法是描述之间的联系。 下丘脑活动和饮食行为只不过是图中的箭头或“+”或“-” （例如，(14, 137) 该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。 首先，超重和肥胖源于正常机制的失败或退化。 与以前的方法不同，我们不会直接关注生理的失败。 （例如，神经、激素）抑制控制机制，但基于学习或环境的破坏 我们认为暴饮暴食是一种“学习障碍”，有助于调节能量摄入。 远离作为调节控制焦点的下丘脑，到海马体，这是一种大脑结构， 长期以来一直被认为是学习和记忆的重要基础 (43, 122)，我们认为这可能是 批判性地参与特定类型的学习，这可能有助于抑制食物摄入 (30) 有了这个新的焦点，肥胖的环境基础的研究将转向一些因素。 已被证明会改变海马功能，例如，超重和体重增加的发生率增加。 一些研究人员将肥胖与加工膳食脂肪和/或糖的摄入量增加联系起来 （即“垃圾”食品）。我们将特别关注这些饮食因素，因为它们也已被 最近与大鼠海马的生化和电生理活动改变（91）以及受损有关 这些发现的一个含义是在某些依赖于海马的学习任务上的表现。 如果食用廉价、美味、高热量的食物会损害大脑功能，而大脑功能则有助于 抑制热量摄入，可以想象，后果之一可能是增加这些食物的摄入量。 一种可能导致肥胖率持续上升的“恶性”循环。以下各项具体情况 目标将评估该能量摄入抑制控制模型的重要方面。