Signals to Feed: Biological and Associative Mechanisms

描述（由申请人提供）：肥胖和认知性痴呆似乎没有什么共同之处，除了两者都可能产生严重的健康后果，而且迄今为止两者都对治疗干预具有高度抗性。传统上，研究人员认为肥胖和代谢综合征的问题，一方面和认知痴呆，涉及不同的病因，针对不同的潜在行为和生物功能，并依赖于很大程度上独立的大脑结构和电路。然而，最近的流行病学调查结果表明，中年肥胖与老年人出现阿尔茨海默病和其他严重认知障碍之间存在联系。这些发现鼓励了肥胖可能与认知障碍有因果关系的假设。使用啮齿动物模型，本项目将探索（可能违反直觉的）过度能量摄入导致肥胖和相关代谢紊乱（例如，糖尿病、高血压）是干扰学习和记忆过程的结果。基于先前对我们工作的支持的结果，我们已经开发了一个模型，该模型描述了包括人类在内的动物使用对应于“饱腹感”的内部线索来发出信号的能力的基础学习和记忆机制，当食物和与食物相关的线索将被食欲或期望的摄食后（即，口服后）刺激。我们的研究表明，这种类型的信号可以通过以下方式降解：（1）食用甜味的无热量或低热量的食物/流体，这可能会削弱食物的口腔感觉特性与进食的热量或营养后果之间的正常强预测关系;（2）食用损害大脑结构功能的饮食（即，海马体），这是大鼠使用饱腹感线索来预测何时进食会或不会产生强化的摄食后结果的能力的基础。降低这些学习机制的运作的结果是过量摄入和体重。目前的研究将检查学习控制机制是否在没有明确的实验室训练的情况下发展，高脂肪饮食的消费是否会干扰这些机制，以及这种干扰是否有可能产生显着的体重增加。这些研究有望产生关于饮食因素在肥胖和认知能力下降中的作用的重要新信息。

DESCRIPTION (provided by applicant): Obesity and cognitive dementia may seem to have little in common other than both can have severe health consequences and both have so far been highly resistant to therapeutic interventions. Traditionally, investigators have viewed the problems of obesity and metabolic syndrome, on one hand and cognitive dementia on the other, as involving distinct etiologies, that target different underlying behavioral and biological functions, and that rely on largely separate brain structures and circuits. However, recent epidemiological findings point to a link between obesity in mid-life and the emergence of Alzheimer's disease and other serious cognitive impairments in the aged. These findings have encouraged the hypothesis that obesity may be causally-linked to cognitive impairment. Using a rodent model, this present project will explore (the perhaps counter-intuitive) idea that excessive energy intake leading to obesity and related metabolic disorders (e.g., diabetes, hypertension) is a consequence of interference with learning and memory processes. Based on the results of prior support for our work, we have developed a model that describes the learning and memory mechanisms that underlie the ability of animals, including humans, to use internal cues corresponding to "satiety" to signal when food and cues related to food will be followed by appetitive or desirable postingestive ( i.e., post oral) stimulation. Our research indicates that this type of signaling can be degraded by (1) the consumption of sweet no- or reduced-calorie foods/fluids that may weaken t he normally strong predictive relationship between the orosensory properties of food and the caloric or nutritive consequences of eating ; (2) consuming diets that impair the functioning of a brain structure (i.e., the hippocampus) that underlies the ability of rats to use their satiety cues to predict when eating food will or will not produce reinforcing postingestive outcomes. A result of degrading the operation of these learning mechanisms is excess intake and body weight. The present research will examine whether learned control mechanisms develop without explicit laboratory training, whether consumption of high-fat diets interferes with these mechanisms, and whether this interference has potential to produce significant weight gain. These studies promise to yield important new information about the role of dietary factors in both obesity and cognitive decline.