Signals to Feed: Biological and Associative Mechanisms

描述(申请人提供)：肥胖症和认知性痴呆症似乎没有什么共同之处，除了两者都会造成严重的健康后果外，到目前为止，两者都高度抵制治疗干预。传统上，研究人员认为肥胖和代谢综合征以及认知痴呆症的问题涉及不同的病因，针对不同的潜在行为和生物功能，并在很大程度上依赖于不同的大脑结构和回路。然而，最近的流行病学发现指出，中年肥胖与阿尔茨海默病和老年人其他严重认知障碍的出现之间存在联系。这些发现支持了一种假设，即肥胖可能与认知障碍存在因果关系。使用啮齿动物模型，本项目将探索(可能与直觉相反的)观点，即过度摄入能量会导致肥胖和相关的代谢紊乱(如糖尿病、高血压)，这是学习和记忆过程受到干扰的结果。基于先前对我们工作的支持结果，我们开发了一个模型，该模型描述了动物(包括人类)使用与“饱腹感”相对应的内部线索来发出信号时，何时会在食物和与食物相关的线索之后出现食欲或理想的进食后(即口腔后)刺激的能力所依据的学习和记忆机制。我们的研究表明，这种类型的信号可能会被以下因素削弱：(1)摄入甜味的无卡路里或低卡路里食物/液体，这可能会削弱食物的味觉特性与进食的卡路里或营养后果之间通常很强的预测关系；(2)食用损害大脑结构(即海马体)功能的饮食，而大脑结构是大鼠使用饱腹感提示来预测何时进食将产生或不会产生强化的进食后结果的能力的基础。这些学习机制的运作退化的结果是过量摄入和体重。目前的研究将检查是否在没有明确的实验室训练的情况下学习控制机制的形成，高脂饮食的摄入是否干扰这些机制，以及这种干扰是否有可能产生显著的体重增加。这些研究有望为饮食因素在肥胖和认知能力下降中的作用提供重要的新信息。 公共卫生相关性：肥胖和认知能力下降都是对公共健康和生活质量的严重威胁。这个项目将探索这两种疾病都有共同的环境起源和大脑基础的可能性。还将研究特定学习过程中的干扰会导致肥胖的观点。

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. PUBLIC HEALTH RELEVANCE: Obesity and cognitive decline are both serious threats to the public health and to the of quality life. This project will explore the possibility that both of these disorders have common environmental origins and brain substrates. The idea that disruption in a specific learning process gives rise to obesity will also be examined.