HIPPOCAMPAL INHIBITION AND OBESITY

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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.