At a simple behavioral level, food intake and body weight regulation depend on one's ability to balance thetendency 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 suppressionof these behaviors could produce caloric intake at a level in excess of caloric need. The global objectiveof this project is to develop and evaluate a model that describes how failures in the ability to inhibit appetitiveand ingestive behaviors might occur.Much research on the causes of overeating and excessive weight gain has been directed at identifying thebrain 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 andbody weight regulation. Early interest in the hypothalamus stemmed from findings that dramatic elevations orreductions in eating and body weight could be produced by lesioning specific hypothalamic nuclei (124). Morerecently, many studies have identified the hypothalamus, especially the arcuate nucleus, as a target for neuropeptidesignals 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 potentialrole 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 theincidence of obesity in the general population (e.g., (45, 57) have not yet been identified. For example, relativelyfew cases of overweight or obesity in humans seem to involve hypothalamic pathologies or malfunctioninghypothalamic signaling systems. Thus, although, surgical, genetic, and pharmacological manipulations ofthe hypothalamus can have profound effects on energy regulation in laboratory settings, it is not clear that disruptionin hypothalamic function can account for the reduced regulatory control that is occurring outside of thelaboratory. Moreover, although eating can be stimulated or suppressed by experimentally manipulating thehypothalamus or the signals it detects, the mechanisms that convert hypothalamic outputs to specific decisionsto eat or to refrain from eating remain largely unspecified. Common practice has been to describe the link betweenhypothalamic 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. Westart with the idea that overweight and obesity stems from a failure or degradation of mechanisms that normallyfunction 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 environmentalcontrols that help to regulate energy intake. Our view of overeating as a type of 'learning disorder' leads usaway from the hypothalamus as focal point for regulatory control, to the hippocampus, a brain structure thathas long been regarded as an important substrate for learning and memory (43, 122) and which we think maybe 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 factorsthat have been shown to alter hippocampal functioning. For example, increased incidence of overweight andobesity 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 beenlinked recently to altered biochemical and electrophysiological activity (91) in the rat hippocampus and to impairedperformance on certain hippocampal-dependent learning tasks (53). One implication of these findings isthat if consumption of inexpensive, highly palatable, high calorie foods can impair brain functions that help toinhibit 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 specificaims will assess important aspects of this model of the inhibitory control of energy intake.
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