When food and stimuli associated with food are encountered, these cues may evoke vigorous appetitive and consummatory responding on some occasions and little or no responding at other times. A common interpretation of this pattern of behavior is that animals engage in appetitive and eating behavior until they become satiated and then refrain from making these responses until satiety wanes [9
]. How does satiety inhibit, and the absence of satiety promote, appetitive responding?
The answer to this question may depend on an animal’s ability to resolve a predictable ambiguity by learning that satiety signals predict when food cues will not be followed by an appetitive postingestive US. In other words, just as experimentally programmed negative occasion setters resolve ambiguity by predicting when a CS will not be followed by its US, interoceptive satiety signals may resolve ambiguity by predicting when food cues will not be followed by appetitive postingestive outcomes [17
The ability of regulatory hormones to modulate the strength of appetitive behavior may also depend on their effects on hippocampal-dependent learning and memory processes. The hippocampus is densely populated with both leptin and insulin receptors [12
] and administration of each of these peptides has been shown to enhance both hippocampal-dependent spatial memory and hippocampal long-term potentiation (LTP) [18
], a reported cellular basis for learning and memory [21
]. Furthermore, mutant rats lacking CCK receptors not only become obese but also exhibit impaired hippocampal-dependent learning [22
]. Recent neuroanatomical findings also directly link the hippocampal CA1 cell field to hypothalamic nuclei and other brain circuits thought to underlie energy regulation [24
]. Other data point more directly to the hippocampus as a processor of satiety information. Using fMRI, Wang et al [25
] reported that, in obese people, the hippocampus is the site of greatest activation following gastric stimulation known to have effects on intake, stomach distention, hormonal and vagal activity similar to those produced by eating a large meal. In addition, fMRI showed that consuming a liquid meal to satiation decreased hippocampal blood flow for people who were obese or were formerly obese, but not for people who had never been obese ([26
], also see [27
]). In sum, these results indicate that (a) the hippocampus is sensitive to satiety signals; (b) at least some these signals induce changes in hippocampal activity that are thought to facilitate learning and memory; (c) the hippocampus is part of a neural circuit whereby the information provided by satiety signals could be transmitted from the gut to the hippocampus and from the hippocampus to forebrain circuits involved with energy regulation; (d) sensitivity of the hippocampus to these signals may be altered in people who have a history of energy dysregulation.
There is also evidence that the inhibitory control of food intake and appetitive behavior depends on the structural integrity of the hippocampus. For example, after eating a full meal densely amnesic human patients with hippocampal damage will eat a full second meal that is offered only minutes later [28
]. Higgs [30
] demonstrated that for neurologically intact humans, memories of a prior meal help to inhibit subsequent intake. Densely amnesic patients may be less able to inhibit intake because their access to these memories is very limited. The results also suggest that hippocampal damage might interfere with satiety signaling by both interoceptive and exteroceptive cues.
Food sated rats with highly selective neurotoxic lesions confined to the hippocampus show increased appetitive behavior (e.g., food cup approach, bar pressing) relative to intact controls [31
] and are impaired in using interoceptive cues arising from low (e.g., 1-hr) and high (e.g., 23-hr) levels of food deprivation as discriminative stimuli ([32
] also see [35
]). Consistent with a role for the hippocampus in negative occasion setting, in these latter problems, lesioned rats were impaired at using deprivation state cues to inhibit their behavior on nonreinforced trials. Furthermore, when intake suppression during recovery from surgery is accounted for, hippocampal-lesioned rats also show increased food intake and body weight gain [17
]. These results suggest that the behavioral inhibition by energy state signals depends on the hippocampus.