While the identification of physiological meal-related and adiposity signals has contributed much to our understanding of the control of food intake and body weight regulation, relatively little is known about how the information provided by these cues is translated by the brain into adaptive behavioral outcomes. Although the hypothalamus and hindbrain have been identified as brain substrates that are involved with the detection of satiety, adiposity, and hunger cues, the ultimate decision to eat or to refrain from eating may depend on the processing of these signals at other brain sites involved with the higher-order control of behavior.

The hippocampus, a medial temporal lobe structure long regarded as an important substrate for learning and memory [10], has received increasing attention for its potential role in energy regulation. While some have suggested that hippocampal participation in energy homeostasis might not rely exclusively on learning and memory [11, 12], findings and theoretical developments encourage the hypothesis that hippocampal-dependent learning and memory mechanisms might contribute directly to the higher-order control of food intake. The purpose of this paper is to summarize and integrate some of these findings and ideas.

Negative occasion setting is a hippocampal-dependent process involved with learning to resolve predictable ambiguities. Rats with hippocampal lesions exhibit impaired negative occasion setting when they readily learn to respond to a conditioned stimulus (CS) that is consistently followed by delivery of a food pellet unconditioned stimulus (US) but are impaired at learning that a different cue (i.e., a negative occasion setter) signals when the CS will not be followed by the US. In this problem, although the ambiguity involved with predicting when the CS will be followed by reinforcement or nonreinforcement is resolved by the presentation of the negative occasion setting cue, rats with hippocampal lesions tend to respond to the CS as much on nonreinforced trials when the negative occasion setter is present as on reinforced trials when the CS occurs alone [14].

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) [18-20], 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, 23]. 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, 29]. 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.

The detrimental effects of high-fat diet on learning and memory may also be related to decreased expression of hippocampal brain-derived neurotrophic factor (BDNF), which is known to play an important role in activity-dependent synaptic plasticity in the adult brain [40,41]. In rodents, administration of exogenous BDNF decreases food intake, whereas genetic models with deficient BDNF signaling exhibit hyperphagia and obesity related primarily to marked increases in meal frequency, but not meal-size or duration [40, 42]. This meal pattern suggests that, like rats with selective hippocampal lesions, BDNF-deficient mice may be impaired at inhibiting responding to pre-oral and oral food cues that evoke learned appetitive responses [31, 32]. Impaired performance on hippocampal-dependent learning and memory tasks and reduced hippocampal BDNF is also found in rats that have been maintained on a high-fat diet [43, 44]. In humans, obese children and adolescents exhibit reduced serum BDNF levels relative to their normal weight counterparts, when variability due to age, gender, race, pubertal status, and platelet count is accounted for ([45] but see [46]). Furthermore, in what appears to be the only study of its kind with humans, an 8-year old female with haploinsufficiency for BDNF exhibited hyperphagia, severe obesity, and cognitive impairments [47].