Vulnerability of the Hippocampus to Insults: Links to Blood-Brain Barrier Dysfunction.

The hippocampus is a critical brain substrate for learning and memory; events that harm the hippocampus can seriously impair mental and behavioral functioning. Hippocampal pathophysiologies have been identified as potential causes and effects of a remarkably diverse array of medical diseases, psychological disorders, and environmental sources of damage. It may be that the hippocampus is more vulnerable than other brain areas to insults that are related to these conditions. One purpose of this review is to assess the vulnerability of the hippocampus to the most prevalent types of insults in multiple biomedical domains (i.e., neuroactive pathogens, neurotoxins, neurological conditions, trauma, aging, neurodegenerative disease, acquired brain injury, mental health conditions, endocrine disorders, developmental disabilities, nutrition) and to evaluate whether these insults affect the hippocampus first and more prominently compared to other brain loci. A second purpose is to consider the role of hippocampal blood-brain barrier (BBB) breakdown in either causing or worsening the harmful effects of each insult. Recent research suggests that the hippocampal BBB is more fragile compared to other brain areas and may also be more prone to the disruption of the transport mechanisms that act to maintain the internal milieu. Moreover, a compromised BBB could be a factor that is common to many different types of insults. Our analysis indicates that the hippocampus is more vulnerable to insults compared to other parts of the brain, and that developing interventions that protect the hippocampal BBB may help to prevent or ameliorate the harmful effects of many insults on memory and cognition.

Western diet consumption does not impact the rewarding and aversive effects of morphine in male Sprague-Dawley rats.

The impacts of high-fat and/or high-sugar diets on opioid-induced effects are well documented; however, little is known about the effect of such diet on the affective responses to opiates. To address this issue, in the present experiment male Sprague-Dawley rats were given ad libitum access to a western-style diet (high in saturated fat and sugar) or a standard laboratory chow diet beginning in adolescence and continuing into adulthood at which point they were trained in a combined conditioned taste avoidance (CTA)/conditioned place preference (CPP) procedure to assess the aversive and rewarding effects of morphine, respectively. On four conditioning cycles, animals were given access to a novel saccharin solution, injected with morphine (1 mg/kg or 5 mg/kg), and then placed on one side of a place preference chamber. Animals were then tested for place preference and saccharin preference. All subjects injected with morphine displayed significant avoidance of the morphine-associated solution (CTA) and preferred the side associated with the drug (CPP). Furthermore, there were no differences between the two diet groups, indicating that chronic exposure to the western diet had no impact on the affective properties of morphine (despite increasing caloric intake, body weight, body fat and lean body mass). Given previously reported increases in drug self-administration in animals with a history of western-diet consumption, this study suggests that western-diet exposure may increase drug intake via mechanisms other than changes in the rewarding or aversive effects of the drug.

Serial feature positive and feature negative discrimination learning in a taste avoidance preparation: implications for interoceptive control of behavior.

BACKGROUND: Psychoactive drugs produce interoceptive stimuli that can guide appropriate behaviors by initiating or inhibiting responding. OBJECTIVE: The current study investigated whether an interoceptive morphine state produces similar patterns of serial feature positive (FP) and feature negative (FN) discrimination learning under comparable conditions in a taste avoidance design. METHODS: Male Sprague-Dawley rats were trained under 10 cycles of FP or FN discrimination. In the FP task, morphine (10 mg/kg, IP) signaled that a saccharin solution was followed by LiCl (1.2 mEq, IP), while the vehicle (saline) signaled that the LiCl was withheld. In the FN task, the contingency was reversed. RESULTS: The FP-trained rats acquired the discrimination after three training cycles, consuming significantly less saccharin on morphine, than on vehicle, sessions ( P  < 0.05). The FN-trained rats acquired the discrimination after six training cycles, consuming more on morphine than on vehicle sessions ( P < 0.05). However, FN-trained rats never recovered saccharin consumption to baseline levels and 40% of the rats continued to avoid saccharin (consuming 0 ml) on morphine sessions. Control rats that never received LiCl consumed high levels of saccharin on morphine and vehicle sessions, indicating that morphine did not produce unconditioned suppression of saccharin consumption. CONCLUSION: The difficulty to acquire FN discrimination might reflect the limitations of learning about safety contingencies in the taste avoidance design. The rapidity of FP learning when a drug state signals an aversive contingency may have implications for the general role of interoceptive stimuli in the control of behavior.

Appetitive interoception, the hippocampus and western-style diet.

Obesity, Type 2 diabetes and other metabolic disorders continue to pose serious challenges to human health and well-being. An important source of these challenges is the overconsumption of saturated fats and sugar, main staples of what has been called the Western-style diet (WD). The current paper describes a theoretical model and supporting evidence that links intake of a WD to interference with a specific brain substrate that underlies processing of interoceptive signals of hunger and satiety. We review findings from rats and humans that the capacity of these signals to modulate the strength of appetitive and eating behavior depends on the functional integrity of the hippocampus and the learning memory operations it performs. Important among these operations is the use of contextual information to retrieve memories that are associated with other events. Within our framework, satiety provides an interoceptive context that informs animals that food cues and appetitive behavior will not be followed by rewarding postingestive outcomes. This serves to prevent those cues and responses from retrieving those reward memories. The findings reviewed provide evidence that consuming a WD and the high amounts of saturated fat and sugar it contains (a) is associated with the emergence of pathophysiologies to which the hippocampus appears selectively vulnerable (b) impairs hippocampal-dependent learning and memory (HDLM) and (c) weakens behavioral control by interoceptive hunger and satiety contextual stimuli. It is hypothesized that these consequences of WD intake may establish the conditions for a vicious cycle of further WD intake, obesity, and potentially cognitive decline.

Retrieval-induced forgetting in children and adolescents with and without obesity.

BACKGROUND/OBJECTIVES: Previous research indicates that youth with obesity exhibit deficits in executive functioning (EF), which often take the form of impaired response inhibition. One aspect of EF not previously studied in obesity is the adaptive process known as retrieval-induced forgetting (RIF), the suppression/inhibition of intrusive or non-target items by the retrieval of specific items from memory. The present study investigated if child or adolescent obesity disrupts the ability to inhibit retrieval of intrusive memories. SUBJECTS/METHODS: We compared the manifestation of RIF in children (ages 8-12) and adolescents (ages 13-18) as a function of their weight status and sex. We also evaluated the effects of these variables on simple recall of items from episodic memory under conditions where competition from intrusive items was reduced. RESULTS: Children with obesity did not demonstrate significant RIF, whereas RIF was exhibited by preteens without obesity and by teenage participants with- and without obesity (Weight Status × Age Group interaction p = 0.028). This pattern of results did not differ as a function of sex for either age group. No differences in episodic memory were found. Additional analyses using Age as continuous covariate (and not as a nominal group) comparing participants who exhibited RIF with those who did not, found that the no RIF group consumed fast-food meals more frequently (p = 0.024) and had higher percentages of total body adiposity and android fat compared to the RIF group (p's < 0.05). CONCLUSIONS: The findings expand what is known about the effects of childhood obesity on cognitive functioning, identify impaired RIF with specific behavioral and dietary factors and increased adiposity, and suggest the possibility that impairments in the ability to inhibit intrusive memories of food and eating may contribute to poor early-life weight control.

The Three-Chamber Choice Behavioral Task using Zebrafish as a Model System.

Neurodegenerative diseases are age-dependent, debilitating, and incurable. Recent reports have also correlated hyperglycemia with changes in memory and/or cognitive impairment. We have modified and developed a three-chamber choice cognitive task similar to that used with rodents for use with hyperglycemic zebrafish. The testing chamber consists of a centrally located starting chamber and two choice compartments on either side, with a shoal of conspecifics used as the reward. We provide data showing that once acquired, zebrafish remember the task at least 8 weeks later. Our data indicate that zebrafish respond robustly to this reward, and we have identified cognitive deficits in hyperglycemic fish after 4 weeks of treatment. This behavioral assay may also be applicable to other studies related to cognition and memory.

Reframing appetitive reinforcement learning and reward valuation as effects mediated by hippocampal-dependent behavioral inhibition.

Traditional theories of neuroeconomics focus on reinforcement learning and reward value. We propose here a novel reframing of reinforcement learning and motivation that includes a hippocampal-dependent regulatory mechanism which balances cue-induced behavioral excitation with behavioral inhibition. This mechanism enables interoceptive cues produced by respective food or drug satiety to antagonize the ability of excitatory food- and drug-related environmental cues to retrieve the memories of food and drug reinforcers, thereby suppressing the power of those cues to evoke appetitive behavior. When the operation of this mechanism is impaired, ability of satiety signals to inhibit appetitive behavior is weakened because the relative balance between inhibition and simple excitation is shifted toward increased retrieval of food and drug memories by environmental cues. In the present paper, we (1) describe the associative processes that constitute this mechanism of hippocampal-dependent behavior inhibition; (2) describe how a prevailing obesity-promoting diet and drugs of abuse produce hippocampal pathophysiologies that can selectively impair this inhibitory function; and (3) propose how glucagon-like peptide 1 (GLP-1), an incretin hormone that is recognized as an important satiety signal, may work to protect the hippocampal-dependent inhibition. Our perspective may add to neuroscientific and neuroeconomic analyses of both overeating and drug abuse by outlining the role of hippocampal-dependent memory processes in the control of both food and drug seeking behaviors. In addition, this view suggests that consideration should be given to diet- and drug induced hippocampal pathophysiologies, as potential novel targets for the treatment of dysregulated energy and drug intake.

Hippocampal-Dependent Inhibitory Learning and Memory Processes in the Control of Eating and Drug Taking.

As manifestations of excessive and uncontrolled intake, obesity and drug addiction have generated much research aimed at identifying common neuroadaptations that could underlie both disorders. Much work has focused on changes in brain reward and motivational circuitry that can overexcite eating and drug-taking behaviors. We suggest that the regulation of both behaviors depends on balancing excitation produced by stimuli associated with food and drug rewards with the behavioral inhibition produced by physiological "satiety" and other stimuli that signal when those rewards are unavailable. Our main hypothesis is that dysregulated eating and drug use are consequences of diet- and drug-induced degradations in this inhibitory power. We first outline a learning and memory mechanism that could underlie the inhibition of both food and drug-intake, and we describe data that identifies the hippocampus as a brain substrate for this mechanism. We then present evidence that obesitypromoting western diets (WD) impair the operation of this process and generate pathophysiologies that disrupt hippocampal functioning. Next, we present parallel evidence that drugs of abuse also impair this same learning and memory process and generate similar hippocampal pathophysiologies. We also describe recent findings that prior WD intake elevates drug self-administration, and the implications of using drugs (i.e., glucagon-like peptide- 1 agonists) that enhance hippocampal functioning to treat both obesity and addiction are also considered. We conclude with a description of how both WD and drugs of abuse could initiate a "vicious-cycle" of hippocampal pathophysiology and impaired hippocampal-dependent behavioral inhibition.

Ad-libitum high fat diet consumption during adolescence and adulthood impacts the intravenous self-administration of cocaine in male Sprague-Dawley rats.

In preclinical populations, binge consumption of a high-fat diet (HFD) initiated during either adolescence or adulthood increases the intravenous self-administration (IVSA) of cocaine, whereas ad lib HFD consumption initiated during adulthood reduces or fails to influence cocaine intake. From this, it appears that binge exposure is a sufficient condition to increase cocaine IVSA and that such effects occur independent of the exposure period. It is not clear, however, if ad lib exposure would be sufficient to affect the IVSA of cocaine if initiated during adolescence, a developmental period associated with high-risk behavior. To investigate this question, the present experiment evaluated the effects of consumption of a HFD given throughout adolescence and adulthood on cocaine IVSA (0.75 mg/kg/infusion). Specifically, male Sprague-Dawley rats were maintained on either a HFD (n = 24) or chow diet (n = 15) beginning on postnatal day (PND) 21 and as adults underwent cocaine IVSA [Fixed Ratio (FR) 1, FR 5, FR 10, FR 20, Progressive Ratio (PR) and cue- and drug + cue-induced responding] from PNDs 77-126. Under all of these conditions, animals maintained on the HFD displayed higher rates of cocaine IVSA than those given access to chow. The present data demonstrate that under these specific conditions long-term exposure during the risk period of adolescence and extended throughout adulthood is capable of impacting the subsequent likelihood of cocaine self-administration and suggest that diet type and the duration of exposure may be important factors influencing the vulnerability to drug intake. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Ad libitum high fat diet consumption during adolescence and adulthood fails to impact the affective properties of cocaine in male Sprague-Dawley rats.

Recent research from our laboratories has demonstrated that long-term and ad libitum high fat diet (HFD) consumption during adolescence and adulthood increases the intravenous self-administration (IVSA) of cocaine in adult male Sprague-Dawley rats. One possible interpretation of these findings is that this dietary history influences the affective properties of cocaine, that is, cocaine's rewarding and/or aversive effects. In this context, our research and others suggest that the overall affective response to a drug, and its potential for use and abuse, reflects a balance between these properties in which the rewarding effects of a drug maintain its use and the aversive effects limit it. Accordingly, long-term HFD consumption might increase the rewarding effects of cocaine and/or decrease its aversive effects, resulting in greater IVSA. To examine this possibility, male Sprague-Dawley rats were maintained on either a HFD (n = 32) or chow diet (n = 32) beginning on postnatal day (PND) 21 and underwent combined cocaine-induced place preference and taste avoidance conditioning from PNDs 78-102. Under these conditions, cocaine (18 and 32 mg/kg, intraperitoneally [IP]), but not vehicle, was effective in inducing both a place preference and a taste avoidance; however, HFD- and chow-fed animals did not differ on either of these behavioral indices. These data suggest that the ability of ad libitum HFD consumption during adolescence to increase cocaine IVSA is not likely due to changes in the affective properties of cocaine. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Differential Effects of Dietary MSG on Hippocampal Dependent Memory Are Mediated by Diet.

INTRODUCTION: Free glutamate is a common dietary flavor enhancer and is also an important excitatory neurotransmitter in the body. A good number of food additives which contain glutamate are found in the Western Diet, and this diet has also been linked to increased risk of cognitive dysfunction. OBJECTIVE: To examine the effects of dietary glutamate on hippocampal and non-hippocampal memory performance, and whether consuming a diet high in fat/sugar could influence any observed associations. METHODS: Sixty-four adult male Sprague-Dawley rats were trained concurrently on two different discrimination problems: (1) Pavlovian serial feature negative (sFN) discrimination, in which a brief tone stimulus was reinforced with sucrose pellets when it was presented alone (T+ trials) and non-reinforced on trials when it was preceded by the presentation of a brief light (LT- trials); and (2) a simple discrimination (SD) problem in which a white noise (WN+) cue was reinforced with sucrose pellets and a clicker (C-) stimulus was not reinforced. Previous research has shown that sFN, but not SD performance, depends on the functional integrity of the hippocampus. After solving both problems, the rats were assigned to one of four ad libitum-fed diet groups, matched on weight and discrimination performance: (1) high fat, high sugar western-style diet (WD), (2) standard laboratory rodent chow diet (chow), (3) WD + monosodium glutamate (MSG), or (4) chow + MSG. RESULTS: After 14 weeks, rats fed WD had higher adiposity than rats fed chow. Consistent with previous findings, rats fed WD exhibited impaired performance on the sFN problem, but not on the SD, relative to rats fed chow. Adding MSG to WD abolished this impairment, whereas rats fed chow + MSG had impaired sFN performance compared to rats fed chow alone. No differences in performance on the SD task were observed. CONCLUSION: This study demonstrates differing effects of dietary glutamate on hippocampal dependent memory function, with MSG impairing hippocampal function in animals receiving chow, while improving hippocampal function in animals receiving a Western-type diet, high in fat and sugar. More research will be needed to explore the cause of these differential effects.

The Cognitive Control of Eating and Body Weight: It's More Than What You "Think".

Over the past decade, a great deal of research has established the importance of cognitive processes in the control of energy intake and body weight. The present paper begins by identifying several of these cognitive processes. We then summarize evidence from human and nonhuman animal models, which shows how excess intake of obesity-promoting Western diet (WD) may have deleterious effects on these cognitive control processes. Findings that these effects may be manifested as early-life deficits in cognitive functioning and may also be associated with the emergence of serious late-life cognitive impairment are described. Consistent with these possibilities, we review evidence, obtained primarily from rodent models, that consuming a WD is associated with the emergence of pathophysiologies in the hippocampus, an important brain substrate for learning, memory, and cognition. The implications of this research for mechanism are discussed within the context of a "vicious-cycle model," which describes how eating a WD could impair hippocampal function, producing cognitive deficits that promote increased WD intake and body weight gain, which could contribute to further hippocampal dysfunction, cognitive decline, and excess eating and weight gain.

The effects of a GLP-1 analog liraglutide on reward value and the learned inhibition of appetitive behavior in male and female rats.

Liraglutide, a relatively long-lasting analog of glucagon-like peptide-1 (GLP-1), has received recent attention as a treatment for obesity. It has been proposed that activation of GLP-1 receptors in mesolimbic reward pathways contributes to this outcome by reducing hedonic value of food. However, other findings suggest that activation of GLP-1 signaling pathways may suppress appetitive behavior by enhancing a hippocampal-dependent form of learned inhibition. The present experiment compares these two alternatives. Rats first solved a hippocampal-dependent discrimination problem in which a target stimulus signaled the delivery of sucrose, except when it was preceded by an inhibitory cue that signaled nonreward. The effects of 12 daily intraperitoneal (i.p.) injections of liraglutide on responding to the target cue was then compared with and without the inhibitory stimulus. Relative to saline, liraglutide suppressed responding to the target cue only on trials when the inhibitory stimulus was also present (p < .05). This outcome was independent of sex and maintenance diet (Western diet or standard chow). The failure of liraglutide to suppress responding in the absence of the inhibitory cue argues against the notion that this GLP-1 agonist reduced the value of food reward and favors the idea that it enhanced a hippocampal-dependent form of behavioral inhibition.

Cocaine impairs serial-feature negative learning and blood-brain barrier integrity.

Previous research has shown that diets high in fat and sugar [a.k.a., Western diets (WD)] can impair performance of rats on hippocampal-dependent learning and memory problems, an effect that is accompanied by selective increases in hippocampal blood brain barrier (BBB) permeability. Based on these types of findings, it has been proposed that overeating of a WD (and its resulting obesity) may be, in part, a consequence of impairments in these anatomical substrates and cognitive processes. Given that drug use (and addiction) represents another behavioral excess, the present experiments assessed if similar outcomes might occur with drug exposure by evaluating the effects of cocaine administration on hippocampal-dependent memory and on the integrity of the BBB. Experiment 1 of the present series of studies found that systemic cocaine administration in rats also appears to have disruptive effects on the same hippocampal-dependent learning and memory mechanism that has been proposed to underlie the inhibition of food intake. Experiment 2 demonstrated that the same regimen of cocaine exposure that produced disruptions in learning and memory in Experiment 1 also produced increased BBB permeability in the hippocampus, but not in the striatum. Although the predominant focus of previous research investigating the etiologies of substance use and abuse has been on the brain circuits that underlie the motivational properties of drugs, the current investigation implicates the possible involvement of hippocampal memory systems in such behaviors. It is important to note that these positions are not mutually exclusive and that neuroadaptations in these two circuits might occur in parallel that generate dysregulated drug use in a manner similar to that of excessive eating.

Associative mechanisms underlying the function of satiety cues in the control of energy intake and appetitive behavior.

While previous research has identified a number of metabolic, neural, and hormonal events that could serve as potential satiety signals, the mechanisms that enable satiety signals to suppress food-seeking and eating behavior remain poorly specified. Here we investigate the idea that the inhibitory power of satiety signals is derived, at least in part, from their ability to signal that foods and food-related stimuli will not be followed by reinforcing postingestive consequences. Viewed in this way, the signaling relationship in which satiety cues are embedded defines what is known in Pavlovian conditioning as a "serial feature negative" (sFN) discrimination problem. In this problem a "negative feature" cue precedes the presentation of a "target" cue on trials without reinforcement. In contrast, the target is reinforced on trials when the negative feature cue is not presented. Satiety cues can be seen as paralleling the function of negative feature cues in that they signal when food-related target cues will be nonreinforced. We conducted two experiments with rats that assessed if satiety signals functioned like negative feature stimuli. Experiment 1 explicitly pretrained satiety cues as negative feature stimuli, irrelevant stimuli, or under conditions where their ability to serve as negative feature stimuli would be attenuated. Control by satiety cues was highly sensitive to these experimental contingencies, with the best performance exhibited by rats given sFN pretraining. This sFN pretraining also transferred to enhance performance during subsequent training on another sFN problem with both external and internal negative feature cues. We also found that discriminative control by satiety cues blocked the development of that control by external cues. Experiment 2 evaluated whether a manipulation known to impair sFN performance with external negative feature cues (i.e., maintenance on a western diet) would also impair sFN performance when satiety cues were trained as negative feature stimuli. The results showed that compared to standard chow, WD intake impaired sFN performance similarly with both types of stimuli. These experiments provide evidence that an associative mechanism, like that underlying sFN performance, is involved with the control of appetitive behavior by satiety cues.

Discriminative control by deprivation states and external cues in male and female rats.

Previous research indicates that decisions about when to eat in response to food cues in the environment are based on interoceptive energy states (i.e., hunger and fullness) and learning about and remembering prior eating experiences. However, this animal model has exclusively been tested on male rodents. Despite evidence that women are more susceptible to obesity and cognitive disorders associated with excess weight (e.g., Alzheimer's disease) than men, the generality of these findings with males to females remains unknown. To address this gap, the current research investigated associative learning mechanisms involved in food intake control in females by training both males and females in a Pavlovian deprivation discrimination in which varying levels of food deprivation are trained with competitive external cues to signal reward. In Experiment 1, male and female rats showed similar performance in discriminating between 0 and 24h deprivation state/external cue compounds and in subsequent tests, confirming stimulus control by deprivation states. Experiment 2 assessed learning about more ecologically valid 0 and 4h deprivation states in competition with external cues in both males and females. With the low-level deprivation state parameters, females outperformed males in discriminative control by deprivation states, particularly on the contingency rewarded under satiation and not deprivation. While females showed an enhanced degree of energy state processing under some deprivation conditions, overall, these findings suggest similar mechanisms of learned appetitive control in both sexes.

Considering sex differences in the cognitive controls of feeding.

Women are disproportionately affected by obesity, and obesity increases women's risk of developing dementia more so than men. Remarkably little is known about how females make decisions about when and how much to eat. Research in animal models with males supports a framework in which previous experiences with external food cues and internal physiological energy states, and the ability to retrieve memories of the consequences of eating, determines subsequent food intake. Additional evidence indicates that consumption of a high-fat, high-sugar diet interferes with hippocampal-dependent mnemonic processes that operate to suppress eating, such as in situations of satiety. Recent findings also indicate that weakening this form of hippocampal-dependent inhibitory control may also extend to other forms of learning and memory, perpetuating a vicious cycle of increased Western diet intake, hippocampal dysfunction, and further impairments in the suppression of appetitive behavior that may ultimately disrupt other types of memorial interference resolution. How these basic learning and memory processes operate in females to guide food intake has received little attention. Ovarian hormones appear to protect females from obesity and metabolic impairments, as well as modulate learning and memory processes, but little is known about how these hormones modulate learned appetitive behavior. Even less is known about how a sex-specific environmental factor - widespread hormonal contraceptive use - affects associative learning and the regulation of food intake. Extending learned models of food intake to females will require considerably investigation at many levels (e.g., reproductive status, hormonal compound, parity). This work could yield critical insights into the etiology of obesity, and its concomitant cognitive impairment, for both sexes.

Western diet and the weakening of the interoceptive stimulus control of appetitive behavior.

In obesogenic environments food-related external cues are thought to overwhelm internal cues that normally regulate energy intake. We investigated how this shift from external to internal stimulus control might occur. Experiment 1 showed that rats could use stimuli arising from 0 and 4h food deprivation to predict sucrose delivery. Experiment 2 then examined (a) the ability of these deprivation cues to compete with external cues and (b) how consuming a Western-style diet (WD) affects that competition. Rats were trained to use both their deprivation cues and external cues as compound discriminative stimuli. Half of the rats were then placed on WD while the others remained on chow, and external cues were removed to assess learning about deprivation state cues. When tested with external cues removed, chow-fed rats continued to discriminate using only deprivation cues, while WD-fed rats did not. The WD-fed group performed similarly to control groups trained with a noncontingent relationship between deprivation cues and sucrose reinforcement. Previous studies provided evidence that discrimination based on interoceptive deprivation cues depends on the hippocampus and that WD intake could interfere with hippocampal functioning. A third experiment assessed the effects of neurotoxic hippocampal lesions on weight gain and on sensitivity to the appetite-suppressing effects of the satiety hormone cholecystokinin (CCK). Relative to controls, hippocampal-lesioned rats gained more weight and showed reduced sensitivity to a 1.0ug but not 2.0 or 4.0ug CCK doses. These findings suggest that WD intake reduces utilization of interoceptive energy state signals to regulate appetitive behavior via a mechanism that involves the hippocampus.