Deficits in episodic memory are related to uncontrolled eating in a sample of healthy adults.

Despite a substantial amount of animal data linking deficits in memory inhibition to the development of overeating and obesity, few studies have investigated the relevance of memory inhibition to uncontrolled eating in humans. Further, although memory for recent eating has been implicated as an important contributor to satiety and energy intake, the possibility that variations in episodic memory relate to individual differences in food intake control has been largely neglected. To examine these relationships, we recruited ninety-three adult subjects to attend a single lab session where we assessed body composition, dietary intake, memory performance, and eating behaviors (Three Factor Eating Questionnaire). Episodic recall and memory inhibition were assessed using a well-established measure of memory interference (Retrieval Practice Paradigm). Hierarchical regression analyses indicated that memory inhibition was largely unrelated to participants' eating behaviors; however, episodic recall was reliably predicted by restrained vs. uncontrolled eating: recall was positively associated with strategic dieting (ß = 2.45, p = 0.02), avoidance of fatty foods (ß = 3.41, p = 0.004), and cognitive restraint (ß = 1.55, p = 0.04). In contrast, recall was negatively associated with uncontrolled eating (ß = -1.15, p = 0.03) and emotional eating (ß = -2.46, p = 0.04). These findings suggest that episodic memory processing is related to uncontrolled eating in humans. The possibility that deficits in episodic memory may contribute to uncontrolled eating by disrupting memory for recent eating is discussed.

Improvements in hippocampal-dependent memory and microglial infiltration with calorie restriction and gastric bypass surgery, but not with vertical sleeve gastrectomy.

BACKGROUND: Much recent evidence suggest that obesity and related comorbidities contribute to cognitive decline, including the development of non age-related dementia and Alzheimer's disease. Obesity is a serious threat to public health, and few treatments offer proven long-term weight loss. In fact, bariatric surgery remains the most effective long-term therapy to reduce weight and alleviate other aspects of the metabolic syndrome (MetS). Unlike the demonstrated benefits of caloric restriction to prevent weight gain, few if any studies have compared various means of weight loss on central nervous system function and hippocampal-dependent cognitive processes. DESIGN AND RESULTS: Our studies comprise the first direct comparisons of caloric restriction to two bariatric surgeries (Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG)) on cognitive function. Weight loss following caloric restriction, RYGB and VSG was associated with generalized improvements in metabolic health and hippocampal-dependent learning, as measured in the radial arm maze and spontaneous alternation tests. However, VSG-treated rats exhibited deficits on spatial learning tasks in the Morris water maze. In addition, whereas VSG animals had elevated hippocampal inflammation, comparable to that of obese controls, RYGB and calorie-restricted (pair-fed, PF) controls exhibited an amelioration of inflammation, as measured by the microglial protein ionized calcium binding adaptor molecule 1 (IBA1). We also assessed whether GHR (ghrelin) replacement would attenuate hippocampal inflammation in VSG, as post-surgical GHR levels are significantly reduced in VSG relative to RYGB and PF rats. However, GHR treatment did not attenuate the hippocampal inflammation. CONCLUSION: Although VSG was comparably effective at reducing body weight and improving glucose regulation as RYGB, VSG did not appear to confer an equal benefit on cognitive function and markers of inflammation.

An application of Pavlovian principles to the problems of obesity and cognitive decline.

An enormous amount of research has been aimed at identifying biological and environmental factors that are contributing to the current global obesity pandemic. The present paper reviews recent findings which suggest that obesity is attributable, at least in part, to a disruption of the Pavlovian control of energy regulation. Within our framework, this disruption occurs when (a) consumption of sweet-tasting, but low calorie or noncaloric, foods and beverages reduces the ability of sweet tastes to predict the postingestive caloric consequences of intake and (b) consuming diets high in saturated fat and sugar (a.k.a., Western diet) impairs hippocampal-dependent learning and memory processes that are involved with the use of interoceptive "satiety" signals to anticipate when food and eating are not followed by appetitive postingestive outcomes. The paper concludes with discussion of a "vicious-cycle" model which links obesity to cognitive decline.

Inter-relationships among diet, obesity and hippocampal-dependent cognitive function.

Intake of a Western diet (WD), which is high in saturated fat and sugar, is associated with deficits in hippocampal-dependent learning and memory processes as well as with markers of hippocampal pathology. In the present study, rats were trained to asymptote on hippocampal-dependent serial feature negative (FN) and hippocampal-independent simple discrimination problems. Performance was then assessed following 7 days on ad libitum chow and after 10, 24, 40, 60, and 90 days of maintenance on WD, on ketogenic (KETO) diet, which is high in saturated fat and low in sugar and other carbohydrates, or continued maintenance on chow (CHOW). Confirming and extending previous findings, diet-induced obese (DIO) rats fed WD showed impaired FN performance, increased blood-brain barrier (BBB) permeability, and increased fasting blood glucose levels compared to CHOW controls and to diet-resistant (DR) rats that did not become obese when maintained on WD. For rats fed the KETO diet, FN performance and BBB integrity were more closely associated with level of circulating ketone bodies than with obesity phenotype (DR or DIO), with higher levels of ketones appearing to provide a protective effect. The evidence also indicated that FN deficits preceded and predicted increased body weight and adiposity. This research (a) further substantiates previous findings of WD-induced deficits in hippocampal-dependent FN discriminations, (b) suggests that ketones may be protective against diet-induced cognitive impairment, and (c) provides evidence that diet-induced cognitive impairment precedes weight gain and obesity.

Saccharin pre-exposure enhances appetitive flavor learning in pre-weanling rats.

In adult rats, data suggest that consumption of sweet tastes that do not deliver anticipated caloric consequences using high-intensity, non-caloric sweeteners, such as saccharin, interferes with learned relations that may contribute to energy balance. The goal of the present study was to assess the development of learning about sweet taste and calories by assessing whether pre-exposure to saccharin solutions reduces cue competition in pre-weanling rats. The results demonstrated that rats pre-exposed to saccharin and then trained with a novel grape flavor paired with a glucose-sweetened solution consumed more of the novel grape flavor presented alone than rats that had been pre-exposed to saccharin and given the grape flavor paired with water alone. No differences in intake of the novel grape flavor were observed in groups given pre-exposure to water or glucose solutions. Thus, by 15 days of age, rats appear to have established an association between sweet tastes and calories, and this association can be weakened by exposure to saccharin.

Experience with the high-intensity sweetener saccharin impairs glucose homeostasis and GLP-1 release in rats.

Previous work from our lab has demonstrated that experience with high-intensity sweeteners in rats leads to increased food intake, body weight gain and adiposity, along with diminished caloric compensation and decreased thermic effect of food. These changes may occur as a result of interfering with learned relations between the sweet taste of food and the caloric or nutritive consequences of consuming those foods. The present experiments determined whether experience with the high-intensity sweetener saccharin versus the caloric sweetener glucose affected blood glucose homeostasis. The results demonstrated that during oral glucose tolerance tests, blood glucose levels were more elevated in animals that had previously consumed the saccharin-sweetened supplements. In contrast, during glucose tolerance tests when a glucose solution was delivered directly into the stomach, no differences in blood glucose levels between the groups were observed. Differences in oral glucose tolerance responses were not accompanied by differences in insulin release; insulin release was similar in animals previously exposed to saccharin and those previously exposed to glucose. However, release of GLP-1 in response to an oral glucose tolerance test, but not to glucose tolerance tests delivered by gavage, was significantly lower in saccharin-exposed animals compared to glucose-exposed animals. Differences in both blood glucose and GLP-1 release in saccharin animals were rapid and transient, and suggest that one mechanism by which exposure to high-intensity sweeteners that interfere with a predictive relation between sweet tastes and calories may impair energy balance is by suppressing GLP-1 release, which could alter glucose homeostasis and reduce satiety.

Body weight gain in rats consuming sweetened liquids. Effects of caffeine and diet composition.

Previous studies show that high-intensity sweeteners can stimulate weight gain in rats. The present studies examined whether caffeine, a stimulant commonly added to beverages consumed by humans, influences intake of saccharin- or glucose-sweetened solutions or body weight gain in rats and whether the nature of the maintenance diet influences the effects of caffeine. In two experiments, rats received glucose or saccharin solution mixed with 0.125 mg/g caffeine or no caffeine. Rats consumed significantly more caffeinated than noncaffeinated solutions when they were maintained on a low-fat chow diet (Experiment 1) and when maintained on a sweet, high-fat, high calorie chow diet (Experiment 2). Consumption of saccharin resulted in higher body weight gain in both experiments. Caffeine reversed this effect in Experiment 1 (low-fat diet) but not Experiment 2 (sweet, high-fat diet). The findings extend what is known about the conditions under which consumption of high intensity sweeteners promote energy dysregulation.

Learned and cognitive controls of food intake.

While much has been elucidated about the hypothalamic controls of energy balance, the epidemic of obesity continues to escalate. Recent work has suggested that extra-hypothalamic central nervous system structures may play a previously un-appreciated role in the control of ingestive behavior and body weight regulation. Because animals can and do learn about food and food-related stimuli, as well as the consequences of eating, we and others have sought to understand the cognitive process that underlies that learning. Additionally, we have begun to investigate the neuro-anatomical bases for complex learning about food and food cues. Here we review some evidence for learning about food as well as evidence that the hippocampus may play a critical role in the brain's ability to regulate body weight through such learning processes.

General and persistent effects of high-intensity sweeteners on body weight gain and caloric compensation in rats.

In an earlier work (S. E. Swithers & T. L. Davidson, 2008), rats provided with a fixed amount of a yogurt diet mixed with saccharin gained more weight and showed impaired caloric compensation relative to rats given the same amount of yogurt mixed with glucose. The present 4 experiments examined the generality of these findings and demonstrated that increased body weight gain was also demonstrated when animals consumed a yogurt diet sweetened with an alternative high-intensity sweetener (acesulfame potassium; AceK) as well as in animals given a saccharin-sweetened base diet (refried beans) that was calorically similar but nutritionally distinct from low-fat yogurt. These studies also extended earlier findings by showing that body weight differences persist after saccharin-sweetened diets are discontinued and following a shift to a diet sweetened with glucose. In addition, rats first exposed to a diet sweetened with glucose still gain additional weight when subsequently exposed to a saccharin-sweetened diet. The results of these experiments add support to the hypothesis that exposure to weak or nonpredictive relationships between sweet tastes and caloric consequences may lead to positive energy balance.

The melanocortin antagonist AgRP (83-132) increases appetitive responding for a fat, but not a carbohydrate, reinforcer.

Consumption of a diet high in fat is a risk factor for a number of health problems, including obesity, type 2 diabetes and cardiovascular disease. Considerable pharmacological, genetic, and molecular evidence suggests that the hypothalamic melanocortin system plays a critical role in the control of food intake and body weight and, specifically, in fat ingestion. Administration of a melanocortin antagonist, agouti-related peptide (AgRP) (83-132) selectively increases intake of pure fat and high-fat mixed diets. Here, we examined possible mechanisms for this fat-specific effect of AgRP (83-132). In Experiment 1, we determined that intracerebroventricular administration of AgRP (83-132) selectively increased operant responding for a peanut oil, but not a sucrose, reinforcer when tested under a progressive ratio schedule. Experiment 2 employed a Pavlovian conditioning paradigm, in which icv AgRP enhanced appetitive responding toward stimuli that had previously been paired with peanut oil and reduced responding toward stimuli previously paired with sucrose, in the absence of consumption of either macronutrient. Finally, in Experiment 3, we tested the hypothesis that the MC system acts in anticipation of a fat consumption and found that hypothalamic AgRP mRNA was slightly, though not significantly, elevated in an environment predicting fat availability relative to one predicting carbohydrate availability. Collectively, these data indicate that, in addition to increasing free intake of dietary fats, AgRP (83-132) promotes responding for the opportunity to consume a fat reinforcer, as well as appetitive responding to fat-paired stimuli in the absence of ingestive stimulation. These results suggest a possible role for AgRP in the increased fat intake associated with obesity.

Interoceptive "satiety" signals produced by leptin and CCK.

The present studies assessed the extent to which the adiposity signal leptin and the brain-gut hormone cholecystokinin (CCK), administered alone or in combination, give rise to interoceptive sensory cues like those that are produced by a low (1h) level of food deprivation. Rats were trained with cues arising from 1 to 24-h food deprivation as discriminative stimuli. For one group, 24-h food deprivation predicted the delivery of sucrose pellets, whereas 1-h food deprivation did not. Another group received the reversed deprivation level-sucrose contingency. After asymptotic performance was achieved, the effects of leptin and CCK on food intake and on discrimination performance were tested under 24-h food deprivation. In Experiment 1a, leptin administered into the third cerebroventricle (i3vt) at 3.5 or 7.0 microg doses had little effect, compared to saline on food intake or discriminative responding. In Experiment 1b, leptin (7.0 microg, i3vt) combined with CCK-8 (2 microg/kg, i.p.) reduced food intake significantly, but the findings indicated that CCK-8 alone produces interoceptive discriminative cues more like those produced by 1- than 24-h food deprivation. Experiment 2a tested rats with i.p. leptin (0.3 and 0.5mg/kg). Although neither dose suppressed intake, the 0.3mg/kg dose produced interoceptive cues like 1-h food deprivation. Experiment 2b tested two doses of CCK-8 (2 and 4 mg/kg, i.p.) and found significant intake suppression and generalization of discrimination with both doses of CCK-8. These findings suggest a role for both leptin and CCK in the production of sensory consequences that correspond to "satiety".

Als2-deficient mice exhibit disturbances in endosome trafficking associated with motor behavioral abnormalities.

ALS2 is an autosomal recessive form of spastic paraparesis (motor neuron disease) with juvenile onset and slow progression caused by loss of function of alsin, an activator of Rac1 and Rab5 small GTPases. To establish an animal model of ALS2 and derive insights into the pathogenesis of this illness, we have generated alsin-null mice. Cytosol from brains of Als2(-/-) mice shows marked diminution of Rab5-dependent endosome fusion activity. Furthermore, primary neurons from Als2(-/-) mice show a disturbance in endosomal transport of insulin-like growth factor 1 (IGF1) and BDNF receptors, whereas neuronal viability and endocytosis of transferrin and dextran seem unaltered. There is a significant decrease in the size of cortical motor neurons, and Als2(-/-) mice are mildly hypoactive. Altered trophic receptor trafficking in neurons of Als2(-/-) mice may underlie the histopathological and behavioral changes observed and the pathogenesis of ALS2.

Consistent relationships between sensory properties of savory snack foods and calories influence food intake in rats.

OBJECTIVE: Determine the influence of experience with consistent or inconsistent relationships between the sensory properties of snack foods and their caloric consequences on the control of food intake or body weight in rats. DESIGN: Rats received plain and BBQ flavored potato chips as a dietary supplement, along with ad lib rat chow. For some rats the potato chips were a consistent source of high fat and high calories (regular potato chips). For other rats, the chips provided high fat and high calories on some occasions (regular potato chips) and provided no digestible fat and fewer calories at other times (light potato chips manufactured with a fat substitute). Thus, animals in the first group were given experiences that the sensory properties of potato chips were strong predictors of high calories, while animals in the second group were given experiences that the sensory properties of potato chips were not predictors of high calories. SUBJECTS: Juvenile and adult male Sprague-Dawley rats. MEASUREMENTS: Following exposure to varying potato chip-calorie contingencies, intake of a novel, high-fat snack food and subsequent chow intake were assessed. Body weight gain and body composition as measured by DEXA were also measured. RESULTS: In juvenile animals, exposure to a consistent relationship between potato chips and calories resulted in reduced chow intake, both when no chips were provided and following consumption of a novel high-fat, high-calorie snack chip. Long-term experience with these contingencies did not affect body weight gain or body composition in juveniles. In adult rats, exposure to an inconsistent relationship between potato chips and calories resulted in increased consumption of a novel high-fat, high-calorie snack chip premeal along with impaired compensation for the calories contained in the premeal. CONCLUSION: Consumption of foods in which the sensory properties are poor predictors of caloric consequences may alter subsequent food intake.

Comparison of nutritive and nonnutritive stimuli in intestinal and oral conditioned taste aversion paradigms.

The intestinal taste aversion paradigm has previously demonstrated that animals could orally discriminate between carbohydrate and fat subsequent to pairing a gastrointestinal (GI) infusion of 1 nutrient with lithium chloride (LiCl), whereas they could not discriminate between 2 nonnutritive flavors (A. L. Tracy, R. J. Phillips, M. M. Chi, T. L. Powley, & T. L. Davidson, 2004). The present experiments assessed the relative salience of nutritive and nonnutritive stimuli when presented either intestinally or orally. Two compound stimuli, each comprising 1 nutrient and 1 nonnutritive flavor, were presented in training and were paired with LiCl or saline. Subsequent oral intake of the nutrients alone, the flavors alone, or the compounds was measured. Results showed that rats discriminated both nutrients and flavors independently after GI or oral training, whereas the compounds were discriminated only after oral training, indicating substantive differences in the processing of these stimuli. This suggests that nutrient activation of the GI tract may potentiate learning about nonnutritive flavors analogously to taste-potentiated odor conditioning. The ability to learn about the oral properties of stimuli in the GI tract suggests a new account of delayed taste aversion learning as well as learning about the positive nutritive consequences of food consumption.

Memory inhibition and energy regulation.

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 (a) caloric intake in excess of caloric need; (b) increases in body weight leading to obesity. This paper starts with the idea that excess body weight and obesity stem from a failure or degradation of mechanisms that normally function to inhibit eating behavior. Unlike previous approaches, we focus not on failures of traditional physiological (e.g., neural, hormonal) regulatory control mechanisms, but on disruptions of inhibitory learning and memory processes that may help to regulate energy intake. This view of energy dysregulation as a type of "learning disorder" leads us to the hippocampus, a brain structure that has long been regarded as an important substrate for learning and memory and which we think may be critically involved with a specific type of memory inhibition function that could contribute to the suppression of food intake. With this focus, the search for environmental origins of the current obesity epidemic in Western populations is directed toward factors that alter hippocampal functioning. We conclude by offering a preliminary account of how consumption of foods high in saturated fats might lead to impaired hippocampal function, reduced ability to inhibit caloric intake and, ultimately, to increased body weight.

The interoceptive cue properties of ghrelin generalize to cues produced by food deprivation.

A number of recent studies implicate the gut-brain peptide ghrelin as a putative "hunger signal". Most of these studies, however, rely on either consummatory behavior (in humans or nonhuman animals) or self-report (in humans) to draw conclusions regarding the orexigenic properties of this peptide. The present study employs the deprivation intensity discrimination paradigm to assess the interoceptive sensory properties of ghrelin in rats. In this paradigm, one group of rats was placed in a training context and presented with sucrose pellets when 24 h food deprived, but not when 1 h food deprived (24+ group). A second group was trained using the opposite sucrose-deprivation level contingency (1+ group). Learning in this paradigm was demonstrated by animals approaching the food delivery location more frequently under their rewarded compared to their non-rewarded deprivation condition (prior to actual pellet delivery). After asymptotic performance of this discrimination was achieved, these animals (1 h food deprived) were administered ghrelin or saline, either i.p. (3 or 6 nmol) or i3vt (0.1 or 1 nmol), placed in the training context, and appetitive responses were measured. Testing was conducted in extinction, eliminating confounding effects of food consumption. Results of these tests showed that 6 nmol i.p. ghrelin and 0.1 and 1 nmol i3vt ghrelin all generalized to a state of 24 h food deprivation, indicating that exogenous ghrelin has sensory properties in common with the stimuli produced by 24 h food deprivation. These results support the notion that endogenous ghrelin contributes to an interoceptive hunger cue, and that this may be a mechanism by which ghrelin influences food intake and appetitive behavior.

The gastrointestinal tract "tastes" nutrients: evidence from the intestinal taste aversion paradigm.

To develop and use a behavioral paradigm for assessments of what nutrient properties are detected by intestinal chemoreceptors, we combined features of the "electronic esophagus" preparation (Elizalde G and Sclafani A. Physiol Behav 47: 63-77, 1990) and the conditioned taste aversion protocol (Garcia J and Koelling RA. Psychon Sci 4: 123-124, 1966). In four experiments, separate groups of food-deprived rats with gastric (experiments 1-4) or duodenal (experiment 4) catheters were infused with either carbohydrates (maltodextrin) or fats (corn oil) into their stomachs or small intestines, either while they consumed nonnutritive flavored solutions (experiments 1 and 2) or in the absence of any intake (experiments 3 and 4). For some animals, one of the macronutrient infusions was paired with lithium chloride injections shown to support conventional conditioned aversions. After training, in various oral preference test trials, animals were given opportunities to taste and consume the nonnutritive solutions that had served as oropharyngeal conditioned stimuli as well as the nutrients that had been infused intragastrically, with or without poisoning, but never sampled by mouth. As previously established, preferences for the nonnutritive flavors were enhanced by association with intragastric infusions of macronutrients, with carbohydrates producing the greater preference. On first exposure to the two macronutrients for oral consumption, animals reduced their intake of the nutrient that had been previously poisoned when it was infused into the gastrointestinal tract. These results, along with additional controls, suggest that nutrient tastes detected in the intestines can be recognized centrally based on oropharyngeal gustatory stimulation.

The hippocampus and inhibitory learning: a 'Gray' area?

Gray's approach to understanding hippocampal functioning [The Neuropsychology of Anxiety: An Enquiry into the Function of the Septo-hippocampal System, 1982; The Neuropsychology of Anxiety, 2000] departs from the prevailing view of that structure as a substrate for memory. Instead, Gray and McNaughton have proposed that hippocampus is involved with a function that is more fundamental than memory, namely the resolution of conflict between competing approach and avoidance tendencies. The present paper attempts to advance this perspective by describing how the effects of selective lesions of the hippocampus on performance in both relatively simple Pavlovian conditioning tasks and in more complex radial maze problems could be a consequence of an impairment in a simple form of inhibitory learning. Specifically, we consider the idea that the hippocampus is needed to form simple inhibitory associations between events that are concurrently embedded in simple excitatory associations [Behav Brain Res 119 (2001) 111]. This idea is compared with the conflict resolution hypothesis offered by Gray and McNaughton and avenues of integration are noted. In addition, the potential role for inhibitory learning in hippocampal-dependent spatial and contextual information processing is also discussed.

A Pavlovian approach to the problem of obesity.

During the past 15-20 y, the incidence of overweight and obesity in the United States has grown rapidly. The processes that underlie this alarming trend remain largely unspecified. We hypothesize that degradation of the ability to use certain orosensory cues to predict the caloric consequences of intake may contribute to overeating and excessive weight gain. The results of two preliminary studies with rats are consistent with this hypothesis. In one study, the ability of rat pups to regulate their caloric intake after consuming a novel high-calorie, sweet food was disrupted if they had received prior training with sweet tastes that failed to predict the caloric consequences of eating. Another study found that altering the normal predictive relationship between food viscosity and calories led to increased body weight in adult rats. Dietary factors that degrade the relationship between sweet tastes, food viscosity and calories may contribute to overeating and weight gain.

The effects of selective ibotenate lesions of the hippocampus on conditioned inhibition and extinction.

Previously, Solomon (1977) reported that aspiration lesions of the dorsal hippocampus in rabbits had no effect either on the acquisition of Pavlovian conditioned inhibition or on performance during a subsequent retardation test. The present experiment confirmed and extended these findings by showing that rats with ibotenate lesions of the complete hippocampus (the dorsal and ventral hippocampus and the dentate gyrus) were also unimpaired on the same types of tasks. Additional tests with the same rats showed that removing the hippocampus significantly impaired extinction of responding to a stimulus that had been previously trained with an appetitive unconditioned stimulus. The performance of the lesioned rats on a summation test was also marginally, but not significantly, different from that of controls. The data are discussed with reference to the idea that the hippocampus is involved with the formation of some, but not all, types of inhibitory associations.