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.

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.

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.

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".

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.

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.

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 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.

The nature and function of interoceptive signals to feed: toward integration of physiological and learning perspectives.

The idea that different states of energy need give rise to distinct interoceptive sensations has been basic to many accounts of the physiological and the learned controls of feeding. Yet, a number of difficulties have complicated attempts to provide direct evidence for this view. The present article describes a research strategy that confirms that food deprivation states produce salient interoceptive stimuli in rats. The implications of this research for the physiological origins of energy state signals, the brain structures involved with processing energy state information, and the manner in which signals of energy need influence feeding were considered. The possibility that food deprivation cues influence feeding by modulating the activation of associations involving external events and their postingestive aftereffects was discussed with reference to earlier associative accounts of the function of hunger signals.

Localization of fluorescent compounds in the firefly light organ.

Two fluorescent materials have been localized in the adult firefly light organ by fluorescence microscopy. One of these is located in photocyte granules, has a maximum emission between 510 and 540 nm, is more fluorescent in basic than acidic solution, and is unstable in ultraviolet light, phosphomolybdic acid, and potassium permanganate. It is thought to be luciferin. The fluorescence of this material is very dim in untreated fireflies but increases substantially following sustained light emission induced by synephrine or prolonged electrical stimulation. It is suggested that the luciferin of untreated animals is bound in the granules and that binding suppresses its fluorescence. The second fluorescent material is located in the dorsal layer of the light organ, particularly in the cells bordering on the photogenic layer. This material has a maximum emission between 510 and 520 nm, is relatively stable in ultraviolet light, and rapidly disappears when light organs are exposed to water. Its identity and function are unknown.

Automated scoring of sleep in the neonatal lamb.

The study of sleep is an important and rapidly expanding area of research that generates large bodies of data. Manual scoring of sleep states from polygraph recordings is a laborious and often subjective task. Even when care is taken, the opportunity for disagreement between investigators and between laboratories remains great. To avoid this difficulty and to reduce the subjectivity of sleep state scoring we have designed a computer-based algorithm for scoring sleep state in the lamb. The algorithm underlying the system relies upon spectral analysis of the electrocorticogram and upon amplitude analysis of the electrooculogram and nuchal electromyogram. Partitioning the spectral power observed within the electrocorticogram (1-4 Hz frequency range) reliably identifies deep quiet sleep. Wakefulness and active sleep are then identified based upon threshold crossings of the electrooculogram and of the electromyogram of the nuchal muscles. We compared the sleep states returned by the algorithm to those scored visually by trained personnel for 1 hour of data collected from each of five 19-day-old lambs. There was good agreement between the two methods of scoring sleep. The percents agreement between the algorithm-derived scores and visual scores were as follows: active wakefulness 97%, quiet wakefulness 87%, quite sleep 85% and phasic active sleep 82%. As such, our algorithm provides a fast, reliable and objective method for scoring sleep state in the young lamb.

Learning about deprivation intensity stimuli.

Rats demonstrated that they can use deprivation-produced stimuli as discriminative signals for shock in three experiments that used observation of freezing behavior as the index of learning. In Experiment 1, one group was shocked under 24-hr, but not under 0-hr food deprivation. Another group received the reversed discrimination. Both groups froze more under their shocked than under their nonshocked deprivation level. Furthermore, freezing was greatest under a given deprivation level for the group shocked under that level. Behavior was shown to be a function of this learning during subsequent testing under other deprivation levels. In Experiment 2, rats discriminated between deprivation intensities approximating those encountered under free-feeding conditions, and behavior under other deprivation levels also depended on this learning. Experiment 3, using 6- and 23-hr food deprivation, showed that discriminative responding occurred in the absence of cues arising from the recent memory of food in the home cage. Generalization of discriminative control to cues produced by intubation of a high calorie load and to injection of insulin (Experiment 3A) provided evidence that animals learned about the interoceptive stimulus consequences of their deprivation states. The results encourage the view that learning about internal stimulus aspects of food deprivation plays a role in appetitive behavior.

Interoceptive sensory signals produced by 24-hr food deprivation, pharmacological glucoprivation, and lipoprivation.

The energy antimetabolites 2-deoxy-D-glucose (2-DG) and Na-2-mercaptoacetate (MA) both reliably augment food intake in rats. The present research was designed to assess if they also give rise to interoceptive cues like 24-hr food deprivation. Rats were first trained to discriminate a mild shock based on interoceptive cues arising from 1- and 24-hr food deprivation. They were then tested for generalized control of conditioned responding to interoceptive cues produced by 2-DG, MA, and saline. Results suggest that 2-DG (350 mg/kg) produces interoceptive sensory cues like those following 24-hr food deprivation. Further, no evidence was found to suggest that MA, either alone or in combination with 2-DG (100 mg/kg), produces interoceptive cues like 2-DG or 24-hr food deprivation.

Comparison of the interoceptive sensory consequences of CCK, LiCl, and satiety in rats.

In three experiments we assessed the degree to which ad lib feeding, injection of cholecystokinin (CCK), and injection of lithium chloride (LiCl) produce states with similar sensory consequences. In each experiment, two groups of rats were trained to use cues arising from food deprivation and satiation as discriminative signals for shock. One group was shocked when deprived but not when nondeprived. The other group received the reversed discrimination. Testing began when incidence of freezing was greater under the shocked deprivation than under the nonshocked deprivation condition. In Experiment 1, the rats were tested under 24-hr food deprivation after injections of CCK, LiCl, and saline (in counterbalanced order). We reasoned that if either CCK or LiCl induce satiety-like states, they should promote patterns of responding different from those produced by saline but similar to those produced by ad lib feeding. The effects of CCK on freezing did not differ from those of saline, whereas both CCK and LiCl had effects that were different from ad lib feeding. This pattern of results was also obtained when deprivation level during training and testing was reduced to 8 hr (Experiment 1A) and also when rats received small amounts of food in conjunction with CCK (Experiment 2). The intubation of a high-calorie stomach load (Experiment 1A) produced a response profile like that observed after free feeding. Freezing after LiCl treatment differed from that observed after free feeding and from that found after injection of CCK. The results indicate that rats can differentiate between the sensory consequences of the states produced by CCK, by LiCl, and by ad lib feeding.

Lesions of the amygdala central nucleus abolish lipoprivic-enhanced responding during oil-predicting conditioned stimuli.

T. L. Davidson, A. M. Altizer, S. C. Benoit, E. K. Walls, and T. L. Powley (1997) reported that rats show facilitated responding to conditioned stimuli (CSs) that predict oil, after administration of the lipoprivic agent, Na-2-mercaptoacetate (MA). This facilitation was blocked by vagal deafferentation. The present article extends that investigation to another structure, the amygdala central nucleus (CN). The CN receives inputs from dorsal vagal nuclei, and neurotoxic lesions of this nucleus are reported to abolish feeding in response to lipoprivic challenges. In Experiment 1, rats with ibotenic acid (IBO) lesions of the CN failed to show enhanced appetitive responding during oil-predicting CSs after administration of MA. Experiment 2 used a conditioned taste-aversion procedure to establish that rats with IBO lesions of the CN were able to discriminate the tastes of sucrose and peanut oil and had intact CS-US representations. It is concluded that the amygdala CN is a necessary structure for the detection of lipoprivic challenges.

Hippocampal lesions do not impair negative patterning: a challenge to configural association theory.

According to configural association (CAS) theory (Sutherland & Rudy, 1989), an intact hippocampus is required for rats to solve learning problems that are based on "configural" processes. This theory identifies the negative patterning discrimination as a critical example of this type of problem. Rudy and Sutherland (1989) reported disruption of negative patterning following hippocampal formation damage produced by intracranial infusion of a mixture of kainic acid + colchicine (KA + COL). We assessed acquisition of negative patterning in rats with hippocampal damage produced by KA + COL compared with rats with more selective ibotenate lesions of hippocampus. Neither group showed impaired negative patterning relative to controls. A transfer test provided evidence that all groups used configural processes to solve the problem. Thus contrary to CAS theory, the hippocampus is not an important substrate for the operation of configural processes.

Encoding and selective activation of "metabolic memories" in the rat.

Experiment 1 used Pavlovian conditioning procedures to show that rats formed distinct memorial representations of 2 (peanut oil and sucrose pellets) unconditioned stimuli (USs) that could be activated by 2 different conditioned stimuli (CSs). After training in Experiment 2, rats injected with the lipid antimetabolite Na-2-mercaptoacetate (MA) responded more to the CS for oil than to the CS for sucrose. This pattern was not shown by rats that received isotonic saline or systemic 2-deoxy-d-glucose (a glucose antimetabolite). By contrast, intracerebroventricular infusion of the glucose antimetabolite 5-thioglucose selectively promoted responding to the CS for sucrose (Experiment 4). Thus, lipoprivic and glucoprivic treatments selectively promoted the activation of the memories of fat and carbohydrate USs, respectively. In Experiment 3, the capacity of MA to augment responding to a CS for oil was abolished for rats that received subdiaphragmatic vagal deafferentation. This indicates that the capacity of lipoprivic signals to selectively activate the representations of fat USs may depend on vagal afferent fibers.