Obesogenic Diet Cycling Produces Graded Effects on Cognition and Microbiota Composition in Rats.

SCOPE: The effects of diet cycling on cognition and fecal microbiota are not well understood. METHOD AND RESULTS: Adult male Sprague-Dawley rats were cycled between a high-fat, high-sugar "cafeteria" diet (Caf) and regular chow. The impairment in place recognition memory produced by 16 days of Caf diet was reduced by switching to chow for 11 but not 4 days. Next, rats received 16 days of Caf diet in 2, 4, 8, or 16-day cycles, each separated by 4-day chow cycles. Place recognition memory declined from baseline in all groups and was impaired in the 16- versus 2-day group. Finally, rats received 24 days of Caf diet continuously or in 3-day cycles separated by 2- or 4-day chow cycles. Any Caf diet access impaired cognition and increased adiposity relative to controls, without altering hippocampal gene expression. Place recognition and adiposity were the strongest predictors of global microbiota composition. Overall, diets with higher Caf > chow ratios produced greater spatial memory impairments and larger shifts in gut microbiota species richness and beta diversity. CONCLUSION: Results suggest that diet-induced cognitive deficits worsen in proportion to unhealthy diet exposure, and that shifting to a healthy chow for at least a week is required for recovery under the conditions tested here.

The neural substrates of higher-order conditioning: A review.

Sensory preconditioned and second-order conditioned responding are each well-documented. The former occurs in subjects (typically rats) exposed to pairings of two relatively neutral stimuli, S2 and S1, and then to pairings of S1 and a motivationally significant event [an unconditioned stimulus (US)]; the latter occurs when the order of these experiences is reversed with rats being exposed to S1-US pairings and then to S2-S1 pairings. In both cases, rats respond when tested with S2 in a manner appropriate to the affective nature of the US, e.g., approach when the US is appetitive and withdrawal when it is aversive. This paper reviews the neural substrates of sensory preconditioning and second-order conditioning. It identifies commonalities and differences in the substrates of these so-called higher-order conditioning protocols and discusses these commonalities/differences in relation to what is learned. In so doing, the review highlights ways in which these types of conditioning enhance our understanding of how the brain encodes and retrieves different types of information to generate appropriate behavior.

Chronic exposure to cafeteria-style diet in rats alters sweet taste preference and reduces motivation for, but not 'liking' of sucrose.

Obesity is associated with changes to taste perception and brain reward circuitry. It is important to understand how these effects alter the preference for palatable foods and drinks, given that these are widely consumed, and leading risk factors for obesity. This study examined the effects of diet-induced obesity on sweet taste preference by analysing the microstructure of licking for sugar solutions and assessing pERK expression in the nucleus accumbens shell and insula. Adult male Sprague-Dawley rats were fed standard chow (Control; n = 16) or a varied, palatable cafeteria diet (Caf; n = 16) for 12 weeks. Two-choice preference tests between 2%, 8% and 32% sucrose solutions were conducted at baseline and in weeks 11-12 of the diet. Rats in the Caf group trebled energy intake and doubled weight gain relative to controls. In tests held under water restriction after 11 weeks of diet, the Control group reliably preferred higher sucrose concentrations (i.e., 32% > 8% > 2%). Relative to controls, the Caf group showed a stronger preference for 32% vs. 2% sucrose, lower preference for 32% vs. 8% sucrose, and were indifferent to 8% vs. 2% sucrose. Testing without water restriction increased preference for higher sucrose concentrations in both groups. Chronic Caf diet increased the latency to lick, decreased total licks and reduced alternations between spouts, but did not alter lick cluster size, a measure of hedonic appraisal, on any test. Following a final exposure to a novel sucrose concentration, neuronal activity (pERK) in the insula and nucleus accumbens shell was significantly reduced in the Caf group. Results indicate that differences in 'liking' do not underlie obesity-induced changes to sweet taste preference.

Not "either-or" but "which-when": A review of the evidence for integration in sensory preconditioning.

Sensory preconditioning protocols can be used to assess how the brain integrates memories that share common features. In these protocols, animals are first exposed to pairings of two relatively innocuous stimuli, S2 and S1 (stage 1), and then to pairings of one of these stimuli, S1, with an event of motivational significance (stage 2). Following this training, test presentations of S2 elicit responses appropriate to the motivationally significant event, and these responses are taken to indicate formation of distinct S2-S1 and S1-event memories that are integrated in some way to generate that responding. This paper reviews studies of sensory preconditioning in rats, mice, rabbits and people to determine whether S2-S1 and S1-event memories are integrated through a chaining process at the time of their retrieval (i.e., test presentations of S2 trigger retrieval of S1, and thereby, responses appropriate to the event); or "online" at the time of memory formation (i.e., in stage 2, S1 activates a representation of S2 such that both stimuli associate with the motivationally significant event). It finds that the type of integration is determined by the manner in which stimuli are presented in preconditioning as well as their familiarity. When the stimuli in preconditioning are presented repeatedly and/or serially (i.e., one after the other), the S2-S1 and S1-event memories are chained at the time of retrieval/testing. In contrast, when the stimuli in preconditioning are relatively novel and/or presented simultaneously, the S2-S1 and S1-event memories are integrated online. These statements are related to prior claims regarding the circumstances that promote different types of memory integration and, more generally, mechanisms of information processing in the mammalian brain.

Protecting the Rescorla-Wagner (1972) theory: A reply to Spicer et al. (2020).

Rescorla (2001) used the compound test procedure to compare associative changes to cues located at different points on a performance scale. He found that associative changes to cues conditioned in compound are not necessarily equal, as predicted by common error term theories like Rescorla and Wagner (1972), but instead are larger for the poorer predictor of a trial outcome. Hence, Rescorla proposed a modification to the Rescorla-Wagner model whereby associative change is calculated as the product of 2 error terms: a common error term, as in the original model, and a unique error term for each cue present, which accounts for his findings that the poorer predictor of a trial outcome undergoes more associative change. In a recent study, Spicer, Mitchell, Wills, and Jones (2020) reported findings that appear to be inconsistent with Rescorla's proposal. These authors compared associative changes to cues that differed in associative strength as well as the certainty with which they predicted a trial outcome: One cue had greater strength than did the other, but its prediction of the trial outcome was less certain. Spicer et al. found that the cue that evoked a larger prediction error (the more certain cue) underwent less (not more) associative change and, thereby, concluded that associative change in people is not primarily determined by prediction error. Instead, they argued that cues that predict certain outcomes are somewhat protected from further associative change (theory protection), resulting in greater change to cues that predict uncertain outcomes. In this article, we offer an alternative explanation for the Spicer et al. findings using an approach described by Holmes, Chan, and Westbrook (2019). We show that if the learning-to-performance mapping function is a double sigmoid across the full range of associative strength, the Rescorla-Wagner model accommodates Rescorla's compound test results, as well as those reported by Spicer et al. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The effect of early list manipulations on the DRM illusion.

The Deese-Roediger-McDermott (DRM) paradigm is widely used to study false memory in the laboratory. It tests memory for lists of semantically related words (correct list item memories) and their non-presented associates (false lure memories). Evidence suggests that early items in DRM lists could make an especially significant contribution to false memories of lures, as they may critically influence the underlying associative activation and/or gist extraction processes. The present study tested this suggestion by using two manipulations that were intended to affect processing of early DRM list items. The first was interpolation of a semantically unrelated distractor item among the list items (Experiments 1 and 2). The second was arranging for these items to be either the strongest or weakest associates of the lure (Experiment 2). In Experiment 1, a distractor item reduced both list item and lure recall when presented early in a DRM list, but selectively disrupted list item recall when presented late in the list. In Experiment 2, arranging for the early list items to be the weakest associates of the lure reduced false recall of the lure but had no effect on list item recall. The findings are discussed with respect to theories that explain false memory in the DRM protocol, including fuzzy trace theory (FTT) and activation-monitoring theory (AMT). They are also discussed with respect to general theories of memory and the potential role of category/context information in generating false memories.

'Online' integration of sensory and fear memories in the rat medial temporal lobe.

How does a stimulus never associated with danger become frightening? The present study addressed this question using a sensory preconditioning task with rats. In this task, rats integrate a sound-light memory formed in stage 1 with a light-danger memory formed in stage 2, as they show fear when tested with the sound in stage 3. Here we show that this integration occurs 'online' during stage 2: when activity in the region that consolidated the sound-light memory (perirhinal cortex) was inhibited during formation of the light-danger memory, rats no longer showed fear when tested with the sound but continued to fear the light. Thus, fear that accrues to a stimulus paired with danger simultaneously spreads to its past associates, thereby roping those associates into a fear memory network.

A combination of common and individual error terms is not needed to explain associative changes when cues with different training histories are conditioned in compound: A review of Rescorla's compound test procedure.

Rescorla (2000) devised the compound test procedure as a means of comparing changes in associative strength when cues with different training histories are conditioned in compound. It was specifically intended to dissociate changes in learning from changes in performance, and thereby, permit inferences about learning independently of assumptions regarding how learning translates into performance. In an elegant series of studies, Rescorla (2000, 2001) used this procedure to show that cues conditioned in compound undergo unequal associative change such that the poorer predictor of the outcome undergoes greater change rather than the equal change predicted by theories (e.g., Rescorla & Wagner, 1972) that rely on a common error term. Rescorla explained the data from the compound test procedure by proposing that associative change is calculated using a combination of two error terms, a common error term that carries the predictions of all cues present on a trial and an individual term that carries the prediction of any cue in isolation. This article is in two parts. The first used simulations to show that a theory, such as Rescorla-Wagner, which just relies on a common error term, can explain the compound test data if the function that translates learning into performance is double-sigmoidal across the full range of associative strength (i.e., from inhibition through to excitation). The second part likewise used simulations to show that a theory, such as the comparator theory (Miller & Matzel, 1988), which does not invoke a common error term, can also explain the compound test data. Thus, a common error term is sufficient to explain the compound test data, but it is not necessary. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Compound Stimulus Presentation Does Not Deepen Extinction in Human Causal Learning.

Models of associative learning have proposed that cue-outcome learning critically depends on the degree of prediction error encountered during training. Two experiments examined the role of error-driven extinction learning in a human causal learning task. Target cues underwent extinction in the presence of additional cues, which differed in the degree to which they predicted the outcome, thereby manipulating outcome expectancy and, in the absence of any change in reinforcement, prediction error. These prediction error manipulations have each been shown to modulate extinction learning in aversive conditioning studies. While both manipulations resulted in increased prediction error during training, neither enhanced extinction in the present human learning task (one manipulation resulted in less extinction at test). The results are discussed with reference to the types of associations that are regulated by prediction error, the types of error terms involved in their regulation, and how these interact with parameters involved in training.

Alternating or continuous exposure to cafeteria diet leads to similar shifts in gut microbiota compared to chow diet.

SCOPE: Overconsumption of energy-rich food is a major contributor to the obesity epidemic. The eating habits of many people are characterized by the cycling between overconsumption of energy-rich foods and dieting, the effects of which on the microbiota are currently unknown. METHODS AND RESULTS: We compared the fecal microbiota of rats either continuously fed chow or palatable cafeteria diet to a "cycled" group switched between the two diets (chow for 4, cafeteria for 3 days/wk, n = 12/group) over 16 wk. Enriched bacterial metabolic pathways were predicted, and a range of metabolic parameters was correlated to microbial taxa and pathways. Cycled rats showed large excursions in food intake on each diet switch. When switched from chow to cafeteria, they overconsumed, and when switched back to chow they underconsumed relative to those maintained on the two diets. Metabolic parameters of cycled rats were intermediate between those of the other diet groups (p < 0.05). The microbiota of cycled rats was nearly indistinguishable from rats under constant cafeteria diet, and both groups were significantly different to the chow group. Correlation analyses identified microbial metabolic pathways associated with an obese phenotype. CONCLUSION: These data suggest that continuous or intermittent exposure to palatable foods have similar effects on the gut microbiota.

Varenicline impairs extinction and enhances reinstatement across repeated cycles of nicotine self-administration in rats.

Varenicline is a partial nicotine receptor agonist widely prescribed as a smoking cessation medication. Repeated (or long-term) use of varenicline has been proposed as a treatment option for tobacco addiction. However the effect of repeated varenicline use on motivation for nicotine is unknown. Here the intravenous nicotine self-administration paradigm in rats was used to model the consequences of varenicline treatment across repeated cycles of administration, extinction and reinstatement. Rats acquired nicotine self-administration across 20 days before undergoing 6 days of extinction, where each extinction session was preceded by a single injection of varenicline or saline. This was followed by a single varenicline-free nicotine-primed reinstatement test. All rats then reacquired nicotine self-administration for 10 days followed by a second cycle of extinction. Across this period, rats either received a second cycle of varenicline (VAR-VAR) or saline (SAL-SAL), or the alternative treatment (SAL-VAR, VAR-SAL), followed by a final reinstatement test. Treatment with varenicline increased responding across the first cycle of extinction, but did not affect responding in the reinstatement test. Across the second cycle, varenicline again increased responding across extinction, and critically, rats treated with varenicline across cycle 1 and saline across cycle 2 (Group VAR-SAL) exhibited more reinstatement than rats in any other group. The effect of VAR on nicotine seeking was not due to its effects on locomotor activity. Instead, the results suggest that a history of VAR can increase vulnerability to reinstatement/relapse when its treatment is discontinued. The possible mechanisms of this increased vulnerability are discussed.

Sex-specific effects of daily exposure to sucrose on spatial memory performance in male and female rats, and implications for estrous cycle stage.

Excessive consumption of sugar sweetened drinks is proposed to produce functional changes in the hippocampus, leading to perturbations in learning and memory. In this study we examined the impact of 2h daily access to 10% sucrose (or no sucrose in controls) on recognition memory tasks in young male and female rats. In Experiment 1 we tested rats on memory tasks reliant on the hippocampus (place recognition), perirhinal cortex (object recognition), and a combination of hippocampus, prefrontal cortex and perirhinal cortex (object-in-place memory). Exposure to sucrose for 2h a day for 14days prior to behavioral testing did not affect object recognition, but impaired spatial memory to an extent in both male and female rats. Male rats exposed to sucrose were impaired at both place recognition and object-in-place recognition, however female rats showed no impairment in object-in-place performance. Plasticity within the hippocampus is known to increase during the proestrus phase of the estrous cycle and is related to higher levels of circulating estrogens. In Experiment 2 we tested place recognition and object-in-place memory in 10% sucrose exposed or non-exposed control female rats both during the metestrus (low estrogen) and proestrus (high estrogen) phases of their cycle on place recognition and object-in-place memory. Both sucrose exposed and control female rats were able to perform place object-in-place recognition correctly during metestrus and proestrus, however sucrose exposed rats were only able to perform place recognition correctly during proestrus. This indicates that when hippocampal function is compromised, endogenous estrogens may boost memory performance in females, and that males may be at more risk of high sugar diet induced cognitive deficits.

Differential motivational profiles following adolescent sucrose access in male and female rats.

Adolescents are the highest consumers of sugar sweetened drinks. Excessive consumption of such drinks is a likely contributor to the development of obesity and may be associated with enduring changes in the systems involved in reward and motivation. We examined the impact of daily sucrose consumption in young male and female rats (N=12 per group) across the adolescent period on the motivation to perform instrumental responses to gain food rewards as adults. Rats were or were not exposed to a sucrose solution for 2 h each day for 28 days across adolescence [postnatal days (P) 28-56]. They were then trained as adults (P70 onward) to lever press for a palatable 15% cherry flavored sucrose reward and tested on a progressive ratio (PR) schedule to assess motivation to respond for reinforcement. Female rats exposed to sucrose had higher breakpoints on the PR schedule than controls, whereas male rats exposed to sucrose had lower breakpoints than controls. These results show that consumption of sucrose during adolescence produced sex-specific behavioral changes in responding for sucrose as adults.

Impact of adolescent sucrose access on cognitive control, recognition memory, and parvalbumin immunoreactivity.

In this study we sought to determine the effect of daily sucrose consumption in young rats on their subsequent performance in tasks that involve the prefrontal cortex and hippocampus. High levels of sugar consumption have been associated with the development of obesity, however less is known about how sugar consumption influences behavioral control and high-order cognitive processes. Of particular concern is the fact that sugar intake is greatest in adolescence, an important neurodevelopmental period. We provided sucrose to rats when they were progressing through puberty and adolescence. Cognitive performance was assessed in adulthood on a task related to executive function, a rodent analog of the Stroop task. We found that sucrose-exposed rats failed to show context-appropriate responding during incongruent stimulus compounds presented at test, indicative of impairments in prefrontal cortex function. Sucrose exposed rats also showed deficits in an on object-in-place recognition memory task, indicating that both prefrontal and hippocampal function was impaired. Analysis of brains showed a reduction in expression of parvalbumin-immunoreactive GABAergic interneurons in the hippocampus and prefrontal cortex, indicating that sucrose consumption during adolescence induced long-term pathology, potentially underpinning the cognitive deficits observed. These results suggest that consumption of high levels of sugar-sweetened beverages by adolescents may also impair neurocognitive functions affecting decision-making and memory, potentially rendering them at risk for developing mental health disorders.

Effects of long-term cycling between palatable cafeteria diet and regular chow on intake, eating patterns, and response to saccharin and sucrose.

When exposed to a diet containing foods that are rich in fat and sugar, rats eat to excess and gain weight. We examined the effects of alternating this diet with laboratory chow on intake of each type of diet, the eating elicited by a palatable food (biscuits), and the drinking elicited by sweet solutions that did (sucrose) or did not (saccharin) contain calories. Each week for 13 weeks, cycled rats were provided with the cafeteria diet for three successive days/nights and the chow diet for the remaining four days/nights, whereas other rats received continuous access to either the cafeteria or the chow diets. On each of the 13 weeks, cycled rats ate more across the first 24 hour exposure to the cafeteria diet than rats continuously fed this diet. In contrast, cycled rats ate less across the first 24 hour exposure to the chow diet than rats continuously fed this diet and ate less when presented a novel palatable biscuit than chow-fed rats. The three groups exhibited similar licks per cluster to saccharin, but cafeteria-fed and cycled rats showed fewer clusters than chow-fed rats. In contrast, chow-fed rats and cycled rats exhibited more licks per cluster to sucrose than cafeteria-fed rats, but all three groups had a similar number of clusters. The results were discussed in relation to the effects of diet cycling on eating patterns, body weight, and 'wanting' and 'liking'. These findings with rats may have important implications for yo-yo dieting in people.

Extended exposure to a palatable cafeteria diet alters gene expression in brain regions implicated in reward, and withdrawal from this diet alters gene expression in brain regions associated with stress.

Like people, rodents exposed to energy-rich foods over-eat and become overweight. Removal of this diet activates stress systems, which may explain why people have difficulty dieting. We exposed rats to energy-rich foods in order to identify changes in the brain induced by that diet and by its removal. Sprague Dawley rats were fed lab-chow or an energy-rich cafeteria diet (plus chow). Following 6 or 15 weeks, half of each group was switched to the opposing diet. Rats were culled 48-h later. We measured fat mass, plasma hormones, and assessed brains for mRNA expression of several genes. Cafeteria-fed rats consumed more kilojoules, weighed more and had elevated leptin (plus reduced CORT at 15 weeks) relative to chow-fed rats. Fifteen weeks of cafeteria diet suppressed µ-opioid and CB1 receptor mRNA in the VTA, but elevated amygdala GR, and 6 weeks of cafeteria diet reduced BDNF, compared to chow-fed rats. Rats switched to the cafeteria diet ate similar amounts as rats maintained on the diet, and switching to cafeteria diet after 15 weeks reduced amygdala GR expression. Rats switched to chow ate less than rats maintained on chow, and switching to chow following 15 weeks of cafeteria diet increased hypothalamic CRH mRNA. Therefore, 15 weeks of cafeteria diet produced changes in brain regions implicated in reward processes. Switching these rats to chow activated the HPA axis, while switching chow-fed rats to the cafeteria diet decreased GR expression in the amygdala, a region associated with stress. These findings have implications for dieting in humans.

Altered feeding patterns in rats exposed to a palatable cafeteria diet: increased snacking and its implications for development of obesity.

BACKGROUND: Rats prefer energy-rich foods over chow and eat them to excess. The pattern of eating elicited by this diet is unknown. We used the behavioral satiety sequence to classify an eating bout as a meal or snack and compared the eating patterns of rats fed an energy rich cafeteria diet or chow. METHODS: Eight week old male Sprague Dawley rats were exposed to lab chow or an energy-rich cafeteria diet (plus chow) for 16 weeks. After 5, 10 and 15 weeks, home-cage overnight feeding behavior was recorded. Eating followed by grooming then resting or sleeping was classified as a meal; whereas eating not followed by the full sequence was classified as a snack. Numbers of meals and snacks, their duration, and waiting times between feeding bouts were compared between the two conditions. RESULTS: Cafeteria-fed rats ate more protein, fat and carbohydrate, consistently ingesting double the energy of chow-fed rats, and were significantly heavier by week 4. Cafeteria-fed rats tended to take multiple snacks between meals and ate fewer meals than chow-fed rats. They also ate more snacks at 5 weeks, were less effective at compensating for snacking by reducing meals, and the number of snacks in the majority of the cafeteria-fed rats was positively related to terminal body weights. CONCLUSIONS: Exposure to a palatable diet had long-term effects on feeding patterns. Rats became overweight because they initially ate more frequently and ultimately ate more of foods with higher energy density. The early increased snacking in young cafeteria-fed rats may represent the establishment of eating habits that promote weight gain.

Induction of Fos proteins in regions of the nucleus accumbens and ventrolateral striatum correlates with catalepsy and stereotypic behaviours induced by morphine.

A history of intermittent exposures to drugs of abuse can cause long-term changes in acute behavioural responses to a subsequent drug exposure. In drug-naive rats, morphine can elicit intermittent cataleptic postures followed by sustained increases in locomotor activity. Chronic intermittent morphine treatment can reduce catalepsy and increase locomotor behaviour and stereotypy induced by morphine, even after prolonged periods of abstinence. The nucleus accumbens and limbic basal ganglia circuitry are implicated in the expression of various morphine-induced motor behaviours and catalepsy. We examined the effect of intermittent morphine exposure on the distribution of Fos proteins in the basal ganglia following a subsequent morphine challenge administered after a period of drug abstinence. We found that such exposures increased c-Fos induced by a morphine challenge in accumbens core regions that were immunoreactive for the micro-opioid receptor, and this correlated with the frequency of stereotypic behaviours displayed by the rats. We also found that a history of morphine exposures increased c-Fos in the ventrolateral striatum in response to a morphine challenge following 14 d but not 24 h of drug abstinence. In contrast, such a history induced acute Fras in the nucleus accumbens in response to a morphine challenge following 24 h but not 14 d of morphine abstinence. These data provide further confirmation that psychomotor sensitisation induced by repetitive morphine exposure involves long-term neuroadaptations in basal ganglia circuitry particularly at the level of the nucleus accumbens.