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.

Western-style diet impairs stimulus control by food deprivation state cues: Implications for obesogenic environments.

In western and westernized societies, large portions of the population live in what are considered to be "obesogenic" environments. Among other things, obesogenic environments are characterized by a high prevalence of external cues that are associated with highly palatable, energy-dense foods. One prominent hypothesis suggests that these external cues become such powerful conditioned elicitors of appetitive and eating behavior that they overwhelm the internal, physiological mechanisms that serve to maintain energy balance. The present research investigated a learning mechanism that may underlie this loss of internal relative to external control. In Experiment 1, rats were provided with both auditory cues (external stimuli) and varying levels of food deprivation (internal stimuli) that they could use to solve a simple discrimination task. Despite having access to clearly discriminable external cues, we found that the deprivation cues gained substantial discriminative control over conditioned responding. Experiment 2 found that, compared to standard chow, maintenance on a "western-style" diet high in saturated fat and sugar weakened discriminative control by food deprivation cues, but did not impair learning when external cues were also trained as relevant discriminative signals for sucrose. Thus, eating a western-style diet contributed to a loss of internal control over appetitive behavior relative to external cues. We discuss how this relative loss of control by food deprivation signals may result from interference with hippocampal-dependent learning and memory processes, forming the basis of a vicious-cycle of excessive intake, body weight gain, and progressive cognitive decline that may begin very early in life.

Top-down processing modulates older adults' susceptibility to noise.

The present study examined older and younger adults' ability to use top-down processes to mitigate the effects of display noise during simple feature, visual search. As display noise levels increased, older adults (age 60-74 years, n = 32) exhibited greater top-down search reaction time (RT) benefits (bottom-up minus top-down search RT), compared to younger adults (age 18-27, n = 32). Older adults' ability to mitigate the effects of noise was further assessed with RT variability, as measured by intra-individual standard deviations across trials. Older adults again exhibited larger top-down benefits (i.e., less RT variability) compared to younger adults, and more so when display noise was present vs. absent. These results suggest a sparing of top-down processes with age (Madden, Whiting, Spaniol, & Bucur, 2005; Psychology and Aging, 20, 317), and that top-down processes in older adults enhance search efficiency by optimizing signal-to-noise ratios.

Adverse effects of high-intensity sweeteners on energy intake and weight control in male and obesity-prone female rats.

The use of high-intensity sweeteners has been proposed as a method to combat increasing rates of overweight and obesity in the human population. However, previous work with male rats suggests that consumption of such sweeteners might contribute to, rather than ameliorate, weight gain. The goals of the present experiments were to assess whether intake of high-intensity sweeteners is associated with increased food intake and body weight gain in female rats; to evaluate whether this effect depends on composition of the maintenance diet (i.e., standard chow compared with diets high in energy, fat, and sugar [HE diets]); and to determine whether the phenotype of the rats with regard to propensity to gain weight on HE diets affects the consequences of consuming high-intensity sweeteners. The data demonstrated that female rats fed a low-fat, standard laboratory chow diet did not gain extra weight when fed yogurt dietary supplements sweetened with saccharin compared with those fed glucose-sweetened dietary supplements. However, female rats maintained on a "Westernized" diet high in fat and sugar (HE diet) showed significant increases in energy intake, weight gain, and adiposity when given saccharin-sweetened compared with glucose-sweetened yogurt supplements. These differences were most pronounced in female rats known to be prone to obesity prior to the introduction of the yogurt diets. Both selectively bred Crl:OP[CD] rats and outbred Sprague-Dawley rats fed an HE diet showing high levels of weight gain (diet-induced obese [DIO] rats) had increased weight gain in response to consuming saccharin-sweetened compared with glucose-sweetened supplements. However, in male rats fed an HE diet, saccharin-sweetened supplements produced extra weight gain regardless of obesity phenotype. These results suggest that the most negative consequences of consuming high-intensity sweeteners may occur in those most likely to use them for weight control, females consuming a "Westernized" diet and already prone to excess weight gain.

Influence of ovarian and non-ovarian estrogens on weight gain in response to disruption of sweet taste--calorie relations in female rats.

Regulation of energy balance in female rats is known to differ along a number of dimensions compared to male rats. Previous work from our lab has demonstrated that in female rats fed dietary supplements containing high-intensity sweeteners that may disrupt a predictive relation between sweet tastes and calories, excess weight gain is demonstrated only when females are also fed a diet high in fat and sugar, and is evidenced primarily in animals already prone to gain excess weight. In contrast, male rats show excess weight gain when fed saccharin-sweetened yogurt supplements when fed both standard chow diets and diets high in fat and sugar, and regardless of their proneness to excess weight gain. The goal of the present experiments was to determine whether ovarian, or other sources of estrogens, contributes to the resistance to excess weight gain in female rats fed standard chow diets along with dietary supplements sweetened with yogurt. Results of the first experiment indicated that when the ovaries were removed surgically in adult female rats, patterns of weight gain were similar in animals fed saccharin-sweetened compared to glucose-sweetened yogurt supplements. In the second experiment, when the ovaries were surgically removed in adult female rats, and local production of estrogens was suppressed with the aromatase inhibitor anastrozole, females fed the saccharin-sweetened yogurt consumed more energy and gained more weight than females fed the glucose-sweetened yogurt. However, when the ovaries were surgically removed prior to the onset of puberty (at 24-25 days of age), females given saccharin-sweetened yogurt along with vehicle gained excess weight. In contrast, weight gain was similar in those given saccharin-sweetened and glucose-sweetened yogurt along with anastrozole. The results suggest that behavioral differences between males and females in response to disruption of sweet→calorie relations may result from differences in patterns of local estrogen production. These differences may be established developmentally during the pubertal period in females.