Camille H. Sample

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.

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.

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.

Top-down processing modulates older adults’ susceptibility to noise

ABSTRACT 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.

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., Alzheimers 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.

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

ABSTRACT 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. HighlightsCocaine exposure impaired hippocampal‐dependent discrimination performance in rats.Cocaine exposure increased BBB permeability in the hippocampus, but not striatum.Cocaine and western diet have similar harmful impact on discrimination and the BBB.Impaired hippocampal memory function may contribute to excess food and drug intake.Obesity and cocaine abuse may involve weakened inhibition of reward memories.

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.

Western Diet and Cognitive Impairment

Epidemiological studies indicate that Western diet intake, and the weight gain and obesity that it promotes, are associated not only with late-life dementia, but also with poorer cognitive flexibility and inhibitory control across the lifespan. In addition, rodents maintained on a Western diet are impaired on hippocampal-dependent inhibitory learning and memory tasks and exhibit increased blood–brain barrier permeability, hippocampal inflammation, and decreased hippocampal neurogenesis and plasticity. Interference with neuroendocrine signaling may also contribute to hippocampal dysfunction. As a consequence of these types of undesirable effects, Western diet intake may initiate a vicious cycle of progressive weight gain and cognitive decline. That is, consuming this diet induces hippocampal pathologies, which impair the ability to suppress retrieval of food-related memories. This impairment could promote further, and ultimately excessive, intake of the Western diet, leading to increasing weight gain and deteriorating cognitive functioning.