Terry L. Davidson

Western Diet Consumption and Cognitive Impairment: Links to Hippocampal Dysfunction and Obesity

Intake of saturated fats and simple carbohydrates, two of the primary components of a modern Western diet, is linked with the development of obesity and Alzheimers Disease. The present paper summarizes research showing that Western diet intake is associated with cognitive impairment, with a specific emphasis on learning and memory functions that are dependent on the integrity of the hippocampus. The paper then considers evidence that saturated fat and simple carbohydrate intake is correlated with neurobiological changes in the hippocampus that may be related to the ability of these dietary components to impair cognitive function. Finally, a model is described proposing that Western diet consumption contributes to the development of excessive food intake and obesity, in part, by interfering with a type of hippocampal-dependent memory inhibition that is critical in the ability of animals to refrain from responding to environmental cues associated with food, and ultimately from consuming energy intake in excess of that driven solely by caloric need.

A Role for Sweet Taste: Calorie Predictive Relations in Energy Regulation by Rats

Animals may use sweet taste to predict the caloric contents of food. Eating sweet noncaloric substances may degrade this predictive relationship, leading to positive energy balance through increased food intake and/or diminished energy expenditure. These experiments were designed to test the hypothesis that experiences that reduce the validity of sweet taste as a predictor of the caloric or nutritive consequences of eating may contribute to deficits in the regulation of energy by reducing the ability of sweet-tasting foods that contain calories to evoke physiological responses that underlie tight regulation. Adult male Sprague-Dawley rats were given differential experience with a sweet taste that either predicted increased caloric content (glucose) or did not predict increased calories (saccharin). We found that reducing the correlation between sweet taste and the caloric content of foods using artificial sweeteners in rats resulted in increased caloric intake, increased body weight, and increased adiposity, as well as diminished caloric compensation and blunted thermic responses to sweet-tasting diets. These results suggest that consumption of products containing artificial sweeteners may lead to increased body weight and obesity by interfering with fundamental homeostatic, physiological processes.

NIH working group report: Innovative research to improve maintenance of weight loss.

The National Institutes of Health, led by the National Heart, Lung, and Blood Institute, organized a working group of experts to discuss the problem of weight regain after weight loss. A number of experts in integrative physiology and behavioral psychology were convened with the goal of merging their perspectives regarding the barriers to scientific progress and the development of novel ways to improve long‐term outcomes in obesity therapeutics. The specific objectives of this working group were to: (1) identify the challenges that make maintaining a reduced weight so difficult; (2) review strategies that have been used to improve success in previous studies; and (3) recommend novel solutions that could be examined in future studies of long‐term weight control.

The Effects of Energy-Rich Diets on Discrimination Reversal Learning and on BDNF in the Hippocampus and Prefrontal Cortex of the Rat

Male rats received normal chow or high-fat diets rich in dextrose (HFD) or sucrose (HFS). Half of the rats received 90-day unrestricted access to their diet prior to training, whereas the other half were food restricted throughout the study. We evaluated the effects of these dietary manipulations on discrimination and reversal performance and on post-training levels of brain-derived neurotrophic factor (BDNF) in the prefrontal cortex and the ventral and dorsal hippocampus. Neither diet nor restriction condition affected discrimination acquisition. However, prior unrestricted access to the HFD diet impaired discrimination reversal learning and reduced BDNF in the prefrontal cortex and ventral hippocampus. Also, rats given the HFD diet responded more than controls to the previously rewarded cue at the outset of discrimination reversal. The results suggest that consumption of the HFD diet may have had enduring effects on learning processes, some of which may contribute to the control of intake regulation.

High-intensity sweeteners and energy balance

Recent epidemiological evidence points to a link between a variety of negative health outcomes (e.g. metabolic syndrome, diabetes and cardiovascular disease) and the consumption of both calorically sweetened beverages and beverages sweetened with high-intensity, non-caloric sweeteners. Research on the possibility that non-nutritive sweeteners promote food intake, body weight gain, and metabolic disorders has been hindered by the lack of a physiologically-relevant model that describes the mechanistic basis for these outcomes. We have suggested that based on Pavlovian conditioning principles, consumption of non-nutritive sweeteners could result in sweet tastes no longer serving as consistent predictors of nutritive postingestive consequences. This dissociation between the sweet taste cues and the caloric consequences could lead to a decrease in the ability of sweet tastes to evoke physiological responses that serve to regulate energy balance. Using a rodent model, we have found that intake of foods or fluids containing non-nutritive sweeteners was accompanied by increased food intake, body weight gain, accumulation of body fat, and weaker caloric compensation, compared to consumption of foods and fluids containing glucose. Our research also provided evidence consistent with the hypothesis that these effects of consuming saccharin may be associated with a decrement in the ability of sweet taste to evoke thermic responses, and perhaps other physiological, cephalic phase, reflexes that are thought to help maintain energy balance.

The Effects of a High-Energy Diet on Hippocampal Function and Blood-Brain Barrier Integrity in the Rat

Cognitive impairment and Alzheimers disease are linked with intake of a Western diet, characterized by high levels of saturated fats and simple carbohydrates. In rats, these dietary components have been shown to disrupt hippocampal-dependent learning and memory processes, particularly those involving spatial memory. Using a rat model, the present research assessed the degree to which consumption of a high-energy (HE) diet, similar to those found in modern Western cultures, produces a selective impairment in hippocampal function as opposed to a more global cognitive disruption. Learning and memory performance was examined following 90-day consumption of an HE-diet in three nonspatial discrimination learning problems that differed with respect to their dependence on the integrity of the hippocampus. The results showed that consumption of the HE-diet impaired performance in a hippocampal-dependent feature negative discrimination problem relative to chow-fed controls, whereas performance was spared on two discrimination problems that do not rely on the hippocampus. To explore the mechanism whereby consuming HE-diets impairs cognitive function, we investigated the effect of HE-diets on the integrity of the blood-brain barrier (BBB). We found that HE-diet consumption produced a decrease in mRNA expression of tight junction proteins, particularly Claudin-5 and -12, in the choroid plexus and the BBB. Consequently, an increased blood-to-brain permeability of sodium fluorescein was observed in the hippocampus, but not in the striatum and prefrontal cortex following HE-diet access. These results indicate that hippocampal function may be particularly vulnerable to disruption by HE-diets, and this disruption may be related to impaired BBB integrity.

The hippocampus and motivation revisited: appetite and activity

After reviewing the available data regarding the various effects of manipulating (e.g. lesions, chemical or electrical stimulation) the hippocampal formation, Jarrard concluded that this structure likely played a role in motivated behaviors, specifically in general behavioral activation and incentive motivation. Since that time there have been technical advances in lesion techniques and conceptual advances in theories of motivation and learning. Here, we present more recent data that demonstrates the effects of hippocampal lesions on general activity, the utilization of interoceptive state cues, ingestive behaviors, and appetitive responding. We critically evaluate several theories of hippocampal function that have been proposed to explain these data, including the hippocampus as an inhibitor of general activation, as a processor of energy state signals and as a mediator of reward valuation. Finally, we propose that these findings may also be accounted for based on a role for the hippocampus in the learned inhibition of appetitive behaviors. We conclude that, while the specific mechanism of hippocampal involvement may not yet be determined, it is clear that this structure is involved in food-related behaviors and we caution researchers to consider this as a possible confound in studies of learning and memory processes.

A role for hippocampus in the utilization of hunger signals

The hippocampus is generally regarded as an important anatomical substrate for learning and memory (e.g., Eichenbaum, Otto, & Cohen, Behavioral and Neural Biology, 57, 2-36, 1992; Squire, Psychological Review, 99, 195-231, 1992). In the present research, we provide evidence that the hippocampus is also involved with another function--utilization of hunger state signals. Rats with selective ibotenate lesions of the hippocampus were found to be impaired in their ability to discriminate between the interoceptive sensory consequences of food deprivation and satiation. At the same time the ability of these rats to discriminate between different exteroceptive cues was unaffected. These results suggest that deficits in discriminative performance were specific to interoceptive state stimuli. In addition, hippocampal-damaged rats also seemed unable to use their food deprivation stimuli as signals to engage in normal feeding behavior. Our results argue that although the hippocampus may be important for learning and memory processes, it also deserves consideration as a neural substrate for the regulation of food intake and perhaps other functions which involve interoceptive signals.

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.

Contributions of the hippocampus and medial prefrontal cortex to energy and body weight regulation.

The effects of selective ibotenate lesions of the complete hippocampus (CHip), the hippocampal ventral pole (VP), or the medial prefrontal cortex (mPFC) in male rats were assessed on several measures related to energy regulation (i.e., body weight gain, food intake, body adiposity, metabolic activity, general behavioral activity, conditioned appetitive responding). The testing conditions were designed to minimize the nonspecific debilitating effects of these surgeries on intake and body weight. Rats with CHip and VP lesions exhibited significantly greater weight gain and food intake compared with controls. Furthermore, CHip‐lesioned rats, but not rats with VP lesions, showed elevated metabolic activity, general activity in the dark phase of the light‐dark cycle, and greater conditioned appetitive behavior, compared with control rats without these brain lesions. In contrast, rats with mPFC lesions were not different from controls on any of these measures. These results indicate that hippocampal damage interferes with energy and body weight regulation, perhaps by disrupting higher‐order learning and memory processes that contribute to the control of appetitive and consummatory behavior.