Deniz Atalayer

Food demand and meal size in mice with single or combined disruption of melanocortin type 3 and 4 receptors

Mice with homozygous genetic disruption of the melanocortin-4 receptor gene (MC4R-/-) are known to be hyperphagic and become obese, while those with disruption of the melanocortin-3 receptor gene (MC3R-/-) do not become markedly obese. The contribution of MC3R signaling in energy homeostasis remains little studied. In the present work, we compare MC3R-/- mice with wild-type (WT), MC4R-/-, and mice bearing disruption of both genes (double knockout, DKO) on select feeding and neuroanatomical dimensions. DKO mice were significantly more obese than MC4R-/-, whereas MC3R-/- weighed the same as WT. In a food demand protocol, DKO and MC4R-/- were hyperphagic at low unit costs for food, due primarily to increased meal size. However, at higher costs, their intake dropped below that of WT and MC3R-/-, indicating increased elasticity of food demand. To determine whether this higher elasticity was due to either the genotype or to the obese phenotype, the same food demand protocol was conducted in dietary obese C57BL6 mice. They showed similar elasticity to lean mice, suggesting that the effect is of genotypic origin. To assess whether the increased meal size in MC4R-/- and DKO might be due to reduced CCK signaling, we examined the acute anorectic effect of peripherally administered CCK and subsequently the induction of c-Fos immunoreactivity in select brain regions. The anorectic effect of CCK was comparable in MC4R-/-, DKO, and WT, but it was unexpectedly absent in MC3R-/-. CCK-induced c-Fos was lower in the paraventricular nucleus in MC3R-/- than the other genotypes. These data are discussed in terms of demand functions for food intake, MC receptors involved in feeding, and their relation to actions of gut hormones, such as CCK, and to obesity.

Meal patterns of mice under systematically varying approach and unit costs for food in a closed economy.

Several field and experimental studies have investigated the behavioral economics of food intake. In the laboratory, operant behavior has been used to emulate cost and to generate demand functions that express the relationship between the price of food and amount consumed. There have been few such studies of motivated food seeking and intake in mice, and none has reported demand functions. Using albino (CD1) male mice, the present study compares food intake and meal patterns across a series of ratio cost schedules. The first experiment examined unit price. A closed economy was used in which the mice were in the test chambers for 23 h/day and earned all of their food via either a nose poke or lever press response under fixed (FUP5, FUP10, FUP25, FUP50), variable (VUP10, VUP20, VUP50), and progressive (PUP1.25, PUP1.5, PUP1.75) unit prices. Mice were run for 4 days at each cost. There were no consistent differences between the first and last day indicating that behavioral adjustments to schedule changes occurred rapidly. When averaged across all price schedules, mice in the nose poke group consumed more food than their lever press counterparts but the overall shapes of the demand curves did not differ between the two operant responses, with intake decreasing as price increased. The number of meals taken per day differed between two meal-defining criteria that we applied, and there were some differences between the types of unit price schedule. In the second experiment, approach cost in the form of nose poke responses was required to activate a response device (lever) on which a fixed unit price for food was in force. These approach and unit costs were varied systematically. Meal number decreased, and meal size increased, with increasing approach cost even though nose pokes accounted for only a small fraction of the total response activity. Thus, meal patterns in mice are sensitive to approach cost while total amount consumed is more sensitive to unit price. These data are discussed in terms of the concept of foraging cost as either a unitary or a multidimensional variable.

Effects of meal frequency and snacking on food demand in mice.

Ad libitum feeding patterns in mice show substantial differences between laboratories, in addition to large individual and time-of-day differences. In the present study, we examine how mice work for food when access to food is temporally restricted and so they are forced to take discrete meals. In a first experiment, separate groups of ICR:CD1 mice were given access to food for 4, 8 or 16 opportunities or meals per day, with the duration of access at each opportunity adjusted reciprocally so that the total time of availability was 160 min per day in all three conditions. During the periods of availability, mice were able to earn food pellets by nose poke responses, according to an incrementing series of fixed unit prices (FUP: 2, 5, 10, 25) with each schedule in force for 3-4 days. Total food intake was similar in all three groups, indicating that mice generally were able to adjust their intake to a range of temporal availabilities. In each group, food demand fell as FUP increased. In the 8 and 16 meal groups, no food was eaten in many of the opportunities. Within an opportunity, the rate of intake generally declined with time, indicative of satiation. At low FUPs, later opportunities in each day were associated with smaller meals than earlier opportunities; in contrast, at high FUPs the first opportunity was also a small meal. Collectively, these results show that mice eat less at higher costs but not because of time constraints of the schedule: instead, they exhibit an elective anorexia. In the second experiment, we examined whether snacking between imposed meals would affect subsequent meal(s). Mice were adapted to the foregoing 8 opportunity protocol. Then, half the mice received free snacks of sugar cubes after the 3rd, 4th and 5th meal opportunities and the intakes of sugar and pellets were examined at low and high unit costs for pellets (FUP2 and 25). At FUP2, mice decreased demand for pellets and compensated energetically for the sugar they consumed. At FUP25, mice also decreased demand, but by less than the energy obtained from sugar. These data show that choice for pellets over a free palatable snack, and subsequent compensation of energy intake, is modified by effort and demand.

Comparison of voluntary and foraging running wheel activity on food demand in mice.

The effects of running wheel activity on food intake and meal patterns were measured under several cost conditions for food in CD1 mice. In a first experiment, voluntary wheel running activity increased daily food intake relative to a sedentary group, and runners consumed bigger but fewer meals. Although they ate more, runners had significantly lower body fat than sedentary mice. In a second experiment, running was used as an approach cost and food access was contingent on running wheel activity. Mice were able to emit more wheel revolution responses compared to a condition in which nose poking was the approach response. In both voluntary and foraging running protocols mice had inelastic demand functions compared to the non-running groups. When running was voluntary (experiment 1), the day-night cycle for activity was more pronounced compared to when running was a foraging or approach activity (experiment 2).

Comparison of C57BL/6 and DBA/2 mice in food motivation and satiety.

Demand functions describe the relationship between the consumption of a commodity and its mean or unit price. In the first experiment, we analyzed food demand in two strains of mice (C57BL/6 and DBA/2) that differ on several behavioral dimensions, but have not been examined extensively for differences in feeding and meal patterns. Mice worked for food pellets in a continuous access closed economy in which total intake and meal patterns could be measured. A series of fixed (FUP), variable (VUP), and progressive (PUP) unit price schedules were imposed. Under all schedules, DBA/2 mice consumed significantly more food than C57BL/6, a difference that was not attributable to disparity in body weight or weight gain. The higher intake of DBA/2 mice was due predominantly to larger meal size compared with C57BL/6, with no strain difference in meal frequency. In a second experiment, strain differences in meal size were not found to correlate with anorectic sensitivity to cholecystokinin (CCK) administration, or with c-Fos expression induced by CCK in PVN, AP and NTS. Thus, DBA/2 mice were motivated to sustain a higher daily food intake and meal size than C57BL/6 under the range of demand costs employed in the present work, but this strain difference is unlikely to be due to CCK action or responsiveness.

Effects of Prior Cocaine Versus Morphine or Heroin Self-Administration on Extinction Learning Driven by Overexpectation Versus Omission of Reward

BACKGROUND Addiction is characterized by an inability to stop using drugs, despite adverse consequences. One contributing factor to this compulsive drug taking could be the impact of drug use on the ability to extinguish drug seeking after changes in expected outcomes. Here, we compared effects of cocaine, morphine, and heroin self-administration on two forms of extinction learning: standard extinction driven by reward omission and extinction driven by reward overexpectation. METHODS In experiment 1, we trained rats to self-administer cocaine, morphine, or sucrose for 3 hours per day (limited access). In experiment 2, we trained rats to self-administer heroin or sucrose for 12 hours per day (extended access). Three weeks later, we trained the rats to associate several cues with palatable food reward, after which we assessed extinction of the learned Pavlovian response, first by pairing two cues together in the overexpectation procedure and later by omitting the food reward. RESULTS Rats trained under limited access conditions to self-administer sucrose or morphine demonstrated normal extinction in response to both overexpectation and reward omission, whereas cocaine-experienced rats or rats trained to self-administer heroin under extended access conditions exhibited normal extinction in response to reward omission but failed to show extinction in response to overexpectation. CONCLUSIONS Here we show that cocaine and heroin can induce long-lasting deficits in the ability to extinguish reward seeking. These deficits were not observed in a standard extinction procedure but instead only affected extinction learning driven by a more complex phenomenon of overexpectation.

Structure of motivation using food demand in mice.

Most animals have evolved to be foragers for food. We discriminate two types of foraging, the cost to locate or obtain access to the food, and the unit cost to consume the food once it is nearby. Using closed economy studies in normal weight and genetically obese mice, we have examined the effect of either access and/or unit cost on food demand and meal patterns. We also have included wheel running either as a voluntary activity or as an access cost. Our results showed that the demand functions differ between normal, exercising, and genetically obese mice, and that changes in intake normally occur via changes in the size of individual feeding bouts or meals. In contrast, changes in access cost have only a small effect on food demand but have large effects on the pattern of intake--on meal size and the number of meals taken. Thus, although food intake is sensitive to effort, the type of effort and the mode in which it is applied is critically important. These data are discussed in terms of potential economic strategies that could address the human obesity epidemic, for example by maximally targeting meal size and/or snacking behavior.

Cost-based anorexia: A novel framework to model anorexia nervosa

Anorexia nervosa (AN) is an eating disorder that is thought to emerge through biological predisposition(s) within sociocultural context(s). Practical and ethical concerns limit study of the etiology of this disorder in humans, and in particular the biological aspects. Laboratory animal models have a pivotal role in advancing our understanding of the neurobiological, physiological and behavioral aspects of this disorder, and developing new treatment strategies. One shortcoming of animal models, including activity based anorexia (ABA) in rodents, is that they cannot fully capture the contextual aspects of AN. In this article we discuss the merits of an alternate approach, cost-based anorexia (CBA). CBA is conceptually founded in behavioral economics and its magnitude is influenced by several relevant contextual aspects of feeding.