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Corticolimbic Mechanisms of Behavioral Inhibition under Threat of Punishment

The Journal of Neuroscience. May 29, 2019 39(22) 4353-4364

Jeroen P.H. Verharen, Mauri W. van den Heuvel, Mieneke Luijendijk,Louk J.M.J. Vanderschuren,
and Roger A.H. Adan

Being able to limit the pursuit of reward to prevent negative consequences is an important expression of behavioral inhibition. Everyday examples of an inability to exert such control over behavior are the overconsumption of food and drugs of abuse, which are important factors in the development of obesity and addiction, respectively. Here, we use a behavioral task that assesses the ability of male rats to exert behavioral restraint at the mere sight of palatable food during the presentation of an audiovisual threat cue to investigate the corticolimbic underpinnings of behavioral inhibition. We demonstrate a prominent role for the medial prefrontal cortex in the exertion of control over behavior under threat of punishment. Moreover, task engagement relies on function of the ventral striatum, whereas the basolateral amygdala mediates processing of the threat cue. Together, these data show that inhibition of reward pursuit requires the
coordinated action of a network of corticolimbic structures.


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Reinforcement learning across the rat estrous cycle

Jeroen P.H. Verharena, Jiska Kentrop, Louk J.M.J. Vanderschuren,  Roger A.H. Adan

Psychoneuroendocrinology 100 (2019) 27–31

Reinforcement learning, the process by which an organism flexibly adapts behavior in response to reward and punishment, is vital for the proper execution of everyday behaviors, and its dysfunction has been implicated in a
wide variety of mental disorders. Here, we use computational trial-by-trial analysis of data of female rats performing a probabilistic reward learning task and demonstrate that core computational processes underlying
value-based decision making fluctuate across the estrous cycle, providing a neuroendocrine substrate by which gonadal hormones may influence adaptive behavior.


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Obese and overweight individuals are less sensitive to information about meal times in portion-size judgemen

AR Zimmerman, A Mason, PJ Rogers and JM Brunstrom

International Journal of Obesity (2018) 42, 905–910

BACKGROUND: Obesity is related to a tendency to discount the future. Information regarding inter-meal interval (IMI) allows meal planning. We sought to assess how obese, overweight and lean people select portion sizes based on the length of an IMI. We hypothesised that individuals with a high body mass index (BMI) would discount information about the IMI. In addition, we investigated how reduced sensitivity to IMIs relates to monetary temporal discounting.
METHODS: Participants (lean, n = 35; overweight, n = 31; obese, n = 22) selected lunchtime portion sizes in response to information about the timings of their next meal. In seven trials, the time of the IMI was systematically manipulated, ranging from ‘right now’ to ‘8 h’. Participants then completed a monetary temporal discounting task. BMI was included as a continuous measure. For each participant, we conducted a linear regression of portion size on IMI to yield a gradient that reflected reduced sensitivity to future
meal timings.
RESULTS: As expected, participants selected larger portion sizes in response to a long IMI. Consistent with our hypothesis, individuals with a high BMI discounted information about the IMI (β = − 3.49, P = 0.015; confidence interval (CI) 6.29 to − 0.70). Monetary discounting also negatively predicted BMI (β = − 8.1, P = 0.003; CI = − 13.43 to − 2.77), but did not correlate with IMI sensitivity (P40.05).
CONCLUSIONS: These results are the first to demonstrate that temporal discounting operates in planning from one meal to the next, and is more prevalent in obese and overweight, relative to lean individuals. Participants with a high BMI discounted concerns about potential future fullness and hunger in the IMI. Our observations might begin to explain associations between obesity and irregular meal timings or help to form the basis for a targeted intervention that promotes future thinking in meal planning

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Assessing “chaotic eating” using self-report and the UK Adult National Diet and Nutrition Survey: No association between BMI and variability in meal or snack timings

Annie R. Zimmerman, Laura Johnson, Jeffrey M. Brunstrom

Physiology & Behavior 192 (2018) 64–71

Although regular meal timings are recommended for weight loss, no study has characterised irregularity in the timing of eating occasions or investigated associations with body-mass index (BMI). Here, we characterise
“chaotic eating” as the tendency to eat at variable times of day. In two studies, we used a novel measure to explore the relationship between BMI and chaotic eating. In Study 1 (N=98) we measured BMI and used a self-report
measure to assess the usual range of times that meals and snacks are consumed over a seven-day period, as well as meal and snack frequency. A separate meal and snack ‘chaotic eating index’ was derived from the number
of possible thirty-minute snack- or meal-slots, divided by the frequency of these eating events. After adjusting for age, gender, and dietary habits (Three-Factor Eating Questionnaire) we found no relationship between BMI and
chaotic eating of meals (β=−0.07, p=0.73) or snacks (β=−0.10, p=0.75). In Study 2, we calculated the same chaotic eating index (meals and snacks) using data from the UK National Diet and Nutrition Survey of adults 2000–2001 (seven-day diet diaries; N=1175). Again, we found little evidence that BMI is associated with chaotic eating of meals (β=0.16, p=0.27) or snacks (β=0.15, p=0.12). Together, these results suggest that irregular eating timings do not promote weight gain and they challenge guidelines that recommend regularity in meal timings for weight loss.


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No effect of focused attention whilst eating on later snack food intake: Two laboratory experiments

Victoria Whitelock, Suzanne Higgs, Jeffrey M. Brunstrom, Jason C.G. Halford, Eric Robinson.

Appetite 128 (2018) 188–196

Focusing attention on food during a meal has been shown to reduce later snack consumption. We report the results of two studies that aimed to replicate this effect and to elucidate the underlying mechanisms. We hypothesised
that focused attention during a lunchtime meal would improve visual memory and/or memory for the satiating effects of the meal, and that this would reduce later food intake. In Study 1, participants (N=108, 52.8% female, BMI M=25.75 kg/m2) were randomly allocated to eat a fixed lunchtime meal while listening to instructions that encouraged them to pay attention to the sensory properties of the meal (focused attention condition), or to one of two control conditions. To determine whether the effect of focused attention on later food intake is influenced by meal satisfaction, in a second study, participants (N=147, 100% female, BMI M=25.15 kg/m2) were given either a satisfying or dissatisfying lunch. In both studies, after 3 h participants ate snack food ad libitum and completed assessments of their memory for the recent lunch. In both studies there was no effect of focused attention on later food intake. In Study 2, the effect of focused attention on later food intake was not moderated by meal satisfaction. In both studies focused attention did not improve memory for the lunch meal. The present studies failed to replicate the effect of focused attention on later food intake and this may be because focused attention did not improve memory for the lunchtime meal. Further research should examine the conditions under which attention during eating influences memory encoding and food intake.


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A neuronal mechanism underlying decision-making deficits during hyperdopaminergic states

Jeroen P.H. Verharen, Johannes W. de Jong, Theresia J.M. Roelofs, Christiaan F.M. Huffels, Ruud van Zessen, Mieneke C.M. Luijendijk, Ralph Hamelink, Ingo Willuhn, Hanneke E.M. den Ouden ,Geoffrey van der Plasse, Roger A.H. Adan & Louk J.M.J. Vanderschuren


Hyperdopaminergic states in mental disorders are associated with disruptive deficits in decision making. However, the precise contribution of topographically distinct mesencephalic dopamine pathways to decision-making processes remains elusive. Here we show, using a multidisciplinary approach, how hyperactivity of ascending projections from the ventral tegmental area (VTA) contributes to impaired flexible decision making in rats. Activation of
the VTA–nucleus accumbens pathway leads to insensitivity to loss and punishment due to impaired processing of negative reward prediction errors. In contrast, activation of the VTA–prefrontal cortex pathway promotes risky decision making without affecting the ability to choose the economically most beneficial option. Together, these findings show how malfunction of ascending VTA projections affects value-based decision making, suggesting a potential mechanism through which increased forebrain dopamine signaling leads to aberrant behavior, as is seen in substance abuse, mania, and after dopamine replacement therapy in Parkinson’s disease.

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The role of low-calorie sweeteners in the prevention and management of overweight and obesity: evidence v. conjecture

Peter J. Rogers

Proceedings of the Nutrition Society (2018), 77, 230–238

Conference on ‘Improving nutrition in metropolitan areas’ Symposium 3: Building a healthier environment

By virtue of reducing dietary energy density, low-calorie sweeteners (LCS) can be expected to decrease overall energy intake and thereby decrease body weight. Such effects will be limited by the amount of sugar replaced by LCS, and the dynamics of appetite and weight control (e.g., acute compensatory eating, and an increase in appetite and decrease in energy expenditure accompanying weight loss). Consistent with these predictions, short-term intervention
studies show incomplete compensation for the consumption of LCS v. sugar, and longer-term intervention studies (from 4 weeks to 40 months duration) show small decreases in energy intake and body weight with LCS v. sugar. Despite this evidence, there are claims that LCS undermine weight management. Three claims are that: (1) LCS disrupt the learned control of energy intake (sweet taste confusion hypothesis); (2) exposure to sweetness
increases desire for sweetness (sweet tooth hypothesis); (3) consumers might consciously overcompensate for ‘calories saved’ when they know they are consuming LCS (conscious overcompensation hypothesis). None of these claims stands up to close examination. In any case, the results of the intervention studies comparing LCS v. sugar indicate that the effect of energy dilution outweighs any tendency LCS might conceivably have to increase
energy intake.

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Body weight homeostat that regulates fat mass independently of leptin in rats and mice

John-Olov Jansson, Vilborg Palsdottir, Daniel A. Hägg, Erik Schéle, Suzanne L. Dickson, Fredrik Anesten, Tina Bake, Mikael Montelius, Jakob Bellman, Maria E. Johansson, Roger D. Cone, Daniel J. Drucker, Jianyao Wu,
Biljana Aleksic, Anna E. Törnqvist, Klara Sjögren, Jan-Åke Gustafsson Sara H. Windahl, and Claes Ohlsson


PNAS January 9, 2018  vol. 115 no. 2  427–432

Subjects spending much time sitting have increased risk of obesity but the mechanism for the antiobesity effect of standing is unknown. We hypothesized that there is a homeostatic regulation of body weight. We demonstrate that increased loading of rodents, achieved using capsules with different weights implanted in the abdomen or s.c. on the back, reversibly decreases the biological body weight via reduced food intake. Importantly, loading relieves diet-induced obesity and improves glucose tolerance. The identified homeostat for body weight regulates body fat mass independently of fat-derived leptin, revealing two independent negative feedback systems for fat mass regulation. It is known that osteocytes can sense changes in bone strain. In this study, the body weight-reducing effect of increased loading was lost in mice depleted of osteocytes. We propose that increased body weight activates a sensor dependent on osteocytes of the weight-bearing bones. This induces an afferent signal, which reduces bodyweight. These findings demonstrate a leptin-independent body weight homeostat (“gravitostat”) that regulates fat mass.

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Central administration of ghrelin induces conditioned avoidance in rodents

Erik Schéle, Christopher Cook, Marie Le May, Tina Bake, Simon M.Luckman, Suzanne L.Dickson

European Neuropsychopharmacology(2017) 27, 809–815


Feelings ofhunger carry a negative-valence (emotion) signal that appears to be conveyedthrough agouti-related peptide (AgRP) neurons in the hypothalamic arcuate nucleus. The circulating hunger hormone, ghrelin, activates these neurons although it remains unclear whether it also carries a negative-valence signal.Given that ghrelin also activates pathways in the mid brain that are important for reward, it remains possible that ghrelin could act as a positive reinforcer and hence, carry a positive-valence signal.  Here we used condition preference/avoidance tests to explore the reinforcing/aversive properties of ghrelin, delivered by intracerebroventricular (ICV) injection (2 mg/injection once a day for 4 days).We found that ICV ghrelin produces conditioned avoidance, both in a conditioned place preference/avoidance test (CPP/CPA, in which the animals avoid a chamber previously paired to ghrelin injection) and in a conditioned flavor preference/avoidance test (CFP/CFA, in which the animals consume/avoid a taste previously paired to ghrelin injection). These effects of ghrelin to induce a CPA were observed when  conditioning to ghrelin occurred in the absence or presence of food. We did not find evidence, however, that brain ghrelin delivery to rats induces malaise (in the pica test). Our data indicate that ICV ghrelin carries a negative-valence signal consistent with its role as a circulating hunger hormone and with its effects to activate AgRPneurones.

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A Comparison of the Satiety Effects of a Fruit Smoothie, Its Fresh Fruit Equivalent and Other Drinks

Peter J. Rogers  and Roya Shahrokni

Nutrients 2018, 10, 431

Energy-containing liquids are claimed to have relatively low satiating power, although energy in liquids is not without effect on appetite. Using the preload test-meal method, effects on fullness and energy intake compensation were compared across four drinks (water, blackcurrant squash, milk and fruit smoothie) and the fresh fruit equivalent of the smoothie. Preload volumes were similar, and the energy value of each preload was 569 kJ, except for water (0 kJ). Healthy, adult participants rated the preloads for liking, enjoyment, satisfaction, familiarity and how ‘food-like’ they seemed. The preload to test-meal interval was 2 min (n = 23) or 2 h (n = 24). The effects of the preloads on fullness varied with food-likeness and the rate at which they were consumed. In contrast, energy intake compensation versus water did not differ between the energy-containing preloads, although it decreased over time (from 82% at 2 min to 12% at 2 h). In conclusion, although fullness increased with food-likeness, subsequent energy intake compensation did not differ for energy/nutrients consumed in drinks compared with a food. The results also support the proposal
that food intake is influenced predominantly by the immediate, but rapidly waning, post-ingestive effects of the previous ‘meal’ (rather than by changes in energy balance).

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