Greater striatopallidal adaptive coding during cue–reward learning and food reward habituation predict future weight gain

Animal experiments indicate that after repeated pairings of palatable food receipt and cues that predict palatable food receipt, dopamine signaling increases in response to predictive cues, but decreases in response to food receipt. Using functional MRI and mixed effects growth curve models with 35 females (M age = 15.5 ± 0.9; M BMI = 24.5 ± 5.4) we documented an increase in BOLD response in the caudate (r = .42) during exposure to cues predicting impending milkshake receipt over repeated exposures, demonstrating a direct measure of in vivo cue-reward learning in humans. Further, we observed a simultaneous decrease in putamen (r = −.33) and ventral pallidum (r = −.45) response during milkshake receipt that occurred over repeated exposures, putatively reflecting food reward habitation. We then tested whether cue-reward learning and habituation slopes predicted future weight over 2-year follow-up. Those who exhibited the greatest escalation in ventral pallidum responsivity to cues and the greatest decrease in caudate response to milkshake receipt showed significantly larger increases in BMI (r = .39 and −.69 respectively). Interestingly, cue-reward learning propensity and food reward habituation were not correlated, implying that these factors may constitute qualitatively distinct vulnerability pathways to excess weight gain. These two individual difference factors may provide insight as to why certain people have shown obesity onset in response to the current obesogenic environment in western cultures, whereas others have not

Dynamics of serotonergic neurons revealed by fiber photometry

This work was developed in the context of the MIT Portugal Program, area of Bioengineering Systems, in collaboration with the Champalimaud Research Programme, Champalimaud Center for the Unknown, Lisbon, Portugal. The project entitled Dynamics of serotonergic neurons revealed by fiber photometry was carried out at Instituto Gulbenkian de Ciência, Oeiras, Portugal and at the Champalimaud Research Programme, Champalimaud Center for the Unknown, Lisbon, PortugalSerotonin is an important neuromodulator implicated in the regulation of many physiological and cognitive processes. It is one of the most studied neuromodulators and one of the main targets of psychoactive drugs, since its dysregulation can contribute to altered perception and pathological conditions such as depression and obsessive-compulsive disorder. However, it is still one of the most mysterious and least understood neuromodulatory systems of the brain. In order to study the activity of serotonergic neurons in behaving mice, we used genetically encoded calcium indicators and developed a fiber photometry system to monitor neural activity from genetically defined populations of neurons. This approach was developed to study serotonin neurons but it can be used in any genetically defined neuronal population. To validate our approach, we first confirmed that increased neural activity, induced by electrical microstimulation, indeed produced increases in fluorescence detected by the system. We then used it to monitor activity in the dorsal striatum of freely behaving mice. We show that the two projection pathways of the basal ganglia are both active during spontaneous contraversive turns. Additionally, we show that this balanced activity in the two pathways is needed for such contraversive movements. Finally, we used the fiber photometry system to study the role of serotonin in learning and behavioral control and to compare it to that of dopamine, another important neuromodulator. Dopamine and serotonin are thought to act jointly to orchestrate learning and behavioral control. While dopamine is thought to invigorate behavior and drive learning by signaling reward prediction errors, i.e. better-than-expected outcomes, serotonin has been implicated in behavioral inhibition and aversive processing. More specifically, serotonin has been implicated in preventing perseverative responses in changing environments. However, whether or how serotonin neurons signal such changes is not clear. To investigate these issues, we used a reversal learning task in which mice first learned to associate different odor cues with specific outcomes and then we unexpectedly reversed these associations. We show that dorsal raphe serotonin neurons, like midbrain dopamine neurons, are specifically recruited following prediction errors that occur after reversal. Yet, unlike dopamine neurons, serotonin neurons are similarly activated by surprising events that are both better and worse than expected. Dopamine and serotonin responses both track learned cue-reward associations, but serotonin neurons are slower to adapt to the changes that occur at reversal. The different dynamics of these neurons following reversal creates an imbalance that favors dopamine activity when invigoration is needed to obtain rewards and serotonin activity when behavior should be inhibited. Our data supports a model in which serotonin acts by rapidly reporting erroneous associations, expectations or priors in order to suppress behaviors driven by such errors and enhance plasticity to facilitate error correction. Contrary to prevailing views, it supports a concept of serotonin based on primary functions in prediction, control and learning rather than affect and mood

Reward Region Responsivity Predicts Future Weight Gain and Moderating Effects of the TaqIA Allele

Because no large prospective study has investigated neural vulnerability factors that predict future weight gain, we tested whether neural response to receipt and anticipated receipt of palatable food and monetary reward predicted body fat gain over a 3-year follow-up in healthy-weight adolescent humans and whether the TaqIA polymorphism moderates these relations. A total of 153 adolescents completed fMRI paradigms assessing response to these events; body fat was assessed annually over follow-up. Elevated orbitofrontal cortex response to cues signaling impending milkshake receipt predicted future body fat gain (r = 0.32), which is a novel finding that provides support for the incentive sensitization theory of obesity. Neural response to receipt and anticipated receipt of monetary reward did not predict body fat gain, which has not been tested previously. Replicating an earlier finding (Stice et al., 2008a), elevated caudate response to milkshake receipt predicted body fat gain for adolescents with a genetic propensity for greater dopamine signaling by virtue of possessing the TaqIA A2/A2 allele, but lower caudate response predicted body fat gain for adolescents with a genetic propensity for less dopamine signaling by virtue of possessing a TaqIA A1 allele, though this interaction was only marginal [p-value <0.05 corrected using voxel-level familywise error rate (pFWE) = 0.06]. Parental obesity, which correlated with TaqIA allele status (odds ratio = 2.7), similarly moderated the relation of caudate response to milkshake receipt to future body fat gain, which is another novel finding. The former interaction implies that too much or too little dopamine signaling and reward region responsivity increases risk for overeating, suggesting qualitatively distinct reward surfeit and reward deficit pathways to obesity

Psychological and Neural Contributions to Appetite Self-Regulation

Objective: This paper reviews the state of the science on psychological and neural contributions to appetite self-regulation in the context of obesity. Methods: Three content areas (neural systems and cognitive functions; parenting and early childhood development; and goal setting and goal striving) served to illustrate different perspectives on the psychological and neural factors that contribute to appetite dysregulation in the context of obesity. Talks were initially delivered at an NIH workshop consisting of experts in these three content areas, and then content areas were further developed through a review of the literature. Results: Self-regulation of appetite involves a complex interaction between multiple domains, including cognitive, neural, social, and goal-directed behaviors and decision-making. Self-regulation failures can arise from any of these factors, and the resulting implications for obesity should be considered in light of each domain. In some cases, self-regulation is amenable to intervention; however, this does not appear to be universally true, which has implications for both prevention and intervention efforts. Conclusions: Appetite regulation is a complex, multifactorial construct. When considering its role in the obesity epidemic, it is advisable to consider its various dimensions together to best inform prevention and treatment efforts

The Effects of Deep Brain Stimulation in the Ventral Pallidum and the Central Nucelus of the Amygdala on Food Consumption, Motivation, and Palatability.

Deep brain stimulation (DBS) has been shown to be an effective treatment for Parkinson’s disease and other movement disorders including essential tremor and dystonia. Given its success, DBS is also being investigated as a potential treatment for psychiatric disorders including depression, obsessive compulsive disorder, eating disorders, and addiction. Although the specific therapeutic mechanisms of DBS are not known, studies suggest that this type of electrical stimulation may be causing an entrainment or regularization of firing patterns in neurons, interfering with the information being processed in the underlying neural circuit. The overall goal of this thesis is to evaluate the potential neural interference effects of DBS-like stimulation on motivation and reward consumption. Two structures were targeted: the ventral pallidum (VP), which is thought to be an area of convergence for processing reward and reward-related information, and the central nucleus of the amygdala (CeA), which is thought to be especially involved in focusing motivation for particular cues and rewards. The effects on DBS in the VP and CeA on reward-seeking behaviors, food consumption, and hedonic value of tastes were assessed. Results showed that DBS in the VP produced complex patterns of neuronal firing; however, it did not disrupt neural coding of reward and had only minimal effects on food consumption and motivation. DBS in the CeA also resulted in similar complex firing patterns, and additionally (in contrast to the VP) disrupted neural coding of reward. This disruption was reflected in altered behavior. DBS in the CeA invoked an immediate and profound decrease in the consumption of (p < 0.001) and motivation to work for (p < 0.001) sucrose pellets by more than a factor of four. DBS in the CeA also decreased the hedonic value of and increased aversive reactions to sucrose (p = 0.003). Overall results suggest the DBS is modulating neural activity in the underlying target structure, but the location of electrode is very important and this DBS-induced change in neuronal firing may or may not disrupt coding for reward. Data suggests that CeA may be an effective target for blocking food consumption and motivation.PHDBiomedical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/102365/1/shross_1.pd

Training motor responses to food: A novel treatment for obesity targeting implicit processes.

PublishedREVIEWJOURNAL ARTICLEThis is the author accepted manuscript. The final version is available from Elsevier via the DOI in this record.The present review first summarizes results from prospective brain imaging studies focused on identifying neural vulnerability factors that predict excessive weight gain. Next, findings from cognitive psychology experiments evaluating various interventions involving food response inhibition training or food response facilitation training are reviewed that appear to target these neural vulnerability factors and that have produced encouraging weight loss effects. Findings from both of these reviewed research fields suggest that interventions that reduce reward and attention region responses to high calorie food cues and increase inhibitory region responses to high calorie food cues could prove useful in the treatment of obesity. Based on this review, a new conceptual model is presented to describe how different cognitive training procedures may contribute to modifying eating behavior and important directions for future research are offered. It is concluded that there is a need for evaluating the effectiveness of more intensive food response training interventions and testing whether adding such training to extant weight loss interventions increases their efficacy

Towards a Translational Approach to Food Addiction: Implications for Bulimia Nervosa

Purpose of review: In recent years, the food addiction hypothesis of loss-of-control eating has gained traction in the field of eating disorders. In particular, the neural process of food addiction plays a dominant role in the recently formulated “addictive appetite” model of bulimia nervosa and binge eating disorder. Nonetheless, several components of the food addiction hypothesis, including the presence of withdrawal and tolerance effects, as well as the proposition that some foods possess “addicting” properties, remain highly controversial. In response, the current review synthesises existing evidence for withdrawal and tolerance effects in people with bulimia nervosa. Recent findings: The recent development of a validated tool to measure withdrawal from highly processed foods will aid in measuring withdrawal symptoms and testing hypotheses related to withdrawal in the context of food addiction. We subsequently describe preclinical and human evidence for a central insulin- and dopamine-mediated pathway by which recurrent loss-of-control binge eating is maintained in bulimia nervosa. Summary: Evidence in populations with bulimia nervosa and loss-of-control eating provides preliminary support for the role of food addiction in the maintenance of bulimia nervosa. Future longitudinal research is needed to develop a clearer profile of illness progression and to clarify the extent to which dysregulation in glucose metabolism contributes to food craving and symptom maintenance in bulimia nervosa

Obese individuals with more components of the metabolic syndrome and/or prediabetes demonstrate decreased activation of reward-related brain centers in response to food cues in both the fed and fasting states: A preliminary fMRI study

It remains unknown whether obese individuals with more components of the metabolic syndrome and/or prediabetes demonstrate altered activation of brain centers in response to food cues. We examined obese prediabetics (n=26) vs. obese nondiabetics (n=11) using fMRI. We also performed regression analyses on the basis of the number of MetS components per subject. Obese individuals with prediabetes have decreased activation of the reward-related putamen in the fasting state and decreased activation of the salience- and reward-related insula after eating. Obese individuals with more components of MetS demonstrate decreased activation of the putamen while fasting. All these activations remain significant when corrected for BMI, waist circumference (WC), HbA1c and gender. Decreased activation in reward-related brain areas between obese individuals is more pronounced in subjects with prediabetes and MetS. Prospective studies are needed to quantify their contributions to the development of prediabetes/MetS and to study whether these conditions may predispose to the exacerbation of obesity and the development of comorbidities over time

Obesity is associated with insufficient behavioral adaptation

Obesity is one of the major health concerns nowadays according to the World Health Organisation (WHO global status report on noncommunicable diseases 2010). Thus, there is an urgent need for understanding obesity-associated alterations in food-related and general cognition and their underlying structural and functional correlates within the central nervous system (CNS). Neuroscientific research of the past decade has mainly focussed on obesity-related differences within homeostatic and hedonic processing of food stimuli. Therein, alterations during anticipation and consumption of food-reward stimuli in obese compared with lean subjects have been highlighted. This points at an altered adaptation of eating behavior in obese individuals. This thesis investigates if adaptation of behavior is attenuated in obese compared to lean individuals in learning-related processes beyond the food domain. In five consecutive experimental studies, we show that obese participants reveal reduced adaptation of behavior within and outside the food context. With the help of MRI, we relate these behavioral findings to alterations in structure and function of the fronto-striatal dopaminergic system in obesity. In more detail, reduced behavioral adaptation seems to be associated with attenuated utilization of negative prediction errors in obese individuals. Within the brain, this relates to reduced functional coupling between subcortical dopaminergic target regions (ventral striatum) and executive cortical structures (supplementary motor area) in obesity, as revealed by fMRI analysis