A focus on reward in anorexia nervosa through the lens of the activity‐based anorexia rodent model

Abstract

Patients suffering anorexia nervosa (AN) become anhedonic, unable or unwilling to derive normal pleasures and tend to avoid rewarding outcomes, most profoundly in food intake. The activity-based anorexia model recapitulates many of the pathophysiological and behavioural hallmarks of the human condition, including a reduction in food intake, excessive exercise, dramatic weight loss, loss of reproductive cycles, hypothermia and anhedonia, and therefore it allows investigation into the underlying neurobiology of anorexia nervosa. The use of this model has directed attention to disruptions in central reward neurocircuitry, which may contribute to disease susceptibility. The purpose of this review is to demonstrate the utility of this unique model to provide insight into the mechanisms of reward relevant to feeding and weight loss, which may ultimately help to unravel the neurobiology of anorexia nervosa and, in a broader sense, the foundation of reward-based feeding. K E Y W O R D Sactivity-based anorexia, animal models, anorexia nervosa, dopamine, mesolimbic reward pathways | ANOREXIA NERVOSA AS A NEUROBIOLOGICAL DISORDERAnorexia nervosa (AN) is a debilitating psychiatric disorder of complex aetiology that is characterised by a relentless pursuit of weight loss through extreme food restriction and excessive exercise, as well as high rates of chronicity, morbidity and mortality.1 AN is accompanied by physiological, biochemical and behavioural disturbances, including a diminished capacity to experience pleasure or reward. Figure 1A). A core aspect of this hypothesis is that "top-down" cognitive modulatory mechanisms exert control over "bottom-up" ap- | NEUROCIRCUITRY MODULATING REWARD AND INHIBITIONIt is likely that AN behaviours are encoded in limbic and cognitive circuits that fall into two categories. The first may be described as "limbic" and involves the amygdala and ventral striatum, as well as regions of the cerebral cortex, including the insula, anterior cingulate and prefrontal regions, which collectively coordinate the affective response to stimuli including food and feeding. The current terminology introduced by Berridge and Kringelbach 11 is that "liking" is the actual pleasure component of reward and "wanting" is the measure of motivation or incentive salience for a reward. The microstructure of neural circuits and transmitters coding for pleasure can be subdivided, in simplistic terms, into (i) those dopaminergic projections originating in the ventral tegmental area (VTA) and extending to the nucleus accumbens (NAc) which account for "wanting" and (ii) the activation of μ-opioid, In addition to the interaction between these two broad determinants of anorexic behaviour, mesolimbic reward and cortical control, there are clearly modulatory influences form other regions that impinge on such circuits. One of these involves serotonin released from neurones originating in the midbrain raphe nuclei, which can influence reward processing and anhedonic behaviours via actions directly on the VTA, indire...

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“…In contrast, rats in cages without a running wheel survive the restricted access to food. Accordingly, it is potentially only the combination of timed availability/shortage of food and access to running wheels that initiates the precipitous reduction in body weight (Foldi et al, 2017a).…”

“…Activity-based anorexia (ABA) recapitulates many of the pathophysiological and behavioral hallmarks of AN, including a reduction in food intake, excessive exercise, dramatic weight loss, loss of reproductive cycles, hypothermia, and anhedonia (Foldi et al, 2017a). ABA also captures the hypoleptinemia-induced up- or downregulation of the hypothalamus-pituitary-end organ axes entailing hypercortisolemia, reduced levels of FSH and LH along with other endocrine alterations including hyperghrelinemia, and physiological changes such as hypothermia (Hebebrand et al, 2003; Ross et al, 2016).…”

“…ABA also captures the hypoleptinemia-induced up- or downregulation of the hypothalamus-pituitary-end organ axes entailing hypercortisolemia, reduced levels of FSH and LH along with other endocrine alterations including hyperghrelinemia, and physiological changes such as hypothermia (Hebebrand et al, 2003; Ross et al, 2016). As pointed out by Foldi et al (2017a), the major obstacle in relation to AN is the utilization of a model that incorporates “voluntary” food restriction rather than imposed starvation. Because rats in the ABA model do not eat sufficiently during the 60–90 min ad libitum access to food to survive (in contrast to control rats without a running wheel in their cage subjected to the same temporal restriction of food intake), this “voluntary” reduction in food intake may appear more similar to the AN phenotype in humans than the SIH model with forced energy restriction.…”

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“…Deregulation of the reward system, accompanied by reduced food intake and increased activity, define AN and are largely captured in the activity-based anorexia (ABA) rodent model. This model, achieved by limiting access to food and offering unrestricted access to running wheels, results in weight loss and has revealed deregulations (i) in the opioid and dopaminergic reward circuitry, (ii) in the expression levels of hormones and neuro-hormones, and (iii) in the HPA axis, supporting observations in patients with AN (23). Rodents that have been submitted to ABA present increased endogenous levels of opioids concomitant with decreased food intake (24).…”

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“…Food-associated reward dysfunction is one of core features of patients with EDs (Fladung et al, 2010;Frank et al, 2016;Foldi et al, 2017). To determine whether mice carrying homozygous Hdac4 A778T mutation have impaired food-associated reward behavior, we performed effortful operant responding test using a progressive ratio schedule; a well-established behavioral paradigm often used to determine the desire and the motivation for an animal to obtain palatable food.…”