Motor- and food-related metabolic cerebral changes in the activity-based rat model for anorexia nervosa: A voxel-based microPET study
Introduction
Anorexia nervosa (AN) is a severe psychiatric disorder characterised by a refusal to maintain body weight at or above a minimally normal weight for age and height, an intense fear of gaining weight or becoming fat, and a disturbance in the way one’s body weight and shape are experienced. In postmenarcheal females, there is an absence of at least three consecutive menstrual cycles (American Psychiatric Association, 1994). In addition, the lifetime occurrence of excessive exercising is between 75% and 84% (Davis et al., 1994).
Despite intensive treatment programs combining nutritional therapy with psychotherapy and/or pharmacotherapy, around 20% of the patients continue to suffer chronically. In accordance, mortality rates are high (Ben-Tovim et al., 2001, Zipfel et al., 2000), with physical complications accompanying extreme starvation and suicide as the most common reported reasons of death. Therefore, developing new treatment interventions is of utmost importance (Agras et al., 2004, Strober, 2005).
Preclinically, the activity-based anorexia rat model is one of the best characterized animal models for anorexia nervosa. The model has been used frequently for investigating the effects of new treatment interventions in anorexia nervosa (Hillebrand et al., 2005c, Hillebrand et al., 2006). In this model, rats have 24 h daily access to a running wheel while the feeding period is limited to 1.5 h per day. After 7 to 10 days, these rats will display hyperactivity and spontaneously restrict their food intake leading to severe emaciation and often even death (Routtenberg, 1968). This behaviour was validated to model symptoms in patients with anorexia nervosa. In contrast, control rats having no access to a running wheel with food provided during 1.5 to 24 h daily, eat sufficiently to sustain or even increase their body weight up to several weeks and even months.
Core symptoms in this model (e.g. decrease in food intake and hyperactivity) are likely attributable to the central nervous system. Therefore, preferential targets for therapeutic intervention encompass neuropharmacia (systemic or local application in the brain) and other modes of neuromodulation (e.g. electrical brain stimulation). In human anorexia nervosa patients, consistent changes in metabolism were observed in the anterior and subgenual cingulate cortex, the parietal cortex and the basal ganglia compared to healthy controls (Frank and Kaye, 2005). However, apart from post-mortem or behavioural studies, little information is available on which brain regions are involved in the activity-based anorexia model. Recent advances in functional neuroimaging of small animals (e.g. microPET (Sossi and Ruth, 2005)) provide an additional tool to investigate in vivo regional molecular brain dysfunctions. Furthermore, sensitive analysis tools such as Statistical Parametric Mapping allow voxel-based data-driven analysis also for microPET imaging where the relative number of resolution elements compared to the human situation is reduced and optimal information usage is warranted (Casteels et al., 2006).
In this study, we have investigated the hypothesis that cerebral metabolism, as measured with FDG uptake by microPET, significantly differs in rats in the activity-based anorexia model (24 h access to a running wheel, 1.5 h feeding period daily) compared to control rats in identical cages but with fixed running wheels and 24 h access to food in areas related to hyperactivity and in cortical areas related to higher-level processing of food-intake.
Section snippets
Subjects
Experiments were conducted on 19 male Wistar rats weighing 200–250 g at arrival (age range 3–6 months). These rats were housed in groups of 2 with food and water ad libitum available until the start of the experiments. A 12-h light portion of the light/dark cycle beginning at 6:00 a.m. was imposed. All experiments were carried out in accordance with protocols approved by the local university animal ethics committee.
Experimental cages
Activity-based anorexia experiments were conducted in custom-made cages (0.36 ×
Subjects and behavioural data
Body weight and food intake over time during the behavioural sessions are shown in Fig. 1, Fig. 2. At the day of scanning (day 10), body weight was significantly lower (p < 0.0001) in the experimental group (197 ± 25 g; mean ± SD) compared to the control group (298 ± 33 g). Likewise, the average daily food intake during the behavioural sessions was significantly lower (p < 0.0001) in the experimental group (9 ± 2 g; mean ± SD) compared to the control group (30 ± 3 g). Two animals received an extra amount of
Discussion
In this study, we have compared brain metabolism between rats in the ABA model and control rats using voxel-based analysis and have correlated brain metabolism with behavioural measures in the rats of the ABA group. Our results suggest a complex interplay between different circuitries involving motor activity, food-related behaviour and somatosensory regions.
As for the motor circuitry, ABA rats contradictorily are hyperactive in the presence of food shortage resulting in severe body weight loss
Acknowledgments
We acknowledge the financial support of the Research Fund K.U. Leuven (project VIS/02/007 OT/03/57 and OT/05/58), the Institute for the Promotion of Innovation by Science and Technology in Flanders (SBO50151) and the Fund for Scientific Research, Flanders (FWO) (G.0598.06 and G.0548.06). KVL is supported by a Clinical Research Mandate of the Fund for Scientific Research, Flanders. Part of this work is also performed under the European Commission FP6-project DiMI, LSHB-CT-2005-512146.
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2020, AppetiteCitation Excerpt :Anomalies in the above mentioned basal ganglia circuitry are believed to play a key role in the maintenance of AN (O'Hara et al., 2015). In preclinical studies, mice exhibiting activity-based anorexia (ABA) show reduced metabolism in regions associated with reward-motivated learning, including the anterior parts of the caudate, NAcc, and putamen (Barbarich-Marsteller, Marsteller, Alexoff, Fowler, & Dewey, 2005; van Kuyck et al., 2007). Furthermore, ABA rats show greater resistance to extinction of food aversion than control rats (Liang, Bello, & Moran, 2011).
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2017, Physiology and BehaviorDysregulation of brain reward systems in eating disorders: Neurochemical information from animal models of binge eating, bulimia nervosa, and anorexia nervosa
2012, NeuropharmacologyCitation Excerpt :MicroPET allows cerebral glucose metabolism to be determined, and this technique has been applied to rats in the ABA model. Low metabolism has been noted in several brain areas, including the ventral striatum, along with a positive correlation noted between body weight loss and brain metabolism in the cingulate cortex (van Kuyck et al., 2007). Clinical studies of anorexia nervosa lend support to the findings described above.
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2011, Neuroscience ResearchCitation Excerpt :These results show that small-animal PET can be useful for studying brain activity and plasticity by means of functional neuroimaging in the rat model. Small-animal PET with [18F]FDG has also been used as a functional neuroimaging method to reveal neural response patterns in the rat brain during acute immobilization stress, during the forced swimming test, in salicylate-induced tinnitus, in a rat model of visceral hypersensitivity, and in a rat model of activity-based anorexia (van Kuyck et al., 2007; Ohashi et al., 2008; Jang et al., 2009; Paul et al., 2009; Sung et al., 2009). Sung et al. (2009) used SPM analysis to study changes in glucose metabolism in different brain areas in rats subjected to immobilization stress for 1 h or 2 h or to 1 h of stress followed by 1 h of recovery.