Elsevier

NeuroImage

Volume 35, Issue 1, March 2007, Pages 214-221
NeuroImage

Motor- and food-related metabolic cerebral changes in the activity-based rat model for anorexia nervosa: A voxel-based microPET study

https://doi.org/10.1016/j.neuroimage.2006.12.009Get rights and content

Abstract

Anorexia nervosa (AN) is a disorder that is difficult to treat with psycho- or pharmacotherapy. In order to identify involved neurocircuitry, we investigated the cerebral metabolic alterations in the activity-based anorexia (ABA) rat model, where restriction of the food intake period induces hyperactivity and decreased body weight.

Cerebral 18F-fluorodeoxyglucose uptake was investigated in rats in the activity-based anorexia model (n = 9) and compared to controls (n = 10), using a CTI Focus microPET 220. Regional metabolic changes were investigated using statistical parametric mapping (SPM2) and correlated to weight and hyperactivity measures on a voxel-by-voxel basis.

Higher regional metabolism was found in ABA rats in the mediodorsal thalamus, ventral pontine nuclei and cerebellum, while hypometabolism was seen in the left rhinal and bilateral insular cortex, and bilateral ventral striatum (p < 0.001). A positive correlation was observed between body weight loss and brain metabolism in the cingulate cortex and surrounding motor and somatosensory cortex (p < 0.001).

Thus, in the ABA model metabolic changes are present in brain areas related to disease status and weight loss, which share several characteristics with the human disease.

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.

References (58)

  • J.J. Hillebrand et al.

    Leptin treatment in activity-based anorexia

    Biol. Psychiatry

    (2005)
  • Y. Iwamoto et al.

    VMH lesions reduce excessive running under the activity-stress paradigm in the rat

    Physiol. Behav.

    (1999)
  • A.E. Kelley et al.

    Corticostriatal-hypothalamic circuitry and food motivation: integration of energy, action and reward

    Physiol. Behav.

    (2005)
  • A.J. King

    The superior colliculus

    Curr. Biol.

    (2004)
  • S. Kojima et al.

    Comparison of regional cerebral blood flow in patients with anorexia nervosa before and after weight gain

    Psychiatry Res.

    (2005)
  • Z. Kopniczky et al.

    Alterations of behavior and spatial learning after unilateral entorhinal ablation of rats

    Life Sci.

    (2006)
  • B.E. Levin

    Glucose-regulated dopamine release from substantia nigra neurons

    Brain Res.

    (2000)
  • A.R. Mayeda et al.

    Activity-wheel stress and serotonergic hypersensitivity in rats

    Pharmacol. Biochem. Behav.

    (1989)
  • K.K. Miller et al.

    Testosterone administration attenuates regional brain hypometabolism in women with anorexia nervosa

    Psychiatry Res.

    (2004)
  • G.J. Mogenson et al.

    Electrophysiological and behavioral evidence of interaction of dopaminergic and gustatory afferents in the amygdala

    Brain Res. Bull.

    (1982)
  • E.J. Neafsey et al.

    The organization of the rat motor cortex: a microstimulation mapping study

    Brain Res.

    (1986)
  • S. Nozoe et al.

    Clinical features of patients with anorexia nervosa: assessment of factors influencing the duration of in-patient treatment

    J. Psychosom. Res.

    (1995)
  • B. Nuttin et al.

    Electrical stimulation in anterior limbs of internal capsules in patients with obsessive–compulsive disorder

    Lancet

    (1999)
  • B.J. Nuttin et al.

    Electrical stimulation of the anterior limbs of the internal capsules in patients with severe obsessive–compulsive disorder: anecdotal reports

    Neurosurg. Clin. N. Am.

    (2003)
  • W.P. Pare

    Body temperature and the activity-stress ulcer in the rat

    Physiol. Behav.

    (1977)
  • N.C. Raymond et al.

    Elevated pain threshold in anorexia nervosa subjects

    Biol. Psychiatry

    (1999)
  • P. Schweinhardt et al.

    A template for spatial normalisation of MR images of the rat brain

    J. Neurosci. Methods

    (2003)
  • A. Takano et al.

    Abnormal neuronal network in anorexia nervosa studied with I-123-IMP SPECT

    Psychiatry Res.

    (2001)
  • A. Tsuda et al.

    Marked enhancement of noradrenaline turnover in extensive brain regions after activity-stress in rats

    Physiol. Behav.

    (1982)
  • Cited by (37)

    • Serotonin in eating behavior

      2020, Handbook of Behavioral Neuroscience
    • Basal ganglia volume and shape in anorexia nervosa

      2020, Appetite
      Citation 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).

    • Dysregulation of brain reward systems in eating disorders: Neurochemical information from animal models of binge eating, bulimia nervosa, and anorexia nervosa

      2012, Neuropharmacology
      Citation 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.

    • Molecular imaging in neuroscience research with small-animal PET in rodents

      2011, Neuroscience Research
      Citation 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.

    View all citing articles on Scopus
    View full text