Beyond the Activity-Based Anorexia Model: Reinforcing Values of Exercise and Feeding Examined in Stressed Adolescent Male and Female Mice.

Imane Hurel,Amandine Scocard,Francis Chaouloff,Bastien Redon,Meryl Malezieux,Giovanni Marsicano

doi:10.3389/fphar.2019.00587

Imane Hurel, Amandine Scocard + Show 4 more

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https://doi.org/10.3389/fphar.2019.00587

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Abstract

Anorexia nervosa (AN), mostly observed in female adolescents, is the most fatal mental illness. Its core is a motivational imbalance between exercise and feeding in favor of the former. The most privileged animal model of AN is the “activity-based anorexia” (ABA) model wherein partly starved rodents housed with running wheels exercise at the expense of feeding. However, the ABA model bears face and construct validity limits, including its inability to specifically assess running motivation and feeding motivation. As infant/adolescent trauma is a precipitating factor in AN, this study first analyzed post-weaning isolation rearing (PWIR) impacts on body weights and wheel-running performances in female mice exposed to an ABA protocol. Next, we studied through operant conditioning protocols i) whether food restriction affects in a sex-dependent manner running motivation before ii) investigating how PWIR and sex affect running and feeding drives under ad libitum fed conditions and food restriction. Besides amplifying ABA-elicited body weight reductions, PWIR stimulated wheel-running activities in anticipation of feeding in female mice, suggesting increased running motivation. To confirm this hypothesis, we used a cued-reward motivated instrumental task wherein wheel-running was conditioned by prior nose poke responses. It was first observed that food restriction increased running motivation in male, but not female, mice. When fed grouped and PWIR mice were tested for their running and palatable feeding drives, all mice, excepted PWIR males, displayed increased nose poke responses for running over feeding. This was true when rewards were proposed alone or within a concurrent test. The increased preference for running over feeding in fed females did not extend to running performances (time, distance) during each rewarded sequence, confirming that motivation for, and performance during, running are independent entities. With food restriction, mice displayed a sex-independent increase in their preference for feeding over running in both group-housed and PWIR conditions. This study shows that the ABA model does not specifically capture running and feeding drives, i.e. components known to be affected in AN.

Highlights

Anorexia nervosa (AN), which mainly affects older adolescent and young adult females, is a psychiatric disorder where self-starvation and dramatic underweight is a core symptom (Kaye et al, 2009; Zipfel et al, 2015)
Food-restricted grouped and PWIR mice displayed a progressive session-dependent shift of wheel-running activity from the dark part of the nycthemeral cycle to its light part (Figure 2A). This shift, which was mainly observed during the hours that preceded food availability (i.e., FAA), concerned to a higher extent the PWIR mice, compared to their grouped counterparts (Figure 2A)
Food restriction, which decreased body weights in all mice (F7,91 = 119.92, p < 0.0001), this decrease being larger in PWIR mice (F1,13 = 24.84, p = 0.0002; Figure 2B), inhibited wheel-running activity in both mouse groups (F7,91 = 18.26, p < 0.0001; Figure 2C)

Summary

Introduction

Anorexia nervosa (AN), which mainly affects older adolescent and young adult females (with a sex ratio of 8 for 1 male), is a psychiatric disorder where self-starvation and dramatic underweight is a core symptom (Kaye et al, 2009; Zipfel et al, 2015). Reinforcing the hypothesis that increased exercise is at the core of AN are the reports that i) exercise dependence might be one cause of altered eating behavior (Cook and Hausenblas, 2008), ii) remitted AN patients still display craving for exercise (Shroff et al, 2006), and that iii) the latter amplifies the anhedonic profile of these patients (Davis and Woodside, 2002). It is this imbalance between energetic supply and energy consumption rates that provides AN with severe and often lethal consequences. The observation that early traumatic events provide a long-term psychoneuroendocrine vulnerability to future stressors in laboratory rodents (Lupien et al, 2009; McCormick et al, 2016) provides support for an etiological role of early trauma in AN

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