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

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.

Animal Models for Anorexia Nervosa—A Systematic Review

“…As infant/adolescent trauma is a risk factor for the development of anorexia nervosa, the study by Hurel et al analyzed the impact of post-weaning isolation on body weight and wheel-running performance in female mice exposed to an ABA protocol (Hurel et al, 2019 ). Post-weaning isolation amplified ABA-elicited body weight reduction and stimulated wheel-running activities in anticipation of feeding in female mice compared to controls (Hurel et al, 2019 ).…”

Exercise craving potentiates excitatory inputs to ventral tegmental area dopaminergic neurons

“…At least 1 week before experiments, all animals were individually housed (to avoid interindividual aggression) with food and water ad libitum in a thermoregulated room (21°C–22°C) placed under a partly reversed 12 h/12 h light/dark cycle (lights off: 9:00–21:00). Mice tested for the synaptic impacts of acute (DAT‐Cre/Ai6 mice) and repeated (CB 1 ‐floxed mice) free wheel‐running were housed with 25‐cm diameter running wheels (IntelliBio, France) 2,12 . All mice were tested during the dark phase (between 10:00 and 18:00) of the light/dark cycle.…”

“…Home cage running wheels were either kept locked (respective control mice) or set 1‐h‐free once (DAT‐Cre/Ai6 mice) or daily for 12 days (CB 1 ‐floxed mice) through their connection to a computer which recorded running performances (ActiviWheel software; IntelliBio, France) 2,12 . To ensure that mice tested for the synaptic impact of an acute 1‐h run would effectively run, these were given a daily 5‐min‐free habituation run during the 3–4 days that preceded the final 1‐h run.…”

“…Operant chambers (28 cm × 26 cm × 38 cm; Imetronic, France) were located in a room adjacent to the housing room 10,12 . These chambers, placed inside wooden casings (60 cm × 62 cm × 49 cm), were ventilated to guarantee air circulation and to provide background noise.…”

“…Definitive evidence for the reinforcing value of wheel‐running stems from operant conditioning procedures 5 wherein performance of a task, that is, cued‐associated lever pressing or nose poking under fixed (FR), variable and/or progressive (PR) ratio reinforcement schedules, was a running prerequisite 8–10 . As opposed to “free” wheel‐running paradigms, in which motivation for running and running performance cannot be disentangled, 11,12 conditioned procedures allow to distinguish each of these two variables 10,12 . This distinction is essential because motivation, but not consumption, of a reward is linked to the activity of ventral tegmental area (VTA) mesocorticolimbic dopaminergic neurones 13,14 .…”