Identifying novel phenotypes of vulnerability and resistance to activity‐based anorexia in adolescent female rats

Abstract

Objective Activity-based anorexia is a translational rodent model that results in severe weight loss, hyperactivity, and voluntary self-starvation. The goal of our investigation was to identify vulnerable and resistant phenotypes of activity-based anorexia in adolescent female rats. Method Sprague-Dawley rats were maintained under conditions of restricted access to food (N = 64; or unlimited access, N = 16) until experimental exit, predefined as a target weight loss of 30–35% or meeting predefined criteria for animal health. Nonlinear mixed effects statistical modeling was used to describe wheel running behavior, time to event analysis was used to assess experimental exit, and a regressive partitioning algorithm was used to classify phenotypes. Results Objective criteria were identified for distinguishing novel phenotypes of activity-based anorexia, including a vulnerable phenotype that conferred maximal hyperactivity, minimal food intake, and the shortest time to experimental exit, and a resistant phenotype that conferred minimal activity and the longest time to experimental exit. Discussion The identification of objective criteria for defining vulnerable and resistant phenotypes of activity-based anorexia in adolescent female rats provides an important framework for studying the neural mechanisms that promote vulnerability to or protection against the development of self-starvation and hyperactivity during adolescence. Ultimately, future studies using these novel phenotypes may provide important translational insights into the mechanisms that promote these maladaptive behaviors characteristic of anorexia nervosa.

Role of spontaneous physical activity in prediction of susceptibility to activity based anorexia in male and female rats

“…Our results add support to the hypothesis that RW activity during ad-libitum feeding has predictive value for body weight changes during ABA in female rats and extend this result to male rats (Figure 4 and 5). Human studies suggest that pre-morbid BW correlates with the severity of body weight loss during AN [57] and linear analysis of ABA susceptibility suggest it can contribute to accuracy of prediction of ABA weight loss [18, 25, 26]. Overall, our results align with previous data suggesting that body weight and RW activity during ad-libitum food intake contribute to susceptibility to weight loss in ABA.…”

“…The best predictive model was a combination of RW activity during ad-libitum feeding, SPA and body weight history (Figures 4 and 5). Previous studies of ABA susceptibility showed that RW activity is a strong predictor of body weight loss during ABA in female rats [18, 25, 26]. Our results add support to the hypothesis that RW activity during ad-libitum feeding has predictive value for body weight changes during ABA in female rats and extend this result to male rats (Figure 4 and 5).…”

“…There is large variability between mouse strains in body weight loss during ABA [18, 24, 25]. Studies in female mice and rats indicate that RW activity during ad-libitum feeding predicts body weight loss during ABA [25, 26]. In female rats, locomotor activity (measured by telemetry) during RW exposure with ad-libitum feeding is a predictor of body weight loss during ABA [25].…”

Interacting Neural Processes of Feeding, Hyperactivity, Stress, Reward, and the Utility of the Activity-Based Anorexia Model of Anorexia Nervosa

“…Recent, elegant studies to determine what underlying factors lead animals to be susceptible to the development of ABA have laid the groundwork for the utility of the ABA model in prevention and treatment studies that will be applicable to human disease. 32 …”

α4βδ-GABAARs in the hippocampal CA1 as a biomarker for resilience to activity-based anorexia

“…The other is voluntary food restriction, as the food restricted animals paradoxically begin to choose exercise over feeding, even during the period of food access. When the ABA-inducing environment is imposed upon adolescent female rats, this combination of behaviors leads to severe body weight loss and mortality, unless removed from the ABA-inducing environment by around the fifth day (Routtenberg and Kuznesof, 1967, Barbarich-Marsteller et al, 2013, Chowdhury et al, 2013, Gutierrez, 2013). Adolescent female rats placed in an ABA-inducing environment for four days exhibit a 500% greater level of non-synaptic α4βδ−GABA A receptors (α4βδ−GABA A Rs) at dendritic spines of CA1 pyramidal cells, relative to controls (Aoki et al, 2012).…”