BDNF-Val66Met variant and adolescent stress interact to promote susceptibility to anorexic behavior in mice.

M Madra,L M Zeltser

doi:10.1038/tp.2016.35

Abstract

There is an urgent need to identify therapeutic targets for anorexia nervosa (AN) because current medications do not impact eating behaviors that drive AN's high mortality rate. A major obstacle to developing new treatments is the lack of animal models that recapitulate the pattern of disease onset typically observed in human populations. Here we describe a translational mouse model to study interactions between genetic, psychological and biological risk factors that promote anorexic behavior. We combined several factors that are consistently associated with increased risk of AN—adolescent females, genetic predisposition to anxiety imposed by the BDNF-Val66Met gene variant, social isolation stress and caloric restriction (CR). Approximately 40% of the mice with all of these risk factors will exhibit severe self-imposed dietary restriction, sometimes to the point of death. We systematically varied the risk factors outlined above to explore how they interact to influence anorexic behavior. We found that the Val66Met genotype markedly increases the likelihood and severity of abnormal feeding behavior triggered by CR, but only when CR is imposed in the peri-pubertal period. Incidence of anorexic behavior in our model is dependent on juvenile exposure to social stress and can be extinguished by adolescent handling, but is discordant from anxiety-like behavior. Thus, this study characterized gene × environment interactions during adolescence that could be the underlying driver of abnormal eating behavior in certain AN patients, and represents a promising system to identify possible targets for therapeutic intervention.

Highlights

Anorexia nervosa (AN) is a complex multi-factorial disease characterized by a compulsive restriction of food intake, resulting in severe weight loss.[1,2] It is the third-most common chronic illness among US adolescent females,[3] with lifetime prevalence estimates of 0.3–0.9% in females and 0.1–0.3% in males.[4,5] There is an urgent need to develop treatments for AN, because it has the highest mortality rate of any psychiatric disease.[6]
While the prevalence of AN is markedly higher in females,[5] we found that the frequency of aphagic episode (AE) in male Val66Met carriers that were exposed to adolescent social stress and caloric restriction (CR) (GED-M) was only 13% lower than in females, a difference that did not reach significance (Figure 2c)
We developed a model to test the hypothesis that the Val66Met allele increases the likelihood of AN by conferring sensitivity to environmental factors

Summary

Introduction

Anorexia nervosa (AN) is a complex multi-factorial disease characterized by a compulsive restriction of food intake, resulting in severe weight loss.[1,2] It is the third-most common chronic illness among US adolescent females,[3] with lifetime prevalence estimates of 0.3–0.9% in females and 0.1–0.3% in males.[4,5] There is an urgent need to develop treatments for AN, because it has the highest mortality rate of any psychiatric disease.[6] Due to AN’s high co-morbidity with anxiety and depression,[7,8,9] the efficacy of psychotropic medications such as serotonin-specific reuptake inhibitors (SSRIs) in AN patients has been examined by several different groups. While data are discordant regarding the benefits of SSRIs in reducing depressive symptoms, these treatments consistently have no impact on the restrictive eating behavior that is responsible for the high mortality.[10,11,12]

Methods

Results

Conclusion