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Updated: Mar 23, 2026
Chronic Social Defeat Stress in Early Adolescent Male Mice
Published on: January 24, 2025
BDNF-Val66Met variant and adolescent stress interact to promote susceptibility to anorexic behavior in mice
M Madra1, L M Zeltser2,3
1Institute of Human Nutrition, Columbia University, New York, NY, USA.
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.
Insights
A new mouse model shows that adolescent females with a specific gene variant and stress exhibit anorexia nervosa behaviors. This model helps identify therapeutic targets for anorexia nervosa (AN).
Area of Science:
- Neuroscience
- Genetics
- Animal Models
Background:
- Anorexia nervosa (AN) has a high mortality rate, with current treatments ineffective against core eating behaviors.
- A significant barrier to AN treatment development is the absence of animal models reflecting human disease onset.
- Understanding gene-environment interactions is crucial for developing targeted AN therapies.
Purpose of the Study:
- To develop a translational mouse model for studying anorexia nervosa (AN) risk factors.
- To investigate the interplay of genetic, psychological, and biological factors in promoting AN-like behaviors.
- To identify potential therapeutic targets for AN.
Main Methods:
- A mouse model was created combining adolescent females, BDNF-Val66Met gene variant (anxiety predisposition), social isolation, and caloric restriction (CR).
- Risk factors were systematically varied to analyze their impact on anorexic behavior.
- Gene-environment interactions during adolescence were assessed for their influence on abnormal eating.
Main Results:
- Approximately 40% of mice with all risk factors developed severe self-imposed dietary restriction.
- The Val66Met genotype significantly increased AN-like behavior severity under CR, specifically during the peri-pubertal period.
- Anorexic behavior incidence depended on juvenile social stress exposure and could be reduced by adolescent handling, independent of anxiety-like behavior.
Conclusions:
- Gene × environment interactions during adolescence contribute to abnormal eating behaviors in some AN patients.
- This mouse model provides a valuable system for identifying therapeutic targets for anorexia nervosa.
- The findings highlight the importance of developmental timing and specific stressors in AN pathogenesis.
