Behavioral Disturbances in Estrogen-Related Receptor alpha-Null Mice

•Esrra expression in the mouse brain is regulated by energy status•Loss of Esrra reduces response to a high-fat diet•Esrra-null mice display behavioral compulsivity and social impairments•Esrra knockdown in mPFC and OFC recapitulates feeding and grooming deficits

SummaryEating disorders, such as anorexia nervosa and bulimia nervosa, are common and severe mental illnesses of unknown etiology. Recently, we identified a rare missense mutation in the transcription factor estrogen-related receptor alpha (ESRRA) that is associated with the development of eating disorders. However, little is known about ESRRA function in the brain. Here, we report that Esrra is expressed in the mouse brain and demonstrate that Esrra levels are regulated by energy reserves. Esrra-null female mice display a reduced operant response to a high-fat diet, compulsivity/behavioral rigidity, and social deficits. Selective Esrra knockdown in the prefrontal and orbitofrontal cortices of adult female mice recapitulates reduced operant response and increased compulsivity, respectively. These results indicate that Esrra deficiency in the mouse brain impairs behavioral responses in multiple functional domains.

Graphical AbstractFigure optionsDownload full-size imageDownload as PowerPoint slide