Behavioral Disturbances in Estrogen-Related Receptor alpha-Null Mice

Abstract

SUMMARY Eating 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.

The Eating-Disorder Associated HDAC4 A778T Mutation Alters Feeding Behaviors in Female Mice

“…We find that HDAC4 A778T mice display several phenotypes with face validity (feeding and behavioral abnormalities), construct validity (reduced preference for high-fat food), and predictive validity (preferentially affects female mice). Furthermore, several behavioral abnormalities reported here are similar to those previously noted in ESRRA-null mice (7), including decreased operant responding for HFD, compulsive grooming, and decreased immobility in the forced swim test. These findings support our overall hypothesis that dysregulation of the HDAC4-ESRRA pathway predisposes to development of EDs in patients (6).…”

“…Because we previously hypothesized that greater HDAC4-mediated repression of ESRRA activity increases the risk of developing an ED in humans (6), and because ESRRA-null (7) and HDAC4 A778T mice share several behavioral deficits relevant to the development of EDs, we decided to focus on the subset of genes regulated by both ESRRA and HDAC4 in cortical neurons.…”

“…Mice were housed in the University of Iowa vivarium in a temperature-controlled environment (lights on: 6:00 AM to 6:00 PM ) with ad libitum access to water and regular chow (7913 NIH-31 modified open formula mouse sterilized diet, Harlan-Teklad, Madison, WI) or high-fat diet (HFD) (42.8% calories from fat, TD.88137; Harlan-Teklad) as noted. Tissue samples from ESRRA-null mice were collected in a previous study (7). …”

“…Importantly, knockout mice lacking ESRRA display behavioral deficits relevant to the study of EDs, including reduced body weight, decreased motivation to work for high-fat diet, behavioral compulsivity, and social subordination (7). Because the HDAC A786T mutation increases transcriptional repression in in vitro transcriptional assays (6), conventional and conditional knockout approaches are not well suited to study the role of HDAC4 on the risk of developing an ED.…”

Emerging Treatments in Eating Disorders

“…Our group has recently identified the first 2 rare, highly penetrant genetic variants that increase the risk of developing an EDs [55]. Importantly, mice that are genetically manipulated to replicate the disease-associated human variants display several behavioral phenotypes relevant to EDs, including decreased willingness to work for a high-fat diet after being fasted overnight [56,57]. These mouse lines with impaired behavioral responses to a negative energy state are the first monogenic models of AN and offer a unique opportunity for screening of novel pharmaceutical compounds.…”