Determining a molecular signature of susceptibility to pathological weight loss in rats

Anorexia nervosa (AN) has clear biological underpinnings, however, the molecular mechanisms that lead to the development of this debilitating disorder are poorly understood. AN has the highest mortality rate of any psychiatric disorder and often has a chronic and relapsing time course that is exacerbated by a lack of effective treatments. What is becoming apparent is that an interaction between genetic, neurobiological and behavioural factors may predispose individuals to AN. Traditional assessment of the genetic contributions to AN, including genome-wide association studies (GWAS) in patient populations and targeted genetic knockout/down in animal models have yielded insufficient evidence to date for a molecular signature of AN. However, it is now possible to examine differential gene expression within specific neuronal projections using TRAP technology. This project will utilise the most well-accepted animal model of AN, known as activity-based anorexia (ABA), which exploits the innate motivation of laboratory rats to run in wheels. When rats with access to running wheels are placed on a restricted feeding schedule, there is a paradoxical increase in running activity despite substantially decreased caloric intake, causing a profound reduction in body weight. Our recent work has revealed that nearly one-third of rats are resistant to body weight loss in the ABA paradigm. This under-reported feature of the model is a compelling rationale to investigate the differences in genetic profiles between rats that are susceptible and resistant to weight loss under the exact same conditions of ABA. Translating ribosome affinity purification (TRAP) technology uses a viral approach to synthesise molecular and neuroanatomical information by allowing the immunoprecipitation of translating mRNAs from any population of neurons that express enhanced green fluorescent protein (eGFP). In collaboration with the Medical Genomics Facility (Monash, Health Translation Precinct), these “trapped” neurons will be sequenced and analysed to identify specific gene expression signatures in susceptible and resistant rats and key metabolic pathways perturbed in different neural circuits.