Toward a genetic signature of resistance to activity-based anorexia in striatal projecting cortical neurons

Objective: Converging evidence from neuroimaging studies and genome-wide association study (GWAS) suggests the involvement of prefrontal cortex (PFC) and striatum dysfunction in the pathophysiology of anorexia nervosa (AN). However, identifying the causal role of circuit-specific genes in the development of AN-like phenotype remains challenging and requires the combination of novel molecular tools and preclinical models. Methods: We used the activity-based anorexia (ABA) rat model in combination with a novel viral-based translating ribosome affinity purification (TRAP) technique to identify transcriptional differences within a specific neural pathway that we have previously demonstrated to mediate pathological weight loss in ABA rats (i.e. medial prefrontal cortex neurons that project to the nucleus accumbens shell). We compared actively transcribed genes in rats susceptible to weight loss to the subpopulation of rats resistant to weight loss under the same experimental conditions. Results: We reveal 1424 differentially expressed genes between Susceptible and Resistant rats, highlighting important transcriptional changes associated with ABA within this pathway. The changes observed were independent of current calorie deficit and associated with metabolic, mitochondrial and neural functions. Further, we show that genes upregulated in Resistant rats were involved in mitochondrial function, while downregulated genes were associated with cytoskeletal, postsynaptic and axonal functions, supporting the hypothesis that hyperexcitability of cortico-striatal circuit function is a critical mediator of pathological weight loss in ABA. Discussion: These findings represent an essential first step in understanding how circuit-specific gene expression patterns may contribute to susceptibility to ABA and provide potential molecular targets for manipulation in this animal model of AN.