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

Anorexia nervosa (AN) is a complex psychiatric disorder characterised by severe pathological weight loss and persistent cognitive inflexibility. 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 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. The activity-based anorexia (ABA) rat model recapitulates many aspects of the behavioural phenotypes of AN in humans and we have previously demonstrated that suppressing neural activity in the medial prefrontal cortex (mPFC)-nucleus accumbens shell (AcbSh) circuit prevented pathological weight loss in ABA rats. Here, we used a novel viral-based translating ribosome affinity purification (TRAP) technique to identify transcriptional changes within this neural pathway associated with susceptibility to ABA in female rats. 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. These findings provide novel insights into circuit-specific gene expression patterns that may contribute to susceptibility to developing AN in humans and highlight potential molecular targets for therapeutic intervention.