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 the 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 PFC 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.

Public significance: This study identifies specific brain gene activity patterns that may explain why some individuals are more vulnerable to extreme weight loss, as seen in AN. Using an advanced molecular technique in a well-established animal model, key differences in a neural pathway linked to cognitive control were observed. These findings pave the way for more targeted treatments that could prevent or reverse this dangerous condition.