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

Abstract

ObjectiveConverging 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. MethodsWe 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. ResultsWe 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. DiscussionThese 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 SignificanceThis study identifies specific brain gene activity patterns that may explain why some individuals are more vulnerable to extreme weight loss, as seen in anorexia nervosa. 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. SummaryO_LITranscriptional differences within medial prefrontal cortex to nucleus accumbens shell (mPFC-AcbSh) neurons distinguish rats highly susceptible to activity-based anorexia (ABA) from those resistant to pathological weight loss. C_LIO_LIResistant rats showed upregulation of mitochondrial function genes, while Susceptible rats had upregulation of genes related to synaptic structure and signalling, implicating excitability of this circuit in driving maladaptive weight loss behaviour. C_LIO_LITranscriptomic changes align with human genome-wide association study (GWAS) findings and support links between anorexia nervosa and both metabolic and psychiatric comorbidities. C_LIO_LIThe study highlights potential molecular targets for future gene manipulation and therapeutic intervention. It also provides a foundation for creating refined genetic animal models that integrate multiple AN-associated variants to better reflect the polygenic nature of the disorder. C_LI