NEURAL CIRCUITRY OF THE NEGATIVE VALENCE DOMAIN IN A COMPULSIVE PHENOTYPE: AN EX VIVO MRI ANALYSIS

Compulsivity involves impaired inhibitory control leading to persistent urges despite negative outcomes. Within the Research Domain Criteria RDoC framework, research has prioritized cognitive and positive valence systems, leaving negative valence processes under-explored. The aim of the present research was to characterize the brain network linked to the RDoC Negative Valence System domain in a compulsive phenotype. Forty-eight male Wistar rats were classified as Low Drinkers (LD) or High Drinkers (HD) using Schedule-Induced Polydipsia (SIP), a preclinical model of compulsivity. Following a one-month washout period, half of the animals in each group were re-exposed (RE) to SIP, while the other half remained non-re-exposed (NRE), resulting in four groups: HD-RE, HD-NRE, LD-RE, and LD-NRE. Immediately following the final SIP session, rats were perfused and skulls were analyzed via Magnetic Resonance Imaging integrating graph-theoretical approaches with fractional anisotropy metrics. Under re-exposure conditions, HD-RE rats exhibited stronger fronto-limbic coupling involving orbitofrontal-amygdala, orbitofrontal-cingulate, and amygdala-insula connections compared to LD-RE rats. When comparing the effect of re-exposure within HD rats, HD-RE rats showed reduced cingulate-centered connectivity but stronger amygdala coupling with orbitofrontal cortex and midbrain, alongside weaker amygdala-cingulate connectivity compared to HD-NRE rats. These findings suggest that compulsivity in the HD phenotype is driven by a shift toward amygdala-centered fronto-limbic circuits during re-exposure. This altered connectivity within the negative valence system may underlie the persistent, irresistible urges characteristic of compulsive behavior in the SIP model.
PID2022-139286NB-I00 Proyectos Generación de Conocimiento PGC, MCIN/AEI/10.13039/501100011033, Government of Spain and FEDER Funds. E.M.G. was supported by JDC2023-051708-I, MCIU/AEI/10.13039/501100011033 and FSE+.