Intrinsic functional connectivity between the anterior insular and retrosplenial cortex as a moderator and consequence of cocaine self-administration in rats

While functional brain imaging studies in humans suggest that chronic cocaine use alters functional connectivity within and between key large-scale brain networks, including the default mode network (DMN), the salience network (SN), and the central executive network (CEN), cross-sectional studies in humans are challenging to obtain brain functional connectivity prior to cocaine use. Such information is critical to reveal the relationship between individual's brain functional connectivity and the subsequent development of cocaine dependence and brain changes during abstinence. Here, we performed a longitudinal study examining functional magnetic resonance imaging (fMRI) data in male rats (n = 7), acquired before cocaine self-administration (baseline), on 1 day of abstinence following 10 days of cocaine self-administration, and again after 30 days of experimenter-imposed abstinence. Using repeated measures analysis of variance (ANOVA) with network-based statistics (NBS), significant connectivity changes were found between anterior insular cortex (AI) of the SN, retrosplenial cortex (RSC) of the DMN, somatosensory cortex, and caudate putamen (CPu), with AI-RSC functional connectivity showing the most robust changes between baseline and 1 day of abstinence. Additionally, the level of escalated cocaine intake is associated with AI-RSC and AI-CPu functional connectivity changes between 1 day and 30 days of abstinence; further, the subjects' AI-RSC functional connectivity prior to cocaine intake is a significant moderator for the AI-RSC changes during abstinence. These results provide novel insights into the roles of AI-RSC functional connectivity before and after cocaine intake and suggest this circuit to be a potential target to modulate large-scale network and associated behavioral changes in cocaine use disorders.Significance Statement This study examines the impact of chronic cocaine self-administration on brain network-level interactions involving the default mode network (DMN; retro-splenial cortex, RSC), salience network (SN; anterior insular, AI), and caudate putamen (CPu). These brain regions have been associated with self-referential functions, emotion, memory, and coordination between internal and external stimuli and align with the "triple network model" of psychopathology and addiction. By identifying relationships between the escalated cocaine self-administration and the changes of functional connectivity across longitudinal measures, this study contributes to the future development of circuit-based treatment strategies and suggests AI and RSC connectivity to be an imaging circuit marker for cocaine use disorders.