Infralimbic-hippocampal activity pattern associated with Pavlovian extinction of cocaine-context associations

Extinction of cocaine-context associations is a valuable strategy to suppress conditioned drug seeking and relapse vulnerability. Prior work has mapped the contribution of multiple corticolimbic regions to the retrieval of instrumental cocaine-context extinction, yet the neurofunctional profile supporting its Pavlovian counterpart remains untested. In this study, we combined c-Fos mapping with multivariate analysis to determine whether extinction expression of a cocaine-induced conditioned place preference (CPP) is supported by a specific neurofunctional signature. Mice underwent CPP conditioning followed by either forced extinction (EXT, n = 9), home-cage withdrawal (No-EXT, n = 6), or a saline procedure without drug exposure (SAL, n = 7), and c-Fos expression was tracked during a subsequent CPP retest. EXT animals both reduced CPP during retesting and displayed more c-Fos⁺ nuclei in the infralimbic cortex (IL) and the ventral CA1 region of the hippocampus relative to No-EXT and SAL mice, as well as increased c-Fos in the dorsal CA1 compared to No-EXT animals. No group differences were found regarding c-Fos expression in the prelimbic cortex, dorsal and ventral striatum, basolateral amygdala, and other hippocampal subfields. Furthermore, a Principal Component Analysis indicated that CPP extinction, together with c-Fos induction in IL and dorsal and ventral CA1, loaded onto a single dimension accounting for ~62.5% of shared variance, suggesting that these variables integrate a specific neurobehavioral profile. These findings identify an infralimbic-hippocampal activity pattern associated with cocaine-context extinction, providing a basis for future investigation of potential interactions between these structures.