THE ROLE OF SATB2 IN COCAINE MEMORY AND RELAPSE

Drug addiction is a chronic relapsing disorder driven by persistent alterations in memory and reward circuits. Satb2, a DNA-binding protein involved in chromatin remodelling, has been identified as a key regulator of long-term memory consolidation. This study investigates the contribution of Satb2 to cocaine-associated memories and the molecular underpinnings of relapse. Initially, using the Conditioned Place Preference (CPP) paradigm, we characterized a conditional mouse model (cKO: Satb2 flox/flox::Camk2a-Cre) lacking Satb2 expression in the cortex and hippocampal CA1. While Satb2 cKO mice showed no differences in extinction rates or reinstatement (induced by cocaine priming or stress) compared to floxed controls, they exhibited increased immobility in the Forced Swim Test (FST), suggesting heightened despair-like behavior. Notably, after targeting layer 2/3 of the Anterior Cingulate Area (ACC), a region critical for drug-seeking and drug-taking processes, cocaine-induced reinstatement in the CPP paradigm was abolished in the group lacking Satb2. To strengthen the translational validity of our findings, we are expanding our behavioral framework to include intravenous self-administration (IVSA), for a refined analysis of Satb2’s role in drug reinforcement and motivation. To achieve a comprehensive systems-level understanding, we are implementing tissue clearing (RatDISCO) with Light Sheet Fluorescence Microscopy (LSFM). This approach enables 3D whole-brain visualisation and quantification of Satb2-expressing neuronal networks and their activation patterns associated with the persistence of drug-related memories. These efforts aim to provide critical insights into the molecular mechanisms of addiction and may inform the development of targeted pharmacological interventions to prevent relapse.
In collaboration with the Institute for Neuroscience