Sequential physical and cognitive training disrupts cocaine-context associations via multi-level stimulation of adult hippocampal neurogenesis

Cocaine-related contextual cues are a recurrent source of craving and relapse. Extinction of cue-driven cocaine seeking remains a clinical challenge, and the search for adjuvants is ongoing. In this regard, combining physical and cognitive training is emerging as a promising strategy that has shown synergistic benefits on brain structure and function, including enhancement of adult hippocampal neurogenesis (AHN), which has been recently linked to reduced maintenance of maladaptive drug seeking. Here, we examined whether this behavioral approach disrupts cocaine-context associations via improved AHN. To this aim, C57BL/6J mice (N = 37) developed a cocaine-induced conditioned place preference (CPP) and underwent interventions consisting of exercise and/or spatial working memory training. Bromodeoxyuridine (BrdU) was administered during early running sessions to tag a subset of new dentate granule cells (DGCs) reaching a critical window of survival during spatial learning. Once these DGCs became functionally mature (∼ 6 weeks-old), mice received extinction training before testing CPP extinction and reinstatement. We found that single and combined treatments accelerated CPP extinction and prevented reinstatement induced by a low cocaine priming (2 mg/kg). Remarkably, the dual-intervention mice showed a significant decrease of CPP after extinction relative to untreated animals. Moreover, combining the two strategies led to increased number and functional integration of BrdU⁺ DGCs, which in turn maximized the effect of spatial training (but not exercise) to reduce CPP persistence. Together, our findings suggests that sequencing physical and cognitive training may redound to decreased maintenance of cocaine-context associations, with multi-level stimulation of AHN as a potential underlying mechanism.