Contextual cues associated with previous drug exposure can trigger drug craving and seeking, and form a substantial obstacle in substance use recovery. Using in vivo imaging in mice, we found that cocaine administration induced a rapid increase in the formation and accumulation of new dendritic spines, and that measures of new persistent spine gain correlated with cocaine conditioned place preference. Our data suggest that new persistent spine formation in the frontal cortex may be involved in stimulant-related learning driving appetitive behavior.

Environmental stress and deprivation increase vulnerability to substance use disorders in humans and promote drug-seeking behavior in animal models. In contrast, experiences of mastery and stability may shape neural circuitry in ways that build resilience to future challenges. Cognitive training offers a potential intervention for reducing vulnerability in the face of environmental stress or deprivation. Here, we test the hypothesis that brief cognitive training can promote long-term resilience to one measure of drug-seeking behavior, cocaine conditioned place preference (CPP), in mice. In young adulthood, mice underwent cognitive training, received rewards while exploring a training arena (i.e. yoked control), or remained in their home cages. Beginning 4 weeks after cessation of training, we conditioned mice in a CPP paradigm and then tested them weekly for CPP maintenance or daily for CPP extinction. We found that a brief 9-day cognitive training protocol reduced maintenance of cocaine CPP when compared to standard housed and yoked conditions. This beneficial effect persisted long after cessation of the training, as mice remained in their home cages for 4 weeks between training and cocaine exposure. When mice were tested for CPP on a daily extinction schedule, we found that all trained and yoked groups that left their home cages to receive rewards in a training arena showed significant extinction of CPP, while mice kept in standard housing for the same period did not extinguish CPP. These data suggest that in early adulthood, deprivation may confer vulnerability to drug-seeking behavior and that brief interventions may promote long-term resilience.

We appreciate the many comments we received on our discussion paper and believe that they reflect a recognition of the importance of this topic worldwide. We point out in this reply that there appears to be a confusion between the role of oscillations in creating white matter and other functions of oscillations in communicating between neural areas during task performance or at rest. We also discuss some mechanisms other than the enhancement of white matter that must influence reaction time. We recognize the limited understanding we have of transfer and outline some future directions designed to improve our understanding of this process.

Why does training on a task reduce the reaction time for performing it? New research points to changes in white matter pathways as one likely mechanism. These pathways connect remote brain areas involved in performing the task. Genetic variations may be involved in individual differences in the extent of this improvement. If white matter change is involved in improved reaction time with training, it may point the way toward understanding where and how generalization occurs. We examine the hypothesis that brain pathways shared by different tasks may result in improved performance of cognitive tasks remote from the training.