Cognitive pathways describing ketamine’s effect on affective memories

The discovery of ketamine’s rapid antidepressant properties in the past two decades put the glutamate system in the spotlight as a neurobiological treatment target for depression. One neurocognitive mechanistic model of ketamine’s antidepressant effect focusses on its impact on negative affective memories, namely making negatively valenced memories less salient. Here, we synthesise translational evidence from human and rodent studies which suggests that affective memory recall engages a distributed network areas including the amygdala, hippocampus and prefrontal cortical regions, with subgenual cingulate cortex potentially playing a key role in how NMDA receptor antagonists modulate the connectivity across this cognitive pathway. We discuss how experimental studies based on reinforcement-learning and value-based recall could be used to probe these systems and build mechanistic models of affective memory recall and fast-acting antidepressant action.