Emotional learning (learning the value of stimuli or contexts) is central to the causative mechanisms of mood and anxiety disorders. During emotional learning, the hippocampus, long implicated in internalizing disorders, receives a snapshot of distributed cortical and subcortical activity. Synaptic plasticity promotes engram formation, the circuit-level instantiation of memory.1 Hippocampal replay, the rapid, coordinated reactivation of encoding-activated cellular ensembles during sleep and resting wakefulness, also supports memory consolidation2 and may contribute to prospection and decision-making. Even in rodent cognitive spatial tasks, learning fundamentally concerns the learning of value, a process critical to psychopathology. While unstudied (to our knowledge) in psychiatric disorders, hippocampal replay abnormalities may critically link animal models with human psychopathology and, in particular, with cognitive symptoms of worry and rumination. Hippocampal replay2 is marked by ripple oscillations in the CA1 local field potential1 of approximately 100 milliseconds at 140 to 250 Hz.2 During replay, which is commonly observed after a rodent traverses a maze (reverse replay) or before it enters a familiar maze (forward replay), the hippocampal firing sequence recapitulates previously observed firing but is accelerated.2 Reverse replay is not observed before an initial maze run, suggesting that replay represents previous experience. Forward replay is observed when, as the rodent approaches a decision point in a familiar maze, hippocampal place cells replay forward the sequences observed previously from that maze.3 Forward replay is associated with the rodent’s ultimate trajectory, potentially representing goal-directed future planning in anticipation of decision-making.3 Hippocampal replay is the replay that has been most extensively studied, yet there is evidence that replay occurs elsewhere, including the prefrontal cortex (PFC), particularly the medial PFC (mPFC). While most evidence supports replay-associated CA1 sharp-wave ripples originating in the CA3, recent findings suggest a role for bidirectional mPFC-hippocampus communication in initiating and, in particular, sustaining replay.4
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Heller AS, Bagot RC. Is Hippocampal Replay a Mechanism for Anxiety and Depression? JAMA Psychiatry. 2020;77(4):431–432. doi:10.1001/jamapsychiatry.2019.4788
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