Effect of electroconvulsive shocks on retrograde memory and engram reactivation

The amnesic effects of electroconvulsive therapy (ECT) are reported in human clinical studies, hindering the wide use of ECT in medication-resistant patients despite a high efficacy rate. The translational potential of animal studies employing electroconvulsive shock (ECS), the animal analog of ECT, remains limited due to the mismatch of widely used acute ECS protocol and clinical ECT. While the neural representation of memory as engrams is well understood in which the same neural ensembles activated during encoding are reactivated for retrieval, neither the specific neural mechanisms underlying memory processing affected by ECS, nor how they are affected, are clear. By applying repeated ECS protocol mimicking the clinical ECT schedule, we aimed to establish the phenotype of long-term retrograde amnesia, and further examine engram reactivation when retrieving ECS-impaired memories with activity-dependent cell labeling. Firstly, mice were treated with ECS between encoding and retrieval of contextual fear conditioning (CFC) memory, and freezing behavior was recorded to quantify the recall of fear memory. Extinction and spontaneous recovery of CFC memory were measured in experiment 1 by returning mice to the context for 7 more days following retrieval and once more 2 months after the last extinction session. Compared to sham controls, ECS-treated animals showed impaired memory retrieval, in which extinction and spontaneous recovery were absent. FosTrap2A transgenic mice were then used to label neural ensembles activated at encoding and retrieval of CFC memory with tdTomato and c-Fos, respectively. ECS treatment decreased c-Fos expression following memory retrieval. Engram reactivation shown as overlapping tdTomato+/c-Fos+ expression was also decreased in ECS-treated mice compared to sham controls. Together, our study showed that ECS impaired the retrieval of long-term memory, and disrupted engram reactivation which displayed the deficit of ECS-induced retrograde amnesia at the neural level.