Nearly 90 years after Ugo Cerletti and Lucio Bini introduced electroconvulsive therapy (ECT), brain stimulation therapies such as ECT and repetitive transcranial magnetic stimulation (rTMS) have become commonplace in psychiatry because they are highly effective in treating depression and schizophrenia, but their cellular mechanisms remain poorly understood. The research team introduced REPOPS, a type of patterned stimulation in mice designed to mimic key features of ECT-like neuron activation.
Mice receiving REPOPS showed increased locomotor activity and decreased depression-like behavior, revealing stimulus-induced sustained behavioral changes similar to an ECT-like state. At the cellular level, this stimulus induced a cytodegenerative state, and adult neurons had gene expression patterns similar to those seen during early postnatal development. Stimulation for 3 days produced only transient changes, whereas stimulation for 10 days resulted in a stable degenerative state that persisted for more than 1 month. Genome-wide chromatin mapping revealed widespread and persistent changes in chromatin accessibility and provided molecular evidence that this condition persists. Reanalysis of postmortem brain RNA-seq data from patients with mood disorders showed that ECT-treated patients showed similar immaturity-like gene expression patterns in the dentate gyrus compared to non-ECT patients, suggesting that similar immaturity-like changes may also occur in the human dentate gyrus after ECT.
The surprising emergence of cell cycle reentry in mature neurons
Gene expression analysis revealed an unexpected discovery. Despite being post-mitotic (cells no longer dividing), post-REPOPS neurons exhibited gene expression patterns characteristic of the G2/M phase of the cell cycle of dividing cells, with histone phosphorylation, nuclear layer disruption, and chromatin condensation characteristic of the nuclear hallmarks of mitosis. These molecular and structural changes suggested nuclear reprogramming. Using genome editing techniques, the researchers demonstrated that mice lacking cyclin B, a key molecular regulator of the G2/M phase transition, had less nuclear reprogramming and behavioral changes, which they identified as drivers of cellular state. It is caused by stimulation of nerve cells.
Intermediate state with increased plasticity
The researchers then asked how nuclear reprogramming affected neuron function. They used microscopic images of calcium flux, a proxy for neural activity in behaving mice. Interestingly, REPOPS did more than simply turn neuron activity on or off. Instead, patterned changes occurred in how neurons encoded different types of information, suppressing spatial encoding and enhancing speed-related encoding, which persisted for more than two weeks.
Taken together, these molecular, nuclear structural, and functional findings led the researchers to propose that the mature cell state induced by ECT-like stimuli represents neither a normal mature state nor a completely immature state, but a highly plastic “intermediate state” whose specific configuration may depend on how strong, how often, and under what conditions neuronal activity is applied. The plasticity that underpins therapeutic efficacy in depression may instead contribute to pathology under various conditions such as epilepsy and neurodegeneration.
Nuclear reprogramming, the ability of neurons to fundamentally reshape their identity, is a potential mechanism that we have not previously considered. These findings provide a new cellular framework for thinking about how durable changes in neural function occur and provide potential avenues for improved treatments. ”
Prof. Tsuyoshi Miyakawa, Fujita Health University
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Reference magazines:
Tetsuya Murano others. (2026). Repetitive neuronal activation modulates cell maturation state through nuclear reprogramming. nature communications. DOI: 10.1038/s41467-026-74202-w. https://www.nature.com/articles/s41467-026-74202-w
