Researchers announced on July 17 that a patterned brain stimulation technique in mice, designed to mimic features of electroconvulsive therapy (ECT), can trigger unexpected nuclear reprogramming in mature neurons. The study introduced REPOPS, a form of patterned neuronal activation, and observed increased locomotor activity and reduced depression-like behavior in mice subjected to the procedure.
At the cellular level, REPOPS induced a state described as 'cellular dematuration,' where adult neurons exhibited gene expression patterns similar to those seen during early postnatal development. Short-term stimulation caused only transient changes, but ten days of stimulation led to a stable dematuration state that persisted for over a month. Genome-wide chromatin mapping revealed persistent changes in chromatin accessibility, supporting the durability of this altered state.
A gene expression analysis showed that even though these neurons were post-mitotic and typically do not divide, they displayed gene expression characteristic of dividing cells' G2/M phase. This was accompanied by nuclear hallmarks such as histone phosphorylation, disruption of the nuclear lamina, and chromatin condensation—features associated with mitosis. Using genome-editing technology, researchers demonstrated that mice lacking Cyclin B—a key regulator of the G2/M phase transition—showed less nuclear reprogramming and behavioral change following REPOPS.
Further investigation using microscopic imaging revealed that REPOPS did not simply increase or decrease neuronal activity but instead shifted how neurons encoded information: spatial coding was suppressed while speed-related coding was enhanced for more than two weeks after treatment.
The researchers concluded that ECT-like neuronal stimulation induces an 'intermediate state' characterized by high plasticity—neither fully mature nor immature—where its specific configuration may depend on various factors such as intensity and duration of neuronal activity. They suggested this plasticity could support therapeutic effects in depression but might also contribute to pathology under conditions like epilepsy or neurodegeneration.
