Activation of neurons triggers plastic changes in neural circuits that are essential for brain development, learning and memory, but overactivation can lead to pathological alterations. Here, we show that repeated neural activation induces long-term changes in the nuclear structure of neurons, persisting for two weeks. These alterations involve the disruption of nuclear lamina and epigenetic changes, which partially resemble the G2-M phase in cycling cells, accompanied by alterations in the transcriptome, chromatin accessibility, neural coding of information, and locomotor activity in mice. These cell cycle-like changes and hyper-locomotor activity were mitigated by in vivo gene knockout of cyclin B, a molecule essential for G2-M phase transition. Our results demonstrate that subchronic neural activation reinstates a cell cycle-like process, leading to chronic changes in neuronal function and abnormal behavior. Our findings provide novel insights into activity-dependent plastic changes in neuronal circuits, which may be relevant to the pathogenesis of neuropsychiatric disorders.
Tomoyuki Murano, Hideo Hagihara, Katsunori Tajinda, Keizo Takao, Yoshihiro Takamiya, Kaoru Katoh, Alfred J Robison, Mitsuyuki Matsumoto, Masakazu Namihira, Tsuyoshi Miyakawa (2026) Repetitive neuronal activation regulates cellular maturation state via nuclear reprogramming., Nature communications, Volume 17, Number 1
Published in July 17, 2026 (Electronic publication in July 17, 2026, midnight )
(Abstract) Neural stimulation, such as electroconvulsive therapy (ECT) and repetitive transcranial magnetic stimulation (rTMS), is highly effective clinical intervention for a broad spectrum of psychiatric disorders, including depression and schizophrenia. However, their mechanism of action at the cellular level remains poorly understood. Here, we model ECT with repeated optogenetic neuronal stimulation in the mouse dentate gyrus, and observe ECT-relevant behavioral changes, including decreased depression-like behavior and increased locomotor activity. At the cellular level, we identify dematuration to a long-term stable state, persisting for more than one month, defined by changes in nuclear structure, gene expression patterns resembling the G(2)/M phase of the cell cycle, and altered neural coding of navigational information. Moreover, knockout of the G(2)/M master regulator Cyclin B attenuates some of behavioral and cellular effects. These findings demonstrate that chronically-repeated brain stimulation triggers plasticity of the cellular state, revealing a form of stimulus-regulated nuclear reprogramming with potential clinical utility.(MeSH Terms)