Repetitive neuronal activation regulates cellular maturation state via nuclear reprogramming
Abstract Neural stimulation, such as electroconvulsive therapy (ECT) and repetitive transcranial magnetic stimulation (rTMS), are highly effective clinical interventions 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 modelled ECT with repeated optogenetic neuronal stimulation in the mouse dentate gyrus, and observed ECT-like behavioral effects, including decreased depression-like behavior and increased locomotor activity. At the cellular level, we found 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 rescued some of behavioral and cellular effects. These findings demonstrate that ECT-like brain stimulation triggers plasticity of the cellular state, revealing a form of stimulus-regulated nuclear reprogramming with potential clinical utility.
Authors
- Yoshihiro Takamiya
- Masakazu Namihira (ORCID: https://orcid.org/0000-0003-2108-5712)
- Alfred J. Robison (ORCID: https://orcid.org/0000-0002-4150-9570)
- Kaoru Katoh (ORCID: https://orcid.org/0000-0001-6590-413X)
- Tomoyuki Murano (ORCID: https://orcid.org/0000-0002-9351-737X)
- Hideo Hagihara (ORCID: https://orcid.org/0000-0001-9602-9518)
- Katsunori Tajinda (ORCID: https://orcid.org/0000-0002-3516-7957)
- Keizo Takao (ORCID: https://orcid.org/0000-0002-4734-3583)
- Mitsuyuki Matsumoto (ORCID: https://orcid.org/0000-0002-1172-2354)
- Tsuyoshi Miyakawa (ORCID: https://orcid.org/0000-0003-0137-8200)
Institutions
- Fujita Health University (JP)
- University of Tsukuba (JP)
- National Institutes of Natural Sciences (JP)
- National Institute of Infectious Diseases (JP)
- Therapeutics Clinical Research (US)
- Astellas Pharma (United States) (US)
- University of Toyama (JP)
- National Institute of Advanced Industrial Science and Technology (JP)
- Nara Institute of Science and Technology (JP)
- Michigan State University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-07-17
- DOI
- https://doi.org/10.1038/s41467-026-74202-w
- Citations
- 1
- Primary Topic
- Pluripotent Stem Cells Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Japan Agency for Medical Research and Development
- Japan Society for the Promotion of Science