Cholinergic neuronal activity promotes diffuse midline glioma growth through muscarinic signaling
Glutamatergic neuronal activity promotes proliferation of both oligodendrocyte precursor cells (OPCs) and gliomas, including diffuse midline glioma (DMG). However, the role of neuromodulatory brainstem neurons projecting to midline structures where DMGs arise remains unexplored. Here, we demonstrate that midbrain cholinergic neuronal activity modulates OPC and DMG proliferation in a circuit-dependent manner. Optogenetic stimulation of the cholinergic pedunculopontine nucleus (PPN) promotes glioma growth in pons, while stimulation of the laterodorsal tegmentum nucleus (LDT) drives proliferation in thalamus. DMG-bearing mice exhibit higher acetylcholine release and increased cholinergic neuronal activity over the disease course. In co-culture, cholinergic neurons enhance DMG proliferation, and acetylcholine directly acts on DMG cells. Single-cell RNA sequencing revealed high CHRM1 and CHRM3 expression in primary DMG samples. Pharmacological or genetic blockade of M1/M3 receptors abolished cholinergic activity-driven DMG proliferation. Taken together, these findings demonstrate that midbrain cholinergic long-range projections promote activity-dependent DMG growth, mirroring a parallel proliferative effect on healthy OPCs.
Authors
- Alberto E. Ayala‐Sarmiento (ORCID: https://orcid.org/0000-0002-0843-6111)
- Kathryn R. Taylor (ORCID: https://orcid.org/0000-0002-5110-8703)
- Belgin Yalçın (ORCID: https://orcid.org/0000-0001-9689-9062)
- Hongkui Zeng (ORCID: https://orcid.org/0000-0002-0326-5878)
- Joshua J. Breunig (ORCID: https://orcid.org/0000-0002-3735-3390)
- Rebecca Mancusi (ORCID: https://orcid.org/0000-0002-4809-5569)
- Michelle Monje (ORCID: https://orcid.org/0000-0002-3547-237X)
- Karl Deisseroth
- Tanya L. Daigle (ORCID: https://orcid.org/0000-0001-9700-8452)
- Vrunda Trivedi (ORCID: https://orcid.org/0000-0001-9781-4761)
- Avishai Gavish (ORCID: https://orcid.org/0000-0002-0359-6642)
- Neeraj Soni (ORCID: https://orcid.org/0000-0002-4191-6723)
- Pamelyn J. Woo (ORCID: https://orcid.org/0009-0008-7509-8061)
- David Rincon Fernandez Pacheco (ORCID: https://orcid.org/0000-0002-6998-4920)
- Abigail Rogers (ORCID: https://orcid.org/0000-0002-2309-3903)
- Ritchie Chen (ORCID: https://orcid.org/0000-0001-5985-8843)
- Antonia Drinnenberg (ORCID: https://orcid.org/0000-0002-8177-9735)
- Minhui Su (ORCID: https://orcid.org/0000-0001-5803-6098)
- Kiarash Shamardani (ORCID: https://orcid.org/0000-0002-2548-705X)
- La’Akea Siverts (ORCID: https://orcid.org/0000-0002-6861-4506)
- Richard Drexler (ORCID: https://orcid.org/0000-0002-4830-3671)
- Samuel H. Wu
- Yoon Seok Kim (ORCID: https://orcid.org/0000-0002-2209-2968)
- Charu Ramakrishnan
- Eva Tatlock
- Alexandre Ravel
- Bosiljka Tasic
- Alexandra Midler
Institutions
- Cedars-Sinai Medical Center (US)
- Allen Institute for Brain Science (US)
- Howard Hughes Medical Institute (US)
- Stanford Medicine (US)
- Allen Institute (US)
- Stanford University (US)
Publication Details
- Journal
- Cell
- Published
- 2025-06-19
- DOI
- https://doi.org/10.1016/j.cell.2025.05.031
- Citations
- 25
- Primary Topic
- Neurogenesis and neuroplasticity mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 32.96
Funders
- Cancer Research UK
- National Cancer Institute