Cholinergic neuronal activity promotes diffuse midline glioma growth through muscarinic signaling

Cell 2025 30 cites
2025:72026:23
2025 2026
30

Drexler, Richard and Drinnenberg, Antonia and Gavish, Avishai and Yalcin, Belgin and Shamardani, Kiarash and Rogers, Abigail E and Mancusi, Rebecca and Trivedi, Vrunda and Taylor, Kathryn R and Kim, Yoon Seok and Woo, Pamelyn J and Soni, Neeraj and Su, Minhui and Ravel, Alexandre and Tatlock, Eva and Midler, Alexandra and Wu, Samuel H and Ramakrishnan, Charu and Chen, Ritchie and AyalaSarmiento, Alberto E and Fernandez Pacheco, David Rincon and Siverts, LaAkea and Daigle, Tanya L and Tasic, Bosiljka and Zeng, Hongkui and Breunig, Joshua J and Deisseroth, Karl and Monje, Michelle

Abstract

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.

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