斯坦福大学Michelle Monje团队宣布他们的论文报道了胆碱能神经元活动通过毒蕈碱信号传导促进弥漫性中线胶质瘤生长。该项研究成果发表在2025年6月19日出版的《细胞》上。
该研究团队证明了中脑胆碱能神经元活动以回路依赖的方式调节OPC和DMG的增殖。光遗传刺激胆碱能桥脑桥脚核（PPN）促进脑桥胶质瘤的生长，而刺激外侧背被核（LDT）促进丘脑的增殖。在疾病期间，携带DMG的小鼠表现出更高的乙酰胆碱释放和增加的胆碱能神经元活动。共培养时，胆碱能神经元促进DMG细胞增殖，乙酰胆碱直接作用于DMG细胞。单细胞RNA测序显示，原代DMG样品中CHRM1和CHRM3高表达。药理或遗传阻断M1/M3受体可消除胆碱能活性驱动的DMG增殖。综上所述，这些研究结果表明，中脑胆碱能远程投射促进活动依赖性DMG生长，反映了健康OPCs的平行增殖效应。
据了解，谷氨酸能神经元活动促进少突胶质前体细胞（OPCs）和胶质瘤的增殖，包括扩散主题中线胶质瘤（DMG）。然而，神经调节性脑干神经元投射到DMG产生的中线结构的作用仍未被探索。
附：英文原文
Title: Cholinergic neuronal activity promotes diffuse midline glioma growth through muscarinic signaling
Author: Richard Drexler, Antonia Drinnenberg, Avishai Gavish, Belgin Yalin, Kiarash Shamardani, Abigail E. Rogers, Rebecca Mancusi, Vrunda Trivedi, Kathryn R. Taylor, Yoon Seok Kim, Pamelyn J. Woo, Neeraj Soni, Minhui Su, Alexandre Ravel, Eva Tatlock, Alexandra Midler, Samuel H. Wu, Charu Ramakrishnan, Ritchie Chen, Alberto E. Ayala-Sarmiento, David Rincon Fernandez Pacheco, LaAkea Siverts, Tanya L. Daigle, Bosiljka Tasic, Hongkui Zeng, Joshua J. Breunig, Karl Deisseroth, Michelle Monje
Issue&Volume: 2025-06-19
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.
DOI: 10.1016/j.cell.2025.05.031
Source: https://www.cell.com/cell/abstract/S0092-8674(25)00618-X