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  • BRAINSTEM NEUROMODULATORY NEURONS PROMOTE GLIOMA GROWTH LOCALLY AND VIA LONG-RANGE PROJECTIONS TO MIDLINE AND CORTICAL STRUCTURES Drexler, R., Drinnenberg, A., Gavish, A., Yalcin, B., Shamardani, K., Rogers, A., Mancusi, R., Taylor, K., Kim, Y., Woo, P., Ravel, A., Tatlock, E., Jokhai, R., Ayala-Sarmiento, A., Rincon-Fernandez, D., Ramakrishnan, C., Siverts, L., Daigle, T., Tasic, B., Zeng, H., Breunig, J., Loh, K., Deisseroth, K., Monje, M. OXFORD UNIV PRESS INC. 2024

    View details for DOI 10.1093/neuonc/noae165.0184

    View details for Web of Science ID 001362572400045

  • Cholinergic Neuronal Activity Promotes Diffuse Midline Glioma Growth through Muscarinic Signaling. bioRxiv : the preprint server for biology Drexler, R., Drinnenberg, A., Gavish, A., Yalcin, B., Shamardani, K., Rogers, A., Mancusi, R., Taylor, K. R., Kim, Y. S., Woo, P. J., Ravel, A., Tatlock, E., Ramakrishnan, C., Ayala-Sarmiento, A. E., Pacheco, D. R., Siverts, L., Daigle, T. L., Tasic, B., Zeng, H., Breunig, J. J., Deisseroth, K., Monje, M. 2024

    Abstract

    Neuronal activity promotes the proliferation of healthy oligodendrocyte precursor cells (OPC) and their malignant counterparts, gliomas. Many gliomas arise from and closely resemble oligodendroglial lineage precursors, including diffuse midline glioma (DMG), a cancer affecting midline structures such as the thalamus, brainstem and spinal cord. In DMG, glutamatergic and GABAergic neuronal activity promotes progression through both paracrine signaling and through bona-fide neuron-to-glioma synapses. However, the putative roles of other neuronal subpopulations - especially neuromodulatory neurons located in the brainstem that project to long-range target sites in midline anatomical locations where DMGs arise - remain largely unexplored. Here, we demonstrate that the activity of cholinergic midbrain neurons modulates both healthy OPC and malignant DMG proliferation in a circuit-specific manner at sites of long-range cholinergic projections. Optogenetic stimulation of the cholinergic pedunculopontine nucleus (PPN) promotes glioma growth in pons, while stimulation of the laterodorsal tegmentum nucleus (LDT) facilitates proliferation in thalamus, consistent with the predominant projection patterns of each cholinergic midbrain nucleus. Reciprocal signaling was evident, as increased activity of cholinergic neurons in the PPN and LDT was observed in pontine DMG-bearing mice. In co-culture, hiPSC-derived cholinergic neurons form neuron-to-glioma networks with DMG cells and robustly promote proliferation. Single-cell RNA sequencing analyses revealed prominent expression of the muscarinic receptor genes CHRM1 and CHRM3 in primary patient DMG samples, particularly enriched in the OPC-like tumor subpopulation. Acetylcholine, the neurotransmitter cholinergic neurons release, exerts a direct effect on DMG tumor cells, promoting increased proliferation and invasion through muscarinic receptors. Pharmacological blockade of M1 and M3 acetylcholine receptors abolished the activity-regulated increase in DMG proliferation in cholinergic neuron-glioma co-culture and in vivo. Taken together, these findings demonstrate that midbrain cholinergic neuron long-range projections to midline structures promote activity-dependent DMG growth through M1 and M3 cholinergic receptors, mirroring a parallel proliferative effect on healthy OPCs.

    View details for DOI 10.1101/2024.09.21.614235

    View details for PubMedID 39386427

    View details for PubMedCentralID PMC11463519

  • Myelin plasticity in the ventral tegmental area is required for opioid reward. Nature Yalçın, B., Pomrenze, M. B., Malacon, K., Drexler, R., Rogers, A. E., Shamardani, K., Chau, I. J., Taylor, K. R., Ni, L., Contreras-Esquivel, D., Malenka, R. C., Monje, M. 2024

    Abstract

    All drugs of abuse induce long-lasting changes in synaptic transmission and neural circuit function that underlie substance-use disorders1,2. Another recently appreciated mechanism of neural circuit plasticity is mediated through activity-regulated changes in myelin that can tune circuit function and influence cognitive behaviour3-7. Here we explore the role of myelin plasticity in dopaminergic circuitry and reward learning. We demonstrate that dopaminergic neuronal activity-regulated myelin plasticity is a key modulator of dopaminergic circuit function and opioid reward. Oligodendroglial lineage cells respond to dopaminergic neuronal activity evoked by optogenetic stimulation of dopaminergic neurons, optogenetic inhibition of GABAergic neurons, or administration of morphine. These oligodendroglial changes are evident selectively within the ventral tegmental area but not along the axonal projections in the medial forebrain bundle nor within the target nucleus accumbens. Genetic blockade of oligodendrogenesis dampens dopamine release dynamics in nucleus accumbens and impairs behavioural conditioning to morphine. Taken together, these findings underscore a critical role for oligodendrogenesis in reward learning and identify dopaminergic neuronal activity-regulated myelin plasticity as an important circuit modification that is required for opioid reward.

    View details for DOI 10.1038/s41586-024-07525-7

    View details for PubMedID 38839962

    View details for PubMedCentralID 4096908