Belgin Yalcin

All Publications

• 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

• Opioid drugs drive electrical insulation of reward circuitry NATURE Yalcin, B., Monje, M. 2024

  View details for DOI 10.1038/d41586-024-01630-3

  View details for Web of Science ID 001262421300018

  View details for PubMedID 38840006

• Nf1 mutation disrupts activity-dependent oligodendroglial plasticity and motor learning in mice. Nature neuroscience Pan, Y., Hysinger, J. D., Yalçın, B., Lennon, J. J., Byun, Y. G., Raghavan, P., Schindler, N. F., Anastasaki, C., Chatterjee, J., Ni, L., Xu, H., Malacon, K., Jahan, S. M., Ivec, A. E., Aghoghovwia, B. E., Mount, C. W., Nagaraja, S., Scheaffer, S., Attardi, L. D., Gutmann, D. H., Monje, M. 2024

  Abstract

  Neurogenetic disorders, such as neurofibromatosis type 1 (NF1), can cause cognitive and motor impairments, traditionally attributed to intrinsic neuronal defects such as disruption of synaptic function. Activity-regulated oligodendroglial plasticity also contributes to cognitive and motor functions by tuning neural circuit dynamics. However, the relevance of oligodendroglial plasticity to neurological dysfunction in NF1 is unclear. Here we explore the contribution of oligodendrocyte progenitor cells (OPCs) to pathological features of the NF1 syndrome in mice. Both male and female littermates (4-24 weeks of age) were used equally in this study. We demonstrate that mice with global or OPC-specific Nf1 heterozygosity exhibit defects in activity-dependent oligodendrogenesis and harbor focal OPC hyperdensities with disrupted homeostatic OPC territorial boundaries. These OPC hyperdensities develop in a cell-intrinsic Nf1 mutation-specific manner due to differential PI3K/AKT activation. OPC-specific Nf1 loss impairs oligodendroglial differentiation and abrogates the normal oligodendroglial response to neuronal activity, leading to impaired motor learning performance. Collectively, these findings show that Nf1 mutation delays oligodendroglial development and disrupts activity-dependent OPC function essential for normal motor learning in mice.

  View details for DOI 10.1038/s41593-024-01654-y

  View details for PubMedID 38816530

  View details for PubMedCentralID 3842597

• Glioma synapses recruit mechanisms of adaptive plasticity. Nature Taylor, K. R., Barron, T., Hui, A., Spitzer, A., Yalcin, B., Ivec, A. E., Geraghty, A. C., Hartmann, G. G., Arzt, M., Gillespie, S. M., Kim, Y. S., Maleki Jahan, S., Zhang, H., Shamardani, K., Su, M., Ni, L., Du, P. P., Woo, P. J., Silva-Torres, A., Venkatesh, H. S., Mancusi, R., Ponnuswami, A., Mulinyawe, S., Keough, M. B., Chau, I., Aziz-Bose, R., Tirosh, I., Suva, M. L., Monje, M. 2023

  Abstract

  The role of the nervous system in the regulation of cancer is increasingly appreciated. In gliomas, neuronal activity drives tumour progression through paracrine signalling factors such as neuroligin-3 and brain-derived neurotrophic factor1-3 (BDNF), and also through electrophysiologically functional neuron-to-glioma synapses mediated by AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors4,5. The consequent glioma cell membrane depolarization drives tumour proliferation4,6. In the healthy brain, activity-regulated secretion of BDNF promotes adaptive plasticity of synaptic connectivity7,8 and strength9-15. Here we show that malignant synapses exhibit similar plasticity regulated by BDNF. Signalling through the receptor tropomyosin-related kinase B16 (TrkB) to CAMKII, BDNF promotes AMPA receptor trafficking to the glioma cell membrane, resulting in increased amplitude of glutamate-evoked currents in the malignant cells. Linking plasticity of glioma synaptic strength to tumour growth, graded optogenetic control of glioma membrane potential demonstrates that greater depolarizing current amplitude promotes increased glioma proliferation. This potentiation of malignant synaptic strength shares mechanistic features with synaptic plasticity17-22 that contributes to memory and learning in the healthy brain23-26. BDNF-TrkB signalling also regulates the number of neuron-to-glioma synapses. Abrogation of activity-regulated BDNF secretion from the brain microenvironment or loss of glioma TrkB expression robustly inhibits tumour progression. Blocking TrkB genetically or pharmacologically abrogates these effects of BDNF on glioma synapses and substantially prolongs survival in xenograft models of paediatric glioblastoma and diffuse intrinsic pontine glioma. Together, these findings indicate that BDNF-TrkB signalling promotes malignant synaptic plasticity and augments tumour progression.

  View details for DOI 10.1038/s41586-023-06678-1

  View details for PubMedID 37914930

• NF1 MUTATION IN OLIGODENDROCYTE PRECURSOR CELLS INDUCES PRENEOPLASTIC LESIONS IN THE BRAIN Pan, Y., Hysinger, J., Yalcin, B., Lennon, J., Raghavan, P., Schindler, N., Anastasaki, C., Chatterjee, J., Mount, C., Nagaraja, S., Scheaffer, S., Attardi, L., Gutmann, D., Monje, M. OXFORD UNIV PRESS INC. 2023

  View details for Web of Science ID 001115245401369

• BMAL1 loss in oligodendroglia contributes to abnormal myelination and sleep. Neuron Rojo, D., Dal Cengio, L., Badner, A., Kim, S., Sakai, N., Greene, J., Dierckx, T., Mehl, L. C., Eisinger, E., Ransom, J., Arellano-Garcia, C., Gumma, M. E., Soyk, R. L., Lewis, C. M., Lam, M., Weigel, M. K., Damonte, V. M., Yalçın, B., Jones, S. E., Ollila, H. M., Nishino, S., Gibson, E. M. 2023

  Abstract

  Myelination depends on the maintenance of oligodendrocytes that arise from oligodendrocyte precursor cells (OPCs). We show that OPC-specific proliferation, morphology, and BMAL1 are time-of-day dependent. Knockout of Bmal1 in mouse OPCs during development disrupts the expression of genes associated with circadian rhythms, proliferation, density, morphology, and migration, leading to changes in OPC dynamics in a spatiotemporal manner. Furthermore, these deficits translate into thinner myelin, dysregulated cognitive and motor functions, and sleep fragmentation. OPC-specific Bmal1 loss in adulthood does not alter OPC density at baseline but impairs the remyelination of a demyelinated lesion driven by changes in OPC morphology and migration. Lastly, we show that sleep fragmentation is associated with increased prevalence of the demyelinating disorder multiple sclerosis (MS), suggesting a link between MS and sleep that requires further investigation. These findings have broad mechanistic and therapeutic implications for brain disorders that include both myelin and sleep phenotypes.

  View details for DOI 10.1016/j.neuron.2023.08.002

  View details for PubMedID 37657440

• GABAERGIC NEURON-TO-GLIOMA SYNAPSES IN DIFFUSE MIDLINE GLIOMAS Barron, T., Yalcin, B., Mochizuki, A., Cantor, E., Shamardani, K., Tlais, D., Franson, A., Lyons, S., Mehta, V., Jahan, S., Taylor, K., Keough, M., Xu, H., Su, M., Quezada, M., Woo, P., Fisher, P., Campen, C., Partap, S., Koschmann, C., Monje, M. OXFORD UNIV PRESS INC. 2023

  View details for DOI 10.1093/neuonc/noad073.044

  View details for Web of Science ID 001023504300045

• Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation. Cell Fernández-Castañeda, A., Lu, P., Geraghty, A. C., Song, E., Lee, M. H., Wood, J., O'Dea, M. R., Dutton, S., Shamardani, K., Nwangwu, K., Mancusi, R., Yalçın, B., Taylor, K. R., Acosta-Alvarez, L., Malacon, K., Keough, M. B., Ni, L., Woo, P. J., Contreras-Esquivel, D., Toland, A. M., Gehlhausen, J. R., Klein, J., Takahashi, T., Silva, J., Israelow, B., Lucas, C., Mao, T., Peña-Hernández, M. A., Tabachnikova, A., Homer, R. J., Tabacof, L., Tosto-Mancuso, J., Breyman, E., Kontorovich, A., McCarthy, D., Quezado, M., Vogel, H., Hefti, M. M., Perl, D. P., Liddelow, S., Folkerth, R., Putrino, D., Nath, A., Iwasaki, A., Monje, M. 2022

  Abstract

  COVID survivors frequently experience lingering neurological symptoms that resemble cancer-therapy-related cognitive impairment, a syndrome for which white matter microglial reactivity and consequent neural dysregulation is central. Here, we explored the neurobiological effects of respiratory SARS-CoV-2 infection and found white-matter-selective microglial reactivity in mice and humans. Following mild respiratory COVID in mice, persistently impaired hippocampal neurogenesis, decreased oligodendrocytes, and myelin loss were evident together with elevated CSF cytokines/chemokines including CCL11. Systemic CCL11 administration specifically caused hippocampal microglial reactivity and impaired neurogenesis. Concordantly, humans with lasting cognitive symptoms post-COVID exhibit elevated CCL11 levels. Compared with SARS-CoV-2, mild respiratory influenza in mice caused similar patterns of white-matter-selective microglial reactivity, oligodendrocyte loss, impaired neurogenesis, and elevated CCL11 at early time points, but after influenza, only elevated CCL11 and hippocampal pathology persisted. These findings illustrate similar neuropathophysiology after cancer therapy and respiratory SARS-CoV-2 infection which may contribute to cognitive impairment following even mild COVID.

  View details for DOI 10.1016/j.cell.2022.06.008

  View details for PubMedID 35768006

• NF1 mutation drives neuronalactivity-dependent initiation of optic glioma. Nature Pan, Y., Hysinger, J. D., Barron, T., Schindler, N. F., Cobb, O., Guo, X., Yalcin, B., Anastasaki, C., Mulinyawe, S. B., Ponnuswami, A., Scheaffer, S., Ma, Y., Chang, K., Xia, X., Toonen, J. A., Lennon, J. J., Gibson, E. M., Huguenard, J. R., Liau, L. M., Goldberg, J. L., Monje, M., Gutmann, D. H. 2021

  Abstract

  Neurons have recently emerged as essential cellular constituents of the tumour microenvironment, and their activity has been shown to increase the growth of a diverse number of solid tumours1. Although the role of neurons in tumour progression has previously been demonstrated2, the importance of neuronal activity to tumour initiation is less clear-particularly in the setting of cancer predisposition syndromes. Fifteen per cent of individuals with theneurofibromatosis1 (NF1) cancer predisposition syndrome (in which tumours arise in close association with nerves) develop low-grade neoplasms of the optic pathway (known as optic pathway gliomas (OPGs)) during early childhood3,4, raising the possibility that postnatal light-induced activity of the optic nerve drives tumour initiation. Here we use an authenticated mouse model of OPG driven by mutations in the neurofibromatosis1 tumour suppressor gene (Nf1)5 to demonstrate that stimulation of optic nerve activity increases optic glioma growth, and that decreasing visual experience via light deprivation prevents tumour formation and maintenance. We show that the initiation of Nf1-driven OPGs (Nf1-OPGs) depends on visual experience during a developmental period in which Nf1-mutant mice are susceptible to tumorigenesis. Germline Nf1 mutation in retinal neurons results in aberrantly increased shedding of neuroligin3 (NLGN3) within the optic nerve in response to retinal neuronal activity. Moreover, genetic Nlgn3 loss or pharmacological inhibition of NLGN3 shedding blocks the formation and progression of Nf1-OPGs. Collectively, our studies establish an obligate role for neuronal activity in the development of some types of brain tumours, elucidate a therapeutic strategy to reduce OPG incidence or mitigate tumour progression, and underscore the role of Nf1mutation-mediated dysregulation of neuronal signalling pathways in mouse models of the NF1 cancer predisposition syndrome.

  View details for DOI 10.1038/s41586-021-03580-6

  View details for PubMedID 34040258

• Microenvironmental interactions of oligodendroglial cells. Developmental cell Yalçın, B., Monje, M. 2021

  Abstract

  Developmental myelination is a protracted process that extends well into postnatal life. Cell-intrinsic mechanisms operate in myelin-forming oligodendrocytes, as well as microenvironmental interactions that guide and modulate every aspect of myelination, from oligodendrocyte precursor cell migration to oligodendrocyte differentiation and the formation of stable myelin internodes. During development and throughout adult life, neuron-oligodendroglial interactions shape activity and experience-dependent myelin adaptations to fine-tune neural circuit dynamics and promote healthy neurological function.

  View details for DOI 10.1016/j.devcel.2021.06.006

  View details for PubMedID 34192527

• How Support of Early Career Researchers Can Reset Science in the Post-COVID19 World. Cell Gibson, E. M., Bennett, F. C., Gillespie, S. M., Guler, A. D., Gutmann, D. H., Halpern, C. H., Kucenas, S. C., Kushida, C. A., Lemieux, M., Liddelow, S., Macauley, S. L., Li, Q., Quinn, M. A., Roberts, L. W., Saligrama, N., Taylor, K. R., Venkatesh, H. S., Yalcin, B., Zuchero, J. B. 2020

  Abstract

  The COVID19 crisis has magnified the issues plaguing academic science, but it has also provided the scientific establishment with an unprecedented opportunity to reset. Shoring up the foundation of academic science will require a concerted effort between funding agencies, universities, and the public to rethink how we support scientists, with a special emphasis on early career researchers.

  View details for DOI 10.1016/j.cell.2020.05.045

  View details for PubMedID 32533917

• Bespoke myelin tailored to neuron type. Science (New York, N.Y.) Yalçın, B. n., Monje, M. n. 2020; 370 (6523): 1414–15

  View details for DOI 10.1126/science.abf4646

  View details for PubMedID 33335053

• Monosynaptic tracing maps brain-wide afferent oligodendrocyte precursor cell connectivity. eLife Mount, C. W., Yalcin, B., Cunliffe-Koehler, K., Sundaresh, S., Monje, M. 2019; 8

  Abstract

  Neurons form bona fide synapses with oligodendrocyte precursor cells (OPCs), but the circuit context of these neuron to OPC synapses remains incompletely understood. Using monosynaptically-restricted rabies virus tracing of OPC afferents, we identified extensive afferent synaptic inputs to OPCs residing in secondary motor cortex, corpus callosum, and primary somatosensory cortex of adult mice. These inputs primarily arise from functionally-interconnecting cortical areas and thalamic nuclei, illustrating that OPCs have strikingly comprehensive synaptic access to brain-wide projection networks. Quantification of these inputs revealed excitatory and inhibitory components that are consistent in number across brain regions and stable in barrel cortex despite whisker trimming-induced sensory deprivation.

  View details for DOI 10.7554/eLife.49291

  View details for PubMedID 31625910

• Modeling of axonal endoplasmic reticulum network by spastic paraplegia proteins ELIFE Yalcin, B., Zhao, L., Stofanko, M., O'Sullivan, N. C., Kang, Z., Roost, A., Thomas, M. R., Zaessinger, S., Blard, O., Patto, A. L., Sohail, A., Baena, V., Terasaki, M., O'Kane, C. J. 2017; 6

  Abstract

  Axons contain a smooth tubular endoplasmic reticulum (ER) network that is thought to be continuous with ER throughout the neuron; the mechanisms that form this axonal network are unknown. Mutations affecting reticulon or REEP proteins, with intramembrane hairpin domains that model ER membranes, cause an axon degenerative disease, hereditary spastic paraplegia (HSP). We show that Drosophila axons have a dynamic axonal ER network, which these proteins help to model. Loss of HSP hairpin proteins causes ER sheet expansion, partial loss of ER from distal motor axons, and occasional discontinuities in axonal ER. Ultrastructural analysis reveals an extensive ER network in axons, which shows larger and fewer tubules in larvae that lack reticulon and REEP proteins, consistent with loss of membrane curvature. Therefore HSP hairpin-containing proteins are required for shaping and continuity of axonal ER, thus suggesting roles for ER modeling in axon maintenance and function.

  View details for DOI 10.7554/eLife.23882

  View details for Web of Science ID 000408627900001

  View details for PubMedID 28742022

  View details for PubMedCentralID PMC5576921