Kiarash Shamardani

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

• Immunotherapy-related cognitive impairment after CAR T cell therapy in mice. bioRxiv : the preprint server for biology Geraghty, A. C., Acosta-Alvarez, L., Rotiroti, M., Dutton, S., O'Dea, M. R., Woo, P. J., Xu, H., Shamardani, K., Mancusi, R., Ni, L., Mulinyawe, S. B., Kim, W. J., Liddelow, S. A., Majzner, R. G., Monje, M. 2024

  Abstract

  Persistent central nervous system (CNS) immune dysregulation and consequent dysfunction of multiple neural cell types is central to the neurobiological underpinnings of a cognitive impairment syndrome that can occur following traditional cancer therapies or certain infections. Immunotherapies have revolutionized cancer care for many tumor types, but the potential long-term cognitive sequelae are incompletely understood. Here, we demonstrate in mouse models that chimeric antigen receptor (CAR) T cell therapy for both CNS and non-CNS cancers can impair cognitive function and induce a persistent CNS immune response characterized by white matter microglial reactivity and elevated cerebrospinal fluid (CSF) cytokines and chemokines. Consequently, oligodendroglial homeostasis and hippocampal neurogenesis are disrupted. Microglial depletion rescues oligodendroglial deficits and cognitive performance in a behavioral test of attention and short-term memory function. Taken together, these findings illustrate similar mechanisms underlying immunotherapy-related cognitive impairment (IRCI) and cognitive impairment following traditional cancer therapies and other immune challenges.

  View details for DOI 10.1101/2024.05.14.594163

  View details for PubMedID 38798554

  View details for PubMedCentralID PMC11118392

• Training the next generation of community-engaged physicians: a mixed-methods evaluation of a novel course for medical service learning in the COVID-19 era. BMC medical education Scala, J. J., Cha, H., Shamardani, K., Rashes, E. R., Acosta-Alvarez, L., Mediratta, R. P. 2024; 24 (1): 426

  Abstract

  Medical school curricula strive to train community-engaged and culturally competent physicians, and many use service learning to instill these values in students. The current standards for medical service learning frameworks have opportunities for improvement, such as encouraging students to have more sustainable and reciprocal impact and to ingrain service learning as a value to carry throughout their careers rather than a one-time experience. PEDS 220: A COVID-19 Elective is a Stanford University course on the frontlines of this shift; it provides timely education on the COVID-19 pandemic, integrating community-oriented public health work to help mitigate its impact.To analyze our medical service learning curriculum, we combined qualitative and quantitative methods to understand our students' experiences. Participants completed the Course Experience Questionnaire via Qualtrics, and were invited to complete an additional interview via Zoom. Interview transcripts were analyzed using an interactive, inductive, and team-based codebook development process, where recurring themes were identified across participant interviews.We demonstrate through self-determination theory that our novel curriculum gives students valuable leadership and project management experience, awards strong academic and community-based connections, and motivates them to pursue future community-engaged work.This educational framework, revolving around students, communities, and diversity, can be used beyond the COVID-19 pandemic at other educational institutions to teach students how to solve other emergent global health problems. Using proven strategies that empower future physicians to view interdisciplinary, community-engaged work as a core pillar of their responsibility to their patients and communities ensures long-term, sustainable positive impact.N/A.

  View details for DOI 10.1186/s12909-024-05372-8

  View details for PubMedID 38649984

  View details for PubMedCentralID PMC11034080

• The logic of recurrent circuits in the primary visual cortex. Nature neuroscience Oldenburg, I. A., Hendricks, W. D., Handy, G., Shamardani, K., Bounds, H. A., Doiron, B., Adesnik, H. 2024

  Abstract

  Recurrent cortical activity sculpts visual perception by refining, amplifying or suppressing visual input. However, the rules that govern the influence of recurrent activity remain enigmatic. We used ensemble-specific two-photon optogenetics in the mouse visual cortex to isolate the impact of recurrent activity from external visual input. We found that the spatial arrangement and the visual feature preference of the stimulated ensemble and the neighboring neurons jointly determine the net effect of recurrent activity. Photoactivation of these ensembles drives suppression in all cells beyond 30 µm but uniformly drives activation in closer similarly tuned cells. In nonsimilarly tuned cells, compact, cotuned ensembles drive net suppression, while diffuse, cotuned ensembles drive activation. Computational modeling suggests that highly local recurrent excitatory connectivity and selective convergence onto inhibitory neurons explain these effects. Our findings reveal a straightforward logic in which space and feature preference of cortical ensembles determine their impact on local recurrent activity.

  View details for DOI 10.1038/s41593-023-01510-5

  View details for PubMedID 38172437

  View details for PubMedCentralID 9925090

• 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

• INVESTIGATING THE EVOLUTION OF NEURON-GLIOMA CIRCUIT DYNAMICS USING AN IN VIVO IMAGING METHOD Shamardani, K., Keough, M., Monje, M. OXFORD UNIV PRESS INC. 2023

  View details for Web of Science ID 001115245400106

• Tumors on different wavelengths. Cancer cell Shamardani, K., Monje, M. 2023

  Abstract

  Brain metastases cause cognitive impairment and impair quality of life. Sanchez-Aguilera et al. examine the effects of metastases on brain function leveraging in vivo electrocorticography and machine learning to reveal tumor model-specific changes in neural circuit dynamics and find that the electrophysiological profile predicts the presence and type of brain metastasis.

  View details for DOI 10.1016/j.ccell.2023.07.009

  View details for PubMedID 37652004

• 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

• Glioblastoma remodelling of human neural circuits decreases survival. Nature Krishna, S., Choudhury, A., Keough, M. B., Seo, K., Ni, L., Kakaizada, S., Lee, A., Aabedi, A., Popova, G., Lipkin, B., Cao, C., Nava Gonzales, C., Sudharshan, R., Egladyous, A., Almeida, N., Zhang, Y., Molinaro, A. M., Venkatesh, H. S., Daniel, A. G., Shamardani, K., Hyer, J., Chang, E. F., Findlay, A., Phillips, J. J., Nagarajan, S., Raleigh, D. R., Brang, D., Monje, M., Hervey-Jumper, S. L. 2023

  Abstract

  Gliomas synaptically integrate into neural circuits1,2. Previous research has demonstrated bidirectional interactions between neurons and glioma cells, with neuronal activity driving glioma growth1-4 and gliomas increasing neuronal excitability2,5-8. Here we sought to determine how glioma-induced neuronal changes influence neural circuits underlying cognition and whether these interactions influence patient survival. Using intracranial brain recordings during lexical retrieval language tasks in awake humans together with site-specific tumour tissue biopsies and cell biology experiments, we find that gliomas remodel functional neural circuitry such that task-relevant neural responses activate tumour-infiltrated cortex well beyond the cortical regions that are normally recruited in the healthy brain. Site-directed biopsies from regions within the tumour that exhibit high functional connectivity between the tumour and the rest of the brain are enriched for a glioblastoma subpopulation that exhibits a distinct synaptogenic and neuronotrophic phenotype. Tumour cells from functionally connected regions secrete the synaptogenic factor thrombospondin-1, which contributes to the differential neuron-glioma interactions observed in functionally connected tumour regions compared with tumour regions with less functional connectivity. Pharmacological inhibition of thrombospondin-1 using the FDA-approved drug gabapentin decreases glioblastoma proliferation. The degree of functional connectivity between glioblastoma and the normal brain negatively affects both patient survival and performance in language tasks. These data demonstrate that high-grade gliomas functionally remodel neural circuits in the human brain, which both promotes tumour progression and impairs cognition.

  View details for DOI 10.1038/s41586-023-06036-1

  View details for PubMedID 37138086

  View details for PubMedCentralID 7038898

• 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

• Applying Kern's Six Steps to the Development of a Community-Engaged, Just-in-Time, Interdisciplinary COVID-19 Curriculum. Journal of medical education and curricular development Scala, J. J., Braun, N. J., Shamardani, K., Rashes, E. R., Wang, W., Mediratta, R. P. 2022; 9: 23821205221096370

  Abstract

  Universities and medical schools often work towards operationalizing their shared mission of facilitating community-engaged work independently. Based on their experience teaching the COVID-19 Elective course at Stanford University School of Medicine, the authors proposed a novel solution for universities and medical schools to achieve an interdisciplinary collaboration within a diverse student population by creating targeted, project-based, and community-engaged courses for addressing emergent health needs. In this article, the authors discuss their curriculum, which was created using Kern's six-step approach for curriculum development, to address emergent health needs related to the novel coronavirus pandemic. The curriculum provides an opportunity for universities and medical schools to advance community health, educate students across the medical and non-medical education continuum, and foster interdisciplinary cooperation.

  View details for DOI 10.1177/23821205221096370

  View details for PubMedID 35509682

  View details for PubMedCentralID PMC9058336

• A silicon-rhodamine chemical-genetic hybrid for far red voltage imaging from defined neurons in brain slice RSC CHEMICAL BIOLOGY Ortiz, G., Liu, P., Deal, P. E., Nensel, A. K., Martinez, K. N., Shamardani, K., Adesnik, H., Miller, E. W. 2021

  View details for DOI 10.1039/d1cb00156f

  View details for Web of Science ID 000704188500001

• Covalently tethered rhodamine voltage reporters for high speed functional imaging in brain tissue. Journal of the American Chemical Society Deal, P. E., Liu, P., Al-Abdullatif, S. H., Muller, V. R., Shamardani, K., Adesnik, H., Miller, E. W. 2019

  Abstract

  Voltage-sensitive fluorophores enable the direct visualization of membrane potential changes in living systems. To pair the speed and sensitivity of chemical synthesized fluorescent indicators with cell-type specific genetic methods, we here develop Rhodamine-based Voltage Reporters (RhoVR) that can be covalently tethered to genetically-encoded, self-labeling enzymes. These chemical-genetic hybrids feature a photoinduced electron transfer (PeT) triggered RhoVR voltage-sensitive indicator coupled to a chloroalkane HaloTag ligand through a long, water-soluble polyethyleneglycol (PEG) linker (RhoVR-Halos). When applied to cells, RhoVR-Halos selectively and covalently bind to surface-expressed HaloTag enzyme on genetically modified cells. RhoVR-Halos maintain high voltage sensitivities-up to 34% ΔF/F per 100 mV-and fast response times typical of untargeted RhoVRs, while gaining the selectivity typical of genetically encodable voltage indicators. We show that RhoVR-Halos can record action potentials in single trials from cultured rat hippocampal neurons and can be used in concert with green-fluorescent Ca2+ indicators like GCaMP to provide simultaneous voltage and Ca2+ imaging. In brain slice, RhoVR-Halos provide exquisite labeling of defined cells and can be imaged using epifluorescence, confocal, or two-photon microscopy. Using high-speed epifluorescence microscopy, RhoVR-Halos provide a read out of action potentials from labeled cortical neurons in rat brain slice, without the need for trial averaging. These results demonstrate the potential of hybrid chemical-genetic voltage indicators to combine the optical performance of small-molecule chromophores with the inherent selectivity of genetically-encodable systems, permitting imaging modalities inaccessible to either technique individually.

  View details for DOI 10.1021/jacs.9b12265

  View details for PubMedID 31829585

• A Map of Toll-like Receptor Expression in the Intestinal Epithelium Reveals Distinct Spatial, Cell Type-Specific, and Temporal Patterns IMMUNITY Price, A. E., Shamardani, K., Lugo, K. A., Deguine, J., Roberts, A. W., Lee, B. L., Barton, G. M. 2018; 49 (3): 560-+

  Abstract

  Signaling by Toll-like receptors (TLRs) on intestinal epithelial cells (IECs) is critical for intestinal homeostasis. To visualize epithelial expression of individual TLRs in vivo, we generated five strains of reporter mice. These mice revealed that TLR expression varied dramatically along the length of the intestine. Indeed, small intestine (SI) IECs expressed low levels of multiple TLRs that were highly expressed by colonic IECs. TLR5 expression was restricted to Paneth cells in the SI epithelium. Intestinal organoid experiments revealed that TLR signaling in Paneth cells or colonic IECs induced a core set of host defense genes, but this set did not include antimicrobial peptides, which instead were induced indirectly by inflammatory cytokines. This comprehensive blueprint of TLR expression and function in IECs reveals unexpected diversity in the responsiveness of IECs to microbial stimuli, and together with the associated reporter strains, provides a resource for further study of innate immunity.

  View details for DOI 10.1016/j.immuni.2018.07.016

  View details for Web of Science ID 000444909600021

  View details for PubMedID 30170812

  View details for PubMedCentralID PMC6152941

• A neural circuit for gamma-band coherence across the retinotopic map in mouse visual cortex ELIFE Hakim, R., Shamardani, K., Adesnik, H. 2018; 7

  Abstract

  Cortical gamma oscillations have been implicated in a variety of cognitive, behavioral, and circuit-level phenomena. However, the circuit mechanisms of gamma-band generation and synchronization across cortical space remain uncertain. Using optogenetic patterned illumination in acute brain slices of mouse visual cortex, we define a circuit composed of layer 2/3 (L2/3) pyramidal cells and somatostatin (SOM) interneurons that phase-locks ensembles across the retinotopic map. The network oscillations generated here emerge from non-periodic stimuli, and are stimulus size-dependent, coherent across cortical space, narrow band (30 Hz), and depend on SOM neuron but not parvalbumin (PV) neuron activity; similar to visually induced gamma oscillations observed in vivo. Gamma oscillations generated in separate cortical locations exhibited high coherence as far apart as 850 μm, and lateral gamma entrainment depended on SOM neuron activity. These data identify a circuit that is sufficient to mediate long-range gamma-band coherence in the primary visual cortex.

  View details for DOI 10.7554/eLife.28569

  View details for Web of Science ID 000426060000001

  View details for PubMedID 29480803

  View details for PubMedCentralID PMC5826269