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HomeNatureStimulation modulates gene-linked cell assemblies in the human brain

Stimulation modulates gene-linked cell assemblies in the human brain

  • Kucewicz, M. T., Worrell, G. A. & Axmacher, N. Direct electrical brain stimulation of human memory: lessons learnt and future perspectives. Brain 146, 2214–2226 (2023).

    Article 
    PubMed 

    Google Scholar
     

  • Ezzyat, Y. et al. Closed-loop stimulation of temporal cortex rescues functional networks and improves memory. Nat. Commun. 9, 365 (2018).

    Article 
    ADS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kahana, M. J. et al. Biomarker-guided neuromodulation aids memory in traumatic brain injury. Brain Stimul. 16, 1086–1093 (2023).

    Article 
    PubMed 

    Google Scholar
     

  • Suthana, N. & Fried, I. Deep brain stimulation for enhancement of learning and memory. Neuroimage 85, 996–1002 (2014).

    Article 
    PubMed 

    Google Scholar
     

  • Bick, S. K. & Eskandar, E. N. Neuromodulation for restoring memory. Neurosurg. Focus 40, E5 (2016).

    Article 
    PubMed 

    Google Scholar
     

  • Dougherty, D. D. Deep brain stimulation: clinical applications. Psychiatr. Clin. North Am. 41, 385–394 (2018).

    Article 
    PubMed 

    Google Scholar
     

  • Widge, A. S. Closing the loop in psychiatric deep brain stimulation: physiology, psychometrics, and plasticity. Neuropsychopharmacology 49, 138–149 (2024).

    Article 
    PubMed 

    Google Scholar
     

  • Herrington, T. M., Cheng, J. J. & Eskandar, E. N. Mechanisms of deep brain stimulation. J. Neurophysiol. 115, 19–38 (2016).

    Article 
    PubMed 

    Google Scholar
     

  • Hebb, D. O. The Organization of Behavior: A Neuropsychological Theory (Wiley, 1949).

  • Buzsáki, G. Neural syntax: cell assemblies, synapsembles, and readers. Neuron 68, 362–385 (2010).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yiu, A. P. et al. Neurons are recruited to a memory trace based on relative neuronal excitability immediately before training. Neuron 83, 722–735 (2014).

    Article 
    PubMed 

    Google Scholar
     

  • Zhou, Y. et al. CREB regulates excitability and the allocation of memory to subsets of neurons in the amygdala. Nat. Neurosci. 12, 1438–1443 (2009).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Santoni, G. et al. Chromatin plasticity predetermines neuronal eligibility for memory trace formation. Science 385, eadg9982 (2024).

    Article 
    PubMed 

    Google Scholar
     

  • van de Ven, G. M., Trouche, S., McNamara, C. G., Allen, K. & Dupret, D. Hippocampal offline reactivation consolidates recently formed cell assembly patterns during sharp wave-ripples. Neuron 92, 968–974 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ikegaya, Y. et al. Synfire chains and cortical songs: temporal modules of cortical activity. Science 304, 559–564 (2004).

    Article 
    ADS 
    PubMed 

    Google Scholar
     

  • Yuste, R., Cossart, R. & Yaksi, E. Neuronal ensembles: building blocks of neural circuits. Neuron 112, 875–892 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Umbach, G., Tan, R., Jacobs, J., Pfeiffer, B. E. & Lega, B. Flexibility of functional neuronal assemblies supports human memory. Nat. Commun. 13, 6162 (2022).

    Article 
    ADS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Tyssowski, K. M. et al. Different neuronal activity patterns induce different gene expression programs. Neuron 98, 530–546 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rial Verde, E. M., Lee-Osbourne, J., Worley, P. F., Malinow, R. & Cline, H. T. Increased expression of the immediate-early gene Arc/Arg3.1 reduces AMPA receptor-mediated synaptic transmission. Neuron 52, 461–474 (2006).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Greenberg, M. E., Ziff, E. B. & Greene, L. A. Stimulation of neuronal acetylcholine receptors induces rapid gene transcription. Science 234, 80–83 (1986).

    Article 
    ADS 
    PubMed 

    Google Scholar
     

  • Sheng, M. & Greenberg, M. E. The regulation and function of c-fos and other immediate early genes in the nervous system. Neuron 4, 477–485 (1990).

    Article 
    PubMed 

    Google Scholar
     

  • Flavell, S. W. & Greenberg, M. E. Signaling mechanisms linking neuronal activity to gene expression and plasticity of the nervous system. Annu. Rev. Neurosci. 31, 563–590 (2008).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Denny, C. A. et al. Hippocampal memory traces are differentially modulated by experience, time, and adult neurogenesis. Neuron 83, 189–201 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Liu, X. et al. Optogenetic stimulation of a hippocampal engram activates fear memory recall. Nature 484, 381–385 (2012).

    Article 
    ADS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lopes-dos-Santos, V., Ribeiro, S. & Tort, A. B. L. Detecting cell assemblies in large neuronal populations. J. Neurosci. Methods 220, 149–166 (2013).

    Article 
    PubMed 

    Google Scholar
     

  • Jorstad, N. L. et al. Transcriptomic cytoarchitecture reveals principles of human neocortex organization. Science 382, eadf6812 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kim, T. K. et al. Widespread transcription at neuronal activity-regulated enhancers. Nature 465, 182–187 (2010).

    Article 
    ADS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Skinnider, M. A. et al. Cell type prioritization in single-cell data. Nat. Biotechnol. 39, 30–34 (2021).

    Article 
    PubMed 

    Google Scholar
     

  • Carter, A. C. et al. FOS binding sites are a hub for the evolution of activity-dependent gene regulatory programs in human neurons. Preprint at bioRxiv https://doi.org/10.1101/2025.03.31.646366 (2025).

  • Su, C., Lee, D., Jin, P. & Zhang, J. scMultiMap: cell-type-specific mapping of enhancers and target genes from single-cell multimodal data. Nat. Commun. 16, 3941 (2025).

    Article 
    ADS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • González-Blas, C. B. et al. SCENIC+: single-cell multiomic inference of enhancers and gene regulatory networks. Nat. Methods 20, 1355–1367 (2023).

    Article 

    Google Scholar
     

  • Aibar, S. et al. SCENIC: single-cell regulatory network inference and clustering. Nat. Methods 14, 1083–1086 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cahill, K. M., Huo, Z., Tseng, G. C., Logan, R. W. & Seney, M. L. Improved identification of concordant and discordant gene expression signatures using an updated rank-rank hypergeometric overlap approach. Sci. Rep. 8, 9588 (2018).

    Article 
    ADS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jiang, W. et al. Identification of protein tyrosine phosphatase receptor type O (PTPRO) as a synaptic adhesion molecule that promotes synapse formation. J. Neurosci. 37, 9828–9843 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Fenoy, A. J., Goetz, L., Chabardès, S. & Xia, Y. Deep brain stimulation: are astrocytes a key driver behind the scene? CNS Neurosci. Ther. 20, 191–201 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chatterjee, S. et al. The gene expression signature of electrical stimulation in the human brain. Preprint at bioRxiv https://doi.org/10.1101/2023.09.21.558812 (2024).

  • Innocenti, B., Parpura, V. & Haydon, P. G. Imaging extracellular waves of glutamate during calcium signaling in cultured astrocytes. J. Neurosci. 20, 1800–1808 (2000).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cornell-Bell, A. H., Finkbeiner, S. M., Cooper, M. S. & Smith, S. J. Glutamate induces calcium waves in cultured astrocytes: long-range glial signaling. Science 247, 470–473 (1990).

    Article 
    ADS 
    PubMed 

    Google Scholar
     

  • Glaum, S. R., Holzwarth, J. A. & Miller, R. J. Glutamate receptors activate Ca2+ mobilization and Ca2+ influx into astrocytes. Proc. Natl Acad. Sci. USA 87, 3454–3458 (1990).

    Article 
    ADS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Araque, A., Parpura, V., Sanzgiri, R. P. & Haydon, P. G. Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci. 22, 208–215 (1999).

    Article 
    PubMed 

    Google Scholar
     

  • Araque, A., Li, N., Doyle, R. T. & Haydon, P. G. SNARE protein-dependent glutamate release from astrocytes. J. Neurosci. 20, 666–673 (2000).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Harris, K. D., Csicsvari, J., Hirase, H., Dragoi, G. & Buzsaki, G. Organization of cell assemblies in the hippocampus. Nature 424, 552–556 (2003).

    Article 
    ADS 
    PubMed 

    Google Scholar
     

  • Markram, H., Lübke, J., Frotscher, M. & Sakmann, B. Regulation of synaptic efficacy by coincidence of postsynaptic APs and EPSPs. Science 275, 213–215 (1997).

    Article 
    ADS 
    PubMed 

    Google Scholar
     

  • Matsuzaki, M., Honkura, N., Ellis-Davies, G. C. & Kasai, H. Structural basis of long-term potentiation in single dendritic spines. Nature 429, 761–766 (2004).

    Article 
    ADS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Komiyama, T. et al. Learning-related fine-scale specificity imaged in motor cortex circuits of behaving mice. Nature 464, 1182–1186 (2010).

    Article 
    ADS 
    PubMed 

    Google Scholar
     

  • Andrews, J. P. et al. Multimodal evaluation of network activity and optogenetic interventions in human hippocampal slices. Nat. Neurosci. 27, 2487–2499 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ide, A. N., Andruska, A., Boehler, M., Wheeler, B. C. & Brewer, G. J. Chronic network stimulation enhances evoked action potentials. J. Neural Eng. 7, 16008 (2010).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Leondopulos, S. S., Boehler, M. D., Wheeler, B. C. & Brewer, G. J. Chronic stimulation of cultured neuronal networks boosts low-frequency oscillatory activity at theta and gamma with spikes phase-locked to gamma frequencies. J. Neural Eng. 9, 026015 (2012).

    Article 
    ADS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Soleng, A. F., Baginskas, A., Andersen, P. & Raastad, M. Activity-dependent excitability changes in hippocampal CA3 cell Schaffer axons. J. Physiol. 560, 491–503 (2004).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wagenaar, D. A., Pine, J. & Potter, S. M. Effective parameters for stimulation of dissociated cultures using multi-electrode arrays. J. Neurosci. Methods 138, 27–37 (2004).

    Article 
    PubMed 

    Google Scholar
     

  • Shannon, R. V. A model of safe levels for electrical stimulation. IEEE Trans. Biomed. Eng. 39, 424–426 (1992).

    Article 
    PubMed 

    Google Scholar
     

  • Reyes-Chapero, R. M. et al. Cortical parvalbumin-expressing interneurons sample network oscillations in their synaptic activity. Neuroscience 573, 25–41 (2025).

    Article 
    PubMed 

    Google Scholar
     

  • Bartolini, G., Ciceri, G. & Marín, O. Integration of GABAergic interneurons into cortical cell assemblies: lessons from embryos and adults. Neuron 79, 849–864 (2013).

    Article 
    PubMed 

    Google Scholar
     

  • Gibson, E. M. et al. Neuronal activity promotes oligodendrogenesis and adaptive myelination in the mammalian brain. Science 344, 1252304 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Li, D. C. & Li, Q. Electrical stimulation of cortical neurons promotes oligodendrocyte development and remyelination in the injured spinal cord. Neural Regen. Res. 12, 1613–1615 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Tawfik, V. L. et al. Deep brain stimulation results in local glutamate and adenosine release: investigation into the role of astrocytes. Neurosurgery 67, 367–375 (2010).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ting, J. T. et al. Preparation of acute brain slices using an optimized N-methyl-d-glucamine protective recovery method. J. Vis. Exp. https://doi.org/10.3791/53825 (2018).

  • Eugene, E. et al. An organotypic brain slice preparation from adult patients with temporal lobe epilepsy. J. Neurosci. Methods 235, 234–244 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Park, T. I. H. et al. Routine culture and study of adult human brain cells from neurosurgical specimens. Nat. Protoc. 17, 190–221 (2022).

    Article 
    PubMed 

    Google Scholar
     

  • Florez, C. M. et al. In vitro recordings of human neocortical oscillations. Cereb. Cortex 25, 578–597 (2015).

    Article 
    PubMed 

    Google Scholar
     

  • Buccino, A. P. et al. SpikeInterface, a unified framework for spike sorting. eLife 9, e61834 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hill, D. N., Mehta, S. B. & Kleinfeld, D. Quality metrics to accompany spike sorting of extracellular signals. J. Neurosci. 31, 8699–8705 (2011).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Someck, S. et al. Positive and biphasic extracellular waveforms correspond to return currents and axonal spikes. Commun. Biol. 6, 950 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Schwarz, N. et al. Long-term adult human brain slice cultures as a model system to study human CNS circuitry and disease. eLife 8, e48417 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lee, K., Carr, N., Perliss, A. & Chandrasekaran, C. WaveMAP for identifying putative cell types from in vivo electrophysiology. STAR Protoc. 4, 102320 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lee, E. K. et al. Non-linear dimensionality reduction on extracellular waveforms reveals cell type diversity in premotor cortex. eLife 10, e67490 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Spix, T. A. et al. Population-specific neuromodulation prolongs therapeutic benefits of deep brain stimulation. Science 374, 201–206 (2021).

    Article 
    ADS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Okun, M. et al. Population rate dynamics and multineuron firing patterns in sensory cortex. J. Neurosci. 32, 17108–17119 (2012).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Okun, M. et al. Diverse coupling of neurons to populations in sensory cortex. Nature 521, 511–515 (2015).

    Article 
    ADS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • van der Molen, T. et al. SpikeLab: agentic tools for spike data analysis. Preprint at bioRxiv https://doi.org/10.64898/2026.04.25.720833 (2026).

  • Biroli, G., Bouchaud, J. P. & Potters, M. On the top eigenvalue of heavy-tailed random matrices. Europhys. Lett. 78, 10001 (2007).

    Article 
    ADS 
    MathSciNet 

    Google Scholar
     

  • Peyrache, A., Benchenane, K., Khamassi, M., Wiener, S. I. & Battaglia, F. P. Principal component analysis of ensemble recordings reveals cell assemblies at high temporal resolution. J. Comput. Neurosci. 29, 309–325 (2010).

    Article 
    PubMed 

    Google Scholar
     

  • Marčenko, V. A. & Pastur, L. A. Distribution of eigenvalues for some sets of random matrices. Math. USSR Sb. 1, 457 (1967).

    Article 

    Google Scholar
     

  • Donoghue, T., Maesta-Pereira, S., Han, C. Z., Qasim, S. E. & Jacobs, J. spiketools: a Python package for analyzing single-unit neural activity. J. Open Source Softw. https://doi.org/10.21105/joss.05268 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ravi, V. M. et al. Human organotypic brain slice culture: a novel framework for environmental research in neuro-oncology. Life Sci. Alliance 2, e201900305 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ayhan, F. et al. Resolving cellular and molecular diversity along the hippocampal anterior-to-posterior axis in humans. Neuron 109, 2091–2105 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ayhan, F., Douglas, C., Lega, B. C. & Konopka, G. Nuclei isolation from surgically resected human hippocampus. STAR Protoc. 2, 100844 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Muskovic, W. & Powell, J. E. DropletQC: improved identification of empty droplets and damaged cells in single-cell RNA-seq data. Genome Biol. 22, 329 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chen, X., Miragaia, R. J., Natarajan, K. N. & Teichmann, S. A. A rapid and robust method for single cell chromatin accessibility profiling. Nat. Commun. 9, 5345 (2018).

    Article 
    ADS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hafemeister, C. & Satija, R. Normalization and variance stabilization of single-cell RNA-seq data using regularized negative binomial regression. Genome Biol. 20, 296 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Amemiya, H. M., Kundaje, A. & Boyle, A. P. The ENCODE Blacklist: identification of problematic regions of the genome. Sci. Rep. 9, 9354 (2019).

    Article 
    ADS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Stuart, T., Srivastava, A., Madad, S., Lareau, C. A. & Satija, R. Single-cell chromatin state analysis with Signac. Nat. Methods 18, 1333–1341 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yu, G., Wang, L. G. & He, Q. Y. ChIPseeker: an R/Bioconductor package for ChIP peak annotation, comparison and visualization. Bioinformatics 31, 2382–2383 (2015).

    Article 
    PubMed 

    Google Scholar
     

  • Hao, Y. et al. Integrated analysis of multimodal single-cell data. Cell 184, 3573–3587 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Germain, P. L., Lun, A., Garcia Meixide, C., Macnair, W. & Robinson, M. D. Doublet identification in single-cell sequencing data using scDblFinder. F1000Res 10, 979 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Korsunsky, I. et al. Fast, sensitive and accurate integration of single-cell data with Harmony. Nat. Methods 16, 1289–1296 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Magi, A. et al. A shifting level model algorithm that identifies aberrations in array-CGH data. Biostatistics 11, 265–280 (2010).

    Article 
    PubMed 

    Google Scholar
     

  • Berto, S., Wang, G. Z., Germi, J., Lega, B. C. & Konopka, G. Human genomic signatures of brain oscillations during memory encoding. Cereb. Cortex 28, 1733–1748 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Berto, S. et al. Gene-expression correlates of the oscillatory signatures supporting human episodic memory encoding. Nat. Neurosci. 24, 554–564 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cavalcante, R. G. & Sartor, M. A. annotatr: genomic regions in context. Bioinformatics 33, 2381–2383 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Heinz, S. et al. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol. Cell 38, 576–589 (2010).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Granger, B. & Berto, S. scToppR: a coding-friendly R interface to ToppGene. Bioinformatics 40, btae582 https://doi.org/10.1093/bioinformatics/btae582 (2024).

  • Yu, G., Wang, L. G., Han, Y. & He, Q. Y. clusterProfiler: an R package for comparing biological themes among gene clusters. Omics 16, 284–287 (2012).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Morabito, S., Reese, F., Rahimzadeh, N., Miyoshi, E. & Swarup, V. hdWGCNA identifies co-expression networks in high-dimensional transcriptomics data. Cell Rep. Methods 3, 100498 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wang, L. et al. Molecular and cellular dynamics of the developing human neocortex. Nature 647, 169–178 (2025).

    Article 
    ADS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Fleming, S. J. et al. Unsupervised removal of systematic background noise from droplet-based single-cell experiments using CellBender. Nat. Methods 20, 1323–1335 (2023).

    Article 
    PubMed 

    Google Scholar
     

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