Presenting measurements of neuronal preparations with a novel CMOS-based microelectrode array at high-spatiotemporal-resolution on subcellular, cellular, and network level.
J. Müller, M. Ballini, P. Livi, Y. Chen, M. Radivojevic, A. Shadmani, V. Viswam, I. L. Jones, M. Fiscella, R. Diggelmann, A. Stettler, U. Frey, D. J. Bakkum, and A. Hierlemann, “High-resolution CMOS MEA platform to study neurons at subcellular, cellular, and network levels,” Lab Chip, vol. 15, no. 13, pp. 2767–2780, May 2015.
Reviewing the current understanding of microelectrode signals and the techniques for analyzing them, with focus on the ongoing advancements in microelectrode technology (in vivo and in vitro) and recent advanced microelectrode array measurement methods that facilitate the understanding of single neurons and network function.
M. E. J. Obien, K. Deligkaris, T. Bullmann, D. J. Bakkum, and U. Frey, “Revealing Neuronal Function through Microelectrode Array Recordings,” Front. Neurosci., 8:423, Jan 2015.
A high-resolution CMOS-based microelectrode array featuring 1,024 low-noise readout channels, 26,400 electrodes at a density of 3,265 electrodes per mm2, including on-chip 10bit ADCs and consuming only 75 mW.
M. Ballini, J. Muller, P. Livi, Y. Chen, U. Frey, A. Stettler, A. Shadmani, V. Viswam, I. L. Jones, D. Jackel, M. Radivojevic, M. K. Lewandowska, W. Gong, M. Fiscella, D. J. Bakkum, F. Heer, and A. Hierlemann, “A 1024-Channel CMOS Microelectrode Array With 26,400 Electrodes for Recording and Stimulation of Electrogenic Cells In Vitro,” IEEE Journal of Solid-State Circuits, vol. 49, no. 11, pp. 2705-2719, 2014.
Demonstrating a method to electrically visualize action potential propagation on axons and revealing
large variations in velocity.
D. J. Bakkum, U. Frey, M. Radivojevic, T. L. Russell, J. Muller, M. Fiscella, H. Takahashi, and A. Hierlemann, “Tracking axonal action potential propagation on a high-density microelectrode array across hundreds of sites,” Nature Communications, 4:2181, Jul 2013.
Recording and modeling extracellular action potentials of Purkinje cells at subcellular resolution.
U. Frey, U. Egert, F. Heer, S. Hafizovic, and A. Hierlemann, “Microelectronic System for High-Resolution Mapping of Extracellular Electric Fields Applied to Brain Slices,” Biosensors and Bioelectronics, vol. 24, no. 7, pp. 2191-2198, 2009.
Controlling BMP-2 expression to modulate the electrophysiological properties of cardiomyocytes using an HD-MEA for detailed monitoring.
C. D. Sanchez-Bustamante, U. Frey, J. M. Kelm, A. Hierlemann, and M. Fussenegger,
“Modulation of Cardiomyocyte Electrical Properties Using Regulated Bone Morphogenetic Protein-2 Expression,” Tissue Engineering Part A, vol. 14, no. 12, pp. 1969-1988, 2008.
@article{Tetzlaff2024,
title = {Characterizing and targeting glioblastoma neuron-tumor networks with retrograde tracing},
author = {Svenja K. Tetzlaff and Ekin Reyhan and C. Peter Bengtson and Julian Schroers and Julia Wagner and Marc C. Schubert and Nikolas Layer and Maria C. Puschhof and Anton J. Faymonville and Nina Drewa and Rangel L. Pramatarov and Niklas Wissmann and Obada Alhalabi and Alina Heuer and Nirosan Sivapalan and Joaquín Campos and Berin Boztepe and Jonas G. Scheck and Giulia Villa and Manuel Schröter and Felix Sahm and Karin Forsberg-Nilsson and Michael O. Breckwoldt and Claudio Acuna and Bogdana Suchorska and Dieter Henrik Heiland and Julio Saez-Rodriguez and Varun Venkataramani},
url = {http://biorxiv.org/lookup/doi/10.1101/2024.03.18.585565},
doi = {10.1101/2024.03.18.585565},
year = {2024},
date = {2024-03-22},
journal = {bioRxiv},
abstract = {Glioblastomas are invasive brain tumors with high therapeutic resistance. Neuron-to-glioma synapses have been shown to promote glioblastoma progression. However, a characterization of tumor-connected neurons has been hampered by a lack of technologies. Here, we adapted retrograde tracing using rabies viruses to investigate and manipulate neuron-tumor networks. Glioblastoma rapidly integrated into neural circuits across the brain engaging in widespread functional communication, with acetylcholinergic neurons driving glioblastoma invasion. We uncovered patient-specific and tumor cell state-dependent differences in synaptogenic gene expression associated with neuron-tumor connectivity and subsequent invasivity. Importantly, radiotherapy enhanced neuron-tumor connectivity by increased neuronal activity. In turn, simultaneous neuronal activity inhibition and radiotherapy showed increased therapeutic effects, indicative of a role for neuron-to-glioma synapses in contributing to therapeutic resistance. Lastly, rabies-mediated genetic ablation of tumor-connected neurons halted glioblastoma progression, offering a viral strategy to tackle glioblastoma. Together, this study provides a framework to comprehensively characterize neuron-tumor networks and target glioblastoma.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Glioblastomas are invasive brain tumors with high therapeutic resistance. Neuron-to-glioma synapses have been shown to promote glioblastoma progression. However, a characterization of tumor-connected neurons has been hampered by a lack of technologies. Here, we adapted retrograde tracing using rabies viruses to investigate and manipulate neuron-tumor networks. Glioblastoma rapidly integrated into neural circuits across the brain engaging in widespread functional communication, with acetylcholinergic neurons driving glioblastoma invasion. We uncovered patient-specific and tumor cell state-dependent differences in synaptogenic gene expression associated with neuron-tumor connectivity and subsequent invasivity. Importantly, radiotherapy enhanced neuron-tumor connectivity by increased neuronal activity. In turn, simultaneous neuronal activity inhibition and radiotherapy showed increased therapeutic effects, indicative of a role for neuron-to-glioma synapses in contributing to therapeutic resistance. Lastly, rabies-mediated genetic ablation of tumor-connected neurons halted glioblastoma progression, offering a viral strategy to tackle glioblastoma. Together, this study provides a framework to comprehensively characterize neuron-tumor networks and target glioblastoma.
@article{Cai2023b,
title = {Brain organoid reservoir computing for artificial intelligence},
author = {Hongwei Cai and Zheng Ao and Chunhui Tian and Zhuhao Wu and Hongcheng Liu and Jason Tchieu and Mingxia Gu and Ken Mackie and Feng Guo },
url = {https://www.nature.com/articles/s41928-023-01069-w},
doi = {10.1038/s41928-023-01069-w},
year = {2023},
date = {2023-12-11},
journal = {Nature Electronics},
abstract = {Brain-inspired computing hardware aims to emulate the structure and working principles of the brain and could be used to address current limitations in artificial intelligence technologies. However, brain-inspired silicon chips are still limited in their ability to fully mimic brain function as most examples are built on digital electronic principles. Here we report an artificial intelligence hardware approach that uses adaptive reservoir computation of biological neural networks in a brain organoid. In this approach—which is termed Brainoware—computation is performed by sending and receiving information from the brain organoid using a high-density multielectrode array. By applying spatiotemporal electrical stimulation, nonlinear dynamics and fading memory properties are achieved, as well as unsupervised learning from training data by reshaping the organoid functional connectivity. We illustrate the practical potential of this technique by using it for speech recognition and nonlinear equation prediction in a reservoir computing framework.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Brain-inspired computing hardware aims to emulate the structure and working principles of the brain and could be used to address current limitations in artificial intelligence technologies. However, brain-inspired silicon chips are still limited in their ability to fully mimic brain function as most examples are built on digital electronic principles. Here we report an artificial intelligence hardware approach that uses adaptive reservoir computation of biological neural networks in a brain organoid. In this approach—which is termed Brainoware—computation is performed by sending and receiving information from the brain organoid using a high-density multielectrode array. By applying spatiotemporal electrical stimulation, nonlinear dynamics and fading memory properties are achieved, as well as unsupervised learning from training data by reshaping the organoid functional connectivity. We illustrate the practical potential of this technique by using it for speech recognition and nonlinear equation prediction in a reservoir computing framework.
@article{Ryu2023,
title = {Stress-free cell aggregation by using the CEPT cocktail enhances embryoid body and organoid fitness},
author = {Seungmi Ryu and Claire Weber and Pei-Hsuan Chu and Ben Ernest and Vukasin M Jovanovic and Tao Deng and Jaroslav Slamecka and Hyenjong Hong and Yogita Jethmalani and Hannah M Baskir and Jason Inman and John Braisted and Marissa B Hirst and Anton Simeonov and Ty C Voss and Carlos A Tristan and Ilyas Singeç},
url = {https://dx.doi.org/10.1088/1758-5090/ad0d13},
doi = {10.1088/1758-5090/ad0d13},
year = {2023},
date = {2023-12-11},
journal = {Biofabrication},
abstract = {Embryoid bodies (EBs) and self-organizing organoids derived from human pluripotent stem cells (hPSCs) recapitulate tissue development in a dish and hold great promise for disease modeling and drug development. However, current protocols are hampered by cellular stress and apoptosis during cell aggregation, resulting in variability and impaired cell differentiation. Here, we demonstrate that EBs and various organoid models (e.g., brain, gut, kidney) can be optimized by using the small molecule cocktail named CEPT (chroman 1, emricasan, polyamines, trans-ISRIB), a polypharmacological approach that ensures cytoprotection and cell survival. Application of CEPT for just 24 h during cell aggregation has long-lasting consequences affecting morphogenesis, gene expression, cellular differentiation, and organoid function. Various qualification methods confirmed that CEPT treatment enhanced experimental reproducibility and consistently improved EB and organoid fitness as compared to the widely used ROCK inhibitor Y-27632. Collectively, we discovered that stress-free cell aggregation and superior cell survival in the presence of CEPT are critical quality control determinants that establish a robust foundation for bioengineering complex tissue and organ models.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Embryoid bodies (EBs) and self-organizing organoids derived from human pluripotent stem cells (hPSCs) recapitulate tissue development in a dish and hold great promise for disease modeling and drug development. However, current protocols are hampered by cellular stress and apoptosis during cell aggregation, resulting in variability and impaired cell differentiation. Here, we demonstrate that EBs and various organoid models (e.g., brain, gut, kidney) can be optimized by using the small molecule cocktail named CEPT (chroman 1, emricasan, polyamines, trans-ISRIB), a polypharmacological approach that ensures cytoprotection and cell survival. Application of CEPT for just 24 h during cell aggregation has long-lasting consequences affecting morphogenesis, gene expression, cellular differentiation, and organoid function. Various qualification methods confirmed that CEPT treatment enhanced experimental reproducibility and consistently improved EB and organoid fitness as compared to the widely used ROCK inhibitor Y-27632. Collectively, we discovered that stress-free cell aggregation and superior cell survival in the presence of CEPT are critical quality control determinants that establish a robust foundation for bioengineering complex tissue and organ models.
Elliott, Matthew A T; Schweiger, Hunter E; Robbins, Ash; Vera-Choqqueccota, Samira; Ehrlich, Drew; Hernandez, Sebastian; Voitiuk, Kateryna; Geng, Jinghui; Sevetson, Jess L; Core, Cordero; Rosen, Yohei M; Teodorescu, Mircea; Wagner, Nico O; Haussler, David; Mostajo-Radji, Mohammed A: Internet-Connected Cortical Organoids for Project-Based Stem Cell and Neuroscience Education. In: eNeuro, 2023.(Type: Journal Article | Abstract | Links | BibTeX)
@article{Elliott2023,
title = {Internet-Connected Cortical Organoids for Project-Based Stem Cell and Neuroscience Education},
author = {Matthew A. T. Elliott and Hunter E. Schweiger and Ash Robbins and Samira Vera-Choqqueccota and Drew Ehrlich and Sebastian Hernandez and Kateryna Voitiuk and Jinghui Geng and Jess L. Sevetson and Cordero Core and Yohei M. Rosen and Mircea Teodorescu and Nico O. Wagner and David Haussler and Mohammed A. Mostajo-Radji},
url = {https://www.eneuro.org/lookup/doi/10.1523/ENEURO.0308-23.2023},
doi = {10.1523/ENEURO.0308-23.2023},
year = {2023},
date = {2023-11-28},
journal = {eNeuro},
abstract = {The introduction of Internet-connected technologies to the classroom has the potential to revolutionize STEM education by allowing students to perform experiments in complex models that are unattainable in traditional teaching laboratories. By connecting laboratory equipment to the cloud, we introduce students to experimentation in pluripotent stem cell (PSC)-derived cortical organoids in two different settings: using microscopy to monitor organoid growth in an introductory tissue culture course and using high-density (HD) multielectrode arrays (MEAs) to perform neuronal stimulation and recording in an advanced neuroscience mathematics course. We demonstrate that this approach develops interest in stem cell and neuroscience in the students of both courses. All together, we propose cloud technologies as an effective and scalable approach for complex project-based university training.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The introduction of Internet-connected technologies to the classroom has the potential to revolutionize STEM education by allowing students to perform experiments in complex models that are unattainable in traditional teaching laboratories. By connecting laboratory equipment to the cloud, we introduce students to experimentation in pluripotent stem cell (PSC)-derived cortical organoids in two different settings: using microscopy to monitor organoid growth in an introductory tissue culture course and using high-density (HD) multielectrode arrays (MEAs) to perform neuronal stimulation and recording in an advanced neuroscience mathematics course. We demonstrate that this approach develops interest in stem cell and neuroscience in the students of both courses. All together, we propose cloud technologies as an effective and scalable approach for complex project-based university training.
@article{Tomoyo2023,
title = {Recapitulation of Perturbed Striatal Gene Expression Dynamics of Donor’s Brains With Ventral Forebrain Organoids Derived From the Same Individuals With Schizophrenia},
author = {Tomoyo Sawada and André R. Barbosa and Bruno Araujo and Alejandra E. McCord and Laura D’Ignazio and Kynon J.M. Benjamin and Bonna Sheehan and Michael Zabolocki and Arthur Feltrin and Ria Arora and Anna C. Brandtjen and Joel E. Kleinman and Thomas M. Hyde and Cedric Bardy and Daniel R. Weinberger and Apuã C.M. Paquola and Jennifer A. Erwin},
url = {https://ajp.psychiatryonline.org/doi/10.1176/appi.ajp.20220723},
doi = {10.1176/appi.ajp.20220723},
issn = {0002-953X},
year = {2023},
date = {2023-11-02},
journal = {American Journal of Psychiatry},
abstract = {Objective:
Schizophrenia is a brain disorder that originates during neurodevelopment and has complex genetic and environmental etiologies. Despite decades of clinical evidence of altered striatal function in affected patients, studies examining its cellular and molecular mechanisms in humans are limited. To explore neurodevelopmental alterations in the striatum associated with schizophrenia, the authors established a method for the differentiation of induced pluripotent stem cells (iPSCs) into ventral forebrain organoids (VFOs).
Methods:
VFOs were generated from postmortem dural fibroblast–derived iPSCs of four individuals with schizophrenia and four neurotypical control individuals for whom postmortem caudate genotypes and transcriptomic data were profiled in the BrainSeq neurogenomics consortium. Individuals were selected such that the two groups had nonoverlapping schizophrenia polygenic risk scores (PRSs).
Results:
Single-cell RNA sequencing analyses of VFOs revealed differences in developmental trajectory between schizophrenia and control individuals in which inhibitory neuronal cells from the patients exhibited accelerated maturation. Furthermore, upregulated genes in inhibitory neurons in schizophrenia VFOs showed a significant overlap with upregulated genes in postmortem caudate tissue of individuals with schizophrenia compared with control individuals, including the donors of the iPSC cohort.
Conclusions:
The findings suggest that striatal neurons derived from high-PRS individuals with schizophrenia carry abnormalities that originated during early brain development and that the VFO model can recapitulate disease-relevant cell type–specific neurodevelopmental phenotypes in a dish.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Schizophrenia is a brain disorder that originates during neurodevelopment and has complex genetic and environmental etiologies. Despite decades of clinical evidence of altered striatal function in affected patients, studies examining its cellular and molecular mechanisms in humans are limited. To explore neurodevelopmental alterations in the striatum associated with schizophrenia, the authors established a method for the differentiation of induced pluripotent stem cells (iPSCs) into ventral forebrain organoids (VFOs).
Methods:
VFOs were generated from postmortem dural fibroblast–derived iPSCs of four individuals with schizophrenia and four neurotypical control individuals for whom postmortem caudate genotypes and transcriptomic data were profiled in the BrainSeq neurogenomics consortium. Individuals were selected such that the two groups had nonoverlapping schizophrenia polygenic risk scores (PRSs).
Results:
Single-cell RNA sequencing analyses of VFOs revealed differences in developmental trajectory between schizophrenia and control individuals in which inhibitory neuronal cells from the patients exhibited accelerated maturation. Furthermore, upregulated genes in inhibitory neurons in schizophrenia VFOs showed a significant overlap with upregulated genes in postmortem caudate tissue of individuals with schizophrenia compared with control individuals, including the donors of the iPSC cohort.
Conclusions:
The findings suggest that striatal neurons derived from high-PRS individuals with schizophrenia carry abnormalities that originated during early brain development and that the VFO model can recapitulate disease-relevant cell type–specific neurodevelopmental phenotypes in a dish.
@article{Metto2023,
title = {Closed-loop neurostimulation via expression of magnetogenetics-sensitive protein in inhibitory neurons leads to reduction of seizure activity in a rat model of epilepsy},
author = {Abigael C. Metto and Petra Telgkamp and Autumn K. McLane-Svoboda and Assaf A. Gilad and Galit Pelled},
url = {https://www.sciencedirect.com/science/article/pii/S0006899323003621},
doi = {https://doi.org/10.1016/j.brainres.2023.148591},
year = {2023},
date = {2023-09-24},
journal = {Brain Research},
abstract = {On-demand neurostimulation has shown success in epilepsy patients with pharmacoresistant seizures. Seizures produce magnetic fields that can be recorded using magnetoencephalography. We developed a new closed-loop approach to control seizure activity based on magnetogenetics using the electromagnetic perceptive gene (EPG) that encodes a protein that responds to magnetic fields. The EPG transgene was expressed in inhibitory interneurons under the hDlx promoter and kainic acid was used to induce acute seizures. In vivo electrophysiological signals were recorded. We found that hDlx EPG rats exhibited a significant delay in the onset of first seizure (1142.72 ± 186.35 s) compared to controls (644.03 ± 15.06 s) and significantly less seizures (4.11 ± 1.03) compared to controls (8.33 ± 1.58). These preliminary findings suggest that on-demand activation of EPG expressed in inhibitory interneurons suppresses seizure activity, and magnetogenetics via EPG may be an effective strategy to alleviate seizure severity in a closed-loop, and cell-specific fashion.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
On-demand neurostimulation has shown success in epilepsy patients with pharmacoresistant seizures. Seizures produce magnetic fields that can be recorded using magnetoencephalography. We developed a new closed-loop approach to control seizure activity based on magnetogenetics using the electromagnetic perceptive gene (EPG) that encodes a protein that responds to magnetic fields. The EPG transgene was expressed in inhibitory interneurons under the hDlx promoter and kainic acid was used to induce acute seizures. In vivo electrophysiological signals were recorded. We found that hDlx EPG rats exhibited a significant delay in the onset of first seizure (1142.72 ± 186.35 s) compared to controls (644.03 ± 15.06 s) and significantly less seizures (4.11 ± 1.03) compared to controls (8.33 ± 1.58). These preliminary findings suggest that on-demand activation of EPG expressed in inhibitory interneurons suppresses seizure activity, and magnetogenetics via EPG may be an effective strategy to alleviate seizure severity in a closed-loop, and cell-specific fashion.
Zhao, Eric T; Hull, Jacob M; Hemed, Nofar Mintz; Ulusan, Hasan; Bartram, Julian; Zhang, Anqi; Wang, Pingyu; Pham, Albert; Silvia Ronchi, John Huguenard R; Hierlemann, Andreas; Melosh, Nicholas A: A CMOS-based highly scalable flexible neural electrode interface. In: Science Advances, 2023.(Type: Journal Article | Abstract | Links | BibTeX)
@article{Zhao2023,
title = {A CMOS-based highly scalable flexible neural electrode interface},
author = {Eric T. Zhao and Jacob M. Hull and Nofar Mintz Hemed and Hasan Ulusan and Julian Bartram and Anqi Zhang and Pingyu Wang and Albert Pham and Silvia Ronchi, John R. Huguenard and Andreas Hierlemann and Nicholas A. Melosh},
url = {https://www.science.org/doi/10.1126/sciadv.adf9524},
doi = {DOI: 10.1126/sciadv.adf9524},
year = {2023},
date = {2023-06-07},
journal = {Science Advances},
abstract = {Perception, thoughts, and actions are encoded by the coordinated activity of large neuronal populations spread over large areas. However, existing electrophysiological devices are limited by their scalability in capturing this cortex-wide activity. Here, we developed an electrode connector based on an ultra-conformable thin-film electrode array that self-assembles onto silicon microelectrode arrays enabling multithousand channel counts at a millimeter scale. The interconnects are formed using microfabricated electrode pads suspended by thin support arms, termed Flex2Chip. Capillary-assisted assembly drives the pads to deform toward the chip surface, and van der Waals forces maintain this deformation, establishing Ohmic contact. Flex2Chip arrays successfully measured extracellular action potentials ex vivo and resolved micrometer scale seizure propagation trajectories in epileptic mice. We find that seizure dynamics in absence epilepsy in the Scn8a+/− model do not have constant propagation trajectories.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Perception, thoughts, and actions are encoded by the coordinated activity of large neuronal populations spread over large areas. However, existing electrophysiological devices are limited by their scalability in capturing this cortex-wide activity. Here, we developed an electrode connector based on an ultra-conformable thin-film electrode array that self-assembles onto silicon microelectrode arrays enabling multithousand channel counts at a millimeter scale. The interconnects are formed using microfabricated electrode pads suspended by thin support arms, termed Flex2Chip. Capillary-assisted assembly drives the pads to deform toward the chip surface, and van der Waals forces maintain this deformation, establishing Ohmic contact. Flex2Chip arrays successfully measured extracellular action potentials ex vivo and resolved micrometer scale seizure propagation trajectories in epileptic mice. We find that seizure dynamics in absence epilepsy in the Scn8a+/− model do not have constant propagation trajectories.
@article{Tetzlaff2024,
title = {Characterizing and targeting glioblastoma neuron-tumor networks with retrograde tracing},
author = {Svenja K. Tetzlaff and Ekin Reyhan and C. Peter Bengtson and Julian Schroers and Julia Wagner and Marc C. Schubert and Nikolas Layer and Maria C. Puschhof and Anton J. Faymonville and Nina Drewa and Rangel L. Pramatarov and Niklas Wissmann and Obada Alhalabi and Alina Heuer and Nirosan Sivapalan and Joaquín Campos and Berin Boztepe and Jonas G. Scheck and Giulia Villa and Manuel Schröter and Felix Sahm and Karin Forsberg-Nilsson and Michael O. Breckwoldt and Claudio Acuna and Bogdana Suchorska and Dieter Henrik Heiland and Julio Saez-Rodriguez and Varun Venkataramani},
url = {http://biorxiv.org/lookup/doi/10.1101/2024.03.18.585565},
doi = {10.1101/2024.03.18.585565},
year = {2024},
date = {2024-03-22},
journal = {bioRxiv},
abstract = {Glioblastomas are invasive brain tumors with high therapeutic resistance. Neuron-to-glioma synapses have been shown to promote glioblastoma progression. However, a characterization of tumor-connected neurons has been hampered by a lack of technologies. Here, we adapted retrograde tracing using rabies viruses to investigate and manipulate neuron-tumor networks. Glioblastoma rapidly integrated into neural circuits across the brain engaging in widespread functional communication, with acetylcholinergic neurons driving glioblastoma invasion. We uncovered patient-specific and tumor cell state-dependent differences in synaptogenic gene expression associated with neuron-tumor connectivity and subsequent invasivity. Importantly, radiotherapy enhanced neuron-tumor connectivity by increased neuronal activity. In turn, simultaneous neuronal activity inhibition and radiotherapy showed increased therapeutic effects, indicative of a role for neuron-to-glioma synapses in contributing to therapeutic resistance. Lastly, rabies-mediated genetic ablation of tumor-connected neurons halted glioblastoma progression, offering a viral strategy to tackle glioblastoma. Together, this study provides a framework to comprehensively characterize neuron-tumor networks and target glioblastoma.},
keywords = {3D Culture, HD-MEA, MaxTwo, MEA Metrics, MEA Technology, Organoids, Primary Neuronal Cell Culture},
pubstate = {published},
tppubtype = {article}
}
Glioblastomas are invasive brain tumors with high therapeutic resistance. Neuron-to-glioma synapses have been shown to promote glioblastoma progression. However, a characterization of tumor-connected neurons has been hampered by a lack of technologies. Here, we adapted retrograde tracing using rabies viruses to investigate and manipulate neuron-tumor networks. Glioblastoma rapidly integrated into neural circuits across the brain engaging in widespread functional communication, with acetylcholinergic neurons driving glioblastoma invasion. We uncovered patient-specific and tumor cell state-dependent differences in synaptogenic gene expression associated with neuron-tumor connectivity and subsequent invasivity. Importantly, radiotherapy enhanced neuron-tumor connectivity by increased neuronal activity. In turn, simultaneous neuronal activity inhibition and radiotherapy showed increased therapeutic effects, indicative of a role for neuron-to-glioma synapses in contributing to therapeutic resistance. Lastly, rabies-mediated genetic ablation of tumor-connected neurons halted glioblastoma progression, offering a viral strategy to tackle glioblastoma. Together, this study provides a framework to comprehensively characterize neuron-tumor networks and target glioblastoma.
@article{Cai2023b,
title = {Brain organoid reservoir computing for artificial intelligence},
author = {Hongwei Cai and Zheng Ao and Chunhui Tian and Zhuhao Wu and Hongcheng Liu and Jason Tchieu and Mingxia Gu and Ken Mackie and Feng Guo },
url = {https://www.nature.com/articles/s41928-023-01069-w},
doi = {10.1038/s41928-023-01069-w},
year = {2023},
date = {2023-12-11},
journal = {Nature Electronics},
abstract = {Brain-inspired computing hardware aims to emulate the structure and working principles of the brain and could be used to address current limitations in artificial intelligence technologies. However, brain-inspired silicon chips are still limited in their ability to fully mimic brain function as most examples are built on digital electronic principles. Here we report an artificial intelligence hardware approach that uses adaptive reservoir computation of biological neural networks in a brain organoid. In this approach—which is termed Brainoware—computation is performed by sending and receiving information from the brain organoid using a high-density multielectrode array. By applying spatiotemporal electrical stimulation, nonlinear dynamics and fading memory properties are achieved, as well as unsupervised learning from training data by reshaping the organoid functional connectivity. We illustrate the practical potential of this technique by using it for speech recognition and nonlinear equation prediction in a reservoir computing framework.},
keywords = {3D Culture, HD-MEA, Machine Learning, MaxOne, MEA Technology, Organoids, Stimulation},
pubstate = {published},
tppubtype = {article}
}
Brain-inspired computing hardware aims to emulate the structure and working principles of the brain and could be used to address current limitations in artificial intelligence technologies. However, brain-inspired silicon chips are still limited in their ability to fully mimic brain function as most examples are built on digital electronic principles. Here we report an artificial intelligence hardware approach that uses adaptive reservoir computation of biological neural networks in a brain organoid. In this approach—which is termed Brainoware—computation is performed by sending and receiving information from the brain organoid using a high-density multielectrode array. By applying spatiotemporal electrical stimulation, nonlinear dynamics and fading memory properties are achieved, as well as unsupervised learning from training data by reshaping the organoid functional connectivity. We illustrate the practical potential of this technique by using it for speech recognition and nonlinear equation prediction in a reservoir computing framework.
@article{Ryu2023,
title = {Stress-free cell aggregation by using the CEPT cocktail enhances embryoid body and organoid fitness},
author = {Seungmi Ryu and Claire Weber and Pei-Hsuan Chu and Ben Ernest and Vukasin M Jovanovic and Tao Deng and Jaroslav Slamecka and Hyenjong Hong and Yogita Jethmalani and Hannah M Baskir and Jason Inman and John Braisted and Marissa B Hirst and Anton Simeonov and Ty C Voss and Carlos A Tristan and Ilyas Singeç},
url = {https://dx.doi.org/10.1088/1758-5090/ad0d13},
doi = {10.1088/1758-5090/ad0d13},
year = {2023},
date = {2023-12-11},
journal = {Biofabrication},
abstract = {Embryoid bodies (EBs) and self-organizing organoids derived from human pluripotent stem cells (hPSCs) recapitulate tissue development in a dish and hold great promise for disease modeling and drug development. However, current protocols are hampered by cellular stress and apoptosis during cell aggregation, resulting in variability and impaired cell differentiation. Here, we demonstrate that EBs and various organoid models (e.g., brain, gut, kidney) can be optimized by using the small molecule cocktail named CEPT (chroman 1, emricasan, polyamines, trans-ISRIB), a polypharmacological approach that ensures cytoprotection and cell survival. Application of CEPT for just 24 h during cell aggregation has long-lasting consequences affecting morphogenesis, gene expression, cellular differentiation, and organoid function. Various qualification methods confirmed that CEPT treatment enhanced experimental reproducibility and consistently improved EB and organoid fitness as compared to the widely used ROCK inhibitor Y-27632. Collectively, we discovered that stress-free cell aggregation and superior cell survival in the presence of CEPT are critical quality control determinants that establish a robust foundation for bioengineering complex tissue and organ models.},
keywords = {3D Culture, Activity Scan Assay, HD-MEA, MEA Technology, Organoids},
pubstate = {published},
tppubtype = {article}
}
Embryoid bodies (EBs) and self-organizing organoids derived from human pluripotent stem cells (hPSCs) recapitulate tissue development in a dish and hold great promise for disease modeling and drug development. However, current protocols are hampered by cellular stress and apoptosis during cell aggregation, resulting in variability and impaired cell differentiation. Here, we demonstrate that EBs and various organoid models (e.g., brain, gut, kidney) can be optimized by using the small molecule cocktail named CEPT (chroman 1, emricasan, polyamines, trans-ISRIB), a polypharmacological approach that ensures cytoprotection and cell survival. Application of CEPT for just 24 h during cell aggregation has long-lasting consequences affecting morphogenesis, gene expression, cellular differentiation, and organoid function. Various qualification methods confirmed that CEPT treatment enhanced experimental reproducibility and consistently improved EB and organoid fitness as compared to the widely used ROCK inhibitor Y-27632. Collectively, we discovered that stress-free cell aggregation and superior cell survival in the presence of CEPT are critical quality control determinants that establish a robust foundation for bioengineering complex tissue and organ models.
@article{Elliott2023,
title = {Internet-Connected Cortical Organoids for Project-Based Stem Cell and Neuroscience Education},
author = {Matthew A. T. Elliott and Hunter E. Schweiger and Ash Robbins and Samira Vera-Choqqueccota and Drew Ehrlich and Sebastian Hernandez and Kateryna Voitiuk and Jinghui Geng and Jess L. Sevetson and Cordero Core and Yohei M. Rosen and Mircea Teodorescu and Nico O. Wagner and David Haussler and Mohammed A. Mostajo-Radji},
url = {https://www.eneuro.org/lookup/doi/10.1523/ENEURO.0308-23.2023},
doi = {10.1523/ENEURO.0308-23.2023},
year = {2023},
date = {2023-11-28},
journal = {eNeuro},
abstract = {The introduction of Internet-connected technologies to the classroom has the potential to revolutionize STEM education by allowing students to perform experiments in complex models that are unattainable in traditional teaching laboratories. By connecting laboratory equipment to the cloud, we introduce students to experimentation in pluripotent stem cell (PSC)-derived cortical organoids in two different settings: using microscopy to monitor organoid growth in an introductory tissue culture course and using high-density (HD) multielectrode arrays (MEAs) to perform neuronal stimulation and recording in an advanced neuroscience mathematics course. We demonstrate that this approach develops interest in stem cell and neuroscience in the students of both courses. All together, we propose cloud technologies as an effective and scalable approach for complex project-based university training.},
keywords = {3D Culture, Activity Scan Assay, HD-MEA, IPSC, MaxOne, MEA Technology, Organoids, Spike Sorting, Stimulation},
pubstate = {published},
tppubtype = {article}
}
The introduction of Internet-connected technologies to the classroom has the potential to revolutionize STEM education by allowing students to perform experiments in complex models that are unattainable in traditional teaching laboratories. By connecting laboratory equipment to the cloud, we introduce students to experimentation in pluripotent stem cell (PSC)-derived cortical organoids in two different settings: using microscopy to monitor organoid growth in an introductory tissue culture course and using high-density (HD) multielectrode arrays (MEAs) to perform neuronal stimulation and recording in an advanced neuroscience mathematics course. We demonstrate that this approach develops interest in stem cell and neuroscience in the students of both courses. All together, we propose cloud technologies as an effective and scalable approach for complex project-based university training.
Sawada, Tomoyo; Barbosa, André R; Araujo, Bruno; McCord, Alejandra E; D’Ignazio, Laura; Benjamin, Kynon J M; Sheehan, Bonna; Zabolocki, Michael; Feltrin, Arthur; Arora, Ria; Brandtjen, Anna C; Kleinman, Joel E; Hyde, Thomas M; Bardy, Cedric; Weinberger, Daniel R; Paquola, Apuã C M; Erwin, Jennifer A
@article{Tomoyo2023,
title = {Recapitulation of Perturbed Striatal Gene Expression Dynamics of Donor’s Brains With Ventral Forebrain Organoids Derived From the Same Individuals With Schizophrenia},
author = {Tomoyo Sawada and André R. Barbosa and Bruno Araujo and Alejandra E. McCord and Laura D’Ignazio and Kynon J.M. Benjamin and Bonna Sheehan and Michael Zabolocki and Arthur Feltrin and Ria Arora and Anna C. Brandtjen and Joel E. Kleinman and Thomas M. Hyde and Cedric Bardy and Daniel R. Weinberger and Apuã C.M. Paquola and Jennifer A. Erwin},
url = {https://ajp.psychiatryonline.org/doi/10.1176/appi.ajp.20220723},
doi = {10.1176/appi.ajp.20220723},
issn = {0002-953X},
year = {2023},
date = {2023-11-02},
journal = {American Journal of Psychiatry},
abstract = {Objective:
Schizophrenia is a brain disorder that originates during neurodevelopment and has complex genetic and environmental etiologies. Despite decades of clinical evidence of altered striatal function in affected patients, studies examining its cellular and molecular mechanisms in humans are limited. To explore neurodevelopmental alterations in the striatum associated with schizophrenia, the authors established a method for the differentiation of induced pluripotent stem cells (iPSCs) into ventral forebrain organoids (VFOs).
Methods:
VFOs were generated from postmortem dural fibroblast–derived iPSCs of four individuals with schizophrenia and four neurotypical control individuals for whom postmortem caudate genotypes and transcriptomic data were profiled in the BrainSeq neurogenomics consortium. Individuals were selected such that the two groups had nonoverlapping schizophrenia polygenic risk scores (PRSs).
Results:
Single-cell RNA sequencing analyses of VFOs revealed differences in developmental trajectory between schizophrenia and control individuals in which inhibitory neuronal cells from the patients exhibited accelerated maturation. Furthermore, upregulated genes in inhibitory neurons in schizophrenia VFOs showed a significant overlap with upregulated genes in postmortem caudate tissue of individuals with schizophrenia compared with control individuals, including the donors of the iPSC cohort.
Conclusions:
The findings suggest that striatal neurons derived from high-PRS individuals with schizophrenia carry abnormalities that originated during early brain development and that the VFO model can recapitulate disease-relevant cell type–specific neurodevelopmental phenotypes in a dish.},
keywords = {3D Culture, Activity Scan Assay, HD-MEA, MaxTwo, Network Assay, Organoids},
pubstate = {published},
tppubtype = {article}
}
Schizophrenia is a brain disorder that originates during neurodevelopment and has complex genetic and environmental etiologies. Despite decades of clinical evidence of altered striatal function in affected patients, studies examining its cellular and molecular mechanisms in humans are limited. To explore neurodevelopmental alterations in the striatum associated with schizophrenia, the authors established a method for the differentiation of induced pluripotent stem cells (iPSCs) into ventral forebrain organoids (VFOs).
Methods:
VFOs were generated from postmortem dural fibroblast–derived iPSCs of four individuals with schizophrenia and four neurotypical control individuals for whom postmortem caudate genotypes and transcriptomic data were profiled in the BrainSeq neurogenomics consortium. Individuals were selected such that the two groups had nonoverlapping schizophrenia polygenic risk scores (PRSs).
Results:
Single-cell RNA sequencing analyses of VFOs revealed differences in developmental trajectory between schizophrenia and control individuals in which inhibitory neuronal cells from the patients exhibited accelerated maturation. Furthermore, upregulated genes in inhibitory neurons in schizophrenia VFOs showed a significant overlap with upregulated genes in postmortem caudate tissue of individuals with schizophrenia compared with control individuals, including the donors of the iPSC cohort.
Conclusions:
The findings suggest that striatal neurons derived from high-PRS individuals with schizophrenia carry abnormalities that originated during early brain development and that the VFO model can recapitulate disease-relevant cell type–specific neurodevelopmental phenotypes in a dish.
@article{Metto2023,
title = {Closed-loop neurostimulation via expression of magnetogenetics-sensitive protein in inhibitory neurons leads to reduction of seizure activity in a rat model of epilepsy},
author = {Abigael C. Metto and Petra Telgkamp and Autumn K. McLane-Svoboda and Assaf A. Gilad and Galit Pelled},
url = {https://www.sciencedirect.com/science/article/pii/S0006899323003621},
doi = {https://doi.org/10.1016/j.brainres.2023.148591},
year = {2023},
date = {2023-09-24},
journal = {Brain Research},
abstract = {On-demand neurostimulation has shown success in epilepsy patients with pharmacoresistant seizures. Seizures produce magnetic fields that can be recorded using magnetoencephalography. We developed a new closed-loop approach to control seizure activity based on magnetogenetics using the electromagnetic perceptive gene (EPG) that encodes a protein that responds to magnetic fields. The EPG transgene was expressed in inhibitory interneurons under the hDlx promoter and kainic acid was used to induce acute seizures. In vivo electrophysiological signals were recorded. We found that hDlx EPG rats exhibited a significant delay in the onset of first seizure (1142.72 ± 186.35 s) compared to controls (644.03 ± 15.06 s) and significantly less seizures (4.11 ± 1.03) compared to controls (8.33 ± 1.58). These preliminary findings suggest that on-demand activation of EPG expressed in inhibitory interneurons suppresses seizure activity, and magnetogenetics via EPG may be an effective strategy to alleviate seizure severity in a closed-loop, and cell-specific fashion.},
keywords = {3D Culture, closed loop stimulation, HD-MEA, MaxOne, Slices},
pubstate = {published},
tppubtype = {article}
}
On-demand neurostimulation has shown success in epilepsy patients with pharmacoresistant seizures. Seizures produce magnetic fields that can be recorded using magnetoencephalography. We developed a new closed-loop approach to control seizure activity based on magnetogenetics using the electromagnetic perceptive gene (EPG) that encodes a protein that responds to magnetic fields. The EPG transgene was expressed in inhibitory interneurons under the hDlx promoter and kainic acid was used to induce acute seizures. In vivo electrophysiological signals were recorded. We found that hDlx EPG rats exhibited a significant delay in the onset of first seizure (1142.72 ± 186.35 s) compared to controls (644.03 ± 15.06 s) and significantly less seizures (4.11 ± 1.03) compared to controls (8.33 ± 1.58). These preliminary findings suggest that on-demand activation of EPG expressed in inhibitory interneurons suppresses seizure activity, and magnetogenetics via EPG may be an effective strategy to alleviate seizure severity in a closed-loop, and cell-specific fashion.
Zhao, Eric T; Hull, Jacob M; Hemed, Nofar Mintz; Ulusan, Hasan; Bartram, Julian; Zhang, Anqi; Wang, Pingyu; Pham, Albert; Silvia Ronchi, John Huguenard R; Hierlemann, Andreas; Melosh, Nicholas A
@article{Zhao2023,
title = {A CMOS-based highly scalable flexible neural electrode interface},
author = {Eric T. Zhao and Jacob M. Hull and Nofar Mintz Hemed and Hasan Ulusan and Julian Bartram and Anqi Zhang and Pingyu Wang and Albert Pham and Silvia Ronchi, John R. Huguenard and Andreas Hierlemann and Nicholas A. Melosh},
url = {https://www.science.org/doi/10.1126/sciadv.adf9524},
doi = {DOI: 10.1126/sciadv.adf9524},
year = {2023},
date = {2023-06-07},
journal = {Science Advances},
abstract = {Perception, thoughts, and actions are encoded by the coordinated activity of large neuronal populations spread over large areas. However, existing electrophysiological devices are limited by their scalability in capturing this cortex-wide activity. Here, we developed an electrode connector based on an ultra-conformable thin-film electrode array that self-assembles onto silicon microelectrode arrays enabling multithousand channel counts at a millimeter scale. The interconnects are formed using microfabricated electrode pads suspended by thin support arms, termed Flex2Chip. Capillary-assisted assembly drives the pads to deform toward the chip surface, and van der Waals forces maintain this deformation, establishing Ohmic contact. Flex2Chip arrays successfully measured extracellular action potentials ex vivo and resolved micrometer scale seizure propagation trajectories in epileptic mice. We find that seizure dynamics in absence epilepsy in the Scn8a+/− model do not have constant propagation trajectories.},
keywords = {3D Culture, HD-MEA, MaxOne, Other Tissues, Slices},
pubstate = {published},
tppubtype = {article}
}
Perception, thoughts, and actions are encoded by the coordinated activity of large neuronal populations spread over large areas. However, existing electrophysiological devices are limited by their scalability in capturing this cortex-wide activity. Here, we developed an electrode connector based on an ultra-conformable thin-film electrode array that self-assembles onto silicon microelectrode arrays enabling multithousand channel counts at a millimeter scale. The interconnects are formed using microfabricated electrode pads suspended by thin support arms, termed Flex2Chip. Capillary-assisted assembly drives the pads to deform toward the chip surface, and van der Waals forces maintain this deformation, establishing Ohmic contact. Flex2Chip arrays successfully measured extracellular action potentials ex vivo and resolved micrometer scale seizure propagation trajectories in epileptic mice. We find that seizure dynamics in absence epilepsy in the Scn8a+/− model do not have constant propagation trajectories.
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