Brain Organoids

Study of Brain Organoids 

Brain organoids are artificially grown 3D aggregates that resemble the embryonic human brain, usually  generated from human induced pluripotent stem cells (h-iPSC).
MaxTwo, a multi-well high resolution microelectrode array (MEA) system, is best suited for long-term and label-free analysis of brain organoids. MaxTwo’s large sensor array at high-resolution enables recording of every active cell across multiple areas of biological samples.

Readout at different scales:

  • Network level (population spike times, bursts)
  • Cell level (individual spike time, waveform)
  • Sub-cellular level (spatially resolved waveforms)

Webinar

Watch our Organoids webinar that introduces high-resolution functional imaging of Brain Organoids

Watch the replay

What You Can Do

Capture high quality activity maps from organoids

MaxTwo enables recording of neuronal activity at high spatio-temporal resolution and label-free electrical  imaging of organoids.

  • “See” all the active cells on top of the array and identify the activity of each cell.
  • Detect small spikes from developing neurons and from cell compartments, such as axonal action potentials.
  • Analyze full organoids and determine initiation and propagation of network activity.

Microscopy image of three h-iPSC-derived organoids (DIV 60) overlaid with firing rate and amplitude activity maps.1

Pharmacological manipulation of network bursts in organoids

The network bursting activity of h-iPSC-derived cortical organoids (DIV 60) was modulated using
NMDA (N-methyl-D-aspartic acid) receptor inhibitor 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and an NMDA noncompetitive antagonist (MK801). CNQX decreased the network activity, but increased the mean spike firing rate and mean spike amplitude. MK801 decreased both the network burst activity and the mean spike firing rate, but did not affect the mean spike amplitude.1

Functional characterization of organoids modeling different brain regions

High-resolution allows to precisely identify and isolate active areas in all the analyzed preparations. The progressive complexity of the modeled regions correlates with an increased synchrony in the recorded network activity.2

Activity maps and distributions of spike amplitude and firing rate for a
h-iPSC-derived fused (dorsal + ventral) cerebral organoid (DIV 56).

Network activity for distinct organoid preparations.

Effects of serotonin exposure during cerebellar maturation

Cerebellar dysfunction often involves a prominent loss of Purkinje cells (Taroni and DiDonato, 2004). Serotonin (5-hydroxytryptoamine, 5-HT) is reported in the regulation of the morphological maturation of Purkinje cells (Kondoh et al., 2004; Oostland and van Hooft, 2013). 5-HT treatment during the maturation protocol of cerebellar organoids is hypothesized to lead to higher efficiency of morphological and physiological maturation of Purkinje cells. Treated organoids showcase synchronized bursting activity, an indicator of synaptic maturation.2

Activity maps and distributions of spike amplitude and firing rate for a
5-HT-treated h-iPSC-derived cerebellar organoid (DIV 56).

Effect of 5-HT treatment on the network activity of a cerebellar organoid.

Single cell tracking in organoids

Neurons up to a depth of 100 μm (Frey et al., 2009; Obien et al., 2019) can be precisely detected and isolated in brain organoids. Electrical footprints and single cell-spiking patterns can be extracted to analyze signal propagation and cell activation dynamics.1

Traces expressing different activation patterns of the three identified neurons (left). Three neurons identified from one area of an organoid; circles indicate the electrode used to obtain the electrical footprints for each neuron (right).

Electrical footprints of the three identified neurons.

1 Data obtained in collaboration with Hopstem Bioengineering Co., Ltd., Hangzhou, Zhejiang, China. Organoid image on the first page, top right is courtesy of Dr. Anxin Wang.
2 Data obtained in collaboration with the Stem Cell Engineering Research Group (SCERG) at iBB – Institute for Biosciences and Bioengineering of Instituto Superior Técnico, Universidade de Lisboa, Portugal. Special thanks to Ana Rita Gomes, MsC, for carrying out the experiments.

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Selected Publications

Protosequences in human cortical organoids model intrinsic states in the developing cortex

van der Molen, Tjitse; Spaeth, Alex; Chini, Mattia; Bartram, Julian; Dendukuri, Aditya; Zhang, Zongren; Bhaskaran-Nair, Kiran; Blauvelt, Lon J; Petzold, Linda R; Hansma, Paul K; Teodorescu, Mircea; Hierlemann, Andreas; Hengen, Keith B; Hanganu-Opatz, Ileana L; Kosik, Kenneth S; Sharf, Tal

Protosequences in human cortical organoids model intrinsic states in the developing cortex Journal Article

bioRxiv, 2023.

Abstract | Links | BibTeX

Brain organoid reservoir computing for artificial intelligence

Cai, Hongwei; Ao, Zheng; Tian, Chunhui; Wu, Zhuhao; Liu, Hongcheng; Tchieu, Jason; Gu, Mingxia; Mackie, Ken; Guo, Feng

Brain organoid reservoir computing for artificial intelligence Journal Article

Nature Electronics, 2023.

Abstract | Links | BibTeX

Stress-free cell aggregation by using the CEPT cocktail enhances embryoid body and organoid fitness

Ryu, Seungmi; Weber, Claire; Chu, Pei-Hsuan; Ernest, Ben; Jovanovic, Vukasin M; Deng, Tao; Slamecka, Jaroslav; Hong, Hyenjong; Jethmalani, Yogita; Baskir, Hannah M; Inman, Jason; Braisted, John; Hirst, Marissa B; Simeonov, Anton; Voss, Ty C; Tristan, Carlos A; Singeç, Ilyas

Stress-free cell aggregation by using the CEPT cocktail enhances embryoid body and organoid fitness Journal Article

Biofabrication, 2023.

Abstract | Links | BibTeX

Internet-Connected Cortical Organoids for Project-Based Stem Cell and Neuroscience Education

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 Journal Article

eNeuro, 2023.

Abstract | Links | BibTeX

Recapitulation of Perturbed Striatal Gene Expression Dynamics of Donor’s Brains With Ventral Forebrain Organoids Derived From the Same Individuals With Schizophrenia

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

Recapitulation of Perturbed Striatal Gene Expression Dynamics of Donor’s Brains With Ventral Forebrain Organoids Derived From the Same Individuals With Schizophrenia Journal Article

American Journal of Psychiatry, 2023, ISSN: 0002-953X.

Abstract | Links | BibTeX

BiœmuS: A new tool for neurological disorders studies through real-time emulation and hybridization using biomimetic Spiking Neural Network

Levi, Timothee; Beaubois, Romain; Cheslet, Jérémy; Duenki, Tomoya; Khoyratee, Farad; Branchereau, Pascal; Ikeuchi, Yoshiho

BiœmuS: A new tool for neurological disorders studies through real-time emulation and hybridization using biomimetic Spiking Neural Network Journal Article

Research Square, 2023.

Abstract | Links | BibTeX

Generation of functional posterior spinal motor neurons from hPSCs-derived human spinal cord neural progenitor cells

Xu, He Jax; Yao, Yao; Yao, Fenyong; Chen, Jiehui; Li, Meishi; Yang, Xianfa; Li, Sheng; Lu, Fangru; Hu, Ping; He, Shuijin; Peng, Guangdun; Jing, Naihe

Generation of functional posterior spinal motor neurons from hPSCs-derived human spinal cord neural progenitor cells Journal Article

Cell Regeneration, 2023.

Abstract | Links | BibTeX

Brain Organoid Computing for Artificial Intelligence

Cai, Hongwei; Ao, Zheng; Tian, Chunhui; Wu, Zhuhao; Liu, Hongcheng; Tchieu, Jason; Gu, Mingxia; Mackie, Ken; and Guo, Feng

Brain Organoid Computing for Artificial Intelligence Journal Article

bioRxiv, 2023.

Abstract | Links | BibTeX

A Neurospheroid-Based Microrobot for Targeted Neural Connections in a Hippocampal Slice

Kim, Eunhee; Jeon, Sungwoong; Yang, Yoon-Sil; Jin, Chaewon; Kim, Jin-young; Oh, Yong- Seok; Rah, Jong-Cheol; and Choi, Hongsoo

A Neurospheroid-Based Microrobot for Targeted Neural Connections in a Hippocampal Slice Journal Article

Advanced Materials, 2023.

Abstract | Links | BibTeX

A functional neuron maturation device provides convenient application on microelectrode array for neural network measurement

Han, Xiaobo; Matsuda, Naoki; Ishibashi, Yuto; Odawara, Aoi; Takahashi, Sayuri; Tooi, Norie; Kinoshita, Koshi; Suzuki, Ikuro

A functional neuron maturation device provides convenient application on microelectrode array for neural network measurement Journal Article

Biomaterials Research, 2022.

Abstract | Links | BibTeX

Downregulation of PMP22 ameliorates myelin defects in iPSC-derived human organoid cultures of CMT1A

Lent, Jonas Van; Vendredy, Leen; Adriaenssens, Elias; Authier, Tatiana Da Silva; Asselbergh, Bob; Kaji, Marcus; Weckhuysen, Sarah; Bosch, Ludo Van Den; Baets, Jonathan; Timmerman, Vincent

Downregulation of PMP22 ameliorates myelin defects in iPSC-derived human organoid cultures of CMT1A Journal Article

Brain, 2022.

Abstract | Links | BibTeX

Generation of Human Striatal-Midbrain Assembloids From Human Pluripotent Stem Cells to Model Alpha-Synuclein Propagation

Tran, Hoang-Dai; Shin, Min-Kyoung; Denman, Charlotte; Han, Run-Run; Kuhn, Bernd; Arbuthnott, Gordon; Jo, Junghyun

Generation of Human Striatal-Midbrain Assembloids From Human Pluripotent Stem Cells to Model Alpha-Synuclein Propagation Journal Article

Sneak Peek - Cell Press, 2022.

Abstract | Links | BibTeX

Functional neuronal circuitry and oscillatory dynamics in human brain organoids

Sharf Tal; Molen, Tjitse; Glasauer Stella; Guzman Elmer; Buccino Alessio; Luna Gabriel; Cheng Zhuowei; Audouard Morgane; Ranasinghe Kamalini; Kudo Kiwamu; Nagarajan Srikantan; Tovar Kenneth; Petzold Linda; Hierlemann Andreas; Hansma Paul; ; Kosik, Kenneth;

Functional neuronal circuitry and oscillatory dynamics in human brain organoids Journal Article

Nature Communications, 2022.

Abstract | Links | BibTeX

Functional imaging of brain organoids using high-density microelectrode arrays

Schröter Manuel; Wang, Congwei; Terrigno Marco; Hornauer Philipp; Huang Ziqiang; Jagasia Ravi; Hierlemann Andreas

Functional imaging of brain organoids using high-density microelectrode arrays Journal Article

MRS Bulletin, 2022.

Abstract | Links | BibTeX

Autism genes converge on asynchronous development of shared neuron classes

Paulsen, Bruna; Velasco, Silvia; Kedaigle, Amanda J; Pigoni, Martina; Quadrato, Giorgia; Deo, Anthony J; Adiconis, Xian; Uzquiano, Ana; Sartore, Rafaela; Yang, Sung Min; Simmons, Sean K; Symvoulidis, Panagiotis; Kim, Kwanho; Tsafou, Kalliopi; Podury, Archana; Abbate, Catherine; Tucewicz, Ashley; Smith, Samantha N; Albanese, Alexandre; Barrett, Lindy; Sanjana, Neville E; Shi, Xi; Chung, Kwanghun; Lage, Kasper; Boyden, Edward S; andJoshua Levin, Aviv Regev Z; Arlotta, Paola

Autism genes converge on asynchronous development of shared neuron classes Journal Article

Nature, 602 , pp. 268–273, 2022.

Abstract | Links | BibTeX

Intrinsic network activity in human brain organoids

Sharf, Tal; van der Molen, Tjitse; Guzman, Elmer; Glasauer, Stella M K; Luna, Gabriel; Cheng, Zhouwei; Audouard, Morgane; Ranasinghe, Kamalini G; Kudo, Kiwamu; Nagarajan, Srikantan S; Tovar, Kenneth R; Petzold, Linda R; Hansma, Paul K; Kosik, Kenneth S

Intrinsic network activity in human brain organoids Journal Article

BioRxiv, 2021.

Abstract | Links | BibTeX

Cell Types of the Human Retina and Its Organoids at Single-Cell Resolution

Cowan, Cameron S; Renner, Magdalena; Gennaro, Martina De; Gross-Scherf, Brigitte; Goldblum, David; Hou, Yanyan; Munz, Martin; Rodrigues, Tiago M; Krol, Jacek; Szikra, Tamas; Cuttat, Rachel; Waldt, Annick; Papasaikas, Panagiotis; Diggelmann, Roland; Patino-Alvarez, Claudia P; Galliker, Patricia; Spirig, Stefan E; Pavlinic, Dinko; Gerber-Hollbach, Nadine; Schuierer, Sven; Srdanovic, Aldin; Balogh, Marton; Panero, Riccardo; Kusnyerik, Akos; Szabo, Arnold; Stadler, Michael B; Orgül, Selim; Picelli, Simone; Hasler, Pascal W; Hierlemann, Andreas; Scholl, Hendrik P N; Roma, Guglielmo; Nigsch, Florian; Roska, Botond

Cell Types of the Human Retina and Its Organoids at Single-Cell Resolution Journal Article

CellPress, 182 , pp. 1623–1640, 2020.

Abstract | Links | BibTeX

Mapping neuronal network dynamics in developing cerebral organoids

Schroter, Manuel; Girr, Monika; Boos, Julia Alicia; Renner, Magdalena; Gazorpak, Mahshid; Gong, Wei; Bartram, Julian; Muller, Jan; Hierlemann, Andreas

Mapping neuronal network dynamics in developing cerebral organoids Conference

11th International Meeting on Substrate Integrated Microelectrode Arrays (MEA Meeting) Reutlingen, Germany, 2018.

Abstract | Links | BibTeX

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