Project

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Microtechnology and microelectronics to study mammalian axons

English title Microtechnology and microelectronics to study mammalian axons
Applicant Hierlemann Andreas
Number 157092
Funding scheme Project funding (Div. I-III)
Research institution Computational Systems Biology Department of Biosystems, D-BSSE ETH Zürich
Institution of higher education ETH Zurich - ETHZ
Main discipline Microelectronics. Optoelectronics
Start/End 01.09.2015 - 31.08.2019
Approved amount 700'000.00
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All Disciplines (3)

Discipline
Microelectronics. Optoelectronics
Biophysics
Cellular Biology, Cytology

Keywords (6)

Neuronal cells and circuits; Electrophysiology; Microelectrode arrays; Microtechnology & Microelectronics ; Axons

Lay Summary (German)

Lead
Anwendung von mikroelektronischen Bauteilen um Signale von Axonen aufzuzeichnen. Axone übermitteln die Ausgangssignale von Neuronen.
Lay summary

Die Informationsverarbeitung in Neuronen ist gerichtet: Neuronen erhalten Input durch die Dendriten, verarbeiten die erhaltene Information und übermitteln dann Ausgangssignale durch die Axone. Da neuronale Signale elektrischer Natur sind, kann man Anordnungen von Mikroelektroden dazu benutzen, um neuronale Signal aufzuzeichnen. Indem man sehr kleine Elektroden und dicht gepackte Elektrodenanordnungen benutzt (mehr als 3000 Elektroden pro Quadratmillimeter), kann man mit mehreren Elektroden Signale von demselben Neuron oder sogar von Axonen erfassen. Das Aufzeichnen axonaler Signal ist shr schwierig mit anderen Methoden, da das Axon einen sehr geringen Durchmesser hat (ca. 100 nm) und die Signalamplituden sehr klein sind (wenige MikroVolt)

Dieses Projekt handelt vom Aufzeichnen und der Charakterisierung axonaler Signale mithilfe von integrierten Elektrodenarraymikrosystemen in CMOS Technologie. Die mikroelektronischen Systeme erlauben die gleichzeitige Aufzeichnung multipler neuronaler Signale in subzellulärerer Auflösung sowie die punktgenaue Stimulierung einzelner Neuronen oder Axone. Die Signal können entlang des ganzen Verlaufs eines Axons gemessen werden über mehrere hundert Elektroden hinweg. Im Projekt werden Signaldetektionsverfahren und Datenanalyseverfahren entwickelt um die sehr kleinen Signale von Axonen mit hoher Auflösung und grosser Treffsicherheit zu erfassen und einzelnen Axonen und Axonzweigen zuzuordnen.

Direct link to Lay Summary Last update: 03.07.2015

Lay Summary (English)

Lead
Use of microelectronics technology to record and detect signals from axons. Axons are the signal output connections of neurons.
Lay summary

Information processing in neurons is directional: Neurons receive input through the dendrites, process the information and then output signals via the axon to other neurons. As neuronal signals are of electric nature, it is possible to use arrays of electrodes to record from neurons and neuronal networks. By using very small (a few micrometer diameter) and densely packed electrodes (more than 3000 per square millimeter) on a microelectronic chip, it is possible to have many electrodes recording from a specific neuron and even from axons, the output connections of the neurons. The recording of axon signals is very difficult with other methods, as the diameter of axons is very small, approximately 100 nanometer and as teh signal amplitudes are very small.

This project is centered around using microelectronic chips featuring extremely dense microelectrode arrays to study information processing and signaling characteristics of axons. The microelectronic chips are fabricated in complementary metal oxide semiconductor (CMOS) technology, and allow for subcellular-resolution recording of many neurons and/or axons in parallel and for precise single-cell stimulation. By using CMOS technology, we will develop measurement strategies for recording and localizing electrical activity along the entire length of multiple axons including branch points. We will develop data evaluation methods to achieve lowest-level signal detection (detection of individual axonal action potentials) and maximum fidelity in signal assignment to axonal branches.



Direct link to Lay Summary Last update: 03.07.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
Accurate signal-source localization in brain slices by means of high-density microelectrode arrays
Obien Marie Engelene J., Hierlemann Andreas, Frey Urs (2019), Accurate signal-source localization in brain slices by means of high-density microelectrode arrays, in Scientific Reports, 9(1), 788-788.
Large-Scale Mapping of Axonal Arbors Using High-Density Microelectrode Arrays
Bullmann Torsten, Radivojevic Milos, Huber Stefan T., Deligkaris Kosmas, Hierlemann Andreas, Frey Urs (2019), Large-Scale Mapping of Axonal Arbors Using High-Density Microelectrode Arrays, in Frontiers in Cellular Neuroscience, 13, 404.
Stimulation and Artifact-Suppression Techniques for In Vitro High-Density Microelectrode Array Systems
Shadmani Amir, Viswam Vijay, Chen Yihui, Bounik Raziyeh, Dragas Jelena, Radivojevic Milos, Geissler Sydney, Sitnikov Sergey, Muller Jan, Hierlemann Andreas (2019), Stimulation and Artifact-Suppression Techniques for In Vitro High-Density Microelectrode Array Systems, in IEEE Transactions on Biomedical Engineering, 66(9), 2481-2490.
Optimal Electrode Size for Multi-Scale Extracellular-Potential Recording From Neuronal Assemblies
Viswam Vijay, Obien Marie Engelene J., Franke Felix, Frey Urs, Hierlemann Andreas (2019), Optimal Electrode Size for Multi-Scale Extracellular-Potential Recording From Neuronal Assemblies, in Frontiers in Neuroscience, 13, 385.
Technologies to Study Action Potential Propagation With a Focus on HD-MEAs
Emmenegger Vishalini, Obien Marie Engelene J., Franke Felix, Hierlemann Andreas (2019), Technologies to Study Action Potential Propagation With a Focus on HD-MEAs, in Frontiers in Cellular Neuroscience, 13, 159.
The axon initial segment is the dominant contributor to the neuron's extracellular electrical potential landscape
BakkumDouglas, Engelene ObienMarie, RadivojevicMilos, JäckelDavid, FreyUrs, TakahashiHiro, HierlemannAndreas (2019), The axon initial segment is the dominant contributor to the neuron's extracellular electrical potential landscape, in Advanced Biosystems, 1800308.
Combination of High-density Microelectrode Array and Patch Clamp Recordings to Enable Studies of Multisynaptic Integration
J?ckel David, Bakkum Douglas J., Russell Thomas L., M?ller Jan, Radivojevic Milos, Frey Urs, Franke Felix, Hierlemann Andreas (2017), Combination of High-density Microelectrode Array and Patch Clamp Recordings to Enable Studies of Multisynaptic Integration, in Scientific Reports, 7(1), 978.
Tracking individual action potentials throughout mammalian axonal arbors
Radivojevic Milos, Franke Felix, Altermatt Michael, Müller Jan, Hierlemann Andreas, Bakkum Douglas J (2017), Tracking individual action potentials throughout mammalian axonal arbors, in eLife, 6, 30198.
Acquisition of bioelectrical signals with small electrodes
Viswam Vijay, Obien Marie, Frey Urs, Franke Felix, Hierlemann Andreas (2017), Acquisition of bioelectrical signals with small electrodes, in 2017 IEEE Biomedical Circuits and Systems Conference (BioCAS), TorinoIEEE, Piscataway.
Direct interfacing of neurons to highly integrated microsystems
Hierlemann Andreas (2017), Direct interfacing of neurons to highly integrated microsystems, in 2017 IEEE 30th International Conference on Micro Electro Mechanical Systems (MEMS), Las Vegas, NV, USAIEEE, Piscataway.
Analyzing Recurrent Activity in Acute Cortical Slices Using High-Density Microelectrode Arrays
Marie J. Obien, Andreas Hierlemann, Urs Frey (2016), Analyzing Recurrent Activity in Acute Cortical Slices Using High-Density Microelectrode Arrays, in Frontiers in Neuroscience, 10, 1.
Cortical Axons, Isolated in Channels, Display Activity-Dependent Signal Modulation as a Result of Targeted Stimulation.
Lewandowska Marta K, Radivojević Miloš, Jäckel David, Müller Jan, Hierlemann Andreas R (2016), Cortical Axons, Isolated in Channels, Display Activity-Dependent Signal Modulation as a Result of Targeted Stimulation., in Frontiers in neuroscience, 10, 83-83.
Electrical Identification and Selective Microstimulation of Neuronal Compartments Based on Features of Extracellular Action Potentials
Milos Radivojevic, David J�ckel, Michael Altermatt, Jan Mu�ller, Vijay Viswam, Andreas Hierlemann, Douglas Bakkum (2016), Electrical Identification and Selective Microstimulation of Neuronal Compartments Based on Features of Extracellular Action Potentials, in Frontiers in Neuroscience, 10, 1.
Electrical Identification and Selective Microstimulation of Neuronal Compartments Based on Features of Extracellular Action Potentials
Radivojevic Milos, Jäckel David, Altermatt Michael, Müller Jan, Viswam Vijay, Hierlemann Andreas, Bakkum Douglas J. (2016), Electrical Identification and Selective Microstimulation of Neuronal Compartments Based on Features of Extracellular Action Potentials, in Scientific Reports, 6, 31332-31332.
Multiple single-unit long-term tracking on organotypic hippocampal slices using high-density microelectrode arrays
GongWei, SencarJure, Bakkum Douglas, Jäckel David, Engelene ObienMarie, HierlemannAndreas (2016), Multiple single-unit long-term tracking on organotypic hippocampal slices using high-density microelectrode arrays, in Frontiers in Neuroscience, 537.
Studying extracellular action potential waveforms using HD MEAs
Sergey Sitnikov, David Jaeckel, Andreas Hierlemann (2016), Studying extracellular action potential waveforms using HD MEAs, in Frontiers in Neuroscience, 10, 1.
Recording large extracellular spikes in microchannels along many axonal sites from individual neurons.
Lewandowska Marta K, Bakkum Douglas J, Rompani Santiago B, Hierlemann Andreas (2015), Recording large extracellular spikes in microchannels along many axonal sites from individual neurons., in PloS one, 10(3), 0118514-0118514.

Collaboration

Group / person Country
Types of collaboration
University of Tokyo Japan (Asia)
- Publication
Riken, Kobe Japan (Asia)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
41st Annual International Conference of the IEEE Engineering in Medicine and Biology Society Talk given at a conference Subcellular-resolution electrophysiology with highly Integrated CMOS-based microelectrode arrays 23.07.2019 Berlin, Germany Hierlemann Andreas;
IEEE EMBS Micro and Nanotechnology in Medicine Conference, Talk given at a conference Direct interfacing of neurons with CMOS microelectronics 10.12.2018 Kauai, Hawaii, United States of America Hierlemann Andreas;
Society for Neuroscience (SfN) Meeting Poster Investigating the analog modulation of action-potential waveforms in axonal arbors of cortical neurons using whole-cell patch-clamp recordings and high-density microelectrode arrays 03.11.2018 San Diego, United States of America Emmenegger Vishalini;
Society for Neuroscience (SfN) Meeting Poster Mechanisms of homeostatic synaptic plasticit 03.11.2018 San Diego, United States of America Bartram Julian;
11th International Meeting on Substrate Integrated Microelectrode Arrays Talk given at a conference Probing synaptic connectivity and function using high-density microelectrode arrays and whole-cell patch-clamp recordings 04.07.2018 Reutlingen, Germany Bartram Julian;
11th International Meeting on Substrate Integrated Microelectrode Arrays Poster Comparison of axonal-conduction velocity in developing primary cells and human iPSC-derived neuron 04.07.2018 Reutlingen, Germany Obien Marie Engelene;
Material Research Society Fall Meeting, Boston Talk given at a conference Highly Integrated CMOS Microsystems to Interface with Neurons at Subcellular Resolution 26.11.2017 Boston, United States of America Hierlemann Andreas;
40th Annual Meeting of the Japan Neuroscience Society Talk given at a conference Mapping neuron cluster development based on axonal action potential propagation 20.07.2017 Chiba, Japan Obien Marie Engelene;
3rd International Workshop on Functionalized Surfaces for Sensor Applications, SURFOCAP Talk given at a conference CMOS-based Monolithic Microelectrode Systems for Subcellular-resolution Electrophysiology and Sensor Applications 30.05.2017 Besancon, France Hierlemann Andreas;
30th IEEE International Conference on Micro Electro Mechanical Systems (MEMS) Talk given at a conference Direct Interfacing of Neurons to Highly Integrated Microsystems 22.01.2017 Las Vegas, United States of America Hierlemann Andreas;
International MicroNanoConference Talk given at a conference Subcellular-resolution Interfacing of Neurons to Highly Integrated CMOS Microelectrode Systems 13.12.2016 Amsterdam, Netherlands Hierlemann Andreas;
Joint Symposium of the 18th Annual Conference of Chinese Society of Micro-Nano Technology and Microsystems & Nanoengineering Summit 2016 (CSMNT2016 & MAN2016) Talk given at a conference Highly integrated CMOS microsystems to interface with neurons at subcellular resolution 29.07.2016 Beijing, China Hierlemann Andreas;
10th International Meeting on Substrate-Integrated Electrode Arrays Poster Analyzing Recurrent Activity in Acute Cortical Slices Using High-Density Microelectrode Arrays 29.06.2016 Reutlingen, Germany Obien Marie Engelene;
10th International Meeting on Substrate-Integrated Electrode Arrays, Poster Studying extracellular action potential waveforms using HD MEAs 01.06.2016 Reutlingen, Germany Sitnikov Sergey;
IEEE International Electron Devices Meeting Talk given at a conference Highly integrated CMOS microsystems to interface with neurons at subcellular resolution 07.12.2015 Washington, United States of America Hierlemann Andreas;


Self-organised

Title Date Place
MicroTAS 2019 02.10.2019 Basel, Switzerland

Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Venture Kick Events Performances, exhibitions (e.g. for education institutions) 30.11.2017 Zurich, Switzerland Obien Marie Engelene;


Communication with the public

Communication Title Media Place Year
Media relations: radio, television Living organs on a chip SRF German-speaking Switzerland 2018

Awards

Title Year
International Global 3Rs Award Europe 2016

Use-inspired outputs


Start-ups

Name Year

Associated projects

Number Title Start Funding scheme
188910 Deciphering Neuronal Networks: Advancing Technology and Model Systems 01.10.2020 Project funding (Div. I-III)
173728 Visual processing in foveated retinæ in the presence of self-motion 01.01.2018 Sinergia
141801 Image processing by mosaics of retinal cells 01.07.2013 Sinergia

Abstract

Motivated by the fact that there is a shortage of technologies to rigorously study the electrophysiology and the information processing capabilities and contributions of mammalian axons in neuronal networks, we propose to apply microelectronics-based high-density microelectrode arrays (HD-MEAs) in complementary metal oxide semiconductor (CMOS) technology, which allow for subcellular-resolution recording of many neurons and/or axons in parallel and for precise single-cell stimulation. We will combine HD-MEA technology with microtunnel devices, which help to spatially confine axons and to boost their small signals, and with patch clamp measurements that will simultaneously be performed on the same chip. Patch clamp will help to detect sub-threshold signals, to stain specific neurons, and to manipulate their resting membrane potential. By using the combined approach detailed above, we will develop measurement strategies for recording and localizing electrical activity along the entire length of multiple axons, including pre-synaptic boutons and branch points. We will develop spike sorting and data evaluation methods to achieve lowest-signal detection (detection of individual axonal action potentials) and maximum fidelity in signal assignment to axonal branches. We will study the cortex, as most of the grey matter contains unmyelinated axons, which can be readily recorded from by using microelectrode arrays. We will investigate the propagation plasticity of cortical axons: Variations within, and blockade of action potentials (APs) after being exposed to external stimuli, especially at regions of axonal inhomogeneity. The hypothesis is that complex but decipherable integrative principles operate in axons; specifically, that long-lasting activity-dependent changes in excitability, conduction velocity, or blockade, and action potential waveform may serve computational roles in the brain. Moreover, we will investigate how pre-synaptic axonal arbors integrate information at branch points and synaptic boutons. These structures represent regions of low conduction safety for action potentials (they may be propagated or not), but have yet been impossible to study in the mammalian brain.
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