Neural Circuits on a Chip

Neural circuits are responsible for the brain’s ability to process and store information. Reductionist approaches to understanding the brain include isolation of individual neurons for detailed characterization. When maintained in vitro for several days or weeks, dissociated neurons self-assemble into randomly connected networks that produce synchronized activity and are capable of learning. This review focuses on efforts to control neuronal connectivity in vitro and construct living neural circuits of increasing complexity and precision. Microfabrication-based methods have been developed to guide network self-assembly, accomplishing control over in vitro circuit size and connectivity. The ability to control neural connectivity and synchronized activity led to the implementation of logic functions using living neurons. Techniques to construct and control three-dimensional circuits have also been established. Advances in multiple electrode arrays as well as genetically encoded, optical activity sensors and transducers enabled highly specific interfaces to circuits composed of thousands of neurons. Further advances in on-chip neural circuits may lead to better understanding of the brain.

[1]  Shimon Marom,et al.  Selective Adaptation in Networks of Cortical Neurons , 2003, The Journal of Neuroscience.

[2]  Menahem Segal,et al.  Neuronal density determines network connectivity and spontaneous activity in cultured hippocampus. , 2010, Journal of neurophysiology.

[3]  Michael Z. Lin,et al.  Designs and sensing mechanisms of genetically encoded fluorescent voltage indicators. , 2015, Current opinion in chemical biology.

[4]  Pascal Monceau,et al.  Combining Microfluidics, Optogenetics and Calcium Imaging to Study Neuronal Communication In Vitro , 2015, PloS one.

[5]  G. Bi,et al.  Distributed synaptic modification in neural networks induced by patterned stimulation , 1999, Nature.

[6]  M. Gillette,et al.  Over a Century of Neuron Culture: From the Hanging Drop to Microfluidic Devices , 2012, The Yale journal of biology and medicine.

[7]  Karl Deisseroth,et al.  Optogenetics in Neural Systems , 2011, Neuron.

[8]  Niraj S. Desai,et al.  Activity-dependent scaling of quantal amplitude in neocortical neurons , 1998, Nature.

[9]  Hiroyuki Fujita,et al.  Constraining the connectivity of neuronal networks cultured on microelectrode arrays with microfluidic techniques: a step towards neuron-based functional chips. , 2006, Biosensors & bioelectronics.

[10]  A van Bergen,et al.  Long-term stimulation of mouse hippocampal slice culture on microelectrode array. , 2003, Brain research. Brain research protocols.

[11]  A. Hodgkin,et al.  Action Potentials Recorded from Inside a Nerve Fibre , 1939, Nature.

[12]  Peter Molnar,et al.  Two cell circuits of oriented adult hippocampal neurons on self-assembled monolayers for use in the study of neuronal communication in a defined system. , 2013, ACS chemical neuroscience.

[13]  S. Shoham,et al.  Hybrid Multiphoton Volumetric Functional Imaging of Large Scale Bioengineered Neuronal Networks , 2014, Nature Communications.

[14]  Younan Xia,et al.  Nanofiber membranes with controllable microwells and structural cues and their use in forming cell microarrays and neuronal networks. , 2011, Small.

[15]  Soheil Feizi,et al.  Microfluidic neurite guidance to study structure-function relationships in topologically-complex population-based neural networks , 2016, Scientific Reports.

[16]  M. Dichter,et al.  Properties of inhibitory and excitatory synapses between hippocampal neurons in very low density cultures , 1994, Synapse.

[17]  Donald E Ingber,et al.  Synaptic Reorganization in Scaled Networks of Controlled Size , 2007, The Journal of Neuroscience.

[18]  Benjamin F. Grewe,et al.  High-speed recording of neural spikes in awake mice and flies with a fluorescent voltage sensor , 2015, Science.

[19]  Bruce C Wheeler,et al.  Novel MEA platform with PDMS microtunnels enables the detection of action potential propagation from isolated axons in culture. , 2009, Lab on a chip.

[20]  Alexei Verkhratsky,et al.  From Galvani to patch clamp: the development of electrophysiology , 2006, Pflügers Archiv.

[21]  Yunyan Xie,et al.  Self-Organizing Circuit Assembly through Spatiotemporally Coordinated Neuronal Migration within Geometric Constraints , 2011, PloS one.

[22]  G J Brewer,et al.  Modulation of neural network activity by patterning. , 2001, Biosensors & bioelectronics.

[23]  David B. Edelman,et al.  A cultural renaissance: in vitro cell biology embraces three-dimensional context , 2005, Experimental Neurology.

[24]  Andreas Offenhäusser,et al.  Signal Propagation between Neuronal Populations Controlled by Micropatterning , 2016, Front. Bioeng. Biotechnol..

[25]  Steve M. Potter,et al.  An extremely rich repertoire of bursting patterns during the development of cortical cultures , 2006, BMC Neuroscience.

[26]  Eric C. Griffith,et al.  An RNAi-Based Approach Identifies Molecules Required for Glutamatergic and GABAergic Synapse Development , 2007, Neuron.

[27]  P. Massobrio,et al.  Network plasticity in cortical assemblies , 2008, The European journal of neuroscience.

[28]  Danny Eytan,et al.  Dynamics and Effective Topology Underlying Synchronization in Networks of Cortical Neurons , 2006, The Journal of Neuroscience.

[29]  H. Markram,et al.  Regulation of Synaptic Efficacy by Coincidence of Postsynaptic APs and EPSPs , 1997, Science.

[30]  N.F. de Rooij,et al.  Microelectrode arrays for electrophysiological monitoring of hippocampal organotypic slice cultures , 1997, IEEE Transactions on Biomedical Engineering.

[31]  Jan M. Rabaey,et al.  Physical principles for scalable neural recording , 2013, Front. Comput. Neurosci..

[32]  Daniel I. C. Wang,et al.  Engineering cell shape and function. , 1994, Science.

[33]  Y. Tai,et al.  The neurochip: a new multielectrode device for stimulating and recording from cultured neurons , 1999, Journal of Neuroscience Methods.

[34]  Joan Cabestany,et al.  Multisite Recording of Extracellular Potentials Produced by Microchannel-Confined Neurons In-Vitro , 2007, IEEE Transactions on Biomedical Engineering.

[35]  Carl W. Cotman,et al.  Microlithographic determination of axonal/dendritic polarity in cultured hippocampal neurons , 1998, Journal of Neuroscience Methods.

[36]  M. Spira,et al.  Multi-electrode array technologies for neuroscience and cardiology. , 2013, Nature nanotechnology.

[37]  Vincent A. Pieribone,et al.  Single Action Potentials and Subthreshold Electrical Events Imaged in Neurons with a Fluorescent Protein Voltage Probe , 2012, Neuron.

[38]  T. Bliss,et al.  Long‐lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path , 1973, The Journal of physiology.

[39]  George M. Whitesides,et al.  Rapid prototyping of complex structures with feature sizes larger than 20 μm , 1996 .

[40]  G. Whitesides,et al.  Soft lithography for micro- and nanoscale patterning , 2010, Nature Protocols.

[41]  Bernardo L. Sabatini,et al.  High Content Image Analysis Identifies Novel Regulators of Synaptogenesis in a High-Throughput RNAi Screen of Primary Neurons , 2014, PloS one.

[42]  Wim L. C. Rutten,et al.  Long-term characterization of firing dynamics of spontaneous bursts in cultured neural networks , 2004, IEEE Transactions on Biomedical Engineering.

[43]  B. Sakmann,et al.  Ca2+ buffering and action potential-evoked Ca2+ signaling in dendrites of pyramidal neurons. , 1996, Biophysical journal.

[44]  Jean-Louis Viovy,et al.  Axon diodes for the reconstruction of oriented neuronal networks in microfluidic chambers. , 2011, Lab on a chip.

[45]  M Bove,et al.  Coupling of organotypic brain slice cultures to silicon-based arrays of electrodes. , 1999, Methods.

[46]  Fred Wolf,et al.  Neurophysics: Logic gates come to life , 2008 .

[47]  Sergio Martinoia,et al.  Network dynamics of 3D engineered neuronal cultures: a new experimental model for in-vitro electrophysiology , 2014, Scientific Reports.

[48]  Luca Berdondini,et al.  Emergent Functional Properties of Neuronal Networks with Controlled Topology , 2012, PloS one.

[49]  Boris Hofmann,et al.  Axon guidance of rat cortical neurons by microcontact printed gradients. , 2011, Biomaterials.

[50]  Sergio Martinoia,et al.  Functional connectivity and dynamics of cortical–thalamic networks co-cultured in a dual compartment device , 2012, Journal of neural engineering.

[51]  J. Csicsvari,et al.  Accuracy of tetrode spike separation as determined by simultaneous intracellular and extracellular measurements. , 2000, Journal of neurophysiology.

[52]  Claire Wyart,et al.  Constrained synaptic connectivity in functional mammalian neuronal networks grown on patterned surfaces , 2002, Journal of Neuroscience Methods.

[53]  Steve M. Potter,et al.  Plasticity of recurring spatiotemporal activity patterns in cortical networks , 2007, Physical biology.

[54]  R. Tsien,et al.  A new generation of Ca2+ indicators with greatly improved fluorescence properties. , 1985, The Journal of biological chemistry.

[55]  B. Gähwiler Organotypic slice cultures of neural tissue , 1991 .

[56]  Angela Tooker,et al.  Caged neuron MEA: A system for long-term investigation of cultured neural network connectivity , 2008, Journal of Neuroscience Methods.

[57]  Michael Riss,et al.  Biophysics of microchannel-enabled neuron–electrode interfaces , 2012, Journal of neural engineering.

[58]  Jack W. Tsao,et al.  Handbook of brain microcircuits Gordon M. Shepherd , 2012, Journal of the Neurological Sciences.

[59]  D Kleinfeld,et al.  Controlled outgrowth of dissociated neurons on patterned substrates , 1988, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[60]  Steve M. Potter,et al.  Shaping Embodied Neural Networks for Adaptive Goal-directed Behavior , 2008, PLoS Comput. Biol..

[61]  C. Cotman,et al.  A microfluidic culture platform for CNS axonal injury, regeneration and transport , 2005, Nature Methods.

[62]  M. Koudelka-Hep,et al.  Biocompatibility of silicon-based arrays of electrodes coupled to organotypic hippocampal brain slice cultures , 2001, Brain Research.

[63]  D. Debanne,et al.  Organotypic slice cultures: a technique has come of age , 1997, Trends in Neurosciences.

[64]  Dong Wang,et al.  Surface Coating as a Key Parameter in Engineering Neuronal Network Structures In Vitro , 2012, Biointerphases.

[65]  Yongxin Zhao,et al.  An Expanded Palette of Genetically Encoded Ca2+ Indicators , 2011, Science.

[66]  Bruce C. Wheeler,et al.  An in vitro method to manipulate the direction and functional strength between neural populations , 2015, Front. Neural Circuits.

[67]  G. Palm,et al.  Density of neurons and synapses in the cerebral cortex of the mouse , 1989, The Journal of comparative neurology.

[68]  Aoi Odawara,et al.  Control of neural network patterning using collagen gel photothermal etching. , 2013, Lab on a chip.

[69]  Antonius M J VanDongen,et al.  Short-Term Memory in Networks of Dissociated Cortical Neurons , 2013, The Journal of Neuroscience.

[70]  Kevin J. Staley,et al.  Microfluidics and multielectrode array-compatible organotypic slice culture method , 2009, Journal of Neuroscience Methods.

[71]  Jing Liu,et al.  Perfused drop microfluidic device for brain slice culture-based drug discovery , 2016, Biomedical microdevices.

[72]  D. Kaplan,et al.  Neural circuits with long-distance axon tracts for determining functional connectivity , 2014, Journal of Neuroscience Methods.

[73]  Xingyu Jiang,et al.  Assembly of functional three-dimensional neuronal networks on a microchip. , 2014, Small.

[74]  Renaud Renault,et al.  Asymmetric axonal edge guidance: a new paradigm for building oriented neuronal networks. , 2016, Lab on a chip.

[75]  G. Whitesides,et al.  Rapid Prototyping of Microfluidic Systems in Poly(dimethylsiloxane). , 1998, Analytical chemistry.

[76]  Y. Berdichevsky,et al.  Multi-electrode array capable of supporting precisely patterned hippocampal neuronal networks , 2015, Biomedical microdevices.

[77]  Shoji Takeuchi,et al.  Millimeter‐Sized Neural Building Blocks for 3D Heterogeneous Neural Network Assembly , 2013, Advanced healthcare materials.

[78]  Zhen Xu,et al.  NeuroArray: A Universal Interface for Patterning and Interrogating Neural Circuitry with Single Cell Resolution , 2014, Scientific Reports.

[79]  Stefan R. Pulver,et al.  Ultra-sensitive fluorescent proteins for imaging neuronal activity , 2013, Nature.

[80]  Juliane Freud,et al.  Culturing Nerve Cells , 2016 .

[81]  Luca Berdondini,et al.  Microelectronics, bioinformatics and neurocomputation for massive neuronal recordings in brain circuits with large scale multielectrode array probes , 2015, Brain Research Bulletin.

[82]  M. Poo,et al.  Propagation of activity-dependent synaptic depression in simple neural networks , 1997, Nature.

[83]  C. Stevens,et al.  Presynaptic mechanism for long-term potentiation in the hippocampus , 1990, Nature.

[84]  Joost le Feber,et al.  Barbed channels enhance unidirectional connectivity between neuronal networks cultured on multi electrode arrays , 2015, Front. Neurosci..

[85]  Stefan R. Pulver,et al.  Genetically encoded calcium indicators for multi-color neural activity imaging and combination with optogenetics , 2013, Front. Mol. Neurosci..

[86]  Claire Wyart,et al.  Colloid-guided assembly of oriented 3D neuronal networks , 2008, Nature Methods.

[87]  Bruce C. Wheeler,et al.  Feed-Forward Propagation of Temporal and Rate Information between Cortical Populations during Coherent Activation in Engineered In Vitro Networks , 2016, Front. Neural Circuits.

[88]  G. Brewer,et al.  Optimized survival of hippocampal neurons in B27‐supplemented neurobasal™, a new serum‐free medium combination , 1993, Journal of neuroscience research.

[89]  Arnold R. Kriegstein,et al.  Whole cell recording from neurons in slices of reptilian and mammalian cerebral cortex , 1989, Journal of Neuroscience Methods.

[90]  Mark A. Scott,et al.  Identification of small molecules that Enhance Synaptogenesis using Synapse Microarrays , 2011, Nature communications.

[91]  Jean-Louis Viovy,et al.  β-amyloid induces a dying-back process and remote trans-synaptic alterations in a microfluidic-based reconstructed neuronal network , 2014, Acta neuropathologica communications.

[92]  R. Yuste,et al.  Detecting action potentials in neuronal populations with calcium imaging. , 1999, Methods.

[93]  J. Csicsvari,et al.  Intracellular features predicted by extracellular recordings in the hippocampus in vivo. , 2000, Journal of neurophysiology.

[94]  E Claverol-Tinturé,et al.  Multielectrode arrays with elastomeric microstructured overlays for extracellular recordings from patterned neurons , 2005, Journal of neural engineering.

[95]  G. Bi,et al.  Synaptic Modifications in Cultured Hippocampal Neurons: Dependence on Spike Timing, Synaptic Strength, and Postsynaptic Cell Type , 1998, The Journal of Neuroscience.

[96]  E. Bamberg,et al.  Channelrhodopsin-2, a directly light-gated cation-selective membrane channel , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[97]  K. Deisseroth,et al.  Millisecond-timescale, genetically targeted optical control of neural activity , 2005, Nature Neuroscience.

[98]  Gregory J Brewer,et al.  Isolation and culture of adult rat hippocampal neurons , 1997, Journal of Neuroscience Methods.

[99]  Bruce C. Wheeler,et al.  Long-term maintenance of patterns of hippocampal pyramidal cells on substrates of polyethylene glycol and microstamped polylysine , 2000, IEEE Transactions on Biomedical Engineering.

[100]  Martin L Yarmush,et al.  Building and manipulating neural pathways with microfluidics. , 2010, Lab on a chip.

[101]  Ofer Feinerman,et al.  Reliable neuronal logic devices from patterned hippocampal cultures , 2008 .

[102]  Charles F Stevens,et al.  Long-Term Depression Properties in a Simple System , 1996, Neuron.

[103]  Bruce C. Wheeler,et al.  Toward a self-wired active reconstruction of the hippocampal trisynaptic loop: DG-CA3 , 2013, Front. Neural Circuits.

[104]  Catherine Villard,et al.  Tuning the adhesive geometry of neurons: length and polarity control. , 2014, Soft matter.