Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Scalable electrophysiology in intact small animals with nanoscale suspended electrode arrays


Electrical measurements from large populations of animals would help reveal fundamental properties of the nervous system and neurological diseases. Small invertebrates are ideal for these large-scale studies; however, patch-clamp electrophysiology in microscopic animals typically requires invasive dissections and is low-throughput. To overcome these limitations, we present nano-SPEARs: suspended electrodes integrated into a scalable microfluidic device. Using this technology, we have made the first extracellular recordings of body-wall muscle electrophysiology inside an intact roundworm, Caenorhabditis elegans. We can also use nano-SPEARs to record from multiple animals in parallel and even from other species, such as Hydra littoralis. Furthermore, we use nano-SPEARs to establish the first electrophysiological phenotypes for C. elegans models for amyotrophic lateral sclerosis and Parkinson's disease, and show a partial rescue of the Parkinson's phenotype through drug treatment. These results demonstrate that nano-SPEARs provide the core technology for microchips that enable scalable, in vivo studies of neurobiology and neurological diseases.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: nano-SPEARs probe muscle cells in intact C. elegans.
Figure 2: nano-SPEAR recordings are due to animal electrophysiology.
Figure 3: nano-SPEARs record electrophysiological activity from C. elegans body-wall muscles.
Figure 4: nano-SPEARs record continuously for tens of minutes.
Figure 5: nano-SPEARs reveal phenotypes for neurodegenerative disease models.


  1. 1

    Davis, R. H. The age of model organisms. Nat. Rev. Genet. 5, 69–76 (2004).

    CAS  Article  Google Scholar 

  2. 2

    Goodman, M. B., Hall, D. H., Avery, L. & Lockery, S. R. Active current regulate sensitivity and dynamic range in C. elegans neurons. Neuron 20, 763–772 (1998).

    CAS  Article  Google Scholar 

  3. 3

    Broadie, S. K. & Bate, M. Development of the embryonic neuromuscular synapse of Drosophila melanogaster. J. Neurosci. 13, 144–166 (1993).

    CAS  Article  Google Scholar 

  4. 4

    Drapeau, P., Ali, D. W., Buss, R. R. & Saint-Amant, L. In vivo recording from identifiable neurons of the locomotor network in the developing zebrafish. J. Neurosci. Methods 88, 1–13 (1999).

    CAS  Article  Google Scholar 

  5. 5

    Richmond, J. E. & Jorgensen, E. M. One GABA and two acetylcholine receptors function at the C. elegans neuromuscular junction. Nat. Neurosci. 2, 791–797 (1999).

    CAS  Article  Google Scholar 

  6. 6

    Goodman, M. B., Lindsay, T. H., Lockery, S. R. & Richmond, J. E. Electrophysiological methods for Caenorhabditis elegans neurobiology. Methods Cell Biol. 107, 409–436 (2012).

    CAS  Article  Google Scholar 

  7. 7

    Liu, P. et al. Genetic dissection of ion currents underlying all-or-none action potentials in C. elegans body-wall muscle cells. J. Physiol. 589, 101–117 (2011).

    CAS  Article  Google Scholar 

  8. 8

    Liu, P., Chen, B. & Wang, Z.-W. Postsynaptic current bursts instruct action potential firing at a graded synapse. Nat. Commun. 4, 1911 (2013).

    Article  Google Scholar 

  9. 9

    Butler, V. J. et al. A consistent muscle activation strategy underlies crawling and swimming in Caenorhabditis elegans. J. R. Soc. Interface 12, 20140963 (2015).

    Article  Google Scholar 

  10. 10

    Kerr, R. et al. Optical imaging of calcium transients in neurons and pharyngeal muscle of C. elegans. Neuron 26, 583–594 (2000).

    CAS  Article  Google Scholar 

  11. 11

    Flytzanis, N. C. et al. Archaerhodopsin variants with enhanced voltage-sensitive fluorescence in mammalian and Caenorhabditis elegans neurons. Nat. Commun. 5, 4894 (2014).

    CAS  Article  Google Scholar 

  12. 12

    Prevedel, R. et al. Simultaneous whole-animal 3D imaging of neuronal activity using light-field microscopy. Nat. Methods 11, 727–730 (2014).

    CAS  Article  Google Scholar 

  13. 13

    Larsch, J., Ventimiglia, D., Bargmann, C. I. & Albrecht, D. R. High-throughput imaging of neuronal activity in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 110, E4266–E4273 (2013).

    CAS  Article  Google Scholar 

  14. 14

    Saul Kato, A. et al. Global brain dynamics embed the motor command sequence of Caenorhabditis elegans. Cell 163, 1–14 (2015).

    Article  Google Scholar 

  15. 15

    Larsch, J. et al. A circuit for gradient climbing in C. elegans chemotaxis. Cell Rep. 12, 1748–1760 (2015).

    CAS  Article  Google Scholar 

  16. 16

    Piggott, B. J., Liu, J., Feng, Z., Wescott, S. A. & Xu, X. Z. S. The neural circuits and synaptic mechanisms underlying motor initiation in C. elegans. Cell 147, 922–933 (2011).

    CAS  Article  Google Scholar 

  17. 17

    Venkatachalam, V. et al. Pan-neuronal imaging in roaming Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 113, E1082–E1088 (2015).

    Article  Google Scholar 

  18. 18

    Nguyen, J. P. et al. Whole-brain calcium imaging with cellular resolution in freely behaving Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 113, E1074–E1081 (2015).

    Article  Google Scholar 

  19. 19

    Broussard, G. J., Liang, R. & Tian, L. Monitoring activity in neural circuits with genetically encoded indicators. Front. Mol. Neurosci. 7, 910 (2014).

    Article  Google Scholar 

  20. 20

    Raizen, D. M. & Avery, L. Electrical activity and behavior in the pharynx of Caenorhabditis elegans. Neuron 12, 483–495 (1994).

    CAS  Article  Google Scholar 

  21. 21

    Lockery, S. R. et al. A microfluidic device for whole-animal drug screening using electrophysiological measures in the nematode C. elegans. Lab Chip. 12, 2211–2220 (2012).

    CAS  Article  Google Scholar 

  22. 22

    Rohde, C. B., Zeng, F., Gonzalez-Rubio, R., Angel, M. & Yanik, M. F. Microfluidic system for on-chip high-throughput whole-animal sorting and screening at subcellular resolution. Proc. Natl Acad. Sci USA 104, 13891–13895 (2007).

    CAS  Article  Google Scholar 

  23. 23

    Chung, K., Crane, M. M. & Lu, H. Automated on-chip rapid microscopy, phenotyping and sorting of C. elegans. Nat. Methods 5, 637–643 (2008).

    CAS  Article  Google Scholar 

  24. 24

    Swierczek, N. A., Giles, A. C., Rankin, C. H. & Kerr, R. A. High-throughput behavioral analysis in C. elegans. Nat. Methods 8, 592–598 (2011).

    CAS  Article  Google Scholar 

  25. 25

    Hai, A., Shappir, J. & Spira, M. E. In-cell recordings by extracellular microelectrodes. Nat. Methods 7, 200–202 (2010).

    CAS  Article  Google Scholar 

  26. 26

    Tian, B. et al. Three-dimensional, flexible nanoscale field-effect transistors as localized bioprobes. Science 329, 830–834 (2010).

    CAS  Article  Google Scholar 

  27. 27

    Duan, X. et al. Intracellular recordings of action potentials by an extracellular nanoscale field-effect transistor. Nat. Nanotech. 7, 174–179 (2011).

    Article  Google Scholar 

  28. 28

    Robinson, J. T. et al. Vertical nanowire electrode arrays as a scalable platform for intracellular interfacing to neuronal circuits. Nat. Nanotech. 7, 180–184 (2012).

    CAS  Article  Google Scholar 

  29. 29

    Xie, C., Lin, Z., Hanson, L., Cui, Y. & Cui, B. Intracellular recording of action potentials by nanopillar electroporation. Nat. Nanotech. 7, 185–190 (2012).

    CAS  Article  Google Scholar 

  30. 30

    Angle, M. R., Cui, B. & Melosh, N. A. Nanotechnology and neurophysiology. Curr. Opin. Neurobiol. 32, 132–140 (2015).

    CAS  Article  Google Scholar 

  31. 31

    Han, X. & Boyden, E. S. Multiple-color optical activation, silencing, and desynchronization of neural activity, with single-spike temporal resolution. PLoS ONE 2, e299 (2007).

    Article  Google Scholar 

  32. 32

    Gao, S. & Zhen, M. Action potentials drive body wall muscle contractions in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 108, 2557–2562 (2011).

    CAS  Article  Google Scholar 

  33. 33

    Jospin, M., Jacquemond, V., Mariol, M.-C., Ségalat, L. & Allard, B. The L-type voltage-dependent Ca2+ channel EGL-19 controls body wall muscle function in Caenorhabditis elegans. J. Cell Biol. 159, 337–348 (2002).

    CAS  Article  Google Scholar 

  34. 34

    Wen, Q. et al. Proprioceptive coupling within motor neurons drives C. elegans forward locomotion. Neuron 76, 750–761 (2012).

    CAS  Article  Google Scholar 

  35. 35

    Westfall, J. A., Yamataka, S. & Enos, P. D. Ultrastructural evidence of polarized synapses in the nerve net of Hydra. J. Cell Biol. 51, 318–323 (1971).

    CAS  Article  Google Scholar 

  36. 36

    Jorgensen, E. M. & Nonet, M. L. Neuromuscular junctions in the nematode C. elegans. Semin. Dev. Biol. 6, 207–220 (1995).

    CAS  Article  Google Scholar 

  37. 37

    Liu, Q., Hollopeter, G. & Jorgensen, E. M. Graded synaptic transmission at the Caenorhabditis elegans neuromuscular junction. Proc. Natl Acad. Sci. USA 106, 10823–10828 (2009).

    CAS  Article  Google Scholar 

  38. 38

    Kaletta, T. & Hengartner, M. O. Finding function in novel targets: C. elegans as a model organism. Nat. Rev. Drug Discov. 5, 387–398 (2006).

    CAS  Article  Google Scholar 

  39. 39

    Jones, A. K., Buckingham, S. D. & Sattelle, D. B. Chemistry-to-gene screens in Caenorhabditis elegans. Nat. Rev. Drug Discov. 4, 321–330 (2005).

    CAS  Article  Google Scholar 

  40. 40

    Bargmann, C. I. Neurobiology of the Caenorhabditis elegans genome. Science 282, 2028–2033 (1998).

    CAS  Article  Google Scholar 

  41. 41

    Lublin, A. L. & Link, C. D. Alzheimer's disease drug discovery: in vivo screening using Caenorhabditis elegans as a model for beta-amyloid peptide-induced toxicity. Drug Discov. Today Technol. 10, e115–e119 (2013).

    CAS  Article  Google Scholar 

  42. 42

    Sin, O., Michels, H. & Nollen, E. A. A. Genetic screens in Caenorhabditis elegans models for neurodegenerative diseases. Biochim. Biophys. Acta Mol. Basis Dis. 1842, 1951–1959 (2014).

    CAS  Article  Google Scholar 

  43. 43

    van Ham, T. J. et al. C. elegans model identifies genetic modifiers of α-synuclein inclusion formation during aging. PLoS Genet. 4, e1000027 (2008).

    Article  Google Scholar 

  44. 44

    Wang, J. et al. An ALS-linked mutant SOD1 produces a locomotor defect associated with aggregation and synaptic dysfunction when expressed in neurons of Caenorhabditis elegans. PLoS Genet. 5, e1000350 (2009).

    Article  Google Scholar 

  45. 45

    Tardiff, D. F., Tucci, M. L., Caldwell, K. A., Caldwell, G. A. & Lindquist, S. Different 8-hydroxyquinolines protect models of TDP-43 protein, alpha-synuclein, and polyglutamine proteotoxicity through distinct mechanisms. J. Biol. Chem. 287, 4107–4120 (2012).

    CAS  Article  Google Scholar 

  46. 46

    Frankowski, H. et al. Dimethyl sulfoxide and dimethyl formamide increase lifespan of C. elegans in liquid. Mech. Ageing Dev. 134, 69–78 (2013).

    CAS  Article  Google Scholar 

  47. 47

    Yanik, M. F., Rohde, C. B. & Pardo-Martin, C. Technologies for micromanipulating, imaging, and phenotyping small invertebrates and vertebrates. Annu. Rev. Biomed. Eng. 13, 185–217 (2011).

    CAS  Article  Google Scholar 

  48. 48

    Cronin, C. J. et al. An automated system for measuring parameters of nematode sinusoidal movement. BMC Genet. 6, 5 (2005).

    Article  Google Scholar 

  49. 49

    Madou, M. J. Manufacturing Techniques for Microfabrication and Nanotechnology (CRC Press, 2011).

    Google Scholar 

  50. 50

    Lockery, S. R. et al. Artificial dirt: microfluidic substrates for nematode neurobiology and behavior. J. Neurophysiol. 99, 3136–3143 (2008).

    CAS  Article  Google Scholar 

  51. 51

    Yu, H. et al. Systematic profiling of Caenorhabditis elegans locomotive behaviors reveals additional components in G-protein Gαq signaling. Proc. Natl Acad. Sci. USA 110, 11940–11945 (2013).

    CAS  Article  Google Scholar 

  52. 52

    Edwards, S. L. et al. A novel molecular solution for ultraviolet light detection in Caenorhabditis elegans. PLoS Biol. 6, 1715–1729 (2008).

    CAS  Google Scholar 

  53. 53

    Passano, L. M. & McCullough, C. B. The light response and the rhythmic potentials of hydra. Proc. Natl Acad. Sci. USA 48, 1376–1382 (1962).

    CAS  Article  Google Scholar 

Download references


We thank C. Kemere for discussions on extracellular recordings and spectral analysis. Several strains were provided by the Caenorhabditis Genetics Center, which is funded by National Institutes of Health (NIH) Office of Research Infrastructure Programs (P40 OD010440). J. Wang provided the ALS worm strains and A. Fouad from the Fang-Yen Lab provided the YX9 animals. This work is funded by the Defense Advanced Research Projects Agency Young Faculty Award D14AP00049 (J.T.R.), NIH grant DA018341 (W.Z.) and the Hamill Foundation (J.T.R. and W.Z.). D.L.G. is funded by the National Science Foundation (NSF) Graduate Research Fellowship Program 0940902. D.L.G. and K.N.B. are funded by training fellowships from the Keck Center of the Gulf Coast Consortia on the NSF Integrative Graduate Education and Research Traineeship (IGERT): Neuroengineering from Cells to Systems 1250104. We also thank the Rice Shared Equipment Authority and the University of Houston Nanofabrication Facility where devices were fabricated.

Author information




D.L.G. performed and analysed C. elegans experiments. K.N.B. performed and analysed fluorescence microscopy measurements and Hydra recordings. D.L.G., K.N.B. and D.G.V. developed the fabrication process. B.W.A. provided hardware and software support. Z.L. outcrossed shk-1(lf). W.Z. provided support in outcrossing and locomotive phenotyping. J.T.R. directed the research. D.L.G. and J.T.R. co-wrote the paper. All authors read and commented on the manuscript.

Corresponding author

Correspondence to Jacob T. Robinson.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary information (PDF 1099 kb)

Supplementary Movie 1

Supplementary Movie 1 (MP4 3666 kb)

Supplementary Movie 2

Supplementary Movie 2 (MP4 4361 kb)

Supplementary Movie 3

Supplementary Movie 3 (MP4 4152 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Gonzales, D., Badhiwala, K., Vercosa, D. et al. Scalable electrophysiology in intact small animals with nanoscale suspended electrode arrays. Nature Nanotech 12, 684–691 (2017).

Download citation

Further reading


Quick links

Find nanotechnology articles, nanomaterial data and patents all in one place. Visit Nano by Nature Research