Skip to main content

Thank you for visiting nature.com. 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.

Next-generation interfaces for studying neural function

Abstract

Monitoring and modulating the diversity of signals used by neurons and glia in a closed-loop fashion is necessary to establish causative links between biochemical processes within the nervous system and observed behaviors. As developments in neural-interface hardware strive to keep pace with rapid progress in genetically encoded and synthetic reporters and modulators of neural activity, the integration of multiple functional features becomes a key requirement and a pressing challenge in the field of neural engineering. Electrical, optical and chemical approaches have been used to manipulate and record neuronal activity in vivo, with a recent focus on technologies that both integrate multiple modes of interaction with neurons into a single device and enable bidirectional communication with neural circuits with enhanced spatiotemporal precision. These technologies not only are facilitating a greater understanding of the brain, spinal cord and peripheral circuits in the context of health and disease, but also are informing the development of future closed-loop therapies for neurological, neuro-immune and neuroendocrine conditions.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Overview of neuronal communication.

Debbie Maizels/Springer Nature

Fig. 2: Probes for electrical stimulation and recording of neural activity.

Debbie Maizels/Springer Nature

Fig. 3: Optical neural stimulation and recording via genetic or non-genetic tools; sensitivity, orthogonality and requirements for hardware.

Debbie Maizels/Springer Nature

Fig. 4: Chemical sensing with voltammetry and microdialysis.

Debbie Maizels/Springer Nature

Fig. 5: Technologies for chemical modulation and delivery.

Debbie Maizels/Springer Nature

Fig. 6: Multimodal integration.

Debbie Maizels/Springer Nature

References

  1. Gooch, C. L., Pracht, E. & Borenstein, A. R. The burden of neurological disease in the United States: a summary report and call to action. Ann. Neurol. 81, 479–484 (2017).

    Article  PubMed  Google Scholar 

  2. Rajasethupathy, P., Ferenczi, E. & Deisseroth, K. Targeting neural circuits. Cell 165, 524–534 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Nordhausen, C. T., Maynard, E. M. & Normann, R. A. Single unit recording capabilities of a 100 microelectrode array. Brain Res. 726, 129–140 (1996).

    Article  CAS  PubMed  Google Scholar 

  4. Berger, H. Uber das Elektrenkephalogramm des Menschen. IV. Nov. Acta Leopoldina 6, 174–309 (1938).

    Google Scholar 

  5. Campbell, P. K., Jones, K. E., Huber, R. J., Horch, K. W. & Normann, R. A. A silicon-based, three-dimensional neural interface: manufacturing processes for an intracortical electrode array. IEEE Trans. Biomed. Eng. 38, 758–768 (1991).

    Article  CAS  PubMed  Google Scholar 

  6. Jun, J. J. et al. Fully integrated silicon probes for high-density recording of neural activity. Nature 551, 232–236 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Ward, M. P., Rajdev, P., Ellison, C. & Irazoqui, P. P. Toward a comparison of microelectrodes for acute and chronic recordings. Brain Res. 1282, 183–200 (2009).

    Article  CAS  PubMed  Google Scholar 

  8. Nolta, N. F., Christensen, M. B., Crane, P. D., Skousen, J. L. & Tresco, P. A. BBB leakage, astrogliosis, and tissue loss correlate with silicon microelectrode array recording performance. Biomaterials 53, 753–762 (2015).

    Article  CAS  PubMed  Google Scholar 

  9. Fu, T. M. et al. Stable long-term chronic brain mapping at the single-neuron level. Nat. Methods 13, 875–882 (2016).

    Article  CAS  PubMed  Google Scholar 

  10. Hong, G. et al. A method for single-neuron chronic recording from the retina in awake mice. Science 360, 1447–1451 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lu, Y., Lyu, H., Richardson, A. G., Lucas, T. H. & Kuzum, D. Flexible neural electrode array based-on porous graphene for cortical microstimulation and sensing. Sci. Rep. 6, 33526 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Tybrandt, K. et al. High-density stretchable electrode grids for chronic neural recording. Adv. Mater. 30, e1706520 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Lu, C. et al. Flexible and stretchable nanowire-coated fibers for optoelectronic probing of spinal cord circuits. Sci. Adv. 3, e1600955 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Choi, S. et al. Highly conductive, stretchable and biocompatible Ag-Au core-sheath nanowire composite for wearable and implantable bioelectronics. Nat Nanotechnol. 13, 1048–1056 (2018).

    Article  CAS  PubMed  Google Scholar 

  15. Inal, S., Rivnay, J., Suiu, A.-O., Malliaras, G. G. & McCulloch, I. Conjugated polymers in bioelectronics. Acc. Chem. Res. 51, 1368–1376 (2018).

    Article  CAS  PubMed  Google Scholar 

  16. Patel, P. R. et al. Insertion of linear 8.4 μm diameter 16 channel carbon fiber electrode arrays for single unit recordings. J. Neural Eng. 12, 046009 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Patel, P. R. et al. Chronic in vivo stability assessment of carbon fiber microelectrode arrays. J. Neural Eng. 13, 066002 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Khodagholy, D. et al. NeuroGrid: recording action potentials from the surface of the brain. Nat. Neurosci. 18, 310–315 (2015).

    Article  CAS  PubMed  Google Scholar 

  19. Rivnay, J. et al. Structural control of mixed ionic and electronic transport in conducting polymers. Nat. Commun. 7, 11287 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Zhou, A., Johnson, B. C. & Muller, R. Toward true closed-loop neuromodulation: artifact-free recording during stimulation. Curr. Opin. Neurobiol. 50, 119–127 (2018).

    Article  CAS  PubMed  Google Scholar 

  21. Zemelman, B. V., Lee, G. A., Ng, M. & Miesenböck, G. Selective photostimulation of genetically chARGed neurons. Neuron 33, 15–22 (2002).

    Article  CAS  PubMed  Google Scholar 

  22. Deisseroth, K. & Hegemann, P. The form and function of channelrhodopsin. Science 357, eaan5544 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Liu, X. et al. Optogenetic stimulation of a hippocampal engram activates fear memory recall. Nature 484, 381–385 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Felix-Ortiz, A. C., Burgos-Robles, A., Bhagat, N. D., Leppla, C. A. & Tye, K. M. Bidirectional modulation of anxiety-related and social behaviors by amygdala projections to the medial prefrontal cortex. Neuroscience 321, 197–209 (2016).

    Article  CAS  PubMed  Google Scholar 

  25. Adamantidis, A. R., Zhang, F., Aravanis, A. M., Deisseroth, K. & de Lecea, L. Neural substrates of awakening probed with optogenetic control of hypocretin neurons. Nature 450, 420–424 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Gradinaru, V., Mogri, M., Thompson, K. R., Henderson, J. M. & Deisseroth, K. Optical deconstruction of parkinsonian neural circuitry. Science 324, 354–359 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Mager, T. et al. High frequency neural spiking and auditory signaling by ultrafast red-shifted optogenetics. Nat. Commun. 9, 1750 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Ronzitti, E. et al. Sub-millisecond optogenetic control of neuronal firing with two-photon holographic photoactivation of Chronos. J. Neurosci. 37, 10679–10689 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Tkatch, T. et al. Optogenetic control of mitochondrial metabolism and Ca2+ signaling by mitochondria-targeted opsins. Proc. Natl Acad. Sci. USA 114, E5167–E5176 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. El-Gaby, M. et al. Archaerhodopsin selectively and reversibly silences synaptic transmission through altered pH. Cell Rep. 16, 2259–2268 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Grimm, C., Silapetere, A., Vogt, A., Bernal Sierra, Y. A. & Hegemann, P. Electrical properties, substrate specificity and optogenetic potential of the engineered light-driven sodium pump eKR2. Sci. Rep. 8, 9316 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Wietek, J. et al. Anion-conducting channelrhodopsins with tuned spectra and modified kinetics engineered for optogenetic manipulation of behavior. Sci. Rep. 7, 14957 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Chuong, A. S. et al. Noninvasive optical inhibition with a red-shifted microbial rhodopsin. Nat. Neurosci. 17, 1123–1129 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Rost, B. R. et al. Optogenetic acidification of synaptic vesicles and lysosomes. Nat. Neurosci. 18, 1845–1852 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Scheib, U. et al. Rhodopsin-cyclases for photocontrol of cGMP/cAMP and 2.3 Å structure of the adenylyl cyclase domain. Nat. Commun. 9, 2046 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Pisanello, F. et al. Dynamic illumination of spatially restricted or large brain volumes via a single tapered optical fiber. Nat. Neurosci. 20, 1180–1188 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Wu, F. et al. Monolithically Integrated μLEDs on silicon neural probes for high-resolution optogenetic studies in behaving animals. Neuron 88, 1136–1148 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Wang, J. et al. Integrated device for combined optical neuromodulation and electrical recording for chronic in vivo applications. J. Neural Eng. 9, 016001 (2012).

    Article  PubMed  Google Scholar 

  39. Jeong, J. W. et al. Wireless optofluidic systems for programmable in vivo pharmacology and optogenetics. Cell 162, 662–674 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Lee, J., Ozden, I., Song, Y.-K. & Nurmikko, A. V. Transparent intracortical microprobe array for simultaneous spatiotemporal optical stimulation and multichannel electrical recording. Nat. Methods 12, 1157–1162 (2015).

    Article  CAS  PubMed  Google Scholar 

  41. Park, S. et al. One-step optogenetics with multifunctional flexible polymer fibers. Nat. Neurosci. 20, 612–619 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Canales, A. et al. Multifunctional fibers for simultaneous optical, electrical and chemical interrogation of neural circuits in vivo. Nat. Biotechnol. 33, 277–284 (2015).

    Article  CAS  PubMed  Google Scholar 

  43. Chen, R., Canales, A. & Anikeeva, P. Neural recording and modulation technologies. Nat. Rev. Mater. 2, 16093 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Rost, B. R., Schneider-Warme, F., Schmitz, D. & Hegemann, P. Optogenetic tools for subcellular applications in neuroscience. Neuron 96, 572–603 (2017).

    Article  CAS  PubMed  Google Scholar 

  45. Wang, W. et al. A light- and calcium-gated transcription factor for imaging and manipulating activated neurons. Nat. Biotechnol. 35, 864–871 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Lee, D., Hyun, J. H., Jung, K., Hannan, P. & Kwon, H. B. A calcium- and light-gated switch to induce gene expression in activated neurons. Nat. Biotechnol. 35, 858–863 (2017).

    Article  CAS  PubMed  Google Scholar 

  47. Taslimi, A. et al. Optimized second-generation CRY2–CIB dimerizers and photoactivatable Cre recombinase. Nat. Chem. Biol. 12, 425–430 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. O’Banion, C. P. et al. Design and profiling of a subcellular targeted optogenetic cAMP-dependent protein kinase. Cell. Chem. Biol. 25, 100–109.e8 (2018).

    Google Scholar 

  49. Kim, E. H., Chin, G., Rong, G., Poskanzer, K. E. & Clark, H. A. Optical probes for neurobiological sensing and imaging. Acc. Chem. Res. 51, 1023–1032 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Allen, W. E. et al. Global representations of goal-directed behavior in distinct cell types of mouse neocortex. Neuron 94, 891–907.e6 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Ohkura, M. et al. Genetically encoded green fluorescent Ca2+ indicators with improved detectability for neuronal Ca2+ signals. PLoS One 7, e51286 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Dana, H. et al. Sensitive red protein calcium indicators for imaging neural activity. eLife 5, e12727 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Piatkevich, K. D. et al. A robotic multidimensional directed evolution approach applied to fluorescent voltage reporters. Nat. Chem. Biol. 14, 352–360 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Lou, S. et al. Genetically targeted all-optical electrophysiology with a transgenic Cre-dependent optopatch mouse. J. Neurosci. 36, 11059–11073 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Bolbat, A. & Schultz, C. Recent developments of genetically encoded optical sensors for cell biology. Biol. Cell 109, 1–23 (2017).

    Article  PubMed  Google Scholar 

  56. Lin, M. Z. & Schnitzer, M. J. Genetically encoded indicators of neuronal activity. Nat. Neurosci. 19, 1142–1153 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Marvin, J. S. et al. Stability, affinity and chromatic variants of the glutamate sensor iGluSnFR. Nat. Methods 15, 936–939 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Patriarchi, T. et al. Ultrafast neuronal imaging of dopamine dynamics with designed genetically encoded sensors. Science 360, eaat4422 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Sun, F. et al. A genetically encoded fluorescent sensor enables rapid and specific detection of dopamine in flies, fish, and mice. Cell 174, 481–496.e19 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Jing, M. et al. A genetically encoded fluorescent acetylcholine indicator for in vitro and in vivo studies. Nat. Biotechnol. 36, 726–737 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Zhang, W. H. et al. Monitoring hippocampal glycine with the computationally designed optical sensor GlyFS. Nat. Chem. Biol. 14, 861–869 (2018).

    Article  CAS  PubMed  Google Scholar 

  62. Flusberg, B. A. et al. High-speed, miniaturized fluorescence microscopy in freely moving mice. Nat. Methods 5, 935–938 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Ghosh, K. K. et al. Miniaturized integration of a fluorescence microscope. Nat. Methods 8, 871–878 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Zong, W. et al. Fast high-resolution miniature two-photon microscopy for brain imaging in freely behaving mice. Nat. Methods 14, 713–719 (2017).

    Article  CAS  PubMed  Google Scholar 

  65. Gunaydin, L. A. et al. Natural neural projection dynamics underlying social behavior. Cell 157, 1535–1551 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Kim, C. K. et al. Simultaneous fast measurement of circuit dynamics at multiple sites across the mammalian brain. Nat. Methods 13, 325–328 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Marshall, J. D. et al. Cell-type-specific optical recording of membrane voltage dynamics in freely moving mice. Cell 167, 1650–1662.e15 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Turtaev, S. et al. High-fidelity multimode fibre-based endoscopy for deep brain in vivo imaging. Light Sci. Appl. 7, 92 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Lu, L. et al. Wireless optoelectronic photometers for monitoring neuronal dynamics in the deep brain. Proc. Natl Acad. Sci. USA 115, E1374–E1383 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Anderzhanova, E. & Wotjak, C. T. Brain microdialysis and its applications in experimental neurochemistry. Cell Tissue Res. 354, 27–39 (2013).

    Article  CAS  PubMed  Google Scholar 

  71. Robinson, D. L., Hermans, A., Seipel, A. T. & Wightman, R. M. Monitoring rapid chemical communication in the brain. Chem. Rev. 108, 2554–2584 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Roberts, J. G. & Sombers, L. A. Fast-scan cyclic voltammetry: chemical sensing in the brain and beyond. Anal. Chem. 90, 490–504 (2018).

    Article  CAS  PubMed  Google Scholar 

  73. Rodeberg, N. T. et al. Construction of training sets for valid calibration of in vivo cyclic voltammetric data by principal component analysis. Anal. Chem. 87, 11484–11491 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Johnson, J. A., Rodeberg, N. T. & Wightman, R. M. Failure of standard training sets in the analysis of fast-scan cyclic voltammetry data. ACS Chem. Neurosci. 7, 349–359 (2016).

    Article  CAS  PubMed  Google Scholar 

  75. Rodeberg, N. T., Sandberg, S. G., Johnson, J. A., Phillips, P. E. M. & Wightman, R. M. Hitchhiker’s Guide to Voltammetry: acute and chronic electrodes for in vivo fast-scan cyclic voltammetry. ACS Chem. Neurosci. 8, 221–234 (2017).

    Article  CAS  PubMed  Google Scholar 

  76. Schwerdt, H. N. et al. Long-term dopamine neurochemical monitoring in primates. Proc. Natl Acad. Sci. USA 114, 13260–13265 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Clark, J. J. et al. Chronic microsensors for longitudinal, subsecond dopamine detection in behaving animals. Nat. Methods 7, 126–129 (2010).

    Article  CAS  PubMed  Google Scholar 

  78. Hobbs, C. N., Johnson, J. A., Verber, M. D. & Mark Wightman, R. An implantable multimodal sensor for oxygen, neurotransmitters, and electrophysiology during spreading depolarization in the deep brain. Analyst 142, 2912–2920 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Hamid, A. A. et al. Mesolimbic dopamine signals the value of work. Nat. Neurosci. 19, 117–126 (2016).

    Article  CAS  PubMed  Google Scholar 

  80. Bennet, K. E. et al. A diamond-based electrode for detection of neurochemicals in the human brain. Front. Hum. Neurosci. 10, 102 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Taylor, I. M. et al. Enhanced dopamine detection sensitivity by PEDOT/graphene oxide coating on in vivo carbon fiber electrodes. Biosens. Bioelectron. 89, 400–410 (2017).

    Article  CAS  PubMed  Google Scholar 

  82. Wilson, L. R., Panda, S., Schmidt, A. C. & Sombers, L. A. Selective and mechanically robust sensors for electrochemical measurements of real-time hydrogen peroxide dynamics in vivo. Anal. Chem. 90, 888–895 (2018).

    Article  CAS  PubMed  Google Scholar 

  83. Smith, S. K. et al. Simultaneous voltammetric measurements of glucose and dopamine demonstrate the coupling of glucose availability with increased metabolic demand in the rat striatum. ACS Chem. Neurosci. 8, 272–280 (2017).

    Article  CAS  PubMed  Google Scholar 

  84. Lugo-Morales, L. Z. et al. Enzyme-modified carbon-fiber microelectrode for the quantification of dynamic fluctuations of nonelectroactive analytes using fast-scan cyclic voltammetry. Anal. Chem. 85, 8780–8786 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Burmeister, J. J., Palmer, M. & Gerhardt, G. A. L-lactate measures in brain tissue with ceramic-based multisite microelectrodes. Biosens. Bioelectron. 20, 1772–1779 (2005).

    Article  CAS  PubMed  Google Scholar 

  86. Burmeister, J. J. et al. Ceramic-based multisite microelectrode arrays for simultaneous measures of choline and acetylcholine in CNS. Biosens. Bioelectron. 23, 1382–1389 (2008).

    Article  CAS  PubMed  Google Scholar 

  87. Day, B. K., Pomerleau, F., Burmeister, J. J., Huettl, P. & Gerhardt, G. A. Microelectrode array studies of basal and potassium-evoked release of L-glutamate in the anesthetized rat brain. J. Neurochem. 96, 1626–1635 (2006).

    Article  CAS  PubMed  Google Scholar 

  88. Ngernsutivorakul, T., White, T. S. & Kennedy, R. T. Microfabricated probes for studying brain chemistry: a review. ChemPhysChem 19, 1128–1142 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Zestos, A. G. & Kennedy, R. T. Microdialysis coupled with LC-MS/MS for in vivo neurochemical monitoring. AAPS J. 19, 1284–1293 (2017).

    Article  CAS  PubMed  Google Scholar 

  90. Wong, J.-M. T. et al. Benzoyl chloride derivatization with liquid chromatography-mass spectrometry for targeted metabolomics of neurochemicals in biological samples. J. Chromatogr. A 1446, 78–90 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Rogers, M. L. et al. Simultaneous monitoring of potassium, glucose and lactate during spreading depolarization in the injured human brain: proof of principle of a novel real-time neurochemical analysis system, continuous online microdialysis. J. Cereb. Blood Flow Metab. 37, 1883–1895 (2017).

    Article  CAS  PubMed  Google Scholar 

  92. Papadimitriou, K. I. et al. High-performance bioinstrumentation for real-time neuroelectrochemical traumatic brain injury monitoring. Front. Hum. Neurosci. 10, 212 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  93. Wang, M., Roman, G. T., Schultz, K., Jennings, C. & Kennedy, R. T. Improved temporal resolution for in vivo microdialysis by using segmented flow. Anal. Chem. 80, 5607–5615 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Lee, W. H. et al. Microfabrication and in vivo performance of a microdialysis probe with embedded membrane. Anal. Chem. 88, 1230–1237 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Quiroz, C. et al. Local control of extracellular dopamine levels in the medial nucleus accumbens by a glutamatergic projection from the infralimbic cortex. J. Neurosci. 36, 851–859 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Al-Hasani, R. et al. In vivo detection of optically-evoked opioid peptide release. eLife 7, e36520 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Alexander, G. M. et al. Remote control of neuronal activity in transgenic mice expressing evolved G protein-coupled receptors. Neuron 63, 27–39 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Vardy, E. et al. A new DREADD facilitates the multiplexed chemogenetic interrogation of behavior. Neuron 86, 936–946 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Hüll, K., Morstein, J. & Trauner, D. In vivo photopharmacology. Chem. Rev. 118, 10710–10747 (2018).

    Article  PubMed  CAS  Google Scholar 

  100. Broichhagen, J., Frank, J. A. & Trauner, D. A roadmap to success in photopharmacology. Acc. Chem. Res. 48, 1947–1960 (2015).

    Article  CAS  PubMed  Google Scholar 

  101. Banala, S. et al. Photoactivatable drugs for nicotinic optopharmacology. Nat. Methods 15, 347–350 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Dong, M., Babalhavaeji, A., Samanta, S., Beharry, A. A. & Woolley, G. A. Red-shifting azobenzene photoswitches for in vivo use. Acc. Chem. Res. 48, 2662–2670 (2015).

    Article  CAS  PubMed  Google Scholar 

  103. Wagner, N., Stephan, M., Höglinger, D. & Nadler, A. A click cage: organelle-specific uncaging of lipid messengers. Angew. Chem. Int. Ed. Engl. 57, 13339–13343 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Nadler, A. et al. Exclusive photorelease of signalling lipids at the plasma membrane. Nat. Commun. 6, 10056 (2015).

    Article  CAS  PubMed  Google Scholar 

  105. Yang, G. et al. Genetic targeting of chemical indicators in vivo. Nat. Methods 12, 137–139 (2015).

    Article  CAS  PubMed  Google Scholar 

  106. Shields, B. C. et al. Deconstructing behavioral neuropharmacology with cellular specificity. Science 356, eaaj1682 (2017).

    Article  CAS  Google Scholar 

  107. Berry, M. H. et al. Restoration of patterned vision with an engineered photoactivatable G protein-coupled receptor. Nat. Commun. 8, 1862 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Levitz, J. et al. Dual optical control and mechanistic insights into photoswitchable group II and III metabotropic glutamate receptors. Proc. Natl Acad. Sci. USA 114, E3546–E3554 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Takemoto, K. et al. Optical inactivation of synaptic AMPA receptors erases fear memory. Nat. Biotechnol. 35, 38–47 (2017).

    Article  CAS  PubMed  Google Scholar 

  110. Tischbirek, C., Birkner, A., Jia, H., Sakmann, B. & Konnerth, A. Deep two-photon brain imaging with a red-shifted fluorometric Ca2+ indicator. Proc. Natl Acad. Sci. USA 112, 11377–11382 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Deal, P. E., Kulkarni, R. U., Al-Abdullatif, S. H. & Miller, E. W. Isomerically pure tetramethylrhodamine voltage reporters. J. Am. Chem. Soc. 138, 9085–9088 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Martineau, M. et al. Semisynthetic fluorescent pH sensors for imaging exocytosis and endocytosis. Nat. Commun. 8, 1412 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Sallin, O. et al. Semisynthetic biosensors for mapping cellular concentrations of nicotinamide adenine dinucleotides. eLife 7, e32638 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  114. Shin, H. et al. Neural probes with multi-drug delivery capability. Lab Chip 15, 3730–3737 (2015).

    Article  CAS  PubMed  Google Scholar 

  115. Uguz, I. et al. A microfluidic ion pump for in vivo drug delivery. Adv. Mater. 29, 1701217 (2017).

    Article  CAS  Google Scholar 

  116. Schubert, R. et al. Virus stamping for targeted single-cell infection in vitro and in vivo. Nat. Biotechnol. 36, 81–88 (2018).

    Article  CAS  PubMed  Google Scholar 

  117. Jackman, S. L. et al. Silk fibroin films facilitate single-step targeted expression of optogenetic proteins. Cell Rep. 22, 3351–3361 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Chan, K. Y. et al. Engineered AAVs for efficient noninvasive gene delivery to the central and peripheral nervous systems. Nat. Neurosci. 20, 1172–1179 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Zhao, Z. et al. Nanoelectronic coating enabled versatile multifunctional neural probes. Nano Lett. 17, 4588–4595 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Dagdeviren, C. et al. Miniaturized neural system for chronic, local intracerebral drug delivery. Sci. Transl. Med. 10, eaan2742 (2018).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  121. Kampasi, K. et al. Fiberless multicolor neural optoelectrode for in vivo circuit analysis. Sci. Rep. 6, 30961 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Kampasi, K. et al. Dual color optogenetic control of neural populations using low-noise, multishank optoelectrodes. Microsyst. Nanoeng. 4, 10 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Minev, I. R. et al. Electronic dura mater for long-term multimodal neural interfaces. Science 347, 159–163 (2015).

    Article  CAS  PubMed  Google Scholar 

  124. Petit-Pierre, G., Bertsch, A. & Renaud, P. Neural probe combining microelectrodes and a droplet-based microdialysis collection system for high temporal resolution sampling. Lab Chip 16, 917–924 (2016).

    Article  CAS  PubMed  Google Scholar 

  125. Lee, W. et al. Transparent, conformable, active multielectrode array using organic electrochemical transistors. Proc. Natl Acad. Sci. USA 114, 10554–10559 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Park, D. W. et al. Electrical neural stimulation and simultaneous in vivo monitoring with transparent graphene electrode arrays implanted in GCaMP6f mice. ACS Nano 12, 148–157 (2018).

    Article  CAS  PubMed  Google Scholar 

  127. Thunemann, M. et al. Deep 2-photon imaging and artifact-free optogenetics through transparent graphene microelectrode arrays. Nat. Commun. 9, 2035 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  128. Kuzum, D. et al. Transparent and flexible low noise graphene electrodes for simultaneous electrophysiology and neuroimaging. Nat. Commun. 5, 5259 (2014).

    Article  CAS  PubMed  Google Scholar 

  129. Jiang, Y. et al. Rational design of silicon structures for optically controlled multiscale biointerfaces. Nat. Biomed. Eng. 2, 508–521 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Kilias, A. et al. Optogenetic entrainment of neural oscillations with hybrid fiber probes. J. Neural Eng. 15, 056006 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  131. Rein, M. et al. Diode fibres for fabric-based optical communications. Nature 560, 214–218 (2018).

    Article  CAS  PubMed  Google Scholar 

  132. Qu, Y. et al. Superelastic multimaterial electronic and photonic fibers and devices via thermal drawing. Adv. Mater. 30, e1707251 (2018).

    Article  PubMed  CAS  Google Scholar 

  133. Grena, B. et al. Thermally-drawn fibers with spatially-selective porous domains. Nat. Commun. 8, 364 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  134. Montgomery, K. L., Iyer, S. M., Christensen, A. J., Deisseroth, K. & Delp, S. L. Beyond the brain: optogenetic control in the spinal cord and peripheral nervous system. Sci. Transl. Med. 8, 337rv5 (2016).

    Article  PubMed  CAS  Google Scholar 

  135. Shemesh, O. A. et al. Temporally precise single-cell-resolution optogenetics. Nat. Neurosci. 20, 1796–1806 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Berlin, S. et al. Photoactivatable genetically encoded calcium indicators for targeted neuronal imaging. Nat. Methods 12, 852–858 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Kandel, E. R. et al. Principles of Neural Science 5th edn (McGraw-Hill Education/Medical, 2012).

  138. Pomeroy, J. E., Nguyen, H. X., Hoffman, B. D. & Bursac, N. Genetically encoded photoactuators and photosensors for characterization and manipulation of pluripotent stem cells. Theranostics 7, 3539–3558 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported in part by the National Institute of Neurological Disorders and Stroke (5R01NS086804), the National Institutes of Health BRAIN Initiative (1R01MH111872), the National Science Foundation through the Center for Materials Science and Engineering (DMR-1419807) and the Center for Neurotechnology (EEC-1028725), and by the McGovern Institute for Brain Research at MIT.

Author information

Authors and Affiliations

Authors

Contributions

J.A.F. and M.-J.A. researched data for the article. J.A.F., M.-J.A. and P.A. discussed the article scope and wrote the manuscript.

Corresponding author

Correspondence to Polina Anikeeva.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Frank, J.A., Antonini, MJ. & Anikeeva, P. Next-generation interfaces for studying neural function. Nat Biotechnol 37, 1013–1023 (2019). https://doi.org/10.1038/s41587-019-0198-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41587-019-0198-8

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing