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Evaluating the potential of using quantum dots for monitoring electrical signals in neurons

Abstract

Success in the projects aimed at providing an advanced understanding of the brain is directly predicated on making critical advances in nanotechnology. This Perspective addresses the unique interface of neuroscience and nanomaterials by considering the foundational problem of sensing neuron membrane voltage and offers a potential solution that may be facilitated by a prototypical nanomaterial. Despite substantial improvements, the visualization of instantaneous voltage changes within individual neurons, whether in cell culture or in vivo, at both the single-cell and network level at high speed remains complex and problematic. The unique properties of semiconductor quantum dots (QDs) have made them powerful fluorophores for bioimaging. What is not widely appreciated, however, is that QD photoluminescence is exquisitely sensitive to proximal electric fields. This property should be suitable for sensing voltage changes that occur in the active neuronal membrane. Here, we examine the potential role of QDs in addressing the important challenge of real-time optical voltage imaging.

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Fig. 1: Schematic of signalling and membrane depolarization along the axon of a neuronal cell.
Fig. 2: QD photophysical properties.
Fig. 3: Effect of electric field on QD PL.
Fig. 4: In vitro and in vivo optical imaging of cortical electrical stimulation using QD−JBD1−C60 bioconjugates.

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References

  1. Kandel, E., Schwartz, J. & Jessell, T. Principles of Neural Science 5 edn (McGraw-Hill Medical, Columbus, OH, 2013).

  2. Nicholls, J. G., Martin, A. R., Wallace, B. G. & Fuchs, P. A. in From Neuron to Brain: A Cellular and Molecular Approach to the Function of the Nervous System 4 edn (Sinauer Associates, Sunderland, MA, 2001).

  3. Denk, W., Briggman, K. L. & Helmstaedter, M. Structural neurobiology: missing link to a mechanistic understanding of neural computation. Nat. Rev. Neurosci. 13, 351–358 (2012).

    Article  Google Scholar 

  4. Harris, K. D. & Mrsic-Flogel, T. D. Cortical connectivity and sensory coding. Nature 503, 51–58 (2013).

    Article  Google Scholar 

  5. Park, H. J. & Friston, K. J. Structural and functional brain networks: from connections to cognition. Science 342, 1238411 (2013).

    Article  Google Scholar 

  6. Hamill, O. P., Marty, A., Neher, E., Sakmann, B. & Sigworth, F. J. Impoved patch-clamp techniques for high-resolution current recording from cells and cell-free membarne patches. Pflugers Archiv-Eur. J. Phys 391, 85–100 (1981).

    Article  Google Scholar 

  7. Peterka, D. S., Takahashi, H. & Yuste, R. Imaging voltage in neurons. Neuron 69, 9–21 (2011).This paper provides a detailed comparison of different techniques available for imaging voltage in neurons and lays out both the benefits and liabilities of each along with what is critically required from the next generation of probes.

    Article  Google Scholar 

  8. Azevedo, F. A. C. et al. Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled-up pimate bain. J. Comp. Neurol. 513, 532–541 (2009).

    Article  Google Scholar 

  9. Alivisatos, A. P. et al. Nanotools for neuroscience and brain activity mapping. ACS Nano 7, 1850–1866 (2013). This paper is a perspective on what nanotechnology and nanomaterials potentially have to contribute to the brain mapping initiatives.

    Article  Google Scholar 

  10. Alivisatos, A. P. et al. The brain activity map. Science 339, 1284–1285 (2013).

    Article  Google Scholar 

  11. Malmivuo, J. & Plonsey, R. Bioelectromagnetism (Oxford University Press, New York, NY, 1995).

  12. Nunez, P. L. & Srinivasan, R. Electric Fields of the Brain: the Neurophysics of EEG 2nd edn (Oxford University Press, New York, NY, 2006).

  13. McRobbie, D. W., Moore, E. A., Graves, M. J. & Prince, M. R. MRI from Picture to Proton 2nd edn (Cambridge Univ. Press, New York, NY, 2007).

  14. Logothetis, N. K. What we can do and what we cannot do with fMRI. Nature 453, 869–878 (2008).

    Article  Google Scholar 

  15. Logothetis, N. K., Pauls, J., Augath, M., Trinath, T. & Oeltermann, A. Neurophysiological investigation of the basis of the fMRI signal. Nature 412, 150–157 (2001).

    Article  Google Scholar 

  16. Wedeen, V. J. et al. The geometric structure of the brain fiber pathways. Science 335, 1628–1634 (2012).

    Article  Google Scholar 

  17. Sakmann, B. & Neher, E. (eds) Single-Channel Recording 2nd edn (Plenum Press, New York, NY, 1995).

  18. Buzsaki, G. Large-scale recording of neuronal ensembles. Nat. Neurosci. 7, 446–451 (2004).

    Article  Google Scholar 

  19. Wise, K. D., Anderson, D. J., Hetke, J. F., Kipke, D. R. & Najafi, K. Wireless implantable microsystems: High-density electronic interfaces to the nervous system. Proc. IEEE 92, 76–97 (2004).

    Article  Google Scholar 

  20. Wise, K. D. et al. Microelectrodes, microelectronics, and implantable neural microsystems. Proc. IEEE 96, 1184–1202 (2008).This paper is an overview of how the methods and techniques adapted from semiconductor fabrication, signal processing and communication microsystems technologies have revolutionized the electrical measurements of brain activity.

    Article  Google Scholar 

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

    Article  Google Scholar 

  22. Lewicki, M. S. A review of methods for spike sorting: the detection and classification of neural action potentials. Netw. Comput. Neural Syst. 9, R53–R78 (1998).

    Article  Google Scholar 

  23. Gibson, S., Judy, J. W. & Markovic, D. Spike sorting the first step in decoding the brain. IEEE Signal Process. Mag. 29, 124–143 (2012).

    Article  Google Scholar 

  24. Stevenson, I. H. & Kording, K. P. How advances in neural recording affect data analysis. Nat. Neurosci. 14, 139–142 (2011).

    Article  Google Scholar 

  25. Spira, M. E. & Hai, A. Multi-electrode array technologies for neuroscience and cardiology. Nat. Nanotech. 8, 83–94 (2013).

    Article  Google Scholar 

  26. Scanziani, M. & Hausser, M. Electrophysiology in the age of light. Nature 461, 930–939 (2009).The paper reports on the tremendous progress and remaining challenges in optical tools developed towards imaging and manipulation of neural populations.

    Article  Google Scholar 

  27. Chemla, S. & Chavane, F. Voltage-sensitive dye imaging: technique review and models. J. Physiol. Paris 104, 40–50 (2010).

    Article  Google Scholar 

  28. Walters, R. et al. Nanoparticle targeting to neurons in a rat hippocampal slice culture model. ASN Neuro 4, 383–392 (2012).

    Article  Google Scholar 

  29. Bradburne, C. E. et al. Cytotoxicity of quantum dots used for in vitro cellular labeling: role of QD surface ligand, delivery modality, cell type and direct comparison to organic fluorophores. Bioconjug. Chem. 24, 1570–1583 (2013).

    Article  Google Scholar 

  30. Agarwal, R. et al. Delivery and tracking of quantum dot peptide bioconjugates in an intact developing avian brain. ACS Chem. Neurosci. 6, 494–504 (2015).

    Article  Google Scholar 

  31. Talapin, D. V., Rogach, A. L., Kornowski, A., Haase, M. & Weller, H. Highly luminescent monodisperse CdSe and CdSe/ZnS nanocrystals synthesized in a hexadecylamine-trioctylphosphine oxide-trioctylphospine mixture. Nano Lett. 1, 207–211 (2001).

    Article  Google Scholar 

  32. Algar, W. R., Susumu, K., Delehanty, J. B. & Medintz, I. L. Semiconductor quantum dots in bioanalysis: crossing the valley of death. Anal. Chem. 83, 8826–8837 (2011).

    Article  Google Scholar 

  33. Chen, Y. et al. “Giant” multishell CdSe nanocrystal quantum dots with suppressed blinking. J. Am. Chem. Soc. 130, 5026–5027 (2008).

    Article  Google Scholar 

  34. Larson, D. R. et al. Water-soluble quantum dots for multiphoton fluorescence imaging in vivo. Science 300, 1434–1436 (2003).

    Article  Google Scholar 

  35. McLaurin, E. J., Greytak, A. B., Bawendi, M. G. & Nocera, D. G. Two-photon absorbing nanocrystal sensors for ratiometric detection of oxygen. J. Am. Chem. Soc. 131, 12994–13001 (2009).

    Article  Google Scholar 

  36. Andrasfalvy, B. K. et al. Quantum dot-based multiphoton fluorescent pipettes for targeted neuronal electrophysiology. Nat. Methods 11, 1237–1241 (2014).

    Article  Google Scholar 

  37. Miller, D. A. B. et al. Band-edge electroabsorption in quantum well structures - the quantum-confined Stark-effect. Phys. Rev. Lett. 53, 2173–2176 (1984).

    Article  Google Scholar 

  38. Gonzalez, J. E. & Tsien, R. Y. Voltage sensing by fluorescence resonance energy-transfer in single cells. Biophys. J. 69, 1272–1280 (1995).

    Article  Google Scholar 

  39. Gonzalez, J. E. & Tsien, R. Y. Improved indicators of cell membrane potential that use fluorescence resonance energy transfer. Chem. Biol. 4, 269–277 (1997).

    Article  Google Scholar 

  40. Algar, W. R., Kim, H., Medintz, I. L. & Hildebrandt, N. Emerging non-traditional Forster resonance energy transfer configurations with semiconductor quantum dots: Investigations and applications. Coord. Chem. Rev. 263, 65–85 (2014).

    Article  Google Scholar 

  41. Miller, E. W. et al. Optically monitoring voltage in neurons by photo-induced electron transfer through molecular wires. Proc. Natl Acad. Sci. USA 109, 2114–211 (2012).

    Article  Google Scholar 

  42. Woodford, C. R. et al. Improved PeT molecules for optically sensing voltage in neurons. J. Am. Chem. Soc. 137, 1817–1824 (2015).

    Article  Google Scholar 

  43. Ekimov, A. I., Efros, Al. L., Shubina, T. V. & Skvortsov, A. P. Quantum-size Stark-effect in semiconductor microcrystals. J. Luminesc. 46, 97–100 (1990).

    Article  Google Scholar 

  44. Empedocles, S. A. & Bawendi, M. G. Quantum-confined Stark effect in single CdSe nanocrystallite quantum dots. Science 278, 2114–2117 (1997).

    Article  Google Scholar 

  45. Achtstein, A. W., Karl, H. & Stritzker, B. Field induced photoluminescence quenching and enhancement of CdSe nanocrystals embedded in SiO2. Appl. Phys. Lett. 89, 061103 (2006).

    Article  Google Scholar 

  46. Bozyigit, D., Yarema, O. & Wood, V. Origins of low quantum efficiencies in quantum dot LEDs. Adv. Funct. Mat 23, 2024–3029 (2013).

    Article  Google Scholar 

  47. Huang, H., Dorn, A., Nair, G. P., Bulovic, V. & Bawendi, M. G. Bias-induced photoluminescence quenching of single colloidal quantum dots embedded in organic semiconductors. Nano Lett. 7, 3781–3786 (2007).

    Article  Google Scholar 

  48. Gurinovich, L. I. et al. Luminescence in quantum-confined cadmium selenide nanocrystals and nanorods in external electric fields. Semiconductors 43, 1008–1016 (2009).

    Article  Google Scholar 

  49. Korlacki, R., Saraf, R. F. & Ducharme, S. Electrical control of photoluminescence wavelength from semiconductor quantum dots in a ferroelectric polymer matrix. Appl. Phys. Lett. 99, 153112 (2011).

    Article  Google Scholar 

  50. Rowland, C. E. et al. Electric field modulation of semiconductor quantum dot photoluminescence: insights into the design of robust voltage- sensitive cellular imaging probes. Nano Lett. 15, 6848–6854 (2015).

    Article  Google Scholar 

  51. Galland, C. et al. Two types of luminescence blinking revealed by spectro -electrochemistry of single quantum dots. Nature 479, 203–207 (2011).

    Article  Google Scholar 

  52. Chepic, D. I. et al. Auger ionization of semiconductor quantum drops in a glass matrix. J. Lumin. 47, 113–127 (1990).

    Article  Google Scholar 

  53. Nirmal, M. et al. Fluorescence intermittency in single cadmium selenide nanocrystals. Nature 383, 802–804 (1996).

    Article  Google Scholar 

  54. Banin, U. et al. Evidence for a thermal contribution to emission intermittency in single CdSe/CdS core/shell nanocrystals. J. Chem. Phys. 110, 1195–1201 (1999).

    Article  Google Scholar 

  55. Kuno, M., Fromm, D. P., Hamann, H. F., Gallagher, A. & Nesbitt, D. J. Nonexponential ‘blinking’ kinetics of single CdSe quantum dots: a universal power law behavior. J. Chem. Phys. 112, 3117–3120 (2000).

    Article  Google Scholar 

  56. Protasenko, V. V., Hull, K. L. & Kuno, M. Disorder-induced optical heterogeneity in single CdSe nanowires. Adv. Mater. 17, 2942–2949 (2005).

    Article  Google Scholar 

  57. Efros, Al. L. & Nesbit, D. Origin and control of blinking in quantum dots. Nat. Nanotech. 11, 661–671 (2016).

    Article  Google Scholar 

  58. Park, K. W., Deutsch, Z., Li, J. J., Oron, D. & Weiss, S. Single molecule quantum-confined Stark effect measurements of semiconductor nanoparticles at room temperature. ACS Nano 6, 10013–10023 (2012).

    Article  Google Scholar 

  59. Leatherdale, C. A. et al. Photoconductivity in CdSe quantum dot solids. Phys. Rev. B 62, 2669–2680 (2000).

    Article  Google Scholar 

  60. Parak, W. J. Controlled interaction of nanoparticles with cells. Science 351, 814–815 (2016).

    Article  Google Scholar 

  61. Čapek, R. K. et al. Synthesis of extremely small CdSe and bright blue luminescent CdSe/ZnS nanoparticles by a prefocused hot-injection approach. Chem. Mater. 21, 1743–1749 (2009).

    Article  Google Scholar 

  62. Pan, D., Wang, Q., Jiang, S., Ji, X. & An, L. Synthesis of extremely small CdSe and highly luminescent CdSe/CdS core-shell nanocrystals via a novel two-phase thermal approach. Adv. Mater. 17, 176–179 (2005).

    Article  Google Scholar 

  63. Molokanova, E. et al. Quantum dots move beyond fluorescence imaging. BioPhotonics 26–31 (2008).

  64. Ignatius, M., Molokanova, E. & Savtchenko, A. Monitoring and manipulating cellular transmembrane potentials using nanostructures. US patent 8,290,714 (2012).

  65. Gopalakrishnan, G. et al. Multifunctional lipid/quantum dot hybrid nanocontainers for controlled targeting of live cells. Angew. Chem. Int. Ed. 45, 5478–5483 (2006).

    Article  Google Scholar 

  66. Marshall, J. D. & Schnitzer, M. J. Optical strategies for sensing neuronal voltage using quantum dots and other semiconductor nanocrystals. ACS Nano 7, 4601–4609 (2013).

    Article  Google Scholar 

  67. Park, K. W. & Weiss, S. Design rules for membrane-embedded voltage-sensing nanoparticles. Biophys. J. 112, 703–713 (2017).

    Article  Google Scholar 

  68. Boeneman, K. et al. Selecting improved peptidyl motifs for cytosolic delivery of disparate protein and nanoparticle materials. ACS Nano 7, 3778–3796 (2013).

    Article  Google Scholar 

  69. Delehanty, J. B. & Bradburne, C. E. Spatiotemporal multicolor labeling of individual cells using peptide-functionalized quantum dots and mixed delivery techniques. J. Am. Chem. Soc. 133, 10482–10489 (2011).

    Article  Google Scholar 

  70. Delehanty, J. B. et al. Site-specific cellular delivery of quantum dots with chemoselectively-assembled modular peptides. Chem. Commun. 49, 7878–7880 (2013).

    Article  Google Scholar 

  71. Wang, H.-Y. et al. Enhanced cell membrane enrichment and subsequent cellular internalization of quantum dots via cell surface engineering: illuminating plasma membranes with quantum dots. J. Mater. Chem. B 4, 834–843 (2016).

    Article  Google Scholar 

  72. Kantner, K. et al. Particle-based optical sensing of intracellular ions at the example of calcium - what are the experimental pitfalls?. Small 11, 896–904 (2015).Example-based description of the challenges of implementing high-resolution cellular sensors with nanoparticle based probes.

    Article  Google Scholar 

  73. Kreyling, W. G. et al. In vivo integrity of polymer-coated gold nanoparticles. Nat. Nanotech. 10, 619–623 (2015).

    Article  Google Scholar 

  74. Susumu, K. et al. Purple-, blue- and green-emitting multishell alloyed quantum dots: synthesis, characterization and application for ratiometric extracellular pH sensing. Chem. Mater. 29, 7330–7344 (2017).

    Article  Google Scholar 

  75. Susumu, K. & Oh, E. Multifunctional compact zwitterionic ligands for preparing robust biocompatible semiconductor quantum dots and gold nanoparticles. J. Am. Chem. Soc. 133, 9480–9496 (2011).

    Article  Google Scholar 

  76. Delehanty, J. B. & Bradburne, C. E. Delivering quantum dot-peptide bioconjugates to the cellular cytosol: escaping from the endolysosomal system. Integr. Biol 2, 265–267 (2010).

    Article  Google Scholar 

  77. Nag, O. K. et al. Quantum dot−peptide−fullerene bioconjugates for visualization of in vitro and in vivo cellular membrane potential. ACS Nano 11, 5598–5613 (2017). This paper provides critical proof-of-concept demonstration that quantum dots can sense and report on real-time changes in neuronal membrane potential in live brain.

    Article  Google Scholar 

  78. Grinvald, A., Lieke, E. E., Frostig, R. D. & Hildesheim, R. Cortical point-spread function and long-range lateral interactions revealed by real-time optical imaging of Macaque monkey primary visual cortex. J. Neurosci. 14, 2545–2568 (1994).

    Article  Google Scholar 

  79. Grandy, T. H., Greenfield, S. A. & Devonshire, I. M. An evaluation of in vivo voltage-sensitive dyes: pharmacological side effects and signal-to-noise ratios after effective removal of brain-pulsation artifacts. J. Neurophysiol. 108, 2931–2945 (2012).

    Article  Google Scholar 

  80. Tsytsarev, V. P. K., Takeshita, D. & Bahar, S. Imaging cortical electrical stimulation in vivo: fast intrinsicoptical signal versus voltage-sensitive dyes. Opt. Lett. 33, 1032–1034 (2008).

    Article  Google Scholar 

  81. Protesescu, L. et al. Nanocrystals of cesium lead halide perovskites (CsPbX3, X = Cl, Br, and I): Novel optoelectronic materials showing bright emission with wide color gamut. Nano Lett. 15, 3692–3696 (2015).

    Article  Google Scholar 

  82. Keller, P. J., Ahrens, M. B. & Freeman, J. Light-sheet imaging for systems neuroscience. Nat. Methods 12, 27–29 (2015).

    Article  Google Scholar 

  83. Keller, P. J. & Ahrens, M. B. Visualizing whole-brain activity and development at the single-cell level using light-sheet. Neuron 85, 462–483 (2015).

    Article  Google Scholar 

  84. Vladimirov, N. et al. Light-sheet functional imaging in fictively behaving zebrafish. Nat. Methods 11, 883–884 (2014).

    Article  Google Scholar 

  85. Truong, T. V., Supatto, W., Koos, D. S., Choi, J. M. & Fraser, S. E. Deep and fast live imaging with two-photon scanned light-sheet microscopy. Nat. Methods 8, 757–760 (2011).

    Article  Google Scholar 

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

    Article  Google Scholar 

  87. Bouchard, M. B. et al. Swept confocally-aligned planar excitation (SCAPE) microscopy for high-speed volumetric imaging of behaving organisms. Nat. Photon 9, 113–119 (2015).

    Article  Google Scholar 

  88. Oh, E. et al. Meta-analysis of cellular toxicity for cadmium-containing quantum dots.Nat. Nanotech. 11, 479–486 (2016).

    Article  Google Scholar 

  89. Walters, R. et al. The role of negative charge in the delivery of quantum dots to neurons. ASN Neuro 7, 1–12 (2015).

    Article  Google Scholar 

  90. Getz, T. et al. Quantum dot-mediated delivery of siRNA to inhibit sphingomyelinase activities in brain-derived cells. J. Neurochem. 139, 872–885 (2016).

    Article  Google Scholar 

  91. Ye, L. et al. A pilot study in non-human primates shows no adverse response to intravenous injection of quantum dots. Nat. Nanotech. 7, 453–458 (2012).

    Article  Google Scholar 

  92. Ballou, B., Lagerholm, C., Ernst, L. A., Bruchez, M. P. & Waggoner, A. S. Noninvasive Imaging of Quantum Dots in Mice. Bioconjug. Chem. 15, 79–86 (2004).

    Article  Google Scholar 

  93. Thomas, A., Nair, P. V. & Thomas, K. G. InP quantum dots: an environmentally friendly material with resonance energy transfer requisites. J. Phys. Chem. C 118, 3838–3845 (2014).

    Article  Google Scholar 

  94. Das, A. & Snee, P. T. Synthetic developments of nontoxic quantum dots. ChemPhysChem 17, 598–617 (2016).

    Article  Google Scholar 

  95. Chen, T. W. et al. Ultra-sensitive fluorescent proteins for imaging neuronal activity. Nature 499, 295–300 (2013). This paper describes state of the art protein engineering of fluorescent probe development foroptical detection of neural activity.

    Article  Google Scholar 

  96. Denk, W., Strickler, J. H. & Webb, W. W. Two-photon laser scanning fluorescence microscopy. Science 248, 73–76 (1990).

    Article  Google Scholar 

  97. Akerboom, J. et al. Optimization of a GCaMP calcium indicator for neural activity imaging. J. Neurosci. 32, 13819–13840 (2012).

    Article  Google Scholar 

  98. Xu, N.-L. et al. Nonlinear dendritic integration of sensory and motor input during an active sensing task. Nature 492, 247–251 (2012).

    Article  Google Scholar 

  99. Klimov, V. I., Mikhailovsky, A. A., McBranch, D. W., Leatherdale, C. A. & Bawendi, M. G. Quantization of multiparticle Auger rates in semiconductor quantum dots. Science 287, 1011–1013 (2000).

    Article  Google Scholar 

  100. Shimizu, K. T. et al. Blinking statistics in single semiconductor nanocrystal quantum dots. Phys. Rev. B 63, 205316 (2001).

    Article  Google Scholar 

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Acknowledgements

A.L.E., J.B.D., A.L.H. and I.L.M. acknowledge the financial support of the Office of Naval Research (ONR) through the Naval Research Laboratory Basic Research Program and the NRL Nanoscience Institute. The work of M.B. and T.D.H. was supported by the Howard Hughes Medical Institute.

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Efros, A.L., Delehanty, J.B., Huston, A.L. et al. Evaluating the potential of using quantum dots for monitoring electrical signals in neurons. Nature Nanotech 13, 278–288 (2018). https://doi.org/10.1038/s41565-018-0107-1

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