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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Kandel, E., Schwartz, J. & Jessell, T. Principles of Neural Science 5 edn (McGraw-Hill Medical, Columbus, OH, 2013).
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).
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).
Harris, K. D. & Mrsic-Flogel, T. D. Cortical connectivity and sensory coding. Nature 503, 51–58 (2013).
Park, H. J. & Friston, K. J. Structural and functional brain networks: from connections to cognition. Science 342, 1238411 (2013).
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).
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.
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).
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.
Alivisatos, A. P. et al. The brain activity map. Science 339, 1284–1285 (2013).
Malmivuo, J. & Plonsey, R. Bioelectromagnetism (Oxford University Press, New York, NY, 1995).
Nunez, P. L. & Srinivasan, R. Electric Fields of the Brain: the Neurophysics of EEG 2nd edn (Oxford University Press, New York, NY, 2006).
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).
Logothetis, N. K. What we can do and what we cannot do with fMRI. Nature 453, 869–878 (2008).
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).
Wedeen, V. J. et al. The geometric structure of the brain fiber pathways. Science 335, 1628–1634 (2012).
Sakmann, B. & Neher, E. (eds) Single-Channel Recording 2nd edn (Plenum Press, New York, NY, 1995).
Buzsaki, G. Large-scale recording of neuronal ensembles. Nat. Neurosci. 7, 446–451 (2004).
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).
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.
Jun, J. J. et al. Fully integrated silicon probes for high-density recording of neural activity. Nature 551, 232–236 (2017).
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).
Gibson, S., Judy, J. W. & Markovic, D. Spike sorting the first step in decoding the brain. IEEE Signal Process. Mag. 29, 124–143 (2012).
Stevenson, I. H. & Kording, K. P. How advances in neural recording affect data analysis. Nat. Neurosci. 14, 139–142 (2011).
Spira, M. E. & Hai, A. Multi-electrode array technologies for neuroscience and cardiology. Nat. Nanotech. 8, 83–94 (2013).
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.
Chemla, S. & Chavane, F. Voltage-sensitive dye imaging: technique review and models. J. Physiol. Paris 104, 40–50 (2010).
Walters, R. et al. Nanoparticle targeting to neurons in a rat hippocampal slice culture model. ASN Neuro 4, 383–392 (2012).
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).
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).
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).
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).
Chen, Y. et al. “Giant” multishell CdSe nanocrystal quantum dots with suppressed blinking. J. Am. Chem. Soc. 130, 5026–5027 (2008).
Larson, D. R. et al. Water-soluble quantum dots for multiphoton fluorescence imaging in vivo. Science 300, 1434–1436 (2003).
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).
Andrasfalvy, B. K. et al. Quantum dot-based multiphoton fluorescent pipettes for targeted neuronal electrophysiology. Nat. Methods 11, 1237–1241 (2014).
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).
Gonzalez, J. E. & Tsien, R. Y. Voltage sensing by fluorescence resonance energy-transfer in single cells. Biophys. J. 69, 1272–1280 (1995).
Gonzalez, J. E. & Tsien, R. Y. Improved indicators of cell membrane potential that use fluorescence resonance energy transfer. Chem. Biol. 4, 269–277 (1997).
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).
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).
Woodford, C. R. et al. Improved PeT molecules for optically sensing voltage in neurons. J. Am. Chem. Soc. 137, 1817–1824 (2015).
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).
Empedocles, S. A. & Bawendi, M. G. Quantum-confined Stark effect in single CdSe nanocrystallite quantum dots. Science 278, 2114–2117 (1997).
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).
Bozyigit, D., Yarema, O. & Wood, V. Origins of low quantum efficiencies in quantum dot LEDs. Adv. Funct. Mat 23, 2024–3029 (2013).
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).
Gurinovich, L. I. et al. Luminescence in quantum-confined cadmium selenide nanocrystals and nanorods in external electric fields. Semiconductors 43, 1008–1016 (2009).
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).
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).
Galland, C. et al. Two types of luminescence blinking revealed by spectro -electrochemistry of single quantum dots. Nature 479, 203–207 (2011).
Chepic, D. I. et al. Auger ionization of semiconductor quantum drops in a glass matrix. J. Lumin. 47, 113–127 (1990).
Nirmal, M. et al. Fluorescence intermittency in single cadmium selenide nanocrystals. Nature 383, 802–804 (1996).
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).
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).
Protasenko, V. V., Hull, K. L. & Kuno, M. Disorder-induced optical heterogeneity in single CdSe nanowires. Adv. Mater. 17, 2942–2949 (2005).
Efros, Al. L. & Nesbit, D. Origin and control of blinking in quantum dots. Nat. Nanotech. 11, 661–671 (2016).
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).
Leatherdale, C. A. et al. Photoconductivity in CdSe quantum dot solids. Phys. Rev. B 62, 2669–2680 (2000).
Parak, W. J. Controlled interaction of nanoparticles with cells. Science 351, 814–815 (2016).
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).
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).
Molokanova, E. et al. Quantum dots move beyond fluorescence imaging. BioPhotonics 26–31 (2008).
Ignatius, M., Molokanova, E. & Savtchenko, A. Monitoring and manipulating cellular transmembrane potentials using nanostructures. US patent 8,290,714 (2012).
Gopalakrishnan, G. et al. Multifunctional lipid/quantum dot hybrid nanocontainers for controlled targeting of live cells. Angew. Chem. Int. Ed. 45, 5478–5483 (2006).
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).
Park, K. W. & Weiss, S. Design rules for membrane-embedded voltage-sensing nanoparticles. Biophys. J. 112, 703–713 (2017).
Boeneman, K. et al. Selecting improved peptidyl motifs for cytosolic delivery of disparate protein and nanoparticle materials. ACS Nano 7, 3778–3796 (2013).
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).
Delehanty, J. B. et al. Site-specific cellular delivery of quantum dots with chemoselectively-assembled modular peptides. Chem. Commun. 49, 7878–7880 (2013).
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).
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.
Kreyling, W. G. et al. In vivo integrity of polymer-coated gold nanoparticles. Nat. Nanotech. 10, 619–623 (2015).
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).
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).
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).
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.
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).
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).
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).
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).
Keller, P. J., Ahrens, M. B. & Freeman, J. Light-sheet imaging for systems neuroscience. Nat. Methods 12, 27–29 (2015).
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).
Vladimirov, N. et al. Light-sheet functional imaging in fictively behaving zebrafish. Nat. Methods 11, 883–884 (2014).
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).
Prevedel, R. et al. Simultaneous whole-animal 3D imaging of neuronal activity using light-field microscopy. Nat. methods 11, 727–730 (2014).
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).
Oh, E. et al. Meta-analysis of cellular toxicity for cadmium-containing quantum dots.Nat. Nanotech. 11, 479–486 (2016).
Walters, R. et al. The role of negative charge in the delivery of quantum dots to neurons. ASN Neuro 7, 1–12 (2015).
Getz, T. et al. Quantum dot-mediated delivery of siRNA to inhibit sphingomyelinase activities in brain-derived cells. J. Neurochem. 139, 872–885 (2016).
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).
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).
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).
Das, A. & Snee, P. T. Synthetic developments of nontoxic quantum dots. ChemPhysChem 17, 598–617 (2016).
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.
Denk, W., Strickler, J. H. & Webb, W. W. Two-photon laser scanning fluorescence microscopy. Science 248, 73–76 (1990).
Akerboom, J. et al. Optimization of a GCaMP calcium indicator for neural activity imaging. J. Neurosci. 32, 13819–13840 (2012).
Xu, N.-L. et al. Nonlinear dendritic integration of sensory and motor input during an active sensing task. Nature 492, 247–251 (2012).
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).
Shimizu, K. T. et al. Blinking statistics in single semiconductor nanocrystal quantum dots. Phys. Rev. B 63, 205316 (2001).
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.
The authors declare no competing interests.
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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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