Abstract
To image neuronal activities down to single spines in freely behaving animal has already been the holy grail of neuroscientists. To achieve that goal, two-photon microscope must be miniaturized to be attached to the animal without interfering animal movements. In the past fifteen years, many groups have published different designs, albeit that none of them is not widely used by the neuroscience community. Here, we have summarized the major challenges that prevent prevalent applications of current miniature two-photon microscopy (TPM) for high-resolution imaging in freely behaving mice, and different configurations that may be used to address each challenge. Based on this theoretical analysis, we have provided detailed design of our high-resolution, miniaturized two-photon microscope (FHIRM-TPM) and its latest revisions that enable volumetric imaging capability and larger field of view and deeper penetration depth.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
M. Minderer, C.D. Harvey, F. Donato, E.I. Moser, Neuroscience: virtual reality explored. Nature 533(7603), 324–325 (2016). https://doi.org/10.1038/nature17899
Z.M. Aghajan, L. Acharya, J.J. Moore, J.D. Cushman, C. Vuong, M.R. Mehta, Impaired spatial selectivity and intact phase precession in two-dimensional virtual reality. Nat. Neurosci. 18(1), 121–128 (2015). https://doi.org/10.1038/nn.3884
E.J. Hamel, B.F. Grewe, J.G. Parker, M.J. Schnitzer, Cellular level brain imaging in behaving mammals: an engineering approach. Neuron 86(1), 140–159 (2015). https://doi.org/10.1016/j.neuron.2015.03.055
C.K. Kim, S.J. Yang, N. Pichamoorthy, N.P. Young, I. Kauvar, J.H. Jennings, T.N. Lerner, A. Berndt, S.Y. Lee, C. Ramakrishnan, T.J. Davidson, M. Inoue, H. Bito, K. Deisseroth, Simultaneous fast measurement of circuit dynamics at multiple sites across the mammalian brain. Nat. Methods 13(4), 325–328 (2016). https://doi.org/10.1038/nmeth.3770
I. Ferezou, S. Bolea, C.C. Petersen, Visualizing the cortical representation of whisker touch: voltage-sensitive dye imaging in freely moving mice. Neuron 50(4), 617–629 (2006). https://doi.org/10.1016/j.neuron.2006.03.043
K.K. Ghosh, L.D. Burns, E.D. Cocker, A. Nimmerjahn, Y. Ziv, A.E. Gamal, M.J. Schnitzer, Miniaturized integration of a fluorescence microscope. Nat. Methods 8(10), 871–878 (2011). https://doi.org/10.1038/nmeth.1694
Z. Gorocs, Y. Rivenson, H. Ceylan Koydemir, D. Tseng, T.L. Troy, V. Demas, A. Ozcan, Quantitative fluorescence sensing through highly autofluorescent, scattering, and absorbing media using mobile microscopy. ACS Nano 10(9), 8989–8999 (2016). https://doi.org/10.1021/acsnano.6b05129
F. Helmchen, M.S. Fee, D.W. Tank, W. Denk, A miniature head-mounted two-photon microscope. Neuron 31(6), 903–912 (2001). https://doi.org/10.1016/s0896-6273(01)00421-4
C.J. Engelbrecht, R.S. Johnston, E.J. Seibel, F. Helmchen, Ultra-compact fiber-optic two-photon microscope for functional fluorescence imaging in vivo. Opt. Express 16(8), 5556 (2008). https://doi.org/10.1364/oe.16.005556
W. Piyawattanametha, E.D. Cocker, L.D. Burns, R.P.J. Barretto, J.C. Jung, H. Ra, O. Solgaard, M.J. Schnitzer, In vivo brain imaging using a portable 2.9 g two-photon microscope based on a microelectromechanical systems scanning mirror. Opt. Lett. 34(15), 2309 (2009). https://doi.org/10.1364/ol.34.002309
J. Sawinski, D.J. Wallace, D.S. Greenberg, S. Grossmann, W. Denk, J.N.D. Kerr, Visually evoked activity in cortical cells imaged in freely moving animals. Proc. Natl. Acad. Sci. 106(46), 19557–19562 (2009). https://doi.org/10.1073/pnas.0903680106
W. Zong, R. Wu, M. Li, Y. Hu, Y. Li, J. Li, H. Rong, H. Wu, Y. Xu, Y. Lu, H. Jia, M. Fan, Z. Zhou, Y. Zhang, A. Wang, L. Chen, H. Cheng, Fast high-resolution miniature two-photon microscopy for brain imaging in freely behaving mice. Nat. Methods 14(7), 713–719 (2017). https://doi.org/10.1038/nmeth.4305
D.R. Rivera, C.M. Brown, D.G. Ouzounov, I. Pavlova, D. Kobat, W.W. Webb, C. Xu, Compact and flexible raster scanning multiphoton endoscope capable of imaging unstained tissue. Proc. Natl. Acad. Sci. U. S. A. 108(43), 17598–17603 (2011). https://doi.org/10.1073/pnas.1114746108
Y. Zhang, M.L. Akins, K. Murari, J. Xi, M.J. Li, K. Luby-Phelps, M. Mahendroo, X. Li, A compact fiber-optic SHG scanning endomicroscope and its application to visualize cervical remodeling during pregnancy. Proc. Natl. Acad. Sci. U. S. A. 109(32), 12878–12883 (2012). https://doi.org/10.1073/pnas.1121495109
F. Helmchen, D.W. Tank, W. Denk, Enhanced two-photon excitation through optical fiber by single-mode propagation in a large core. Appl. Opt. 41(15), 2930 (2002). https://doi.org/10.1364/ao.41.002930
G.P. Agrawal, Applications of nonlinear fiber optics. Optics and Photonics (2001)
W. Gobel, A. Nimmerjahn, F. Helmchen, Distortion-free delivery of nanojoule femtosecond pulses from a Ti:sapphire laser through a hollow-core photonic crystal fiber. Opt. Lett. 29(11), 1285–1287 (2004)
C. Wang, N. Ji, Characterization and improvement of three-dimensional imaging performance of GRIN-lens-based two-photon fluorescence endomicroscopes with adaptive optics. Opt. Express 21(22), 27142–27154 (2013). https://doi.org/10.1364/OE.21.027142
Sawinski Jr, W. Denk, Miniature random-access fiber scanner for in vivo multiphoton imaging. J. Appl. Phys. 102(3), 034701 (2007). https://doi.org/10.1063/1.2763945
M.T. Myaing, D.J. MacDonald, X. Li, Fiber-optic scanning two-photon fluorescence endoscope. Opt. Lett. 31(8), 1076 (2006). https://doi.org/10.1364/ol.31.001076
W. Piyawattanametha, R.P.J. Barretto, T.H. Ko, B.A. Flusberg, E.D. Cocker, H. Ra, D. Lee, O. Solgaard, M.J. Schnitzer, Fast-scanning two-photon fluorescence imaging based on a microelectromechanical systems two- dimensional scanning mirror. Opt. Lett. 31(13), 2018 (2006). https://doi.org/10.1364/ol.31.002018
W. Jung, S. Tang, D.T. McCormic, T. Xie, Y.-C. Ahn, J. Su, I.V. Tomov, T.B. Krasieva, B.J. Tromberg, Z. Chen, Miniaturized probe based on a microelectromechanical system mirror for multiphoton microscopy. Opt. Lett. 33(12), 1324 (2008). https://doi.org/10.1364/ol.33.001324
A. Grayson, A BioMEMS review: MEMS technology for physiologically integrated devices. Proc. IEEE 92(1), 6–21 (2004)
V. Milanovic, Gimbal-less monolithic silicon actuators for tip–tilt–piston micromirror applications. J. Sel. Topics Quantum Electron. 10(3), 462–471 (2004)
R. Prakash, O. Yizhar, B. Grewe, C. Ramakrishnan, N. Wang, I. Goshen, A.M. Packer, D.S. Peterka, R. Yuste, M.J. Schnitzer, K. Deisseroth, Two-photon optogenetic toolbox for fast inhibition, excitation and bistable modulation. Nat. Methods 9(12), 1171–1179 (2012). https://doi.org/10.1038/nmeth.2215
J.P. Rickgauer, K. Deisseroth, D.W. Tank, Simultaneous cellular-resolution optical perturbation and imaging of place cell firing fields. Nat. Neurosci. 17(12), 1816–1824 (2014). https://doi.org/10.1038/nn.3866
G. Matz, B. Messerschmidt, H. Gross, Design and evaluation of new color-corrected rigid endomicroscopic high NA GRIN-objectives with a sub-micron resolution and large field of view. Opt. Express 24(10), 10987–11001 (2016). https://doi.org/10.1364/OE.24.010987
Author information
Authors and Affiliations
Corresponding authors
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2019 Springer Nature Singapore Pte Ltd.
About this chapter
Cite this chapter
Zong, W., Chen, L. (2019). Advanced Miniature Microscopy for Brain Imaging. In: Kao, FJ., Keiser, G., Gogoi, A. (eds) Advanced Optical Methods for Brain Imaging. Progress in Optical Science and Photonics, vol 5. Springer, Singapore. https://doi.org/10.1007/978-981-10-9020-2_9
Download citation
DOI: https://doi.org/10.1007/978-981-10-9020-2_9
Published:
Publisher Name: Springer, Singapore
Print ISBN: 978-981-10-9019-6
Online ISBN: 978-981-10-9020-2
eBook Packages: EngineeringEngineering (R0)