Abstract

Elucidating the neural pathways that underlie brain function is one of the greatest challenges in neuroscience. Light sheet based microscopy is a cutting edge method to map cerebral circuitry through optical sectioning of cleared mouse brains. However, the image contrast provided by this method is not sufficient to resolve and reconstruct the entire neuronal network. Here we combined the advantages of light sheet illumination and confocal slit detection to increase the image contrast in real time, with a frame rate of 10 Hz. In fact, in confocal light sheet microscopy (CLSM), the out-of-focus and scattered light is filtered out before detection, without multiple acquisitions or any post-processing of the acquired data. The background rejection capabilities of CLSM were validated in cleared mouse brains by comparison with a structured illumination approach. We show that CLSM allows reconstructing macroscopic brain volumes with sub-cellular resolution. We obtained a comprehensive map of Purkinje cells in the cerebellum of L7-GFP transgenic mice. Further, we were able to trace neuronal projections across brain of thy1-GFP-M transgenic mice. The whole-brain high-resolution fluorescence imaging assured by CLSM may represent a powerful tool to navigate the brain through neuronal pathways. Although this work is focused on brain imaging, the macro-scale high-resolution tomographies affordable with CLSM are ideally suited to explore, at micron-scale resolution, the anatomy of different specimens like murine organs, embryos or flies.

© 2012 OSA

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2012 (5)

P. J. Keller and H. U. Dodt, “Light sheet microscopy of living or cleared specimens,” Curr. Opin. Neurobiol.22(1), 138–143 (2012).
[CrossRef] [PubMed]

F. O. Fahrbach and A. Rohrbach, “Propagation stability of self-reconstructing Bessel beams enables contrast-enhanced imaging in thick media,” Nat Commun3, 632 (2012).
[CrossRef] [PubMed]

K. Becker, N. Jährling, S. Saghafi, R. Weiler, and H. U. Dodt, “Chemical clearing and dehydration of GFP expressing mouse brains,” PLoS ONE7(3), e33916 (2012).
[CrossRef] [PubMed]

U. Krzic, S. Gunther, T. E. Saunders, S. J. Streichan, and L. Hufnagel, “Multiview light-sheet microscope for rapid in toto imaging,” Nat. Methods9(7), 730–733 (2012).
[CrossRef] [PubMed]

R. Tomer, K. Khairy, F. Amat, and P. J. Keller, “Quantitative high-speed imaging of entire developing embryos with simultaneous multiview light-sheet microscopy,” Nat. Methods9(7), 755–763 (2012).
[CrossRef] [PubMed]

2011 (5)

A. Ertürk, C. P. Mauch, F. Hellal, F. Förstner, T. Keck, K. Becker, N. Jährling, H. Steffens, M. Richter, M. Hübener, E. Kramer, F. Kirchhoff, H. U. Dodt, and F. Bradke, “Three-dimensional imaging of the unsectioned adult spinal cord to assess axon regeneration and glial responses after injury,” Nat. Med.18(1), 166–171 (2011).
[CrossRef] [PubMed]

T. A. Planchon, L. Gao, D. E. Milkie, M. W. Davidson, J. A. Galbraith, C. G. Galbraith, and E. Betzig, “Rapid three-dimensional isotropic imaging of living cells using Bessel beam plane illumination,” Nat. Methods8(5), 417–423 (2011).
[CrossRef] [PubMed]

H. Hama, H. Kurokawa, H. Kawano, R. Ando, T. Shimogori, H. Noda, K. Fukami, A. Sakaue-Sawano, and A. Miyawaki, “Scale: a chemical approach for fluorescence imaging and reconstruction of transparent mouse brain,” Nat. Neurosci.14(11), 1481–1488 (2011).
[CrossRef] [PubMed]

K. L. Briggman, M. Helmstaedter, and W. Denk, “Wiring specificity in the direction-selectivity circuit of the retina,” Nature471(7337), 183–188 (2011).
[CrossRef] [PubMed]

J. Mertz, “Optical sectioning microscopy with planar or structured illumination,” Nat. Methods8(10), 811–819 (2011).
[CrossRef] [PubMed]

2010 (7)

P. J. Keller, A. D. Schmidt, A. Santella, K. Khairy, Z. Bao, J. Wittbrodt, and E. H. Stelzer, “Fast, high-contrast imaging of animal development with scanned light sheet-based structured-illumination microscopy,” Nat. Methods7(8), 637–642 (2010).
[CrossRef] [PubMed]

J. Mertz and J. Kim, “Scanning light-sheet microscopy in the whole mouse brain with HiLo background rejection,” J. Biomed. Opt.15(1), 016027 (2010).
[CrossRef] [PubMed]

W. K. Jeong, J. Schneider, S. G. Turney, B. E. Faulkner-Jones, D. Meyer, R. Westermann, R. C. Reid, J. Lichtman, and H. Pfister, “Interactive histology of large-scale biomedical image stacks,” IEEE Trans. Vis. Comput. Graph.16(6), 1386–1395 (2010).
[CrossRef] [PubMed]

A. Li, H. Gong, B. Zhang, Q. Wang, C. Yan, J. Wu, Q. Liu, S. Zeng, and Q. Luo, “Micro-optical sectioning tomography to obtain a high-resolution atlas of the mouse brain,” Science330(6009), 1404–1408 (2010).
[CrossRef] [PubMed]

N. Jährling, K. Becker, C. Schönbauer, F. Schnorrer, and H. U. Dodt, “Three-dimensional reconstruction and segmentation of intact Drosophila by ultramicroscopy,” Front Syst Neurosci4, 1 (2010).
[PubMed]

A. B. Arrenberg, D. Y. Stainier, H. Baier, and J. Huisken, “Optogenetic control of cardiac function,” Science330(6006), 971–974 (2010).
[CrossRef] [PubMed]

S. Kalchmair, N. Jährling, K. Becker, and H. U. Dodt, “Image contrast enhancement in confocal ultramicroscopy,” Opt. Lett.35(1), 79–81 (2010).
[CrossRef] [PubMed]

2009 (3)

S. Mori, K. Oishi, and A. V. Faria, “White matter atlases based on diffusion tensor imaging,” Curr. Opin. Neurol.22(4), 362–369 (2009).
[CrossRef] [PubMed]

J. Huisken and D. Y. Stainier, “Selective plane illumination microscopy techniques in developmental biology,” Development136(12), 1963–1975 (2009).
[CrossRef] [PubMed]

J. Jankowski, A. Miething, K. Schilling, and S. L. Baader, “Physiological purkinje cell death is spatiotemporally organized in the developing mouse cerebellum,” Cerebellum8(3), 277–290 (2009).
[CrossRef] [PubMed]

2008 (7)

M. Helmstaedter, K. L. Briggman, and W. Denk, “3D structural imaging of the brain with photons and electrons,” Curr. Opin. Neurobiol.18(6), 633–641 (2008).
[CrossRef] [PubMed]

J. W. Lichtman, J. Livet, and J. R. Sanes, “A technicolour approach to the connectome,” Nat. Rev. Neurosci.9(6), 417–422 (2008).
[CrossRef] [PubMed]

D. Mayerich, L. Abbott, and B. McCormick, “Knife-edge scanning microscopy for imaging and reconstruction of three-dimensional anatomical structures of the mouse brain,” J. Microsc.231(1), 134–143 (2008).
[CrossRef] [PubMed]

C. Dunsby, “Optically sectioned imaging by oblique plane microscopy,” Opt. Express16(25), 20306–20316 (2008).
[CrossRef] [PubMed]

P. J. Keller, A. D. Schmidt, J. Wittbrodt, and E. H. Stelzer, “Reconstruction of zebrafish early embryonic development by scanned light sheet microscopy,” Science322(5904), 1065–1069 (2008).
[CrossRef] [PubMed]

M. Tokunaga, N. Imamoto, and K. Sakata-Sogawa, “Highly inclined thin illumination enables clear single-molecule imaging in cells,” Nat. Methods5(2), 159–161 (2008).
[CrossRef] [PubMed]

T. F. Holekamp, D. Turaga, and T. E. Holy, “Fast three-dimensional fluorescence imaging of activity in neural populations by objective-coupled planar illumination microscopy,” Neuron57(5), 661–672 (2008).
[CrossRef] [PubMed]

2007 (4)

P. J. Verveer, J. Swoger, F. Pampaloni, K. Greger, M. Marcello, and E. H. Stelzer, “High-resolution three-dimensional imaging of large specimens with light sheet-based microscopy,” Nat. Methods4(4), 311–313 (2007).
[PubMed]

J. Huisken and D. Y. Stainier, “Even fluorescence excitation by multidirectional selective plane illumination microscopy (mSPIM),” Opt. Lett.32(17), 2608–2610 (2007).
[CrossRef] [PubMed]

J. A. Buytaert and J. J. Dirckx, “Design and quantitative resolution measurements of an optical virtual sectioning three-dimensional imaging technique for biomedical specimens, featuring two-micrometer slicing resolution,” J. Biomed. Opt.12(1), 014039 (2007).
[CrossRef] [PubMed]

H. U. Dodt, U. Leischner, A. Schierloh, N. Jährling, C. P. Mauch, K. Deininger, J. M. Deussing, M. Eder, W. Zieglgänsberger, and K. Becker, “Ultramicroscopy: three-dimensional visualization of neuronal networks in the whole mouse brain,” Nat. Methods4(4), 331–336 (2007).
[CrossRef] [PubMed]

2006 (2)

P. J. Keller, F. Pampaloni, and E. H. Stelzer, “Life sciences require the third dimension,” Curr. Opin. Cell Biol.18(1), 117–124 (2006).
[CrossRef] [PubMed]

R. R. Buss, W. Sun, and R. W. Oppenheim, “Adaptive roles of programmed cell death during nervous system development,” Annu. Rev. Neurosci.29(1), 1–35 (2006).
[CrossRef] [PubMed]

2005 (2)

J. A. Conchello and J. W. Lichtman, “Optical sectioning microscopy,” Nat. Methods2(12), 920–931 (2005).
[CrossRef] [PubMed]

O. Sporns, G. Tononi, and R. Kötter, “The human connectome: A structural description of the human brain,” PLOS Comput. Biol.1(4), e42 (2005).
[CrossRef] [PubMed]

2004 (2)

G. Cox and C. J. Sheppard, “Practical limits of resolution in confocal and non-linear microscopy,” Microsc. Res. Tech.63(1), 18–22 (2004).
[CrossRef] [PubMed]

J. Huisken, J. Swoger, F. Del Bene, J. Wittbrodt, and E. H. Stelzer, “Optical sectioning deep inside live embryos by selective plane illumination microscopy,” Science305(5686), 1007–1009 (2004).
[CrossRef] [PubMed]

2003 (2)

W. R. Zipfel, R. M. Williams, and W. W. Webb, “Nonlinear magic: multiphoton microscopy in the biosciences,” Nat. Biotechnol.21(11), 1369–1377 (2003).
[CrossRef] [PubMed]

C. Sotelo, “Viewing the brain through the master hand of Ramon y Cajal,” Nat. Rev. Neurosci.4(1), 71–77 (2003).
[CrossRef] [PubMed]

2002 (2)

2001 (2)

M. J. Booth and T. Wilson, “Refractive-index-mismatch induced aberrations in single-photon and two-photon microscopy and the use of aberration correction,” J. Biomed. Opt.6(3), 266–272 (2001).
[CrossRef] [PubMed]

M. Tomomura, D. S. Rice, J. I. Morgan, and M. Yuzaki, “Purification of Purkinje cells by fluorescence-activated cell sorting from transgenic mice that express green fluorescent protein,” Eur. J. Neurosci.14(1), 57–63 (2001).
[CrossRef] [PubMed]

2000 (1)

G. Feng, R. H. Mellor, M. Bernstein, C. Keller-Peck, Q. T. Nguyen, M. Wallace, J. M. Nerbonne, J. W. Lichtman, and J. R. Sanes, “Imaging neuronal subsets in transgenic mice expressing multiple spectral variants of GFP,” Neuron28(1), 41–51 (2000).
[CrossRef] [PubMed]

1998 (1)

T. L. Kemper and M. Bauman, “Neuropathology of infantile autism,” J. Neuropathol. Exp. Neurol.57(7), 645–652 (1998).
[CrossRef] [PubMed]

1993 (1)

A. H. Voie, D. H. Burns, and F. A. Spelman, “Orthogonal-plane fluorescence optical sectioning: three-dimensional imaging of macroscopic biological specimens,” J. Microsc.170(3), 229–236 (1993).
[CrossRef] [PubMed]

1987 (1)

1986 (1)

E. R. Ritvo, B. J. Freeman, A. B. Scheibel, T. Duong, H. Robinson, D. Guthrie, and A. Ritvo, “Lower Purkinje cell counts in the cerebella of four autistic subjects: initial findings of the UCLA-NSAC Autopsy Research Report,” Am. J. Psychiatry143(7), 862–866 (1986).
[PubMed]

1985 (2)

M. Bauman and T. L. Kemper, “Histoanatomic observations of the brain in early infantile autism,” Neurology35(6), 866–874 (1985).
[CrossRef] [PubMed]

J. Altman and S. A. Bayer, “Embryonic development of the rat cerebellum. III. Regional differences in the time of origin, migration, and settling of Purkinje cells,” J. Comp. Neurol.231(1), 42–65 (1985).
[CrossRef] [PubMed]

1903 (1)

H. Siedentopf and R. Zsigmondy, “Uber Sichtbarmachung und Grössenbestimmung ultramikroskopischer Teilchen, mit besonderer Anwendung auf Goldrubingläser,” Annalen der Physik10, 1–39 (1903).

Abbott, L.

D. Mayerich, L. Abbott, and B. McCormick, “Knife-edge scanning microscopy for imaging and reconstruction of three-dimensional anatomical structures of the mouse brain,” J. Microsc.231(1), 134–143 (2008).
[CrossRef] [PubMed]

Altman, J.

J. Altman and S. A. Bayer, “Embryonic development of the rat cerebellum. III. Regional differences in the time of origin, migration, and settling of Purkinje cells,” J. Comp. Neurol.231(1), 42–65 (1985).
[CrossRef] [PubMed]

Amat, F.

R. Tomer, K. Khairy, F. Amat, and P. J. Keller, “Quantitative high-speed imaging of entire developing embryos with simultaneous multiview light-sheet microscopy,” Nat. Methods9(7), 755–763 (2012).
[CrossRef] [PubMed]

Ando, R.

H. Hama, H. Kurokawa, H. Kawano, R. Ando, T. Shimogori, H. Noda, K. Fukami, A. Sakaue-Sawano, and A. Miyawaki, “Scale: a chemical approach for fluorescence imaging and reconstruction of transparent mouse brain,” Nat. Neurosci.14(11), 1481–1488 (2011).
[CrossRef] [PubMed]

Arrenberg, A. B.

A. B. Arrenberg, D. Y. Stainier, H. Baier, and J. Huisken, “Optogenetic control of cardiac function,” Science330(6006), 971–974 (2010).
[CrossRef] [PubMed]

Azam, F.

Baader, S. L.

J. Jankowski, A. Miething, K. Schilling, and S. L. Baader, “Physiological purkinje cell death is spatiotemporally organized in the developing mouse cerebellum,” Cerebellum8(3), 277–290 (2009).
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Supplementary Material (3)

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Figures (7)

Fig. 1
Fig. 1

Confocal light sheet microscopy (CLSM). (a) Side (upper panel) and top (lower panel) views of the spatial filter operation scheme. The diffraction limited excitation beam (black dashed line) is blurred (blue area) because of sample-induced scattering. The fluorescence light is then emitted both in-focus (green continuous lines) and out-of-focus (green dashed lines): only the in-focus ballistic photons are properly focused in the aperture of the spatial filter (Slit) by the first 4f optical system (objective, Obj and tube lens, TL). The second 4f system (L1, L2) images ballistic photons on the EM-CCD sensor. In the top view, rays originating from different positions are depicted with different hues of green. (b) CLSM optical scheme. The excitation laser beam is scanned by a first galvo mirror (GM1) and focused by a scanning lens (SL) on the specimen. The fluorescence emission orthogonally collected by Obj is de-scanned by a second galvo (GM2) pivoting the linear image onto the slit aperture. A third scanning mirror (GM3) recreates the wide field-like image on the EM-CCD sensor after filtering out of the excitation light by a fluorescence filter (FF). Precision micro-translators allow both 3D motion of the specimen chamber (3D stage) and the movement of excitation (SL) and detection (Obj) optics.

Fig. 2
Fig. 2

Measurement of radial and axial CLSM point spread functions. Axial (purple circles) and radial (green circles) point spread functions (PSFs) measured in conventional (a) and in confocal modality (b). The best Gaussian fits for axial and radial PSFs are shown by the blue and red lines, respectively. Experimental data have been normalized in area.

Fig. 3
Fig. 3

Background rejection. (a) Comparison between LSM, SI-LSM and CLSM performed in: excised hippocampus (EH) of a thy1-GFP-M mouse, cerebellum (C) of a L7-GFP mouse and whole brain (WB) of a thy1-GFP-M mouse; post natal day (PND) 15 for all samples. Images are maximum intensity projections of 40 sections (z-step 1 µm). The lookup table saturates 4% of pixels for better visibility and comparison. Scale bars, 100 µm. (b) Intensity profiles (green: LSM; blue: SI-LSM; red: CLSM) along the dotted purple lines highlighted in panel (a). The profiles are normalized with respect to their maximum intensity value. (c) Contrast enhancement of SI-LSM (in blue) and CLSM (in red) with respect to LSM, calculated from data acquired in EH, C, WB. Each bar represents the mean and standard error of the mean. The green line refers to no contrast enhancement.

Fig. 4
Fig. 4

Background rejection using higher NA optics. Purkinje cells in the cerebellum of a PND 15 L7-GFP mouse, imaged with LSM (a) and CLSM (b) using an objective with higher numerical aperture (Nikon 50 × , NA = 0.45). Slit width was 15 µm, corresponding to 0.6 µm in object space. Images are maximum intensity projections of 160 sections (z-step 1 µm). For better visibility and comparison a nonlinear gamma transformation (γ = 0.35) was applied to the images, and the lookup table was linearly modified to eliminate 4% outliers. Scale bars, 100 µm

Fig. 5
Fig. 5

Purkinje cells micron-scale neuroanatomy in the whole cerebellum. (a) 3D volume rendering of a PND-10 L7-GFP mouse cerebellum. The superimposed planes refer to transverse (red), sagittal (green) and coronal (blue) digital sections shown in panel (b), (c) and (d) respectively. (b-d) Maximum intensity projections of 40 µm thick slabs. Scale bars, 1 mm. (e, f) 10 × magnification of the regions highlighted by the yellow boxes in panels (b) and (d). The lookup table saturates 2% of pixels for better visibility.

Fig. 6
Fig. 6

Micron-scale neuroanatomy of a whole thy1-GFP-M brain. (a) Isosurface perspective (P) and transverse (T), coronal (C) and sagittal (S) contours of an entire PND-15 mouse brain. The volumes highlighted by the blue and red boxes are magnified in panel (b) and (c) respectively. (b) Volume rendering of a portion of hippocampus. (c) Volume rendering of a portion of superior colliculus. (d) Soma segmentation and process tracing of selected fluorescent neurons present in the red box (c). For clarity, each neuron was drawn with a different color. Scale bars, 200 µm.

Fig. 7
Fig. 7

Stitching processing pipeline. All the processing steps and their action on both data and metadata are illustrated. On the right, for each step, it is indicated the number of reading and writing operations. Steps that are performed at the same time are connected with arrowless lines.

Tables (1)

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Table 1 Comparison of Different Techniques for the Study of Neuronal Anatomy

Equations (2)

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f'f=d'dd'( 11/n )0.36d'
I( x,y ) = i=1,...,20 max I i ( x,y ) γ i=1,...,20 min I i ( x,y )

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