Abstract

Two-photon microscopy has been used in conjunction with micro-optics, such as GRIN lenses, to access subcortical structures in the intact mouse brain. In this study, we demonstrate the use of thick glass windows, or plugs, for high-resolution, large field-of-view two-photon imaging of the hippocampus in a live mouse. These plugs are less expensive, yield larger fields-of-view and are simpler to use than GRIN lenses while requiring less tissue removal compared to previous methods based on cortical ablation. To demonstrate the capabilities of our system, we show fluorescence images of dendritic spines in the CA1 region of the hippocampus in THY1-YFP transgenic mice.

© 2014 Optical Society of America

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2013 (4)

N. G. Horton, K. Wang, D. Kobat, C. G. Clark, F. W. Wise, C. B. Schaffer, and C. Xu, “In vivo three-photon microscopy of subcortical structures within an intact mouse brain,” Nat. Photonics7(3), 205–209 (2013).
[CrossRef] [PubMed]

M. L. Andermann, N. B. Gilfoy, G. J. Goldey, R. N. Sachdev, M. Wölfel, D. A. McCormick, R. C. Reid, and M. J. Levene, “Chronic Cellular Imaging of Entire Cortical Columns in Awake Mice Using Microprisms,” Neuron80(4), 900–913 (2013).
[CrossRef] [PubMed]

Y. Ziv, L. D. Burns, E. D. Cocker, E. O. Hamel, K. K. Ghosh, L. J. Kitch, A. El Gamal, and M. J. Schnitzer, “Long-term dynamics of CA1 hippocampal place codes,” Nat. Neurosci.16(3), 264–266 (2013).
[CrossRef] [PubMed]

C. Wang and N. Ji, “Characterization and improvement of three-dimensional imaging performance of GRIN-lens-based two-photon fluorescence endomicroscopes with adaptive optics,” Opt. Express21(22), 27142–27154 (2013).
[CrossRef] [PubMed]

2012 (4)

N. L. Rochefort and A. Konnerth, “Dendritic spines: from structure to in vivo function,” EMBO Rep.13(8), 699–708 (2012).
[CrossRef] [PubMed]

J. del Valle, S. Bayod, A. Camins, C. Beas-Zárate, D. A. Velázquez-Zamora, I. González-Burgos, and M. Pallàs, “Dendritic spine abnormalities in hippocampal CA1 pyramidal neurons underlying memory deficits in the SAMP8 mouse model of Alzheimer’s disease,” J. Alzheimers Dis.32(1), 233–240 (2012).
[PubMed]

S. J. Bulley, C. J. G. Drew, and A. J. Morton, “Direct visualisation of abnormal dendritic spine morphology in the hippocampus of the R6/2 transgenic mouse model of Huntington's Disease,” Journal of Huntington's Disease1, 267–273 (2012).

T. A. Murray and M. J. Levene, “Singlet gradient index lens for deep in vivo multiphoton microscopy,” J. Biomed. Opt.17(2), 021106 (2012).
[CrossRef] [PubMed]

2011 (3)

D. Kobat, N. G. Horton, and C. Xu, “In vivo two-photon microscopy to 1.6-mm depth in mouse cortex,” J. Biomed. Opt.16(10), 106014 (2011).
[CrossRef] [PubMed]

W. Mittmann, D. J. Wallace, U. Czubayko, J. T. Herb, A. T. Schaefer, L. L. Looger, W. Denk, and J. N. D. Kerr, “Two-photon calcium imaging of evoked activity from L5 somatosensory neurons in vivo,” Nat. Neurosci.14(8), 1089–1093 (2011).
[CrossRef] [PubMed]

R. P. J. Barretto, T. H. Ko, J. C. Jung, T. J. Wang, G. Capps, A. C. Waters, Y. Ziv, A. Attardo, L. Recht, and M. J. Schnitzer, “Time-lapse imaging of disease progression in deep brain areas using fluorescence microendoscopy,” Nat. Med.17(2), 223–228 (2011).
[CrossRef] [PubMed]

2009 (5)

A. Auffret, V. Gautheron, M. Repici, R. Kraftsik, H. T. Mount, J. Mariani, and C. Rovira, “Age-dependent impairment of spine morphology and synaptic plasticity in hippocampal CA1 neurons of a presenilin 1 transgenic mouse model of Alzheimer's disease,” The Journal of Neuroscience29, 10144–10152 (2009).

R. P. Barretto, B. Messerschmidt, and M. J. Schnitzer, “In vivo fluorescence imaging with high-resolution microlenses,” Nat. Methods6(7), 511–512 (2009).
[CrossRef] [PubMed]

T. H. Chia and M. J. Levene, “Microprisms for in vivo multilayer cortical imaging,” J. Neurophysiol.102(2), 1310–1314 (2009).
[CrossRef] [PubMed]

A. Holtmaat, T. Bonhoeffer, D. K. Chow, J. Chuckowree, V. De Paola, S. B. Hofer, M. Hübener, T. Keck, G. Knott, W.-C. A. Lee, R. Mostany, T. D. Mrsic-Flogel, E. Nedivi, C. Portera-Cailliau, K. Svoboda, J. T. Trachtenberg, and L. Wilbrecht, “Long-term, high-resolution imaging in the mouse neocortex through a chronic cranial window,” Nat. Protoc.4(8), 1128–1144 (2009).
[CrossRef] [PubMed]

D. Kobat, M. E. Durst, N. Nishimura, A. W. Wong, C. B. Schaffer, and C. Xu, “Deep tissue multiphoton microscopy using longer wavelength excitation,” Opt. Express17(16), 13354–13364 (2009).
[CrossRef] [PubMed]

2005 (1)

F. Helmchen and W. Denk, “Deep tissue two-photon microscopy,” Nat. Methods2(12), 932–940 (2005).
[CrossRef] [PubMed]

2004 (2)

M. J. Levene, D. A. Dombeck, K. A. Kasischke, R. P. Molloy, and W. W. Webb, “In vivo multiphoton microscopy of deep brain tissue,” J. Neurophysiol.91(4), 1908–1912 (2004).
[CrossRef] [PubMed]

A. Mizrahi, J. C. Crowley, E. Shtoyerman, and L. C. Katz, “High-resolution in vivo imaging of hippocampal dendrites and spines,” The Journal of Neuroscience24, 3147–3151 (2004).

2003 (2)

1994 (1)

M. B. Moser, M. Trommald, and P. Andersen, “An increase in dendritic spine density on hippocampal CA1 pyramidal cells following spatial learning in adult rats suggests the formation of new synapses,” Proc. Natl. Acad. Sci. U.S.A.91(26), 12673–12675 (1994).
[CrossRef] [PubMed]

1990 (1)

W. Denk, J. H. Strickler, and W. W. Webb, “Two-photon laser scanning fluorescence microscopy,” Science248(4951), 73–76 (1990).
[CrossRef] [PubMed]

Andermann, M. L.

M. L. Andermann, N. B. Gilfoy, G. J. Goldey, R. N. Sachdev, M. Wölfel, D. A. McCormick, R. C. Reid, and M. J. Levene, “Chronic Cellular Imaging of Entire Cortical Columns in Awake Mice Using Microprisms,” Neuron80(4), 900–913 (2013).
[CrossRef] [PubMed]

Andersen, P.

M. B. Moser, M. Trommald, and P. Andersen, “An increase in dendritic spine density on hippocampal CA1 pyramidal cells following spatial learning in adult rats suggests the formation of new synapses,” Proc. Natl. Acad. Sci. U.S.A.91(26), 12673–12675 (1994).
[CrossRef] [PubMed]

Attardo, A.

R. P. J. Barretto, T. H. Ko, J. C. Jung, T. J. Wang, G. Capps, A. C. Waters, Y. Ziv, A. Attardo, L. Recht, and M. J. Schnitzer, “Time-lapse imaging of disease progression in deep brain areas using fluorescence microendoscopy,” Nat. Med.17(2), 223–228 (2011).
[CrossRef] [PubMed]

Auffret, A.

A. Auffret, V. Gautheron, M. Repici, R. Kraftsik, H. T. Mount, J. Mariani, and C. Rovira, “Age-dependent impairment of spine morphology and synaptic plasticity in hippocampal CA1 neurons of a presenilin 1 transgenic mouse model of Alzheimer's disease,” The Journal of Neuroscience29, 10144–10152 (2009).

Barretto, R. P.

R. P. Barretto, B. Messerschmidt, and M. J. Schnitzer, “In vivo fluorescence imaging with high-resolution microlenses,” Nat. Methods6(7), 511–512 (2009).
[CrossRef] [PubMed]

Barretto, R. P. J.

R. P. J. Barretto, T. H. Ko, J. C. Jung, T. J. Wang, G. Capps, A. C. Waters, Y. Ziv, A. Attardo, L. Recht, and M. J. Schnitzer, “Time-lapse imaging of disease progression in deep brain areas using fluorescence microendoscopy,” Nat. Med.17(2), 223–228 (2011).
[CrossRef] [PubMed]

Bayod, S.

J. del Valle, S. Bayod, A. Camins, C. Beas-Zárate, D. A. Velázquez-Zamora, I. González-Burgos, and M. Pallàs, “Dendritic spine abnormalities in hippocampal CA1 pyramidal neurons underlying memory deficits in the SAMP8 mouse model of Alzheimer’s disease,” J. Alzheimers Dis.32(1), 233–240 (2012).
[PubMed]

Beas-Zárate, C.

J. del Valle, S. Bayod, A. Camins, C. Beas-Zárate, D. A. Velázquez-Zamora, I. González-Burgos, and M. Pallàs, “Dendritic spine abnormalities in hippocampal CA1 pyramidal neurons underlying memory deficits in the SAMP8 mouse model of Alzheimer’s disease,” J. Alzheimers Dis.32(1), 233–240 (2012).
[PubMed]

Bonhoeffer, T.

A. Holtmaat, T. Bonhoeffer, D. K. Chow, J. Chuckowree, V. De Paola, S. B. Hofer, M. Hübener, T. Keck, G. Knott, W.-C. A. Lee, R. Mostany, T. D. Mrsic-Flogel, E. Nedivi, C. Portera-Cailliau, K. Svoboda, J. T. Trachtenberg, and L. Wilbrecht, “Long-term, high-resolution imaging in the mouse neocortex through a chronic cranial window,” Nat. Protoc.4(8), 1128–1144 (2009).
[CrossRef] [PubMed]

Bulley, S. J.

S. J. Bulley, C. J. G. Drew, and A. J. Morton, “Direct visualisation of abnormal dendritic spine morphology in the hippocampus of the R6/2 transgenic mouse model of Huntington's Disease,” Journal of Huntington's Disease1, 267–273 (2012).

Burns, L. D.

Y. Ziv, L. D. Burns, E. D. Cocker, E. O. Hamel, K. K. Ghosh, L. J. Kitch, A. El Gamal, and M. J. Schnitzer, “Long-term dynamics of CA1 hippocampal place codes,” Nat. Neurosci.16(3), 264–266 (2013).
[CrossRef] [PubMed]

Camins, A.

J. del Valle, S. Bayod, A. Camins, C. Beas-Zárate, D. A. Velázquez-Zamora, I. González-Burgos, and M. Pallàs, “Dendritic spine abnormalities in hippocampal CA1 pyramidal neurons underlying memory deficits in the SAMP8 mouse model of Alzheimer’s disease,” J. Alzheimers Dis.32(1), 233–240 (2012).
[PubMed]

Capps, G.

R. P. J. Barretto, T. H. Ko, J. C. Jung, T. J. Wang, G. Capps, A. C. Waters, Y. Ziv, A. Attardo, L. Recht, and M. J. Schnitzer, “Time-lapse imaging of disease progression in deep brain areas using fluorescence microendoscopy,” Nat. Med.17(2), 223–228 (2011).
[CrossRef] [PubMed]

Chia, T. H.

T. H. Chia and M. J. Levene, “Microprisms for in vivo multilayer cortical imaging,” J. Neurophysiol.102(2), 1310–1314 (2009).
[CrossRef] [PubMed]

Chow, D. K.

A. Holtmaat, T. Bonhoeffer, D. K. Chow, J. Chuckowree, V. De Paola, S. B. Hofer, M. Hübener, T. Keck, G. Knott, W.-C. A. Lee, R. Mostany, T. D. Mrsic-Flogel, E. Nedivi, C. Portera-Cailliau, K. Svoboda, J. T. Trachtenberg, and L. Wilbrecht, “Long-term, high-resolution imaging in the mouse neocortex through a chronic cranial window,” Nat. Protoc.4(8), 1128–1144 (2009).
[CrossRef] [PubMed]

Chuckowree, J.

A. Holtmaat, T. Bonhoeffer, D. K. Chow, J. Chuckowree, V. De Paola, S. B. Hofer, M. Hübener, T. Keck, G. Knott, W.-C. A. Lee, R. Mostany, T. D. Mrsic-Flogel, E. Nedivi, C. Portera-Cailliau, K. Svoboda, J. T. Trachtenberg, and L. Wilbrecht, “Long-term, high-resolution imaging in the mouse neocortex through a chronic cranial window,” Nat. Protoc.4(8), 1128–1144 (2009).
[CrossRef] [PubMed]

Clark, C. G.

N. G. Horton, K. Wang, D. Kobat, C. G. Clark, F. W. Wise, C. B. Schaffer, and C. Xu, “In vivo three-photon microscopy of subcortical structures within an intact mouse brain,” Nat. Photonics7(3), 205–209 (2013).
[CrossRef] [PubMed]

Cocker, E. D.

Y. Ziv, L. D. Burns, E. D. Cocker, E. O. Hamel, K. K. Ghosh, L. J. Kitch, A. El Gamal, and M. J. Schnitzer, “Long-term dynamics of CA1 hippocampal place codes,” Nat. Neurosci.16(3), 264–266 (2013).
[CrossRef] [PubMed]

Crowley, J. C.

A. Mizrahi, J. C. Crowley, E. Shtoyerman, and L. C. Katz, “High-resolution in vivo imaging of hippocampal dendrites and spines,” The Journal of Neuroscience24, 3147–3151 (2004).

Czubayko, U.

W. Mittmann, D. J. Wallace, U. Czubayko, J. T. Herb, A. T. Schaefer, L. L. Looger, W. Denk, and J. N. D. Kerr, “Two-photon calcium imaging of evoked activity from L5 somatosensory neurons in vivo,” Nat. Neurosci.14(8), 1089–1093 (2011).
[CrossRef] [PubMed]

De Paola, V.

A. Holtmaat, T. Bonhoeffer, D. K. Chow, J. Chuckowree, V. De Paola, S. B. Hofer, M. Hübener, T. Keck, G. Knott, W.-C. A. Lee, R. Mostany, T. D. Mrsic-Flogel, E. Nedivi, C. Portera-Cailliau, K. Svoboda, J. T. Trachtenberg, and L. Wilbrecht, “Long-term, high-resolution imaging in the mouse neocortex through a chronic cranial window,” Nat. Protoc.4(8), 1128–1144 (2009).
[CrossRef] [PubMed]

del Valle, J.

J. del Valle, S. Bayod, A. Camins, C. Beas-Zárate, D. A. Velázquez-Zamora, I. González-Burgos, and M. Pallàs, “Dendritic spine abnormalities in hippocampal CA1 pyramidal neurons underlying memory deficits in the SAMP8 mouse model of Alzheimer’s disease,” J. Alzheimers Dis.32(1), 233–240 (2012).
[PubMed]

Denk, W.

W. Mittmann, D. J. Wallace, U. Czubayko, J. T. Herb, A. T. Schaefer, L. L. Looger, W. Denk, and J. N. D. Kerr, “Two-photon calcium imaging of evoked activity from L5 somatosensory neurons in vivo,” Nat. Neurosci.14(8), 1089–1093 (2011).
[CrossRef] [PubMed]

F. Helmchen and W. Denk, “Deep tissue two-photon microscopy,” Nat. Methods2(12), 932–940 (2005).
[CrossRef] [PubMed]

P. Theer, M. T. Hasan, and W. Denk, “Two-photon imaging to a depth of 1000 microm in living brains by use of a Ti:Al2O3 regenerative amplifier,” Opt. Lett.28(12), 1022–1024 (2003).
[CrossRef] [PubMed]

W. Denk, J. H. Strickler, and W. W. Webb, “Two-photon laser scanning fluorescence microscopy,” Science248(4951), 73–76 (1990).
[CrossRef] [PubMed]

Dombeck, D. A.

M. J. Levene, D. A. Dombeck, K. A. Kasischke, R. P. Molloy, and W. W. Webb, “In vivo multiphoton microscopy of deep brain tissue,” J. Neurophysiol.91(4), 1908–1912 (2004).
[CrossRef] [PubMed]

Drew, C. J. G.

S. J. Bulley, C. J. G. Drew, and A. J. Morton, “Direct visualisation of abnormal dendritic spine morphology in the hippocampus of the R6/2 transgenic mouse model of Huntington's Disease,” Journal of Huntington's Disease1, 267–273 (2012).

Durst, M. E.

El Gamal, A.

Y. Ziv, L. D. Burns, E. D. Cocker, E. O. Hamel, K. K. Ghosh, L. J. Kitch, A. El Gamal, and M. J. Schnitzer, “Long-term dynamics of CA1 hippocampal place codes,” Nat. Neurosci.16(3), 264–266 (2013).
[CrossRef] [PubMed]

Gautheron, V.

A. Auffret, V. Gautheron, M. Repici, R. Kraftsik, H. T. Mount, J. Mariani, and C. Rovira, “Age-dependent impairment of spine morphology and synaptic plasticity in hippocampal CA1 neurons of a presenilin 1 transgenic mouse model of Alzheimer's disease,” The Journal of Neuroscience29, 10144–10152 (2009).

Ghosh, K. K.

Y. Ziv, L. D. Burns, E. D. Cocker, E. O. Hamel, K. K. Ghosh, L. J. Kitch, A. El Gamal, and M. J. Schnitzer, “Long-term dynamics of CA1 hippocampal place codes,” Nat. Neurosci.16(3), 264–266 (2013).
[CrossRef] [PubMed]

Gilfoy, N. B.

M. L. Andermann, N. B. Gilfoy, G. J. Goldey, R. N. Sachdev, M. Wölfel, D. A. McCormick, R. C. Reid, and M. J. Levene, “Chronic Cellular Imaging of Entire Cortical Columns in Awake Mice Using Microprisms,” Neuron80(4), 900–913 (2013).
[CrossRef] [PubMed]

Goldey, G. J.

M. L. Andermann, N. B. Gilfoy, G. J. Goldey, R. N. Sachdev, M. Wölfel, D. A. McCormick, R. C. Reid, and M. J. Levene, “Chronic Cellular Imaging of Entire Cortical Columns in Awake Mice Using Microprisms,” Neuron80(4), 900–913 (2013).
[CrossRef] [PubMed]

González-Burgos, I.

J. del Valle, S. Bayod, A. Camins, C. Beas-Zárate, D. A. Velázquez-Zamora, I. González-Burgos, and M. Pallàs, “Dendritic spine abnormalities in hippocampal CA1 pyramidal neurons underlying memory deficits in the SAMP8 mouse model of Alzheimer’s disease,” J. Alzheimers Dis.32(1), 233–240 (2012).
[PubMed]

Hamel, E. O.

Y. Ziv, L. D. Burns, E. D. Cocker, E. O. Hamel, K. K. Ghosh, L. J. Kitch, A. El Gamal, and M. J. Schnitzer, “Long-term dynamics of CA1 hippocampal place codes,” Nat. Neurosci.16(3), 264–266 (2013).
[CrossRef] [PubMed]

Hasan, M. T.

Helmchen, F.

F. Helmchen and W. Denk, “Deep tissue two-photon microscopy,” Nat. Methods2(12), 932–940 (2005).
[CrossRef] [PubMed]

Herb, J. T.

W. Mittmann, D. J. Wallace, U. Czubayko, J. T. Herb, A. T. Schaefer, L. L. Looger, W. Denk, and J. N. D. Kerr, “Two-photon calcium imaging of evoked activity from L5 somatosensory neurons in vivo,” Nat. Neurosci.14(8), 1089–1093 (2011).
[CrossRef] [PubMed]

Hofer, S. B.

A. Holtmaat, T. Bonhoeffer, D. K. Chow, J. Chuckowree, V. De Paola, S. B. Hofer, M. Hübener, T. Keck, G. Knott, W.-C. A. Lee, R. Mostany, T. D. Mrsic-Flogel, E. Nedivi, C. Portera-Cailliau, K. Svoboda, J. T. Trachtenberg, and L. Wilbrecht, “Long-term, high-resolution imaging in the mouse neocortex through a chronic cranial window,” Nat. Protoc.4(8), 1128–1144 (2009).
[CrossRef] [PubMed]

Holtmaat, A.

A. Holtmaat, T. Bonhoeffer, D. K. Chow, J. Chuckowree, V. De Paola, S. B. Hofer, M. Hübener, T. Keck, G. Knott, W.-C. A. Lee, R. Mostany, T. D. Mrsic-Flogel, E. Nedivi, C. Portera-Cailliau, K. Svoboda, J. T. Trachtenberg, and L. Wilbrecht, “Long-term, high-resolution imaging in the mouse neocortex through a chronic cranial window,” Nat. Protoc.4(8), 1128–1144 (2009).
[CrossRef] [PubMed]

Horton, N. G.

N. G. Horton, K. Wang, D. Kobat, C. G. Clark, F. W. Wise, C. B. Schaffer, and C. Xu, “In vivo three-photon microscopy of subcortical structures within an intact mouse brain,” Nat. Photonics7(3), 205–209 (2013).
[CrossRef] [PubMed]

D. Kobat, N. G. Horton, and C. Xu, “In vivo two-photon microscopy to 1.6-mm depth in mouse cortex,” J. Biomed. Opt.16(10), 106014 (2011).
[CrossRef] [PubMed]

Hübener, M.

A. Holtmaat, T. Bonhoeffer, D. K. Chow, J. Chuckowree, V. De Paola, S. B. Hofer, M. Hübener, T. Keck, G. Knott, W.-C. A. Lee, R. Mostany, T. D. Mrsic-Flogel, E. Nedivi, C. Portera-Cailliau, K. Svoboda, J. T. Trachtenberg, and L. Wilbrecht, “Long-term, high-resolution imaging in the mouse neocortex through a chronic cranial window,” Nat. Protoc.4(8), 1128–1144 (2009).
[CrossRef] [PubMed]

Ji, N.

Jung, J. C.

R. P. J. Barretto, T. H. Ko, J. C. Jung, T. J. Wang, G. Capps, A. C. Waters, Y. Ziv, A. Attardo, L. Recht, and M. J. Schnitzer, “Time-lapse imaging of disease progression in deep brain areas using fluorescence microendoscopy,” Nat. Med.17(2), 223–228 (2011).
[CrossRef] [PubMed]

J. C. Jung and M. J. Schnitzer, “Multiphoton endoscopy,” Opt. Lett.28(11), 902–904 (2003).
[CrossRef] [PubMed]

Kasischke, K. A.

M. J. Levene, D. A. Dombeck, K. A. Kasischke, R. P. Molloy, and W. W. Webb, “In vivo multiphoton microscopy of deep brain tissue,” J. Neurophysiol.91(4), 1908–1912 (2004).
[CrossRef] [PubMed]

Katz, L. C.

A. Mizrahi, J. C. Crowley, E. Shtoyerman, and L. C. Katz, “High-resolution in vivo imaging of hippocampal dendrites and spines,” The Journal of Neuroscience24, 3147–3151 (2004).

Keck, T.

A. Holtmaat, T. Bonhoeffer, D. K. Chow, J. Chuckowree, V. De Paola, S. B. Hofer, M. Hübener, T. Keck, G. Knott, W.-C. A. Lee, R. Mostany, T. D. Mrsic-Flogel, E. Nedivi, C. Portera-Cailliau, K. Svoboda, J. T. Trachtenberg, and L. Wilbrecht, “Long-term, high-resolution imaging in the mouse neocortex through a chronic cranial window,” Nat. Protoc.4(8), 1128–1144 (2009).
[CrossRef] [PubMed]

Kerr, J. N. D.

W. Mittmann, D. J. Wallace, U. Czubayko, J. T. Herb, A. T. Schaefer, L. L. Looger, W. Denk, and J. N. D. Kerr, “Two-photon calcium imaging of evoked activity from L5 somatosensory neurons in vivo,” Nat. Neurosci.14(8), 1089–1093 (2011).
[CrossRef] [PubMed]

Kitch, L. J.

Y. Ziv, L. D. Burns, E. D. Cocker, E. O. Hamel, K. K. Ghosh, L. J. Kitch, A. El Gamal, and M. J. Schnitzer, “Long-term dynamics of CA1 hippocampal place codes,” Nat. Neurosci.16(3), 264–266 (2013).
[CrossRef] [PubMed]

Knott, G.

A. Holtmaat, T. Bonhoeffer, D. K. Chow, J. Chuckowree, V. De Paola, S. B. Hofer, M. Hübener, T. Keck, G. Knott, W.-C. A. Lee, R. Mostany, T. D. Mrsic-Flogel, E. Nedivi, C. Portera-Cailliau, K. Svoboda, J. T. Trachtenberg, and L. Wilbrecht, “Long-term, high-resolution imaging in the mouse neocortex through a chronic cranial window,” Nat. Protoc.4(8), 1128–1144 (2009).
[CrossRef] [PubMed]

Ko, T. H.

R. P. J. Barretto, T. H. Ko, J. C. Jung, T. J. Wang, G. Capps, A. C. Waters, Y. Ziv, A. Attardo, L. Recht, and M. J. Schnitzer, “Time-lapse imaging of disease progression in deep brain areas using fluorescence microendoscopy,” Nat. Med.17(2), 223–228 (2011).
[CrossRef] [PubMed]

Kobat, D.

N. G. Horton, K. Wang, D. Kobat, C. G. Clark, F. W. Wise, C. B. Schaffer, and C. Xu, “In vivo three-photon microscopy of subcortical structures within an intact mouse brain,” Nat. Photonics7(3), 205–209 (2013).
[CrossRef] [PubMed]

D. Kobat, N. G. Horton, and C. Xu, “In vivo two-photon microscopy to 1.6-mm depth in mouse cortex,” J. Biomed. Opt.16(10), 106014 (2011).
[CrossRef] [PubMed]

D. Kobat, M. E. Durst, N. Nishimura, A. W. Wong, C. B. Schaffer, and C. Xu, “Deep tissue multiphoton microscopy using longer wavelength excitation,” Opt. Express17(16), 13354–13364 (2009).
[CrossRef] [PubMed]

Konnerth, A.

N. L. Rochefort and A. Konnerth, “Dendritic spines: from structure to in vivo function,” EMBO Rep.13(8), 699–708 (2012).
[CrossRef] [PubMed]

Kraftsik, R.

A. Auffret, V. Gautheron, M. Repici, R. Kraftsik, H. T. Mount, J. Mariani, and C. Rovira, “Age-dependent impairment of spine morphology and synaptic plasticity in hippocampal CA1 neurons of a presenilin 1 transgenic mouse model of Alzheimer's disease,” The Journal of Neuroscience29, 10144–10152 (2009).

Lee, W.-C. A.

A. Holtmaat, T. Bonhoeffer, D. K. Chow, J. Chuckowree, V. De Paola, S. B. Hofer, M. Hübener, T. Keck, G. Knott, W.-C. A. Lee, R. Mostany, T. D. Mrsic-Flogel, E. Nedivi, C. Portera-Cailliau, K. Svoboda, J. T. Trachtenberg, and L. Wilbrecht, “Long-term, high-resolution imaging in the mouse neocortex through a chronic cranial window,” Nat. Protoc.4(8), 1128–1144 (2009).
[CrossRef] [PubMed]

Levene, M. J.

M. L. Andermann, N. B. Gilfoy, G. J. Goldey, R. N. Sachdev, M. Wölfel, D. A. McCormick, R. C. Reid, and M. J. Levene, “Chronic Cellular Imaging of Entire Cortical Columns in Awake Mice Using Microprisms,” Neuron80(4), 900–913 (2013).
[CrossRef] [PubMed]

T. A. Murray and M. J. Levene, “Singlet gradient index lens for deep in vivo multiphoton microscopy,” J. Biomed. Opt.17(2), 021106 (2012).
[CrossRef] [PubMed]

T. H. Chia and M. J. Levene, “Microprisms for in vivo multilayer cortical imaging,” J. Neurophysiol.102(2), 1310–1314 (2009).
[CrossRef] [PubMed]

M. J. Levene, D. A. Dombeck, K. A. Kasischke, R. P. Molloy, and W. W. Webb, “In vivo multiphoton microscopy of deep brain tissue,” J. Neurophysiol.91(4), 1908–1912 (2004).
[CrossRef] [PubMed]

Looger, L. L.

W. Mittmann, D. J. Wallace, U. Czubayko, J. T. Herb, A. T. Schaefer, L. L. Looger, W. Denk, and J. N. D. Kerr, “Two-photon calcium imaging of evoked activity from L5 somatosensory neurons in vivo,” Nat. Neurosci.14(8), 1089–1093 (2011).
[CrossRef] [PubMed]

Mariani, J.

A. Auffret, V. Gautheron, M. Repici, R. Kraftsik, H. T. Mount, J. Mariani, and C. Rovira, “Age-dependent impairment of spine morphology and synaptic plasticity in hippocampal CA1 neurons of a presenilin 1 transgenic mouse model of Alzheimer's disease,” The Journal of Neuroscience29, 10144–10152 (2009).

McCormick, D. A.

M. L. Andermann, N. B. Gilfoy, G. J. Goldey, R. N. Sachdev, M. Wölfel, D. A. McCormick, R. C. Reid, and M. J. Levene, “Chronic Cellular Imaging of Entire Cortical Columns in Awake Mice Using Microprisms,” Neuron80(4), 900–913 (2013).
[CrossRef] [PubMed]

Messerschmidt, B.

R. P. Barretto, B. Messerschmidt, and M. J. Schnitzer, “In vivo fluorescence imaging with high-resolution microlenses,” Nat. Methods6(7), 511–512 (2009).
[CrossRef] [PubMed]

Mittmann, W.

W. Mittmann, D. J. Wallace, U. Czubayko, J. T. Herb, A. T. Schaefer, L. L. Looger, W. Denk, and J. N. D. Kerr, “Two-photon calcium imaging of evoked activity from L5 somatosensory neurons in vivo,” Nat. Neurosci.14(8), 1089–1093 (2011).
[CrossRef] [PubMed]

Mizrahi, A.

A. Mizrahi, J. C. Crowley, E. Shtoyerman, and L. C. Katz, “High-resolution in vivo imaging of hippocampal dendrites and spines,” The Journal of Neuroscience24, 3147–3151 (2004).

Molloy, R. P.

M. J. Levene, D. A. Dombeck, K. A. Kasischke, R. P. Molloy, and W. W. Webb, “In vivo multiphoton microscopy of deep brain tissue,” J. Neurophysiol.91(4), 1908–1912 (2004).
[CrossRef] [PubMed]

Morton, A. J.

S. J. Bulley, C. J. G. Drew, and A. J. Morton, “Direct visualisation of abnormal dendritic spine morphology in the hippocampus of the R6/2 transgenic mouse model of Huntington's Disease,” Journal of Huntington's Disease1, 267–273 (2012).

Moser, M. B.

M. B. Moser, M. Trommald, and P. Andersen, “An increase in dendritic spine density on hippocampal CA1 pyramidal cells following spatial learning in adult rats suggests the formation of new synapses,” Proc. Natl. Acad. Sci. U.S.A.91(26), 12673–12675 (1994).
[CrossRef] [PubMed]

Mostany, R.

A. Holtmaat, T. Bonhoeffer, D. K. Chow, J. Chuckowree, V. De Paola, S. B. Hofer, M. Hübener, T. Keck, G. Knott, W.-C. A. Lee, R. Mostany, T. D. Mrsic-Flogel, E. Nedivi, C. Portera-Cailliau, K. Svoboda, J. T. Trachtenberg, and L. Wilbrecht, “Long-term, high-resolution imaging in the mouse neocortex through a chronic cranial window,” Nat. Protoc.4(8), 1128–1144 (2009).
[CrossRef] [PubMed]

Mount, H. T.

A. Auffret, V. Gautheron, M. Repici, R. Kraftsik, H. T. Mount, J. Mariani, and C. Rovira, “Age-dependent impairment of spine morphology and synaptic plasticity in hippocampal CA1 neurons of a presenilin 1 transgenic mouse model of Alzheimer's disease,” The Journal of Neuroscience29, 10144–10152 (2009).

Mrsic-Flogel, T. D.

A. Holtmaat, T. Bonhoeffer, D. K. Chow, J. Chuckowree, V. De Paola, S. B. Hofer, M. Hübener, T. Keck, G. Knott, W.-C. A. Lee, R. Mostany, T. D. Mrsic-Flogel, E. Nedivi, C. Portera-Cailliau, K. Svoboda, J. T. Trachtenberg, and L. Wilbrecht, “Long-term, high-resolution imaging in the mouse neocortex through a chronic cranial window,” Nat. Protoc.4(8), 1128–1144 (2009).
[CrossRef] [PubMed]

Murray, T. A.

T. A. Murray and M. J. Levene, “Singlet gradient index lens for deep in vivo multiphoton microscopy,” J. Biomed. Opt.17(2), 021106 (2012).
[CrossRef] [PubMed]

Nedivi, E.

A. Holtmaat, T. Bonhoeffer, D. K. Chow, J. Chuckowree, V. De Paola, S. B. Hofer, M. Hübener, T. Keck, G. Knott, W.-C. A. Lee, R. Mostany, T. D. Mrsic-Flogel, E. Nedivi, C. Portera-Cailliau, K. Svoboda, J. T. Trachtenberg, and L. Wilbrecht, “Long-term, high-resolution imaging in the mouse neocortex through a chronic cranial window,” Nat. Protoc.4(8), 1128–1144 (2009).
[CrossRef] [PubMed]

Nishimura, N.

Pallàs, M.

J. del Valle, S. Bayod, A. Camins, C. Beas-Zárate, D. A. Velázquez-Zamora, I. González-Burgos, and M. Pallàs, “Dendritic spine abnormalities in hippocampal CA1 pyramidal neurons underlying memory deficits in the SAMP8 mouse model of Alzheimer’s disease,” J. Alzheimers Dis.32(1), 233–240 (2012).
[PubMed]

Portera-Cailliau, C.

A. Holtmaat, T. Bonhoeffer, D. K. Chow, J. Chuckowree, V. De Paola, S. B. Hofer, M. Hübener, T. Keck, G. Knott, W.-C. A. Lee, R. Mostany, T. D. Mrsic-Flogel, E. Nedivi, C. Portera-Cailliau, K. Svoboda, J. T. Trachtenberg, and L. Wilbrecht, “Long-term, high-resolution imaging in the mouse neocortex through a chronic cranial window,” Nat. Protoc.4(8), 1128–1144 (2009).
[CrossRef] [PubMed]

Recht, L.

R. P. J. Barretto, T. H. Ko, J. C. Jung, T. J. Wang, G. Capps, A. C. Waters, Y. Ziv, A. Attardo, L. Recht, and M. J. Schnitzer, “Time-lapse imaging of disease progression in deep brain areas using fluorescence microendoscopy,” Nat. Med.17(2), 223–228 (2011).
[CrossRef] [PubMed]

Reid, R. C.

M. L. Andermann, N. B. Gilfoy, G. J. Goldey, R. N. Sachdev, M. Wölfel, D. A. McCormick, R. C. Reid, and M. J. Levene, “Chronic Cellular Imaging of Entire Cortical Columns in Awake Mice Using Microprisms,” Neuron80(4), 900–913 (2013).
[CrossRef] [PubMed]

Repici, M.

A. Auffret, V. Gautheron, M. Repici, R. Kraftsik, H. T. Mount, J. Mariani, and C. Rovira, “Age-dependent impairment of spine morphology and synaptic plasticity in hippocampal CA1 neurons of a presenilin 1 transgenic mouse model of Alzheimer's disease,” The Journal of Neuroscience29, 10144–10152 (2009).

Rochefort, N. L.

N. L. Rochefort and A. Konnerth, “Dendritic spines: from structure to in vivo function,” EMBO Rep.13(8), 699–708 (2012).
[CrossRef] [PubMed]

Rovira, C.

A. Auffret, V. Gautheron, M. Repici, R. Kraftsik, H. T. Mount, J. Mariani, and C. Rovira, “Age-dependent impairment of spine morphology and synaptic plasticity in hippocampal CA1 neurons of a presenilin 1 transgenic mouse model of Alzheimer's disease,” The Journal of Neuroscience29, 10144–10152 (2009).

Sachdev, R. N.

M. L. Andermann, N. B. Gilfoy, G. J. Goldey, R. N. Sachdev, M. Wölfel, D. A. McCormick, R. C. Reid, and M. J. Levene, “Chronic Cellular Imaging of Entire Cortical Columns in Awake Mice Using Microprisms,” Neuron80(4), 900–913 (2013).
[CrossRef] [PubMed]

Schaefer, A. T.

W. Mittmann, D. J. Wallace, U. Czubayko, J. T. Herb, A. T. Schaefer, L. L. Looger, W. Denk, and J. N. D. Kerr, “Two-photon calcium imaging of evoked activity from L5 somatosensory neurons in vivo,” Nat. Neurosci.14(8), 1089–1093 (2011).
[CrossRef] [PubMed]

Schaffer, C. B.

N. G. Horton, K. Wang, D. Kobat, C. G. Clark, F. W. Wise, C. B. Schaffer, and C. Xu, “In vivo three-photon microscopy of subcortical structures within an intact mouse brain,” Nat. Photonics7(3), 205–209 (2013).
[CrossRef] [PubMed]

D. Kobat, M. E. Durst, N. Nishimura, A. W. Wong, C. B. Schaffer, and C. Xu, “Deep tissue multiphoton microscopy using longer wavelength excitation,” Opt. Express17(16), 13354–13364 (2009).
[CrossRef] [PubMed]

Schnitzer, M. J.

Y. Ziv, L. D. Burns, E. D. Cocker, E. O. Hamel, K. K. Ghosh, L. J. Kitch, A. El Gamal, and M. J. Schnitzer, “Long-term dynamics of CA1 hippocampal place codes,” Nat. Neurosci.16(3), 264–266 (2013).
[CrossRef] [PubMed]

R. P. J. Barretto, T. H. Ko, J. C. Jung, T. J. Wang, G. Capps, A. C. Waters, Y. Ziv, A. Attardo, L. Recht, and M. J. Schnitzer, “Time-lapse imaging of disease progression in deep brain areas using fluorescence microendoscopy,” Nat. Med.17(2), 223–228 (2011).
[CrossRef] [PubMed]

R. P. Barretto, B. Messerschmidt, and M. J. Schnitzer, “In vivo fluorescence imaging with high-resolution microlenses,” Nat. Methods6(7), 511–512 (2009).
[CrossRef] [PubMed]

J. C. Jung and M. J. Schnitzer, “Multiphoton endoscopy,” Opt. Lett.28(11), 902–904 (2003).
[CrossRef] [PubMed]

Shtoyerman, E.

A. Mizrahi, J. C. Crowley, E. Shtoyerman, and L. C. Katz, “High-resolution in vivo imaging of hippocampal dendrites and spines,” The Journal of Neuroscience24, 3147–3151 (2004).

Strickler, J. H.

W. Denk, J. H. Strickler, and W. W. Webb, “Two-photon laser scanning fluorescence microscopy,” Science248(4951), 73–76 (1990).
[CrossRef] [PubMed]

Svoboda, K.

A. Holtmaat, T. Bonhoeffer, D. K. Chow, J. Chuckowree, V. De Paola, S. B. Hofer, M. Hübener, T. Keck, G. Knott, W.-C. A. Lee, R. Mostany, T. D. Mrsic-Flogel, E. Nedivi, C. Portera-Cailliau, K. Svoboda, J. T. Trachtenberg, and L. Wilbrecht, “Long-term, high-resolution imaging in the mouse neocortex through a chronic cranial window,” Nat. Protoc.4(8), 1128–1144 (2009).
[CrossRef] [PubMed]

Theer, P.

Trachtenberg, J. T.

A. Holtmaat, T. Bonhoeffer, D. K. Chow, J. Chuckowree, V. De Paola, S. B. Hofer, M. Hübener, T. Keck, G. Knott, W.-C. A. Lee, R. Mostany, T. D. Mrsic-Flogel, E. Nedivi, C. Portera-Cailliau, K. Svoboda, J. T. Trachtenberg, and L. Wilbrecht, “Long-term, high-resolution imaging in the mouse neocortex through a chronic cranial window,” Nat. Protoc.4(8), 1128–1144 (2009).
[CrossRef] [PubMed]

Trommald, M.

M. B. Moser, M. Trommald, and P. Andersen, “An increase in dendritic spine density on hippocampal CA1 pyramidal cells following spatial learning in adult rats suggests the formation of new synapses,” Proc. Natl. Acad. Sci. U.S.A.91(26), 12673–12675 (1994).
[CrossRef] [PubMed]

Velázquez-Zamora, D. A.

J. del Valle, S. Bayod, A. Camins, C. Beas-Zárate, D. A. Velázquez-Zamora, I. González-Burgos, and M. Pallàs, “Dendritic spine abnormalities in hippocampal CA1 pyramidal neurons underlying memory deficits in the SAMP8 mouse model of Alzheimer’s disease,” J. Alzheimers Dis.32(1), 233–240 (2012).
[PubMed]

Wallace, D. J.

W. Mittmann, D. J. Wallace, U. Czubayko, J. T. Herb, A. T. Schaefer, L. L. Looger, W. Denk, and J. N. D. Kerr, “Two-photon calcium imaging of evoked activity from L5 somatosensory neurons in vivo,” Nat. Neurosci.14(8), 1089–1093 (2011).
[CrossRef] [PubMed]

Wang, C.

Wang, K.

N. G. Horton, K. Wang, D. Kobat, C. G. Clark, F. W. Wise, C. B. Schaffer, and C. Xu, “In vivo three-photon microscopy of subcortical structures within an intact mouse brain,” Nat. Photonics7(3), 205–209 (2013).
[CrossRef] [PubMed]

Wang, T. J.

R. P. J. Barretto, T. H. Ko, J. C. Jung, T. J. Wang, G. Capps, A. C. Waters, Y. Ziv, A. Attardo, L. Recht, and M. J. Schnitzer, “Time-lapse imaging of disease progression in deep brain areas using fluorescence microendoscopy,” Nat. Med.17(2), 223–228 (2011).
[CrossRef] [PubMed]

Waters, A. C.

R. P. J. Barretto, T. H. Ko, J. C. Jung, T. J. Wang, G. Capps, A. C. Waters, Y. Ziv, A. Attardo, L. Recht, and M. J. Schnitzer, “Time-lapse imaging of disease progression in deep brain areas using fluorescence microendoscopy,” Nat. Med.17(2), 223–228 (2011).
[CrossRef] [PubMed]

Webb, W. W.

M. J. Levene, D. A. Dombeck, K. A. Kasischke, R. P. Molloy, and W. W. Webb, “In vivo multiphoton microscopy of deep brain tissue,” J. Neurophysiol.91(4), 1908–1912 (2004).
[CrossRef] [PubMed]

W. Denk, J. H. Strickler, and W. W. Webb, “Two-photon laser scanning fluorescence microscopy,” Science248(4951), 73–76 (1990).
[CrossRef] [PubMed]

Wilbrecht, L.

A. Holtmaat, T. Bonhoeffer, D. K. Chow, J. Chuckowree, V. De Paola, S. B. Hofer, M. Hübener, T. Keck, G. Knott, W.-C. A. Lee, R. Mostany, T. D. Mrsic-Flogel, E. Nedivi, C. Portera-Cailliau, K. Svoboda, J. T. Trachtenberg, and L. Wilbrecht, “Long-term, high-resolution imaging in the mouse neocortex through a chronic cranial window,” Nat. Protoc.4(8), 1128–1144 (2009).
[CrossRef] [PubMed]

Wise, F. W.

N. G. Horton, K. Wang, D. Kobat, C. G. Clark, F. W. Wise, C. B. Schaffer, and C. Xu, “In vivo three-photon microscopy of subcortical structures within an intact mouse brain,” Nat. Photonics7(3), 205–209 (2013).
[CrossRef] [PubMed]

Wölfel, M.

M. L. Andermann, N. B. Gilfoy, G. J. Goldey, R. N. Sachdev, M. Wölfel, D. A. McCormick, R. C. Reid, and M. J. Levene, “Chronic Cellular Imaging of Entire Cortical Columns in Awake Mice Using Microprisms,” Neuron80(4), 900–913 (2013).
[CrossRef] [PubMed]

Wong, A. W.

Xu, C.

N. G. Horton, K. Wang, D. Kobat, C. G. Clark, F. W. Wise, C. B. Schaffer, and C. Xu, “In vivo three-photon microscopy of subcortical structures within an intact mouse brain,” Nat. Photonics7(3), 205–209 (2013).
[CrossRef] [PubMed]

D. Kobat, N. G. Horton, and C. Xu, “In vivo two-photon microscopy to 1.6-mm depth in mouse cortex,” J. Biomed. Opt.16(10), 106014 (2011).
[CrossRef] [PubMed]

D. Kobat, M. E. Durst, N. Nishimura, A. W. Wong, C. B. Schaffer, and C. Xu, “Deep tissue multiphoton microscopy using longer wavelength excitation,” Opt. Express17(16), 13354–13364 (2009).
[CrossRef] [PubMed]

Ziv, Y.

Y. Ziv, L. D. Burns, E. D. Cocker, E. O. Hamel, K. K. Ghosh, L. J. Kitch, A. El Gamal, and M. J. Schnitzer, “Long-term dynamics of CA1 hippocampal place codes,” Nat. Neurosci.16(3), 264–266 (2013).
[CrossRef] [PubMed]

R. P. J. Barretto, T. H. Ko, J. C. Jung, T. J. Wang, G. Capps, A. C. Waters, Y. Ziv, A. Attardo, L. Recht, and M. J. Schnitzer, “Time-lapse imaging of disease progression in deep brain areas using fluorescence microendoscopy,” Nat. Med.17(2), 223–228 (2011).
[CrossRef] [PubMed]

EMBO Rep. (1)

N. L. Rochefort and A. Konnerth, “Dendritic spines: from structure to in vivo function,” EMBO Rep.13(8), 699–708 (2012).
[CrossRef] [PubMed]

J. Alzheimers Dis. (1)

J. del Valle, S. Bayod, A. Camins, C. Beas-Zárate, D. A. Velázquez-Zamora, I. González-Burgos, and M. Pallàs, “Dendritic spine abnormalities in hippocampal CA1 pyramidal neurons underlying memory deficits in the SAMP8 mouse model of Alzheimer’s disease,” J. Alzheimers Dis.32(1), 233–240 (2012).
[PubMed]

J. Biomed. Opt. (2)

T. A. Murray and M. J. Levene, “Singlet gradient index lens for deep in vivo multiphoton microscopy,” J. Biomed. Opt.17(2), 021106 (2012).
[CrossRef] [PubMed]

D. Kobat, N. G. Horton, and C. Xu, “In vivo two-photon microscopy to 1.6-mm depth in mouse cortex,” J. Biomed. Opt.16(10), 106014 (2011).
[CrossRef] [PubMed]

J. Neurophysiol. (2)

T. H. Chia and M. J. Levene, “Microprisms for in vivo multilayer cortical imaging,” J. Neurophysiol.102(2), 1310–1314 (2009).
[CrossRef] [PubMed]

M. J. Levene, D. A. Dombeck, K. A. Kasischke, R. P. Molloy, and W. W. Webb, “In vivo multiphoton microscopy of deep brain tissue,” J. Neurophysiol.91(4), 1908–1912 (2004).
[CrossRef] [PubMed]

Journal of Huntington's Disease (1)

S. J. Bulley, C. J. G. Drew, and A. J. Morton, “Direct visualisation of abnormal dendritic spine morphology in the hippocampus of the R6/2 transgenic mouse model of Huntington's Disease,” Journal of Huntington's Disease1, 267–273 (2012).

Nat. Med. (1)

R. P. J. Barretto, T. H. Ko, J. C. Jung, T. J. Wang, G. Capps, A. C. Waters, Y. Ziv, A. Attardo, L. Recht, and M. J. Schnitzer, “Time-lapse imaging of disease progression in deep brain areas using fluorescence microendoscopy,” Nat. Med.17(2), 223–228 (2011).
[CrossRef] [PubMed]

Nat. Methods (2)

F. Helmchen and W. Denk, “Deep tissue two-photon microscopy,” Nat. Methods2(12), 932–940 (2005).
[CrossRef] [PubMed]

R. P. Barretto, B. Messerschmidt, and M. J. Schnitzer, “In vivo fluorescence imaging with high-resolution microlenses,” Nat. Methods6(7), 511–512 (2009).
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Nat. Neurosci. (2)

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Figures (6)

Fig. 1
Fig. 1

Glass plug optics and placement in the brain. (a) Removal of a 1.5-mm-diameter cortical region above hippocampus would normally result in significant clipping of rays from high-numerical aperture objectives. (b) The higher refractive index of the plug prevents the clipping of rays by cortical tissue and maximizes the available numerical aperture.

Fig. 2
Fig. 2

Key steps in glass plug implantation surgery. (a) Five aspirated cavities converge to form a larger ~1.5 mm diameter cavity centered within a 3 mm × 3 mm craniotomy. The craniotomy, in turn, is centered 2 mm below bregma and 1.5 mm to the right of midline. (b) A 1-20 µl pipette tip connected to a vacuum source is used to hold the glass plug and insert it into the excavated column of cortical tissue immediately above the hippocampus. (c) The plug is attached to a washer to facilitate attachment to the skull. A titanium head post is glued directly to the skull and can be attached to the gimbal mount assembly to immobilize the mouse during imaging.

Fig. 3
Fig. 3

Two-photon images of yellow fluorescent protein expressing neurons in the CA1 region of the hippocampus acquired in vivo using the glass plug. Images in (a)-(c), (e)-(g) and (i)-(k) were acquired between 4.5 and 5 months post-surgery. Depths were measured optically from the bottom surface of white matter. Arrowheads in (c) and (g) identify spines that have withdrawn and arrows in (d) and (h) identify spines that have developed over a time period (Δt) of 26-days ((c) to (d)) and 19-days ((g) to (h)). Δt describes the amount of time that elapsed between the acquisition dates of the two images. Scale bars for (c), (d), (g), (h) and (k) are 5 μm.

Fig. 4
Fig. 4

Resolution of glass plug system. (a) PSF characterization using 100 nm barium titanate crystals for the 40X 0.6 NA objective alone (red) and coupled to the plug with the correction collar optimized (black) indicates near diffraction-limited resolution in both cases. 1/e half widths are 105% and 110% of the diffraction-limited value, respectively. (b) Ray fans with NA = 0.6 for plug tilts of 0°, 2.5°, and 5° demonstrate loss of resolution for small tilts. (c) The square of the Strehl ratio versus plug tilt for NA = 0.6 (black), 0.45 (red), and 0.28 (blue). Lower NA systems are much less sensitive to tilt.

Fig. 5
Fig. 5

Quantification of the effective field-of-view accessed through the glass plug via (a) the 4X 0.28 NA objective, and (b) the 40X 0.6 NA objective. The distance from the center of the plug to the boundary at which fluorescence falls to half its maximum value is approximately 540 µm for the 4X objective and 490 µm for the 40X objective. These correspond to fields-of-view that are 70% and 60% of the plug diameter, respectively.

Fig. 6
Fig. 6

H&E histological images of the tissue surrounding the glass plug cavity. The slices imaged above were harvested 9 months after plug insertion surgery, from the same animal imaged in Fig. 3. (a) The tissue is maintained in its natural state and appears unaffected by the surgery and the long-term implantation of the plug. An indentation to the left of the imaged tissue surface suggests that the sub-region may have been slightly over-aspirated. (b) Neurons of the underlying hippocampus are largely intact and the smooth curvature of the cell body layer suggest that the region suffered no compression damage due to the placement of the glass plug.

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