Abstract

Microendoscopy incorporating a gradient index (GRIN) lens has emerged as a powerful tool for in vivo imaging. The lack of optical sectioning capability of widefield microendoscopy and the intrinsic optical aberrations of the GRIN lens itself, however, limit the achievable image contrast and resolution in three-dimensional (3D) tissues. In this study, we applied HiLo, a structured illumination method, to widefield microendoscopy in order to achieve optical sectioning. We also utilized adaptive optics (AO) to measure and correct GRIN lens aberrations. Together, HiLo and AO enabled subcellular-resolution microendoscopy imaging with optical sectioning and allowed us to image fine neuronal processes and synapses in the mouse brain in vivo.

© 2020 Optical Society of America under the terms of the OSA Open Access Publishing Agreement

The imaging depth of conventional optical microscopy methods is limited to 1–2 mm in scattering biological tissues [1]. Microendoscopy, utilizing micro-optical probes such as gradient index (GRIN) lenses, has enabled in vivo imaging of previously inaccessible regions and been employed in a broad range of biomedical applications [24].

GRIN-lens-based microendoscopy is commonly implemented with widefield excitation and detection of single-photon fluorescence. However, because fluorescence photons from both in-focus and out-of-focus structures are captured by the imaging camera [57], the resulting lack of optical sectioning reduces image contrast in three-dimensional (3D) samples. GRIN lenses also suffer from intrinsic optical aberrations coming from their parabolic refractive index profile, resulting in images of poorer spatial resolution than allowed by the diffraction limit [811]. These two factors limit GRIN-lens-based widefield microendoscopy to generating low-contrast images of cellular resolution in tissue samples.

A powerful approach that imparts optical sectioning capability to widefield fluorescence microscopy utilizes structured illumination (SI) light, which modulates in-focus signal selectively and enables computational optical sectioning of 3D samples. One of the implementations of SI [1215], HiLo microscopy, reconstructs one optically sectioned image from two raw images, one acquired with standard uniform illumination and the other with a SI pattern, providing high and low spatial-frequency in-focus information, respectively [13,14]. Compared with other SI methods, HiLo has faster imaging speed and is insensitive to illumination distortion and sample motion. It has been applied to micro-objective-based and fiber-bundle-based microendoscopy for optical sectioning [1619]. However, due to the substantial intrinsic aberrations of GRIN lenses, it is unknown whether HiLo can provide high-resolution optical-sectioning images in GRIN-lens-based microendoscopes.

In this study, we applied HiLo and adaptive optics (AO) [20] to GRIN-lens-based microendoscopy and discovered that correcting the intrinsic aberrations of GRIN lenses via AO is essential for HiLo to achieve optical-sectioning widefield microendoscopy with subcellular resolution in both in vitro and in vivo samples. We demonstrated, for the first time, synapse-resolving widefield microendoscopy imaging in the mouse brain in vivo.

The AO HiLo microendoscopy system consisted of two modules: a GRIN-lens-based microendoscope of NA 0.45 equipped with a spatial light modulator for SI (Fig. 1, HiLo GRIN module, insets 1 and 2) and an AO module utilizing direct wavefront sensing via a Shack–Hartmann sensor [21] and a deformable mirror for wavefront correction on the emitted fluorescence (Fig. 1, AO module, insets 3 and 4). A grating pattern was used for SI, and the standard HiLo reconstruction algorithm [13,14] was used for reconstructing the optically sectioned images. Aberrations within the system itself (except those associated with GRIN lens) were corrected prior to all experiments (see Supplement 1 for detailed information and imaging parameters). All image quality improvement therefore came from correcting the GRIN-lens aberrations.

 

Fig. 1. Schematic diagram of the AO HiLo microendoscope. Gray dashed polygon, HiLo GRIN module; red dashed polygon, AO module. Inset 1: grating SI generated by two-beam interference. Inset 2: optical relay of illumination and fluorescence emission by a GRIN lens (1 mm diameter and 0.5 NA). Inset 3: direct wavefront sensing with a Shack–Hartmann (SH) sensor composed of a lenslet array and a camera. Inset 4: aberration correction by a segmented deformable mirror. SLM, spatial light modulator; Di, dichroic mirror; OBJ, air objective of 0.45 NA; DM, deformable mirror; MM, movable mirror switching beam paths between aberration measurement and correction. Beam in blue, 488 nm illumination; beam in green, emitted green fluorescence.

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We first characterized the intrinsic aberrations of the GRIN lens and their effects on image quality using 2 µm diameter green fluorescent beads (Fig. 2). Through the microendoscope (Supplement 1, Fig. S1), bead images were increasingly distorted at locations further away from the field of view (FOV) center. Measuring aberrations experienced by the fluorescence of a 2 µm diameter bead at the center and eight edge locations [Fig. 2(b), 150 µm away from the center, every 45º angle], we found that the GRIN lens introduced on-axis spherical aberration and off-axis astigmatism to the single-photon fluorescence wavefronts [Fig. 2(e)], consistent with earlier results from two-photon fluorescence microendoscopy [10,11]. Correcting the aberrations using the deformable mirror recovered diffraction-limited resolution. For example, the bead image at an edge location showed a ${1.5} \times$ increase in brightness [Fig. 2(g)] and the residual aberrations were minimized [Fig. 2(f)]. In contrast, bead images at the FOV center only suffered slight signal decrease by the on-axis spherical aberration and minimal degradation in lateral resolution (see Supplement 1, Fig. S3). Applying the nine location-specific corrective wavefronts while imaging a dense bead sample, we took nine 40 µm thick stacks and stitched their maximum intensity projections (MIPs) together. For both widefield [Figs. 2(a) and 2(b)] and HiLo [Figs. 2(c) and 2(d)] images, we observed substantial improvements in image quality and contrast after aberration correction. Only with AO was it possible to resolve neighboring beads at edge locations [Figs. 2(a)–2(d), insets], with the aberration-corrected images having higher signal and contrast, as indicated by the signal comparison over four beads [along the dashed line in Fig. 2(d); Figs. 2(h) and 2(i)]. Using the ability of resolving individual beads as a criterion, the usable FOV was enlarged by ${2.7} \times$ ( Supplement 1, Fig. S4). Our results indicated that aberration correction is essential for GRIN-lens-based microendoscopes to achieve high spatial resolution, both in conventional widefield and HiLo modes.

 

Fig. 2. AO is required for high-resolution imaging in both widefield and HiLo microendoscopy. (a)–(d) Maximum intensity projections (MIPs) of 40 µm thick widefield (WF) and HiLo image stacks of 2 µm diameter green fluorescent beads, measured (a) and (c) without and (b) and (d) with AO, respectively. Orange asterisks, aberration measurement/correction sites. Insets: single optical sections. Images normalized individually (0 to maximum signal). Scale bar: 100 µm; insets: 5 µm. (e) Representative corrective wavefronts for FOV center and edge (150 µm from center). (f) Residual wavefront after aberration correction at the edge. $\sigma$, rms of the residual wavefront. (g) Representative widefield lateral and axial images of a 2 µm diameter bead at FOV edge before (“No AO”) and after (“AO”) aberration correction. ${1.5} \times$ gain was applied to “No AO” image for better visualization. Scale bars: 5 µm. (h) and (i) WF and HiLo signal profiles along red dashed line in (d), inset ii. Imaging area: ${{460}}\;{{\unicode{x00B5}{\rm m}}} \times {{460}}\;{{\unicode{x00B5}{\rm m}}}$. HiLo frame rate: 5 Hz.

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Measuring and correcting location-specific aberrations enabled high-quality imaging throughout the GRIN lens FOV. Because of the cylindrical symmetry of the GRIN lens, the number of aberration measurements can be reduced to two [11]: one at the center and one at the edge [e.g., white asterisks, Fig. 3(a)]. To get the corrective wavefronts at other locations at the same distance (in this case, 150 µm) away from but different orientations relative to the FOV center, we computed the difference wavefront between the edge and center corrective wavefronts, rotated it by the desired orientation, and then added to it the center corrective wavefront. We validated this approach by comparing the effectiveness of aberration correction using the computed versus the directly measured corrective wavefronts on 2 µm diameter green fluorescent beads [Fig. 3(b)]. Across all five locations investigated [orange asterisks, Fig. 3(a); data from three locations shown in Fig. 3(c)], the computed and the directly measured corrective wavefronts gave similar improvement in image quality and signal enhancement (< 6% difference). Similar to before, larger signal enhancement was observed for HiLo images than for widefield images. Two aberration measurements and computed corrective wavefronts were used for consequent experiments.

 

Fig. 3. Aberration correction using measured versus computed corrective wavefronts. (a) MIP of a 20 µm thick HiLo image stack of 2 µm diameter green fluorescent beads, with aberration measurement locations indicated by white and orange asterisks. White asterisks: measurement locations used for computing corrective wavefronts. Scale bar: 100 µm. (b) Measured corrective wavefronts at the edge locations. (c) MIPs of 20 µm thick WF and HiLo image stacks, measured without AO (“No AO”), with computed corrective wavefronts (“Comp. AO”), and with directly measured corrective wavefronts (“Meas. AO”). Images were individually normalized for better visualization (with gains listed). Scale bar: 10 µm. Imaging area: ${{460}}\;{{\unicode{x00B5}{\rm m}}} \times {{460}}\;{{\unicode{x00B5}{\rm m}}}$. HiLo frame rate: 10 Hz.

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Next, we imaged a fixed brain slice from a Thy1-GFP line M mouse with a subset of cortical neurons expressing green fluorescent protein. We acquired 80 µm thick widefield and HiLo image stacks without and with AO, and compared their MIP images (Fig. 4). In widefield images without and with AO [Figs. 4(a) and 4(b)], the strong out-of-focus fluorescence made it impossible to visualize fine neuronal processes at the FOV center. In HiLo images [Figs. 4(c) and 4(d)], where out-of-focus background was suppressed, fine neurites were easily resolved. Line signal profiles across the neuronal processes in the FOV centers of widefield and HiLo images [Fig. 4(f); dashed line a] showed a drastic enhancement in the contrast of these subcellular structures, demonstrating the necessity of having optical sectioning in imaging fine structures. For both widefield and HiLo images, aberration correction was needed for artefact-free images of higher signal and larger contrast [Figs. 4(e)], especially at edge locations. Comparing the line signal profiles across two dendrites [Figs. 4(g) and 4(h); dashed line b], we found that similar to the bead data, HiLo images exhibited more improvement in image quality than widefield images after AO correction, with larger enhancements in signal and contrast and a narrower dendrite profile.

 

Fig. 4. Widefield and HiLo microendoscopy imaging of a fixed mouse brain slice (Thy1-GFP line M). (a)–(d) MIPs of 80 µm thick WF and HiLo image stacks, measured (a) and (c) without and (b) and (d) with AO, respectively. Scale bar: 100 µm. (e) Zoomed-in views from (a)–(d). Scale bars: 20 µm. (f) Line profiles across neuronal processes in (b) and (d) (orange dashed line a). (g) and (h) WF and HiLo line profiles across two dendrites (orange dashed line b). Imaging area: ${{460}}\;{{\unicode{x00B5}{\rm m}}} \times {{460}}\;{{\unicode{x00B5}{\rm m}}}$. All images were individually normalized. HiLo frame rate: 5 Hz.

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Last, we used our system for high-resolution imaging of the mouse brain in vivo. We positioned our microendoscope over a cranial window on the left cortex of a Thy1-GFP line M mouse, so as to image the apical dendritic and axonal processes of the GFP-expressing pyramidal neurons (Fig. 5). In the widefield images [Fig. 5(a)], the strong out-of-focus fluorescence made it difficult to detect smaller neuronal processes or synapses such as dendritic spines or axonal boutons. In contrast, HiLo successfully suppressed the out-of-focus fluorescence and enhanced image contrast, allowing the finer neuronal processes to be resolved [Figs. 5(b)]. Zooming in onto an edge location [insets, white dashed boxes in Figs. 5(a) and 5(b)], we observed that AO improved the ability of both imaging modes to detect dendrites [Figs. 5(c) and 5(d), line signal profiles along dashed line a]. However, synaptic features such as dendritic spines [white arrows, Fig. 5(b)] and axonal boutons [orange arrowhead b, Fig. 5(b)] required both optical sectioning from HiLo and aberration correction by AO to be resolved. Comparing the axial profiles of the bouton [Fig. 5(e)], we observed that HiLo provided excellent optical sectioning, whereas AO improved the HiLo fluorescence signal by ${2.5} \times$. Therefore, for in vivo widefield microendoscopy, both optical sectioning and aberration correction are required to resolve subcellular structures such as synapses.

 

Fig. 5. In vivo widefield and HiLo microendoscopy imaging of a Thy1-GFP line M mouse brain. (a) and (b) MIPs of 100 µm thick WF and HiLo image stacks before AO. Images were individually normalized. Scale bar: 100 µm; white-box insets: 30 µm; orange-box insets: 5 µm. (c) and (d) WF and HiLo signal profiles across three dendrites (orange dashed line a). (e) WF and HiLo axial profiles of an axonal bouton (orange arrowhead b). Imaging area: ${{515}}\;{{\unicode{x00B5}{\rm m}}} \times {{515}}\;{{\unicode{x00B5}{\rm m}}}$. HiLo frame rate: 5 Hz.

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For all experiments, aberration measurements were performed by directly measuring the wavefront of the fluorescence emitted by a 2 µm diameter bead prior to imaging. Because GRIN lens aberrations do not change with time, a one-time characterization is sufficient for subsequent applications. However, sequential region-specific aberration corrections reduce the frame rate of full-FOV images. For applications where high-resolution imaging is required only from a few areas within the FOV (e.g., those containing dendrites and synapses), fewer number of AO corrections are required, which increases the effective frame rate. In some in vivo imaging applications, the GRIN lens is stationary relative to the sample (e.g., with the GRIN lens embedded within the tissue) and 3D imaging is achieved by moving the GRIN lens and the sample relative to the rest of the microendoscope. In this case, the on-axis and off-axis aberrations depend on the image working distance (WD). We measured GRIN lens aberrations at five different image WDs: ${-}{{200}}$, ${-}{{100}}$, 0, 100, and 200 µm, and found that both on-axis and off-axis aberrations became more severe with the increase of image WD (Supplement 1, Fig. S5). Therefore, to achieve high-resolution widefield microendoscopy in 3D, different corrective wavefronts are required at different imaging depths.

Previously, an imaged-based AO approach was used to correct sample-induced aberrations and improve HiLo widefield microscopy images [22]. Direct wavefront sensing was applied to widefield microscopy (but not widefield microendoscopy) to measure the wavefront of fluorescence generated by nonlinear excitation [2325] or from an isolated exogenous guide star with an emission wavelength range different from that of the biological sample fluorescence [21]. The former approach requires a costly ultrafast laser, while the latter may lead to corrective errors caused by chromatic aberrations. In this paper, because we measured the GRIN lens aberrations prior to imaging, we used single-photon fluorescence emission of the same wavelength as the sample and demonstrated robust AO correction in restoring diffraction-limited imaging performance throughout the entire FOV of the GRIN lens. Our approach can be applied to other GRIN-lens-based widefield microendoscopy imaging modalities including light sheets [26]. Since higher-NA GRIN lenses used in multiphoton fluorescence microendoscopy [27] were found to have even larger aberrations [10,11], AO would be essential if they were to be used for widefield microendoscopy. Furthermore, although not considered here, polarization aberrations of GRIN lenses [28,29] are worth exploring in future work, especially for GRIN lenses of larger lengths or higher NA.

In conclusion, for the first time to our knowledge, we demonstrated that the combination of HiLo and AO ensured high-resolution optical-sectioning widefield microendoscopy imaging from both in vitro and in vivo samples. Applying HiLo, a SI approach for computational optical sectioning, successfully suppressed out-of-focus fluorescence and gave rise to enhanced contrast, allowing fine neuronal structures including synapses to be resolved in 3D tissues. By incorporating AO for measuring and correcting intrinsic aberrations of GRIN lenses, we were able to further improve image quality and enlarge the usable FOV. Whereas the resolution, signal, and contrast of both widefield and HiLo images were improved by AO, the largest improvements were observed in the optically sectioned HiLo images, because the in-focus spatial information is more affected by aberrations than out-of-focus background. Given these results, we expect that AO would be essential for all optical-sectioning microendoscopy applications that require high spatial resolution.

Funding

National Institutes of Health (U01NS103573, UF1NS107696).

Acknowledgment

We thank Guanghan Meng for helpful discussion and Jiang Lan Fan for help with the microendoscopy setup.

Disclosures

The authors declare no conflicts of interest.

 

See Supplement 1 for supporting content.

REFERENCES

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2. A. D. Mehta, J. C. Jung, B. A. Flusberg, and M. J. Schnitzer, Curr. Opin. Neurobiol. 14, 617 (2004). [CrossRef]  

3. A. Klimas and E. Entcheva, J. Biomed. Opt. 19, 080701 (2014). [CrossRef]  

4. R. S. Ajlan, A. A. Desai, and M. A. Mainster, Int. J. Retin. Vitr. 5, 15 (2019). [CrossRef]  

5. K. K. Ghosh, L. D. Burns, E. D. Cocker, A. Nimmerjahn, Y. Ziv, A. El Gamal, and M. J. Schnitzer, Nat. Methods 8, 871 (2011). [CrossRef]  

6. G. Matz, B. Messerschmidt, W. Göbel, S. Filser, C. S. Betz, M. Kirsch, O. Uckermann, M. Kunze, S. Flämig, A. Ehrhardt, K.-M. Irion, M. Haack, M. M. Dorostkar, J. Herms, and H. Gross, Biomed. Opt. Express 8, 3329 (2017). [CrossRef]  

7. S. Izawa, S. Chowdhury, T. Miyazaki, Y. Mukai, D. Ono, R. Inoue, Y. Ohmura, H. Mizoguchi, K. Kimura, M. Yoshioka, A. Terao, T. S. Kilduff, and A. Yamanaka, Science 365, 1308 (2019). [CrossRef]  

8. W. M. Lee and S. H. Yun, Opt. Lett. 36, 4608 (2011). [CrossRef]  

9. F. Bortoletto, C. Bonoli, P. Panizzolo, C. D. Ciubotaru, and F. Mammano, PLoS One 6, e22321 (2011). [CrossRef]  

10. C. Wang and N. Ji, Opt. Lett. 37, 2001 (2012). [CrossRef]  

11. C. Wang and N. Ji, Opt. Express 21, 27142 (2013). [CrossRef]  

12. M. A. A. Neil, R. Juškaitis, and T. Wilson, Opt. Lett. 22, 1905 (1997). [CrossRef]  

13. D. Lim, K. K. Chu, and J. Mertz, Opt. Lett. 33, 1819 (2008). [CrossRef]  

14. J. Mertz and J. Kim, J. Biomed. Opt. 15, 016027 (2010). [CrossRef]  

15. D. H. Kim, J. Kim, J. C. Marques, A. Grama, D. G. C. Hildebrand, W. Gu, J. M. Li, and D. N. Robson, Nat. Methods 14, 1107 (2017). [CrossRef]  

16. S. Santos, K. K. Chu, D. Lim, N. Bozinovic, T. N. Ford, C. Hourtoule, A. C. Bartoo, S. K. Singh, and J. Mertz, J. Biomed. Opt. 14, 030502 (2009). [CrossRef]  

17. T. N. Ford, D. Lim, and J. Mertz, J. Biomed. Opt. 17, 021105 (2012). [CrossRef]  

18. P. A. Keahey, T. S. Tkaczyk, K. M. Schmeler, and R. R. Richards-Kortum, Biomed. Opt. Express 6, 870 (2015). [CrossRef]  

19. P. Keahey, P. Ramalingam, K. Schmeler, and R. R. Richards-Kortum, Proc. Natl. Acad. Sci. USA 113, 10769 (2016). [CrossRef]  

20. N. Ji, Nat. Methods 14, 374 (2017). [CrossRef]  

21. O. Azucena, J. Crest, S. Kotadia, W. Sullivan, X. Tao, M. Reinig, D. Gavel, S. Olivier, and J. Kubby, Opt. Lett. 36, 825 (2011). [CrossRef]  

22. M. Pedrazzani, V. Loriette, P. Tchenio, S. Benrezzak, D. Nutarelli, and A. Fragola, J. Biomed. Opt. 21, 036006 (2016). [CrossRef]  

23. T.-L. Liu, S. Upadhyayula, D. E. Milkie, V. Singh, K. Wang, I. A. Swinburne, K. R. Mosaliganti, Z. M. Collins, T. W. Hiscock, J. Shea, A. Q. Kohrman, T. N. Medwig, D. Dambournet, R. Forster, B. Cunniff, Y. Ruan, H. Yashiro, S. Scholpp, E. M. Meyerowitz, D. Hockemeyer, D. G. Drubin, B. L. Martin, D. Q. Matus, M. Koyama, S. G. Megason, T. Kirchhausen, and E. Betzig, Science 360, eaaq1392 (2018). [CrossRef]  

24. R. Turcotte, Y. Liang, M. Tanimoto, Q. Zhang, Z. Li, M. Koyama, E. Betzig, and N. Ji, Proc. Natl. Acad. Sci. USA 116, 9586 (2019). [CrossRef]  

25. Z. Li, Q. Zhang, S.-W. Chou, Z. Newman, R. Turcotte, R. Natan, Q. Dai, E. Y. Isacoff, and N. Ji, Sci. Adv. 6, eaaz3870 (2020). [CrossRef]  

26. C. J. Engelbrecht, F. Voigt, and F. Helmchen, Opt. Lett. 35, 1413 (2010). [CrossRef]  

27. R. P. J. Barretto, B. Messerschmidt, and M. J. Schnitzer, Nat. Methods 6, 511 (2009). [CrossRef]  

28. J. L. Rouke and D. T. Moore, Appl. Opt. 38, 6574 (1999). [CrossRef]  

29. C. He, J. Chang, Q. Hu, J. Wang, J. Antonello, H. He, S. Liu, J. Lin, B. Dai, D. S. Elson, P. Xi, H. Ma, and M. J. Booth, Nat. Commun. 10, 4264 (2019). [CrossRef]  

References

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  1. N. Ji, J. Freeman, and S. L. Smith, Nat. Neurosci. 19, 1154 (2016).
    [Crossref]
  2. A. D. Mehta, J. C. Jung, B. A. Flusberg, and M. J. Schnitzer, Curr. Opin. Neurobiol. 14, 617 (2004).
    [Crossref]
  3. A. Klimas and E. Entcheva, J. Biomed. Opt. 19, 080701 (2014).
    [Crossref]
  4. R. S. Ajlan, A. A. Desai, and M. A. Mainster, Int. J. Retin. Vitr. 5, 15 (2019).
    [Crossref]
  5. K. K. Ghosh, L. D. Burns, E. D. Cocker, A. Nimmerjahn, Y. Ziv, A. El Gamal, and M. J. Schnitzer, Nat. Methods 8, 871 (2011).
    [Crossref]
  6. G. Matz, B. Messerschmidt, W. Göbel, S. Filser, C. S. Betz, M. Kirsch, O. Uckermann, M. Kunze, S. Flämig, A. Ehrhardt, K.-M. Irion, M. Haack, M. M. Dorostkar, J. Herms, and H. Gross, Biomed. Opt. Express 8, 3329 (2017).
    [Crossref]
  7. S. Izawa, S. Chowdhury, T. Miyazaki, Y. Mukai, D. Ono, R. Inoue, Y. Ohmura, H. Mizoguchi, K. Kimura, M. Yoshioka, A. Terao, T. S. Kilduff, and A. Yamanaka, Science 365, 1308 (2019).
    [Crossref]
  8. W. M. Lee and S. H. Yun, Opt. Lett. 36, 4608 (2011).
    [Crossref]
  9. F. Bortoletto, C. Bonoli, P. Panizzolo, C. D. Ciubotaru, and F. Mammano, PLoS One 6, e22321 (2011).
    [Crossref]
  10. C. Wang and N. Ji, Opt. Lett. 37, 2001 (2012).
    [Crossref]
  11. C. Wang and N. Ji, Opt. Express 21, 27142 (2013).
    [Crossref]
  12. M. A. A. Neil, R. Juškaitis, and T. Wilson, Opt. Lett. 22, 1905 (1997).
    [Crossref]
  13. D. Lim, K. K. Chu, and J. Mertz, Opt. Lett. 33, 1819 (2008).
    [Crossref]
  14. J. Mertz and J. Kim, J. Biomed. Opt. 15, 016027 (2010).
    [Crossref]
  15. D. H. Kim, J. Kim, J. C. Marques, A. Grama, D. G. C. Hildebrand, W. Gu, J. M. Li, and D. N. Robson, Nat. Methods 14, 1107 (2017).
    [Crossref]
  16. S. Santos, K. K. Chu, D. Lim, N. Bozinovic, T. N. Ford, C. Hourtoule, A. C. Bartoo, S. K. Singh, and J. Mertz, J. Biomed. Opt. 14, 030502 (2009).
    [Crossref]
  17. T. N. Ford, D. Lim, and J. Mertz, J. Biomed. Opt. 17, 021105 (2012).
    [Crossref]
  18. P. A. Keahey, T. S. Tkaczyk, K. M. Schmeler, and R. R. Richards-Kortum, Biomed. Opt. Express 6, 870 (2015).
    [Crossref]
  19. P. Keahey, P. Ramalingam, K. Schmeler, and R. R. Richards-Kortum, Proc. Natl. Acad. Sci. USA 113, 10769 (2016).
    [Crossref]
  20. N. Ji, Nat. Methods 14, 374 (2017).
    [Crossref]
  21. O. Azucena, J. Crest, S. Kotadia, W. Sullivan, X. Tao, M. Reinig, D. Gavel, S. Olivier, and J. Kubby, Opt. Lett. 36, 825 (2011).
    [Crossref]
  22. M. Pedrazzani, V. Loriette, P. Tchenio, S. Benrezzak, D. Nutarelli, and A. Fragola, J. Biomed. Opt. 21, 036006 (2016).
    [Crossref]
  23. T.-L. Liu, S. Upadhyayula, D. E. Milkie, V. Singh, K. Wang, I. A. Swinburne, K. R. Mosaliganti, Z. M. Collins, T. W. Hiscock, J. Shea, A. Q. Kohrman, T. N. Medwig, D. Dambournet, R. Forster, B. Cunniff, Y. Ruan, H. Yashiro, S. Scholpp, E. M. Meyerowitz, D. Hockemeyer, D. G. Drubin, B. L. Martin, D. Q. Matus, M. Koyama, S. G. Megason, T. Kirchhausen, and E. Betzig, Science 360, eaaq1392 (2018).
    [Crossref]
  24. R. Turcotte, Y. Liang, M. Tanimoto, Q. Zhang, Z. Li, M. Koyama, E. Betzig, and N. Ji, Proc. Natl. Acad. Sci. USA 116, 9586 (2019).
    [Crossref]
  25. Z. Li, Q. Zhang, S.-W. Chou, Z. Newman, R. Turcotte, R. Natan, Q. Dai, E. Y. Isacoff, and N. Ji, Sci. Adv. 6, eaaz3870 (2020).
    [Crossref]
  26. C. J. Engelbrecht, F. Voigt, and F. Helmchen, Opt. Lett. 35, 1413 (2010).
    [Crossref]
  27. R. P. J. Barretto, B. Messerschmidt, and M. J. Schnitzer, Nat. Methods 6, 511 (2009).
    [Crossref]
  28. J. L. Rouke and D. T. Moore, Appl. Opt. 38, 6574 (1999).
    [Crossref]
  29. C. He, J. Chang, Q. Hu, J. Wang, J. Antonello, H. He, S. Liu, J. Lin, B. Dai, D. S. Elson, P. Xi, H. Ma, and M. J. Booth, Nat. Commun. 10, 4264 (2019).
    [Crossref]

2020 (1)

Z. Li, Q. Zhang, S.-W. Chou, Z. Newman, R. Turcotte, R. Natan, Q. Dai, E. Y. Isacoff, and N. Ji, Sci. Adv. 6, eaaz3870 (2020).
[Crossref]

2019 (4)

R. Turcotte, Y. Liang, M. Tanimoto, Q. Zhang, Z. Li, M. Koyama, E. Betzig, and N. Ji, Proc. Natl. Acad. Sci. USA 116, 9586 (2019).
[Crossref]

C. He, J. Chang, Q. Hu, J. Wang, J. Antonello, H. He, S. Liu, J. Lin, B. Dai, D. S. Elson, P. Xi, H. Ma, and M. J. Booth, Nat. Commun. 10, 4264 (2019).
[Crossref]

R. S. Ajlan, A. A. Desai, and M. A. Mainster, Int. J. Retin. Vitr. 5, 15 (2019).
[Crossref]

S. Izawa, S. Chowdhury, T. Miyazaki, Y. Mukai, D. Ono, R. Inoue, Y. Ohmura, H. Mizoguchi, K. Kimura, M. Yoshioka, A. Terao, T. S. Kilduff, and A. Yamanaka, Science 365, 1308 (2019).
[Crossref]

2018 (1)

T.-L. Liu, S. Upadhyayula, D. E. Milkie, V. Singh, K. Wang, I. A. Swinburne, K. R. Mosaliganti, Z. M. Collins, T. W. Hiscock, J. Shea, A. Q. Kohrman, T. N. Medwig, D. Dambournet, R. Forster, B. Cunniff, Y. Ruan, H. Yashiro, S. Scholpp, E. M. Meyerowitz, D. Hockemeyer, D. G. Drubin, B. L. Martin, D. Q. Matus, M. Koyama, S. G. Megason, T. Kirchhausen, and E. Betzig, Science 360, eaaq1392 (2018).
[Crossref]

2017 (3)

2016 (3)

N. Ji, J. Freeman, and S. L. Smith, Nat. Neurosci. 19, 1154 (2016).
[Crossref]

P. Keahey, P. Ramalingam, K. Schmeler, and R. R. Richards-Kortum, Proc. Natl. Acad. Sci. USA 113, 10769 (2016).
[Crossref]

M. Pedrazzani, V. Loriette, P. Tchenio, S. Benrezzak, D. Nutarelli, and A. Fragola, J. Biomed. Opt. 21, 036006 (2016).
[Crossref]

2015 (1)

2014 (1)

A. Klimas and E. Entcheva, J. Biomed. Opt. 19, 080701 (2014).
[Crossref]

2013 (1)

2012 (2)

C. Wang and N. Ji, Opt. Lett. 37, 2001 (2012).
[Crossref]

T. N. Ford, D. Lim, and J. Mertz, J. Biomed. Opt. 17, 021105 (2012).
[Crossref]

2011 (4)

W. M. Lee and S. H. Yun, Opt. Lett. 36, 4608 (2011).
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F. Bortoletto, C. Bonoli, P. Panizzolo, C. D. Ciubotaru, and F. Mammano, PLoS One 6, e22321 (2011).
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K. K. Ghosh, L. D. Burns, E. D. Cocker, A. Nimmerjahn, Y. Ziv, A. El Gamal, and M. J. Schnitzer, Nat. Methods 8, 871 (2011).
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O. Azucena, J. Crest, S. Kotadia, W. Sullivan, X. Tao, M. Reinig, D. Gavel, S. Olivier, and J. Kubby, Opt. Lett. 36, 825 (2011).
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2010 (2)

2009 (2)

S. Santos, K. K. Chu, D. Lim, N. Bozinovic, T. N. Ford, C. Hourtoule, A. C. Bartoo, S. K. Singh, and J. Mertz, J. Biomed. Opt. 14, 030502 (2009).
[Crossref]

R. P. J. Barretto, B. Messerschmidt, and M. J. Schnitzer, Nat. Methods 6, 511 (2009).
[Crossref]

2008 (1)

2004 (1)

A. D. Mehta, J. C. Jung, B. A. Flusberg, and M. J. Schnitzer, Curr. Opin. Neurobiol. 14, 617 (2004).
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1999 (1)

1997 (1)

Ajlan, R. S.

R. S. Ajlan, A. A. Desai, and M. A. Mainster, Int. J. Retin. Vitr. 5, 15 (2019).
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Antonello, J.

C. He, J. Chang, Q. Hu, J. Wang, J. Antonello, H. He, S. Liu, J. Lin, B. Dai, D. S. Elson, P. Xi, H. Ma, and M. J. Booth, Nat. Commun. 10, 4264 (2019).
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Azucena, O.

Barretto, R. P. J.

R. P. J. Barretto, B. Messerschmidt, and M. J. Schnitzer, Nat. Methods 6, 511 (2009).
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Bartoo, A. C.

S. Santos, K. K. Chu, D. Lim, N. Bozinovic, T. N. Ford, C. Hourtoule, A. C. Bartoo, S. K. Singh, and J. Mertz, J. Biomed. Opt. 14, 030502 (2009).
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Benrezzak, S.

M. Pedrazzani, V. Loriette, P. Tchenio, S. Benrezzak, D. Nutarelli, and A. Fragola, J. Biomed. Opt. 21, 036006 (2016).
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Betz, C. S.

Betzig, E.

R. Turcotte, Y. Liang, M. Tanimoto, Q. Zhang, Z. Li, M. Koyama, E. Betzig, and N. Ji, Proc. Natl. Acad. Sci. USA 116, 9586 (2019).
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T.-L. Liu, S. Upadhyayula, D. E. Milkie, V. Singh, K. Wang, I. A. Swinburne, K. R. Mosaliganti, Z. M. Collins, T. W. Hiscock, J. Shea, A. Q. Kohrman, T. N. Medwig, D. Dambournet, R. Forster, B. Cunniff, Y. Ruan, H. Yashiro, S. Scholpp, E. M. Meyerowitz, D. Hockemeyer, D. G. Drubin, B. L. Martin, D. Q. Matus, M. Koyama, S. G. Megason, T. Kirchhausen, and E. Betzig, Science 360, eaaq1392 (2018).
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Bonoli, C.

F. Bortoletto, C. Bonoli, P. Panizzolo, C. D. Ciubotaru, and F. Mammano, PLoS One 6, e22321 (2011).
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Booth, M. J.

C. He, J. Chang, Q. Hu, J. Wang, J. Antonello, H. He, S. Liu, J. Lin, B. Dai, D. S. Elson, P. Xi, H. Ma, and M. J. Booth, Nat. Commun. 10, 4264 (2019).
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Bortoletto, F.

F. Bortoletto, C. Bonoli, P. Panizzolo, C. D. Ciubotaru, and F. Mammano, PLoS One 6, e22321 (2011).
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Bozinovic, N.

S. Santos, K. K. Chu, D. Lim, N. Bozinovic, T. N. Ford, C. Hourtoule, A. C. Bartoo, S. K. Singh, and J. Mertz, J. Biomed. Opt. 14, 030502 (2009).
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Burns, L. D.

K. K. Ghosh, L. D. Burns, E. D. Cocker, A. Nimmerjahn, Y. Ziv, A. El Gamal, and M. J. Schnitzer, Nat. Methods 8, 871 (2011).
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Chang, J.

C. He, J. Chang, Q. Hu, J. Wang, J. Antonello, H. He, S. Liu, J. Lin, B. Dai, D. S. Elson, P. Xi, H. Ma, and M. J. Booth, Nat. Commun. 10, 4264 (2019).
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Chou, S.-W.

Z. Li, Q. Zhang, S.-W. Chou, Z. Newman, R. Turcotte, R. Natan, Q. Dai, E. Y. Isacoff, and N. Ji, Sci. Adv. 6, eaaz3870 (2020).
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Chowdhury, S.

S. Izawa, S. Chowdhury, T. Miyazaki, Y. Mukai, D. Ono, R. Inoue, Y. Ohmura, H. Mizoguchi, K. Kimura, M. Yoshioka, A. Terao, T. S. Kilduff, and A. Yamanaka, Science 365, 1308 (2019).
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Chu, K. K.

S. Santos, K. K. Chu, D. Lim, N. Bozinovic, T. N. Ford, C. Hourtoule, A. C. Bartoo, S. K. Singh, and J. Mertz, J. Biomed. Opt. 14, 030502 (2009).
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D. Lim, K. K. Chu, and J. Mertz, Opt. Lett. 33, 1819 (2008).
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Ciubotaru, C. D.

F. Bortoletto, C. Bonoli, P. Panizzolo, C. D. Ciubotaru, and F. Mammano, PLoS One 6, e22321 (2011).
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Cocker, E. D.

K. K. Ghosh, L. D. Burns, E. D. Cocker, A. Nimmerjahn, Y. Ziv, A. El Gamal, and M. J. Schnitzer, Nat. Methods 8, 871 (2011).
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Collins, Z. M.

T.-L. Liu, S. Upadhyayula, D. E. Milkie, V. Singh, K. Wang, I. A. Swinburne, K. R. Mosaliganti, Z. M. Collins, T. W. Hiscock, J. Shea, A. Q. Kohrman, T. N. Medwig, D. Dambournet, R. Forster, B. Cunniff, Y. Ruan, H. Yashiro, S. Scholpp, E. M. Meyerowitz, D. Hockemeyer, D. G. Drubin, B. L. Martin, D. Q. Matus, M. Koyama, S. G. Megason, T. Kirchhausen, and E. Betzig, Science 360, eaaq1392 (2018).
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Crest, J.

Cunniff, B.

T.-L. Liu, S. Upadhyayula, D. E. Milkie, V. Singh, K. Wang, I. A. Swinburne, K. R. Mosaliganti, Z. M. Collins, T. W. Hiscock, J. Shea, A. Q. Kohrman, T. N. Medwig, D. Dambournet, R. Forster, B. Cunniff, Y. Ruan, H. Yashiro, S. Scholpp, E. M. Meyerowitz, D. Hockemeyer, D. G. Drubin, B. L. Martin, D. Q. Matus, M. Koyama, S. G. Megason, T. Kirchhausen, and E. Betzig, Science 360, eaaq1392 (2018).
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Dai, B.

C. He, J. Chang, Q. Hu, J. Wang, J. Antonello, H. He, S. Liu, J. Lin, B. Dai, D. S. Elson, P. Xi, H. Ma, and M. J. Booth, Nat. Commun. 10, 4264 (2019).
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Dai, Q.

Z. Li, Q. Zhang, S.-W. Chou, Z. Newman, R. Turcotte, R. Natan, Q. Dai, E. Y. Isacoff, and N. Ji, Sci. Adv. 6, eaaz3870 (2020).
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Dambournet, D.

T.-L. Liu, S. Upadhyayula, D. E. Milkie, V. Singh, K. Wang, I. A. Swinburne, K. R. Mosaliganti, Z. M. Collins, T. W. Hiscock, J. Shea, A. Q. Kohrman, T. N. Medwig, D. Dambournet, R. Forster, B. Cunniff, Y. Ruan, H. Yashiro, S. Scholpp, E. M. Meyerowitz, D. Hockemeyer, D. G. Drubin, B. L. Martin, D. Q. Matus, M. Koyama, S. G. Megason, T. Kirchhausen, and E. Betzig, Science 360, eaaq1392 (2018).
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Desai, A. A.

R. S. Ajlan, A. A. Desai, and M. A. Mainster, Int. J. Retin. Vitr. 5, 15 (2019).
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Dorostkar, M. M.

Drubin, D. G.

T.-L. Liu, S. Upadhyayula, D. E. Milkie, V. Singh, K. Wang, I. A. Swinburne, K. R. Mosaliganti, Z. M. Collins, T. W. Hiscock, J. Shea, A. Q. Kohrman, T. N. Medwig, D. Dambournet, R. Forster, B. Cunniff, Y. Ruan, H. Yashiro, S. Scholpp, E. M. Meyerowitz, D. Hockemeyer, D. G. Drubin, B. L. Martin, D. Q. Matus, M. Koyama, S. G. Megason, T. Kirchhausen, and E. Betzig, Science 360, eaaq1392 (2018).
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Ehrhardt, A.

El Gamal, A.

K. K. Ghosh, L. D. Burns, E. D. Cocker, A. Nimmerjahn, Y. Ziv, A. El Gamal, and M. J. Schnitzer, Nat. Methods 8, 871 (2011).
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Elson, D. S.

C. He, J. Chang, Q. Hu, J. Wang, J. Antonello, H. He, S. Liu, J. Lin, B. Dai, D. S. Elson, P. Xi, H. Ma, and M. J. Booth, Nat. Commun. 10, 4264 (2019).
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Engelbrecht, C. J.

Entcheva, E.

A. Klimas and E. Entcheva, J. Biomed. Opt. 19, 080701 (2014).
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Filser, S.

Flämig, S.

Flusberg, B. A.

A. D. Mehta, J. C. Jung, B. A. Flusberg, and M. J. Schnitzer, Curr. Opin. Neurobiol. 14, 617 (2004).
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Ford, T. N.

T. N. Ford, D. Lim, and J. Mertz, J. Biomed. Opt. 17, 021105 (2012).
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S. Santos, K. K. Chu, D. Lim, N. Bozinovic, T. N. Ford, C. Hourtoule, A. C. Bartoo, S. K. Singh, and J. Mertz, J. Biomed. Opt. 14, 030502 (2009).
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Forster, R.

T.-L. Liu, S. Upadhyayula, D. E. Milkie, V. Singh, K. Wang, I. A. Swinburne, K. R. Mosaliganti, Z. M. Collins, T. W. Hiscock, J. Shea, A. Q. Kohrman, T. N. Medwig, D. Dambournet, R. Forster, B. Cunniff, Y. Ruan, H. Yashiro, S. Scholpp, E. M. Meyerowitz, D. Hockemeyer, D. G. Drubin, B. L. Martin, D. Q. Matus, M. Koyama, S. G. Megason, T. Kirchhausen, and E. Betzig, Science 360, eaaq1392 (2018).
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Fragola, A.

M. Pedrazzani, V. Loriette, P. Tchenio, S. Benrezzak, D. Nutarelli, and A. Fragola, J. Biomed. Opt. 21, 036006 (2016).
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Freeman, J.

N. Ji, J. Freeman, and S. L. Smith, Nat. Neurosci. 19, 1154 (2016).
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Gavel, D.

Ghosh, K. K.

K. K. Ghosh, L. D. Burns, E. D. Cocker, A. Nimmerjahn, Y. Ziv, A. El Gamal, and M. J. Schnitzer, Nat. Methods 8, 871 (2011).
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Göbel, W.

Grama, A.

D. H. Kim, J. Kim, J. C. Marques, A. Grama, D. G. C. Hildebrand, W. Gu, J. M. Li, and D. N. Robson, Nat. Methods 14, 1107 (2017).
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Gross, H.

Gu, W.

D. H. Kim, J. Kim, J. C. Marques, A. Grama, D. G. C. Hildebrand, W. Gu, J. M. Li, and D. N. Robson, Nat. Methods 14, 1107 (2017).
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Haack, M.

He, C.

C. He, J. Chang, Q. Hu, J. Wang, J. Antonello, H. He, S. Liu, J. Lin, B. Dai, D. S. Elson, P. Xi, H. Ma, and M. J. Booth, Nat. Commun. 10, 4264 (2019).
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He, H.

C. He, J. Chang, Q. Hu, J. Wang, J. Antonello, H. He, S. Liu, J. Lin, B. Dai, D. S. Elson, P. Xi, H. Ma, and M. J. Booth, Nat. Commun. 10, 4264 (2019).
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Helmchen, F.

Herms, J.

Hildebrand, D. G. C.

D. H. Kim, J. Kim, J. C. Marques, A. Grama, D. G. C. Hildebrand, W. Gu, J. M. Li, and D. N. Robson, Nat. Methods 14, 1107 (2017).
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Hiscock, T. W.

T.-L. Liu, S. Upadhyayula, D. E. Milkie, V. Singh, K. Wang, I. A. Swinburne, K. R. Mosaliganti, Z. M. Collins, T. W. Hiscock, J. Shea, A. Q. Kohrman, T. N. Medwig, D. Dambournet, R. Forster, B. Cunniff, Y. Ruan, H. Yashiro, S. Scholpp, E. M. Meyerowitz, D. Hockemeyer, D. G. Drubin, B. L. Martin, D. Q. Matus, M. Koyama, S. G. Megason, T. Kirchhausen, and E. Betzig, Science 360, eaaq1392 (2018).
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Hockemeyer, D.

T.-L. Liu, S. Upadhyayula, D. E. Milkie, V. Singh, K. Wang, I. A. Swinburne, K. R. Mosaliganti, Z. M. Collins, T. W. Hiscock, J. Shea, A. Q. Kohrman, T. N. Medwig, D. Dambournet, R. Forster, B. Cunniff, Y. Ruan, H. Yashiro, S. Scholpp, E. M. Meyerowitz, D. Hockemeyer, D. G. Drubin, B. L. Martin, D. Q. Matus, M. Koyama, S. G. Megason, T. Kirchhausen, and E. Betzig, Science 360, eaaq1392 (2018).
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Hourtoule, C.

S. Santos, K. K. Chu, D. Lim, N. Bozinovic, T. N. Ford, C. Hourtoule, A. C. Bartoo, S. K. Singh, and J. Mertz, J. Biomed. Opt. 14, 030502 (2009).
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Hu, Q.

C. He, J. Chang, Q. Hu, J. Wang, J. Antonello, H. He, S. Liu, J. Lin, B. Dai, D. S. Elson, P. Xi, H. Ma, and M. J. Booth, Nat. Commun. 10, 4264 (2019).
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Inoue, R.

S. Izawa, S. Chowdhury, T. Miyazaki, Y. Mukai, D. Ono, R. Inoue, Y. Ohmura, H. Mizoguchi, K. Kimura, M. Yoshioka, A. Terao, T. S. Kilduff, and A. Yamanaka, Science 365, 1308 (2019).
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Irion, K.-M.

Isacoff, E. Y.

Z. Li, Q. Zhang, S.-W. Chou, Z. Newman, R. Turcotte, R. Natan, Q. Dai, E. Y. Isacoff, and N. Ji, Sci. Adv. 6, eaaz3870 (2020).
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Izawa, S.

S. Izawa, S. Chowdhury, T. Miyazaki, Y. Mukai, D. Ono, R. Inoue, Y. Ohmura, H. Mizoguchi, K. Kimura, M. Yoshioka, A. Terao, T. S. Kilduff, and A. Yamanaka, Science 365, 1308 (2019).
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Ji, N.

Z. Li, Q. Zhang, S.-W. Chou, Z. Newman, R. Turcotte, R. Natan, Q. Dai, E. Y. Isacoff, and N. Ji, Sci. Adv. 6, eaaz3870 (2020).
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R. Turcotte, Y. Liang, M. Tanimoto, Q. Zhang, Z. Li, M. Koyama, E. Betzig, and N. Ji, Proc. Natl. Acad. Sci. USA 116, 9586 (2019).
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N. Ji, Nat. Methods 14, 374 (2017).
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N. Ji, J. Freeman, and S. L. Smith, Nat. Neurosci. 19, 1154 (2016).
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C. Wang and N. Ji, Opt. Express 21, 27142 (2013).
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C. Wang and N. Ji, Opt. Lett. 37, 2001 (2012).
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Jung, J. C.

A. D. Mehta, J. C. Jung, B. A. Flusberg, and M. J. Schnitzer, Curr. Opin. Neurobiol. 14, 617 (2004).
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Juškaitis, R.

Keahey, P.

P. Keahey, P. Ramalingam, K. Schmeler, and R. R. Richards-Kortum, Proc. Natl. Acad. Sci. USA 113, 10769 (2016).
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Keahey, P. A.

Kilduff, T. S.

S. Izawa, S. Chowdhury, T. Miyazaki, Y. Mukai, D. Ono, R. Inoue, Y. Ohmura, H. Mizoguchi, K. Kimura, M. Yoshioka, A. Terao, T. S. Kilduff, and A. Yamanaka, Science 365, 1308 (2019).
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Kim, D. H.

D. H. Kim, J. Kim, J. C. Marques, A. Grama, D. G. C. Hildebrand, W. Gu, J. M. Li, and D. N. Robson, Nat. Methods 14, 1107 (2017).
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Kim, J.

D. H. Kim, J. Kim, J. C. Marques, A. Grama, D. G. C. Hildebrand, W. Gu, J. M. Li, and D. N. Robson, Nat. Methods 14, 1107 (2017).
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J. Mertz and J. Kim, J. Biomed. Opt. 15, 016027 (2010).
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Kimura, K.

S. Izawa, S. Chowdhury, T. Miyazaki, Y. Mukai, D. Ono, R. Inoue, Y. Ohmura, H. Mizoguchi, K. Kimura, M. Yoshioka, A. Terao, T. S. Kilduff, and A. Yamanaka, Science 365, 1308 (2019).
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Kirchhausen, T.

T.-L. Liu, S. Upadhyayula, D. E. Milkie, V. Singh, K. Wang, I. A. Swinburne, K. R. Mosaliganti, Z. M. Collins, T. W. Hiscock, J. Shea, A. Q. Kohrman, T. N. Medwig, D. Dambournet, R. Forster, B. Cunniff, Y. Ruan, H. Yashiro, S. Scholpp, E. M. Meyerowitz, D. Hockemeyer, D. G. Drubin, B. L. Martin, D. Q. Matus, M. Koyama, S. G. Megason, T. Kirchhausen, and E. Betzig, Science 360, eaaq1392 (2018).
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Kirsch, M.

Klimas, A.

A. Klimas and E. Entcheva, J. Biomed. Opt. 19, 080701 (2014).
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Kohrman, A. Q.

T.-L. Liu, S. Upadhyayula, D. E. Milkie, V. Singh, K. Wang, I. A. Swinburne, K. R. Mosaliganti, Z. M. Collins, T. W. Hiscock, J. Shea, A. Q. Kohrman, T. N. Medwig, D. Dambournet, R. Forster, B. Cunniff, Y. Ruan, H. Yashiro, S. Scholpp, E. M. Meyerowitz, D. Hockemeyer, D. G. Drubin, B. L. Martin, D. Q. Matus, M. Koyama, S. G. Megason, T. Kirchhausen, and E. Betzig, Science 360, eaaq1392 (2018).
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Kotadia, S.

Koyama, M.

R. Turcotte, Y. Liang, M. Tanimoto, Q. Zhang, Z. Li, M. Koyama, E. Betzig, and N. Ji, Proc. Natl. Acad. Sci. USA 116, 9586 (2019).
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T.-L. Liu, S. Upadhyayula, D. E. Milkie, V. Singh, K. Wang, I. A. Swinburne, K. R. Mosaliganti, Z. M. Collins, T. W. Hiscock, J. Shea, A. Q. Kohrman, T. N. Medwig, D. Dambournet, R. Forster, B. Cunniff, Y. Ruan, H. Yashiro, S. Scholpp, E. M. Meyerowitz, D. Hockemeyer, D. G. Drubin, B. L. Martin, D. Q. Matus, M. Koyama, S. G. Megason, T. Kirchhausen, and E. Betzig, Science 360, eaaq1392 (2018).
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Kubby, J.

Kunze, M.

Lee, W. M.

Li, J. M.

D. H. Kim, J. Kim, J. C. Marques, A. Grama, D. G. C. Hildebrand, W. Gu, J. M. Li, and D. N. Robson, Nat. Methods 14, 1107 (2017).
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Li, Z.

Z. Li, Q. Zhang, S.-W. Chou, Z. Newman, R. Turcotte, R. Natan, Q. Dai, E. Y. Isacoff, and N. Ji, Sci. Adv. 6, eaaz3870 (2020).
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R. Turcotte, Y. Liang, M. Tanimoto, Q. Zhang, Z. Li, M. Koyama, E. Betzig, and N. Ji, Proc. Natl. Acad. Sci. USA 116, 9586 (2019).
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Liang, Y.

R. Turcotte, Y. Liang, M. Tanimoto, Q. Zhang, Z. Li, M. Koyama, E. Betzig, and N. Ji, Proc. Natl. Acad. Sci. USA 116, 9586 (2019).
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T. N. Ford, D. Lim, and J. Mertz, J. Biomed. Opt. 17, 021105 (2012).
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S. Santos, K. K. Chu, D. Lim, N. Bozinovic, T. N. Ford, C. Hourtoule, A. C. Bartoo, S. K. Singh, and J. Mertz, J. Biomed. Opt. 14, 030502 (2009).
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D. Lim, K. K. Chu, and J. Mertz, Opt. Lett. 33, 1819 (2008).
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Lin, J.

C. He, J. Chang, Q. Hu, J. Wang, J. Antonello, H. He, S. Liu, J. Lin, B. Dai, D. S. Elson, P. Xi, H. Ma, and M. J. Booth, Nat. Commun. 10, 4264 (2019).
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Liu, S.

C. He, J. Chang, Q. Hu, J. Wang, J. Antonello, H. He, S. Liu, J. Lin, B. Dai, D. S. Elson, P. Xi, H. Ma, and M. J. Booth, Nat. Commun. 10, 4264 (2019).
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Liu, T.-L.

T.-L. Liu, S. Upadhyayula, D. E. Milkie, V. Singh, K. Wang, I. A. Swinburne, K. R. Mosaliganti, Z. M. Collins, T. W. Hiscock, J. Shea, A. Q. Kohrman, T. N. Medwig, D. Dambournet, R. Forster, B. Cunniff, Y. Ruan, H. Yashiro, S. Scholpp, E. M. Meyerowitz, D. Hockemeyer, D. G. Drubin, B. L. Martin, D. Q. Matus, M. Koyama, S. G. Megason, T. Kirchhausen, and E. Betzig, Science 360, eaaq1392 (2018).
[Crossref]

Loriette, V.

M. Pedrazzani, V. Loriette, P. Tchenio, S. Benrezzak, D. Nutarelli, and A. Fragola, J. Biomed. Opt. 21, 036006 (2016).
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Ma, H.

C. He, J. Chang, Q. Hu, J. Wang, J. Antonello, H. He, S. Liu, J. Lin, B. Dai, D. S. Elson, P. Xi, H. Ma, and M. J. Booth, Nat. Commun. 10, 4264 (2019).
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F. Bortoletto, C. Bonoli, P. Panizzolo, C. D. Ciubotaru, and F. Mammano, PLoS One 6, e22321 (2011).
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D. H. Kim, J. Kim, J. C. Marques, A. Grama, D. G. C. Hildebrand, W. Gu, J. M. Li, and D. N. Robson, Nat. Methods 14, 1107 (2017).
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T.-L. Liu, S. Upadhyayula, D. E. Milkie, V. Singh, K. Wang, I. A. Swinburne, K. R. Mosaliganti, Z. M. Collins, T. W. Hiscock, J. Shea, A. Q. Kohrman, T. N. Medwig, D. Dambournet, R. Forster, B. Cunniff, Y. Ruan, H. Yashiro, S. Scholpp, E. M. Meyerowitz, D. Hockemeyer, D. G. Drubin, B. L. Martin, D. Q. Matus, M. Koyama, S. G. Megason, T. Kirchhausen, and E. Betzig, Science 360, eaaq1392 (2018).
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Medwig, T. N.

T.-L. Liu, S. Upadhyayula, D. E. Milkie, V. Singh, K. Wang, I. A. Swinburne, K. R. Mosaliganti, Z. M. Collins, T. W. Hiscock, J. Shea, A. Q. Kohrman, T. N. Medwig, D. Dambournet, R. Forster, B. Cunniff, Y. Ruan, H. Yashiro, S. Scholpp, E. M. Meyerowitz, D. Hockemeyer, D. G. Drubin, B. L. Martin, D. Q. Matus, M. Koyama, S. G. Megason, T. Kirchhausen, and E. Betzig, Science 360, eaaq1392 (2018).
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T.-L. Liu, S. Upadhyayula, D. E. Milkie, V. Singh, K. Wang, I. A. Swinburne, K. R. Mosaliganti, Z. M. Collins, T. W. Hiscock, J. Shea, A. Q. Kohrman, T. N. Medwig, D. Dambournet, R. Forster, B. Cunniff, Y. Ruan, H. Yashiro, S. Scholpp, E. M. Meyerowitz, D. Hockemeyer, D. G. Drubin, B. L. Martin, D. Q. Matus, M. Koyama, S. G. Megason, T. Kirchhausen, and E. Betzig, Science 360, eaaq1392 (2018).
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T. N. Ford, D. Lim, and J. Mertz, J. Biomed. Opt. 17, 021105 (2012).
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T.-L. Liu, S. Upadhyayula, D. E. Milkie, V. Singh, K. Wang, I. A. Swinburne, K. R. Mosaliganti, Z. M. Collins, T. W. Hiscock, J. Shea, A. Q. Kohrman, T. N. Medwig, D. Dambournet, R. Forster, B. Cunniff, Y. Ruan, H. Yashiro, S. Scholpp, E. M. Meyerowitz, D. Hockemeyer, D. G. Drubin, B. L. Martin, D. Q. Matus, M. Koyama, S. G. Megason, T. Kirchhausen, and E. Betzig, Science 360, eaaq1392 (2018).
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S. Izawa, S. Chowdhury, T. Miyazaki, Y. Mukai, D. Ono, R. Inoue, Y. Ohmura, H. Mizoguchi, K. Kimura, M. Yoshioka, A. Terao, T. S. Kilduff, and A. Yamanaka, Science 365, 1308 (2019).
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S. Izawa, S. Chowdhury, T. Miyazaki, Y. Mukai, D. Ono, R. Inoue, Y. Ohmura, H. Mizoguchi, K. Kimura, M. Yoshioka, A. Terao, T. S. Kilduff, and A. Yamanaka, Science 365, 1308 (2019).
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S. Izawa, S. Chowdhury, T. Miyazaki, Y. Mukai, D. Ono, R. Inoue, Y. Ohmura, H. Mizoguchi, K. Kimura, M. Yoshioka, A. Terao, T. S. Kilduff, and A. Yamanaka, Science 365, 1308 (2019).
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Zhang, Q.

Z. Li, Q. Zhang, S.-W. Chou, Z. Newman, R. Turcotte, R. Natan, Q. Dai, E. Y. Isacoff, and N. Ji, Sci. Adv. 6, eaaz3870 (2020).
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Appl. Opt. (1)

Biomed. Opt. Express (2)

Curr. Opin. Neurobiol. (1)

A. D. Mehta, J. C. Jung, B. A. Flusberg, and M. J. Schnitzer, Curr. Opin. Neurobiol. 14, 617 (2004).
[Crossref]

Int. J. Retin. Vitr. (1)

R. S. Ajlan, A. A. Desai, and M. A. Mainster, Int. J. Retin. Vitr. 5, 15 (2019).
[Crossref]

J. Biomed. Opt. (5)

A. Klimas and E. Entcheva, J. Biomed. Opt. 19, 080701 (2014).
[Crossref]

J. Mertz and J. Kim, J. Biomed. Opt. 15, 016027 (2010).
[Crossref]

S. Santos, K. K. Chu, D. Lim, N. Bozinovic, T. N. Ford, C. Hourtoule, A. C. Bartoo, S. K. Singh, and J. Mertz, J. Biomed. Opt. 14, 030502 (2009).
[Crossref]

T. N. Ford, D. Lim, and J. Mertz, J. Biomed. Opt. 17, 021105 (2012).
[Crossref]

M. Pedrazzani, V. Loriette, P. Tchenio, S. Benrezzak, D. Nutarelli, and A. Fragola, J. Biomed. Opt. 21, 036006 (2016).
[Crossref]

Nat. Commun. (1)

C. He, J. Chang, Q. Hu, J. Wang, J. Antonello, H. He, S. Liu, J. Lin, B. Dai, D. S. Elson, P. Xi, H. Ma, and M. J. Booth, Nat. Commun. 10, 4264 (2019).
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Nat. Methods (4)

R. P. J. Barretto, B. Messerschmidt, and M. J. Schnitzer, Nat. Methods 6, 511 (2009).
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N. Ji, Nat. Methods 14, 374 (2017).
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D. H. Kim, J. Kim, J. C. Marques, A. Grama, D. G. C. Hildebrand, W. Gu, J. M. Li, and D. N. Robson, Nat. Methods 14, 1107 (2017).
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K. K. Ghosh, L. D. Burns, E. D. Cocker, A. Nimmerjahn, Y. Ziv, A. El Gamal, and M. J. Schnitzer, Nat. Methods 8, 871 (2011).
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Nat. Neurosci. (1)

N. Ji, J. Freeman, and S. L. Smith, Nat. Neurosci. 19, 1154 (2016).
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Opt. Express (1)

Opt. Lett. (6)

PLoS One (1)

F. Bortoletto, C. Bonoli, P. Panizzolo, C. D. Ciubotaru, and F. Mammano, PLoS One 6, e22321 (2011).
[Crossref]

Proc. Natl. Acad. Sci. USA (2)

P. Keahey, P. Ramalingam, K. Schmeler, and R. R. Richards-Kortum, Proc. Natl. Acad. Sci. USA 113, 10769 (2016).
[Crossref]

R. Turcotte, Y. Liang, M. Tanimoto, Q. Zhang, Z. Li, M. Koyama, E. Betzig, and N. Ji, Proc. Natl. Acad. Sci. USA 116, 9586 (2019).
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Sci. Adv. (1)

Z. Li, Q. Zhang, S.-W. Chou, Z. Newman, R. Turcotte, R. Natan, Q. Dai, E. Y. Isacoff, and N. Ji, Sci. Adv. 6, eaaz3870 (2020).
[Crossref]

Science (2)

T.-L. Liu, S. Upadhyayula, D. E. Milkie, V. Singh, K. Wang, I. A. Swinburne, K. R. Mosaliganti, Z. M. Collins, T. W. Hiscock, J. Shea, A. Q. Kohrman, T. N. Medwig, D. Dambournet, R. Forster, B. Cunniff, Y. Ruan, H. Yashiro, S. Scholpp, E. M. Meyerowitz, D. Hockemeyer, D. G. Drubin, B. L. Martin, D. Q. Matus, M. Koyama, S. G. Megason, T. Kirchhausen, and E. Betzig, Science 360, eaaq1392 (2018).
[Crossref]

S. Izawa, S. Chowdhury, T. Miyazaki, Y. Mukai, D. Ono, R. Inoue, Y. Ohmura, H. Mizoguchi, K. Kimura, M. Yoshioka, A. Terao, T. S. Kilduff, and A. Yamanaka, Science 365, 1308 (2019).
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Supplementary Material (1)

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Figures (5)

Fig. 1.
Fig. 1. Schematic diagram of the AO HiLo microendoscope. Gray dashed polygon, HiLo GRIN module; red dashed polygon, AO module. Inset 1: grating SI generated by two-beam interference. Inset 2: optical relay of illumination and fluorescence emission by a GRIN lens (1 mm diameter and 0.5 NA). Inset 3: direct wavefront sensing with a Shack–Hartmann (SH) sensor composed of a lenslet array and a camera. Inset 4: aberration correction by a segmented deformable mirror. SLM, spatial light modulator; Di, dichroic mirror; OBJ, air objective of 0.45 NA; DM, deformable mirror; MM, movable mirror switching beam paths between aberration measurement and correction. Beam in blue, 488 nm illumination; beam in green, emitted green fluorescence.
Fig. 2.
Fig. 2. AO is required for high-resolution imaging in both widefield and HiLo microendoscopy. (a)–(d) Maximum intensity projections (MIPs) of 40 µm thick widefield (WF) and HiLo image stacks of 2 µm diameter green fluorescent beads, measured (a) and (c) without and (b) and (d) with AO, respectively. Orange asterisks, aberration measurement/correction sites. Insets: single optical sections. Images normalized individually (0 to maximum signal). Scale bar: 100 µm; insets: 5 µm. (e) Representative corrective wavefronts for FOV center and edge (150 µm from center). (f) Residual wavefront after aberration correction at the edge. $\sigma$, rms of the residual wavefront. (g) Representative widefield lateral and axial images of a 2 µm diameter bead at FOV edge before (“No AO”) and after (“AO”) aberration correction. ${1.5} \times$ gain was applied to “No AO” image for better visualization. Scale bars: 5 µm. (h) and (i) WF and HiLo signal profiles along red dashed line in (d), inset ii. Imaging area: ${{460}}\;{{\unicode{x00B5}{\rm m}}} \times {{460}}\;{{\unicode{x00B5}{\rm m}}}$. HiLo frame rate: 5 Hz.
Fig. 3.
Fig. 3. Aberration correction using measured versus computed corrective wavefronts. (a) MIP of a 20 µm thick HiLo image stack of 2 µm diameter green fluorescent beads, with aberration measurement locations indicated by white and orange asterisks. White asterisks: measurement locations used for computing corrective wavefronts. Scale bar: 100 µm. (b) Measured corrective wavefronts at the edge locations. (c) MIPs of 20 µm thick WF and HiLo image stacks, measured without AO (“No AO”), with computed corrective wavefronts (“Comp. AO”), and with directly measured corrective wavefronts (“Meas. AO”). Images were individually normalized for better visualization (with gains listed). Scale bar: 10 µm. Imaging area: ${{460}}\;{{\unicode{x00B5}{\rm m}}} \times {{460}}\;{{\unicode{x00B5}{\rm m}}}$. HiLo frame rate: 10 Hz.
Fig. 4.
Fig. 4. Widefield and HiLo microendoscopy imaging of a fixed mouse brain slice (Thy1-GFP line M). (a)–(d) MIPs of 80 µm thick WF and HiLo image stacks, measured (a) and (c) without and (b) and (d) with AO, respectively. Scale bar: 100 µm. (e) Zoomed-in views from (a)–(d). Scale bars: 20 µm. (f) Line profiles across neuronal processes in (b) and (d) (orange dashed line a). (g) and (h) WF and HiLo line profiles across two dendrites (orange dashed line b). Imaging area: ${{460}}\;{{\unicode{x00B5}{\rm m}}} \times {{460}}\;{{\unicode{x00B5}{\rm m}}}$. All images were individually normalized. HiLo frame rate: 5 Hz.
Fig. 5.
Fig. 5. In vivo widefield and HiLo microendoscopy imaging of a Thy1-GFP line M mouse brain. (a) and (b) MIPs of 100 µm thick WF and HiLo image stacks before AO. Images were individually normalized. Scale bar: 100 µm; white-box insets: 30 µm; orange-box insets: 5 µm. (c) and (d) WF and HiLo signal profiles across three dendrites (orange dashed line a). (e) WF and HiLo axial profiles of an axonal bouton (orange arrowhead b). Imaging area: ${{515}}\;{{\unicode{x00B5}{\rm m}}} \times {{515}}\;{{\unicode{x00B5}{\rm m}}}$. HiLo frame rate: 5 Hz.

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