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35878Baee661421e9c01779292 Volume 9, Number 2; 262-272, April 2018 http://dx.doi.org/10.14336/AD.2017.0613 Original Article CLARITY for High-resolution Imaging and Quantification of Vasculature in the Whole Mouse Brain Lin-Yuan Zhang1,#, Pan Lin2,#, Jiaji Pan3,#, Yuanyuan Ma1, Zhenyu Wei4, Lu Jiang3, Liping Wang1, Yaying Song1, Yongting Wang3, Zhijun Zhang3, Kunlin Jin5, Qian Wang2,*, Guo-Yuan Yang1, 3,* 1Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China 2Medical Image Computing Lab and 3Neuroscience and Neuroengineering Research Center, Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China 4Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201999, China 5Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, TX76107, USA [Received May 3, 2017; Revised June 10, 2017; Accepted June 13, 2017] ABSTRACT: Elucidating the normal structure and distribution of cerebral vascular system is fundamental for understanding its function. However, studies on visualization and whole-brain quantification of vasculature with cellular resolution are limited. Here, we explored the structure of vasculature at the whole-brain level using the newly developed CLARITY technique. Adult male C57BL/6J mice undergoing transient middle cerebral artery occlusion and Tie2-RFP transgenic mice were used. Whole mouse brains were extracted for CLARITY processing. Immunostaining was performed to label vessels. Customized MATLAB code was used for image processing and quantification. Three-dimensional images were visualized using the Vaa3D software. Our results showed that whole mouse brain became transparent using the CLARITY method. Three- dimensional imaging and visualization of vasculature were achieved at the whole-brain level with a 1-μm voxel resolution. The quantitative results showed that the fractional vascular volume was 0.018 ± 0.004 mm3 per mm3, the normalized vascular length was 0.44 ± 0.04 m per mm3, and the mean diameter of the microvessels was 4.25 ± 0.08 μm. Furthermore, a decrease in the fractional vascular volume and a decrease in the normalized vascular length were found in the penumbra of ischemic mice compared to controls (p < 0.05). In conclusion, CLARITY provides a novel approach for mapping vasculature in the whole mouse brain at cellular resolution. CLARITY- optimized algorithms facilitate the assessment of structural change in vasculature after brain injury. Key words: brain, clarity, imaging process, mouse, vasculature Cerebral blood vessels are channels for supplying oxygen, functional domain termed the neurovascular unit [5]. glucose and other nutrients to and removing wastes from Cerebral vascular density is closely related to neurological the brain tissue. Numerous studies have demonstrated that functional recovery after ischemic stroke [6]. Therefore, the cerebral vasculature is an extremely important part for elucidating the spatial structure and distribution of the the brain survival and function [1-3]. Our previous study cerebral vasculature is a basis for understanding brain showed that alterations in vascular structure and function. However, studies on visualization and distribution were associated with cerebral hemodynamic quantification of the vasculature in the whole mouse brain changes in rats following ischemic stroke [4]. at a cellular resolution are limited. Furthermore, recent studies unveiled an intimate Conventional methods for evaluating tissue structure structural and functional relationship between brain rely on histological sections and immunohistochemistry vasculature and other brain cells, with the formation of a techniques. The brain sections are typically less than 50 *Correspondence should be addressed to: Drs. Guo-Yuan Yang and Qian Wang, Ruijin Hospital, Med-X Research Institute, Shanghai Jiao Tong University, China. E-mail: [email protected]; [email protected]. #The authors contributed equally to this work. Copyright: © 2017. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ISSN: 2152-5250 262 Zhang L. et al CLARITY for mapping brain vasculature μm in thickness to allow for antibody penetration. The from cerebral vascular system. In addition, we validated thin sections also facilitate cellular and molecular CLARITY in the evaluations of vascular aberration in an observation by reducing light scattering. However, this ischemic mouse model. could induce potential bias in quantification and interpretation due to insufficient spatial sampling [7]. To MATERIALS AND METHODS obtain unbiased information from whole-brain, new approaches have been proposed for whole brain imaging Experimental animals at high resolutions. One approach was a combination of block-face microscopy and tissue sectioning, and The animal experimental procedure was approved by the included two-photon tissue cytometry [8], serial two- Institutional Animal Care and Use Committee (IACUC) photon (STP) tomography [9], knife-edge scanning of Shanghai Jiao Tong University, Shanghai, China. We microscopy (KESM) [10], and micro-optical sectioning performed animal experiments in accordance with the tomography (MOST) [11]. The MOST technique could guidelines of The Laboratory Animal Resource Center, visualize and quantify cells and blood vessels in the whole Shanghai Jiao Tong University. Ten-week-old male wild mouse brain at 1-μm voxel resolution [12]. The MOST type C57BL/6J mice (Sippr-BK, Shanghai, China) and technique has been used to analyze the vascular B6.Cg-Tg (Tie2-RFP)1Ywa/J mice (Jackson Laboratory, distribution in the mouse barrel cortex [13]. However, the Bar Harbor, ME, USA) weighting 25-30 grams were used procedure was time-consuming, requiring approximately in this study. Tie2-RFP transgenic mice express uniform 19 days accomplishing simultaneously sectioning and red fluorescence in endothelial cells. imaging of one mouse brain [11-14]. Conversely, optical clearing approaches enable whole Transient middle cerebral artery occlusion mouse brain imaging at a cellular resolution by using microscopy without mechanical sectioning. Tissue Adult male wild-type C57BL/6J mice were used for the clearing was achieved by matching the refractive index of transient middle cerebral artery occlusion (tMCAO) the tissue to the clearing reagent. The clearing reagents surgery. The process was described previously [29]. included ScaleA2 [15], ClearT2 [16], 3DISCO [7, 17, 18], Briefly, the mice were anesthetized with ketamine/ SeeDB [19, 20], CUBIC [21-23], and iDISCO [24]. xylazine (100 mg/10 mg/kg, Sigma, St. Louis, MO). 3DISCO was applied to visualize and quantify axonal During the surgery, the body temperature was maintained regeneration and glial reaction after acute spinal cord at 37 ± 0.5 °C using a heating pad (RWD life science, injury in an unsectioned spinal cord from an adult mouse Shenzhen, China). The left common carotid artery, [7]. However, the drawback of these methods was the external carotid artery, and internal carotid artery were limited depth of exogenous antibody penetration into the isolated after midline inclusion. A nylon suture with a 6- brain. To overcome challenge, a new clearing technique 0 silicone-coated tip (Covidien, Mansfield, MA, USA) termed CLARITY was developed. The technique was gently inserted from the external carotid artery to the transformed the entire tissue into a hydrogel-hybridized internal carotid artery ending at the opening of the MCA form to preserve the tissue architecture, protein and to induce brain ischemia. Ninety minutes later, the suture nuclear acid molecules, and endogenous fluorescence was withdrawn to allow reperfusion. Surface cerebral [25-27]. CLARITY not only made the brain tissues blood flow (CBF) was monitored with a laser Doppler transparent but also allowed antibody diffusion deep into flowmetry (Moor Instruments, Axminster, Devon, UK). the brain parenchyma by removing lipid bilayers during The suture was withdrawn immediately after insertion in the procedure. Structural and molecular information from the internal carotid artery in the sham mice. Mice were the whole brain was obtained by imaging at a cellular sacrificed 24 hours after reperfusion. resolution. The CLARITY technique has been used to image the whole brain and spinal cord to assess axonal CLARITY pathology in a mouse experimental autoimmune encephalomyelitis model [28]. However, CLARITY All mouse brain clearing procedures were performed technique has not been used to visualize the entire brain according to the optimized CLARITY protocol [30]. In vasculature. Furthermore, computational processing brief, animals were deeply anesthetized with an compatible for CLARITY imaging of vasculature should intraperitoneal injection of ketamine/xylazine (100 mg/10 be optimized to analyze the 3-dimensional vasculature mg/kg, Sigma-Aldrich, St. Louis, MO) and perfused structure of the mouse brain. transcardially with ice-cold 0.1 M phosphate buffer saline In the present study, we mapped the vascular network (PBS) and then 4% paraformaldehyde. Subsequently, at the whole-brain level with cellular resolution using the each mouse brain was rapidly extracted. The brain tissue CLARITY technique and extracted spatial information was incubated in ice cold hydrogel solution (4% Aging
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