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      Time-lapse imaging of disease progression in deep brain areas using fluorescence microendoscopy

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          Abstract

          The combination of intravital microscopy and animal models of disease has propelled studies of disease mechanisms and treatments. However, many disorders afflict tissues inaccessible to light microscopy in live subjects. Here we introduce cellular-level time-lapse imaging deep within the live mammalian brain by one- and two-photon fluorescence microendoscopy over multiple weeks. Bilateral imaging sites allowed longitudinal comparisons within individual subjects, including of normal and diseased tissues. Using this approach we tracked CA1 hippocampal pyramidal neuron dendrites in adult mice, revealing these dendrites' extreme stability (>8,000 day mean lifetime) and rare examples of their structural alterations. To illustrate disease studies, we tracked deep lying gliomas by observing tumor growth, visualizing three-dimensional vasculature structure, and determining microcirculatory speeds. Average erythrocyte speeds in gliomas declined markedly as the disease advanced, notwithstanding significant increases in capillary diameters. Time-lapse microendoscopy will be applicable to studies of numerous disorders, including neurovascular, neurological, cancerous, and trauma-induced conditions.

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          Angiogenesis in brain tumours.

          Despite aggressive surgery, radiotherapy and chemotherapy, malignant gliomas remain uniformly fatal. To progress, these tumours stimulate the formation of new blood vessels through processes driven primarily by vascular endothelial growth factor (VEGF). However, the resulting vessels are structurally and functionally abnormal, and contribute to a hostile microenvironment (low oxygen tension and high interstitial fluid pressure) that selects for a more malignant phenotype with increased morbidity and mortality. Emerging preclinical and clinical data indicate that anti-VEGF therapies are potentially effective in glioblastoma--the most frequent primary brain tumour--and can transiently normalize tumour vessels. This creates a window of opportunity for optimally combining chemotherapeutics and radiation.
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            Deep tissue two-photon microscopy.

            With few exceptions biological tissues strongly scatter light, making high-resolution deep imaging impossible for traditional-including confocal-fluorescence microscopy. Nonlinear optical microscopy, in particular two photon-excited fluorescence microscopy, has overcome this limitation, providing large depth penetration mainly because even multiply scattered signal photons can be assigned to their origin as the result of localized nonlinear signal generation. Two-photon microscopy thus allows cellular imaging several hundred microns deep in various organs of living animals. Here we review fundamental concepts of nonlinear microscopy and discuss conditions relevant for achieving large imaging depths in intact tissue.
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              Imaging Neuronal Subsets in Transgenic Mice Expressing Multiple Spectral Variants of GFP

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                Author and article information

                Journal
                9502015
                8791
                Nat Med
                Nat. Med.
                Nature medicine
                1078-8956
                1546-170X
                12 September 2013
                16 January 2011
                February 2011
                19 November 2013
                : 17
                : 2
                : 10.1038/nm.2292
                Affiliations
                [1 ]James H. Clark Center for Biomedical Engineering & Sciences, Stanford University, Stanford CA 94305
                [2 ]Departments of Neurological Sciences and Neurosurgery, Stanford University, Stanford CA 94305
                [3 ]Howard Hughes Medical Institute, Stanford University, Stanford CA 94305
                Author notes
                Correspondence should be sent to M.J.S. ( mschnitz@ 123456stanford.edu )
                [*]

                These authors contributed equally.

                Article
                NIHMS243659
                10.1038/nm.2292
                3833825
                21240263
                28cb04ba-865f-4d8a-aef4-81734f498eca

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                History
                Funding
                Funded by: National Institute on Drug Abuse : NIDA
                Award ID: R21 DA017895 || DA
                Funded by: National Institute of Neurological Disorders and Stroke : NINDS
                Award ID: R01 NS050533 || NS
                Funded by: National Cancer Institute : NCI
                Award ID: P50 CA114747 || CA
                Categories
                Article

                Medicine
                Medicine

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