In vivo imaging of the diseased nervous system (original) (raw)

• Lichtman, J. W. & Fraser, S. E. The neuronal naturalist: watching neurons in their native habitat. Nature Neurosci. 4 (Suppl.), 1215–1220 (2001). An overview of the conceptual advantages of in vivo imaging studies in the nervous system.
  Article CAS PubMed Google Scholar
• Trachtenberg, J. T. et al. Long-term in vivo imaging of experience-dependent synaptic plasticity in adult cortex. Nature 420, 788–794 (2002).
  Article CAS PubMed Google Scholar
• Grutzendler, J., Kasthuri, N. & Gan, W. B. Long-term dendritic spine stability in the adult cortex. Nature 420, 812–816 (2002).
  Article CAS PubMed Google Scholar
• Davalos, D. et al. ATP mediates rapid microglial response to local brain injury in vivo. Nature Neurosci. 8, 752–758 (2005).
  Article CAS PubMed Google Scholar
• Nimmerjahn, A., Kirchhoff, F. & Helmchen, F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308, 1314–1318 (2005). References 4 and 5 are the first reports to illustrate the remarkable in vivo dynamics of microglia cells in the brain.
  Article CAS PubMed Google Scholar
• Steward, O., Zheng, B. & Tessier-Lavigne, M. False resurrections: distinguishing regenerated from spared axons in the injured central nervous system. J. Comp. Neurol. 459, 1–8 (2003).
  Article PubMed Google Scholar
• Medana, I., Martinic, M. A., Wekerle, H. & Neumann, H. Transection of major histocompatibility complex class I-induced neurites by cytotoxic T lymphocytes. Am. J. Pathol. 159, 809–815 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Merrill, J. E. & Scolding, N. J. Mechanisms of damage to myelin and oligodendrocytes and their relevance to disease. Neuropathol. Appl. Neurobiol. 25, 435–458 (1999).
  Article CAS PubMed Google Scholar
• Griffiths, I. et al. Axonal swellings and degeneration in mice lacking the major proteolipid of myelin. Science 280, 1610–1613 (1998).
  Article CAS PubMed Google Scholar
• Bjartmar, C., Wujek, J. R. & Trapp, B. D. Axonal loss in the pathology of MS: consequences for understanding the progressive phase of the disease. J. Neurol. Sci. 206, 165–171 (2003).
  Article CAS PubMed Google Scholar
• Jensen, M. B., Hegelund, I. V., Lomholt, N. D., Finsen, B. & Owens, T. IFNγ enhances microglial reactions to hippocampal axonal degeneration. J. Neurosci. 20, 3612–3621 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Bacskai, B. J. et al. Imaging of amyloid-ß deposits in brains of living mice permits direct observation of clearance of plaques with immunotherapy. Nature Med. 7, 369–372 (2001). Introduces important tools for in vivo multiphoton studies in animal models of Alzheimer's disease.
  Article CAS PubMed Google Scholar
• Weiss, P. A. Neuronal dynamics and axonal flow: axonal peristalsis. Proc. Natl Acad. Sci. USA 69, 1309–1312 (1972).
  Article CAS PubMed PubMed Central Google Scholar
• Bray, D. Surface movements during the growth of single explanted neurons. Proc. Natl Acad. Sci. USA 65, 905–910 (1970).
  Article CAS PubMed PubMed Central Google Scholar
• Lichtman, J. W. & Conchello, J. A. Fluorescence microscopy. Nature Methods 2, 910–919 (2005).
  Article CAS PubMed Google Scholar
• Denk, W., Strickler, J. H. & Webb, W. W. Two-photon laser scanning fluorescence microscopy. Science 248, 73–76 (1990).
  Article CAS PubMed Google Scholar
• Zipfel, W. R., Williams, R. M. & Webb, W. W. Nonlinear magic: multiphoton microscopy in the biosciences. Nature Biotechnol. 21, 1369–1377 (2003).
  Article CAS Google Scholar
• Helmchen, F. & Denk, W. Deep tissue two-photon microscopy. Nature Methods 2, 932–940 (2005).
  Article CAS PubMed Google Scholar
• Theer, P., Hasan, M. T. & Denk, W. Two-photon imaging to a depth of 1000 μm in living brains by use of a Ti:Al2O3 regenerative amplifier. Opt. Lett. 28, 1022–1024 (2003).
  Article CAS PubMed Google Scholar
• Mizrahi, A., Crowley, J. C., Shtoyerman, E. & Katz, L. C. High-resolution in vivo imaging of hippocampal dendrites and spines. J. Neurosci. 24, 3147–3151 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Levene, M. J., Dombeck, D. A., Kasischke, K. A., Molloy, R. P. & Webb, W. W. In vivo multiphoton microscopy of deep brain tissue. J. Neurophysiol. 91, 1908–1912 (2004).
  Article PubMed Google Scholar
• Helmchen, F., Fee, M. S., Tank, D. W. & Denk, W. A miniature head-mounted two-photon microscope. High-resolution brain imaging in freely moving animals. Neuron 31, 903–912 (2001). Describes a new approach for in vivo imaging with cellular resolution in awake, behaving rodents.
  Article CAS PubMed Google Scholar
• Flusberg, B. A. et al. Fiber-optic fluorescence imaging. Nature Methods 2, 941–950 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Young, P. & Feng, G. Labeling neurons in vivo for morphological and functional studies. Curr. Opin. Neurobiol. 14, 642–646 (2004).
  Article CAS PubMed Google Scholar
• Feng, G. et al. Imaging neuronal subsets in transgenic mice expressing multiple spectral variants of GFP. Neuron 28, 41–51 (2000). The introduction of Thy1-XFP transgenic mice, which are the basis for most in vivo imaging studies of neurons.
  Article CAS PubMed Google Scholar
• Portera-Cailliau, C., Weimer, R. M., De Paola, V., Caroni, P. & Svoboda, K. Diverse modes of axon elaboration in the developing neocortex. PLoS Biol. 3, e272 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Lee, W. C. et al. Dynamic remodeling of dendritic arbors in GABAergic interneurons of adult visual cortex. PLoS Biol. 4, e29 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Keller-Peck, C. R. et al. Asynchronous synapse elimination in neonatal motor units: studies using GFP transgenic mice. Neuron 31, 381–394 (2001).
  Article CAS PubMed Google Scholar
• Bareyre, F. M., Kerschensteiner, M., Misgeld, T. & Sanes, J. R. Transgenic labeling of the corticospinal tract for monitoring axonal responses to spinal cord injury. Nature Med. 11, 1355–1360 (2005).
  Article CAS PubMed Google Scholar
• Vives, V., Alonso, G., Solal, A. C., Joubert, D. & Legraverend, C. Visualization of S100B-positive neurons and glia in the central nervous system of EGFP transgenic mice. J. Comp. Neurol. 457, 404–419 (2003).
  Article CAS PubMed Google Scholar
• Zuo, Y. et al. Fluorescent proteins expressed in mouse transgenic lines mark subsets of glia, neurons, macrophages, and dendritic cells for vital examination. J. Neurosci. 24, 10999–11009 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Zhuo, L. et al. Live astrocytes visualized by green fluorescent protein in transgenic mice. Dev. Biol. 187, 36–42 (1997).
  Article CAS PubMed Google Scholar
• Nolte, C. et al. GFAP promoter-controlled EGFP-expressing transgenic mice: a tool to visualize astrocytes and astrogliosis in living brain tissue. Glia 33, 72–86 (2001).
  Article CAS PubMed Google Scholar
• Hirrlinger, P. G. et al. Expression of reef coral fluorescent proteins in the central nervous system of transgenic mice. Mol. Cell. Neurosci. 30, 291–303 (2005).
  Article CAS PubMed Google Scholar
• Fuss, B. et al. Purification and analysis of _in vivo_-differentiated oligodendrocytes expressing the green fluorescent protein. Dev. Biol. 218, 259–274 (2000).
  Article CAS PubMed Google Scholar
• Jung, S. et al. Analysis of fractalkine receptor CX3CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Mol. Cell. Biol. 20, 4106–4114 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Mempel, T. R., Scimone, M. L., Mora, J. R. & von Andrian, U. H. In vivo imaging of leukocyte trafficking in blood vessels and tissues. Curr. Opin. Immunol. 16, 406–417 (2004).
  Article CAS PubMed Google Scholar
• Dittgen, T. et al. Lentivirus-based genetic manipulations of cortical neurons and their optical and electrophysiological monitoring in vivo. Proc. Natl Acad. Sci. USA 101, 18206–18211 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Flugel, A., Willem, M., Berkowicz, T. & Wekerle, H. Gene transfer into CD4+ T lymphocytes: green fluorescent protein-engineered, encephalitogenic T cells illuminate brain autoimmune responses. Nature Med. 5, 843–847 (1999).
  Article CAS PubMed Google Scholar
• Borrell, V., Yoshimura, Y. & Callaway, E. M. Targeted gene delivery to telencephalic inhibitory neurons by directional in utero electroporation. J. Neurosci. Methods 143, 151–158 (2005).
  Article CAS PubMed Google Scholar
• Haas, K., Sin, W. C., Javaherian, A., Li, Z. & Cline, H. T. Single-cell electroporation for gene transfer in vivo. Neuron 29, 583–591 (2001).
  Article CAS PubMed Google Scholar
• Nimmerjahn, A., Kirchhoff, F., Kerr, J. N. & Helmchen, F. Sulforhodamine 101 as a specific marker of astroglia in the neocortex in vivo. Nature Methods 1, 31–37 (2004).
  Article CAS PubMed Google Scholar
• LaMantia, A. S. & Purves, D. Development of glomerular pattern visualized in the olfactory bulbs of living mice. Nature 341, 646–649 (1989).
  Article CAS PubMed Google Scholar
• Williams, P. L. & Hall, S. M. In vivo observations on mature myelinated nerve fibres of the mouse. J. Anat. 107, 31–38 (1970).
  CAS PubMed PubMed Central Google Scholar
• Maiti, S., Shear, J. B., Williams, R. M., Zipfel, W. R. & Webb, W. W. Measuring serotonin distribution in live cells with three-photon excitation. Science 275, 530–532 (1997).
  Article CAS PubMed Google Scholar
• Magrassi, L., Purves, D. & Lichtman, J. W. Fluorescent probes that stain living nerve terminals. J. Neurosci. 7, 1207–1214 (1987).
  Article CAS PubMed PubMed Central Google Scholar
• Lichtman, J. W., Wilkinson, R. S. & Rich, M. M. Multiple innervation of tonic endplates revealed by activity-dependent uptake of fluorescent probes. Nature 314, 357–359 (1985).
  Article CAS PubMed Google Scholar
• Cochilla, A. J., Angleson, J. K. & Betz, W. J. Monitoring secretory membrane with FM1–43 fluorescence. Annu. Rev. Neurosci. 22, 1–10 (1999).
  Article CAS PubMed Google Scholar
• De, G. F. et al. Targeting GFP to organelles. Methods Cell Biol. 58, 75–85 (1999).
  Google Scholar
• DePaola, V., Arber, S. & Caroni, P. AMPA receptors regulate dynamic equilibrium of presynaptic terminals in mature hippocampal networks. Nature Neurosci. 6, 491–500 (2003).
  Article CAS Google Scholar
• Umemori, H., Linhoff, M. W., Ornitz, D. M. & Sanes, J. R. FGF22 and its close relatives are presynaptic organizing molecules in the mammalian brain. Cell 118, 257–270 (2004).
  Article CAS PubMed Google Scholar
• Li, Z. et al. Synaptic vesicle recycling studied in transgenic mice expressing synaptopHluorin. Proc. Natl Acad. Sci. USA 102, 6131–6136 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Miesenbock, G. Genetic methods for illuminating the function of neural circuits. Curr. Opin. Neurobiol. 14, 395–402 (2004).
  Article CAS PubMed Google Scholar
• Bonhoeffer, T. & Grinvald, A. The layout of iso-orientation domains in area 18 of cat visual cortex: optical imaging reveals a pinwheel-like organization. J. Neurosci. 13, 4157–4180 (1993).
  Article CAS PubMed PubMed Central Google Scholar
• Sasaki, S. et al. Optical imaging of intrinsic signals induced by peripheral nerve stimulation in the in vivo rat spinal cord. Neuroimage 17, 1240–1255 (2002).
  Article PubMed Google Scholar
• Haglund, M. M., Ojemann, G. A. & Hochman, D. W. Optical imaging of epileptiform and functional activity in human cerebral cortex. Nature 358, 668–671 (1992). This study was one of the first to show that intrinsic optical imaging can be used to generate maps of epileptiform or physiological activity in the human cortex.
  Article CAS PubMed Google Scholar
• Konnerth, A. & Yuste, R. Imaging in Neurosciences and Development — a Laboratory Manual (Cold Spring Harbor Laboratory Press, New York, 2006).
  Google Scholar
• Svoboda, K., Denk, W., Kleinfeld, D. & Tank, D. W. In vivo dendritic calcium dynamics in neocortical pyramidal neurons. Nature 385, 161–165 (1997). Illustrates that multiphoton imaging can be used to follow stimulation-induced calcium dynamics in cortical dendrites in vivo.
  Article CAS PubMed Google Scholar
• Yuste, R. & Katz, L. C. Control of postsynaptic Ca2+ influx in developing neocortex by excitatory and inhibitory neurotransmitters. Neuron 6, 333–344 (1991).
  Article CAS PubMed Google Scholar
• Stosiek, C., Garaschuk, O., Holthoff, K. & Konnerth, A. In vivo two-photon calcium imaging of neuronal networks. Proc. Natl Acad. Sci. USA 100, 7319–7324 (2003). Introduces the 'multicell bolus loading' technique that is used widely to label neurons and glial cells with calcium indicators in vivo.
  Article CAS PubMed PubMed Central Google Scholar
• Ohki, K., Chung, S., Ch'ng, Y. H., Kara, P. & Reid, R. C. Functional imaging with cellular resolution reveals precise micro-architecture in visual cortex. Nature 433, 597–603 (2005).
  Article CAS PubMed Google Scholar
• Adelsberger, H., Garaschuk, O. & Konnerth, A. Cortical calcium waves in resting newborn mice. Nature Neurosci. 8, 988–990 (2005).
  Article CAS PubMed Google Scholar
• Hasan, M. T. et al. Functional fluorescent Ca2+ indicator proteins in transgenic mice under TET control. PLoS Biol. 2, e163 (2004).
  Article PubMed PubMed Central Google Scholar
• Miyawaki, A. Innovations in the imaging of brain functions using fluorescent proteins. Neuron 48, 189–199 (2005).
  Article CAS PubMed Google Scholar
• Dombeck, D. A., Blanchard-Desce, M. & Webb, W. W. Optical recording of action potentials with second-harmonic generation microscopy. J. Neurosci. 24, 999–1003 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Nuriya, M., Jiang, J., Nemet, B., Eisenthal, K. B. & Yuste, R. Imaging membrane potential in dendritic spines. Proc. Natl Acad. Sci. USA 103, 786–790 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Kuhn, B., Fromherz, P. & Denk, W. High sensitivity of Stark-shift voltage-sensing dyes by one- or two-photon excitation near the red spectral edge. Biophys. J. 87, 631–639 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Guerrero, G., Siegel, M. S., Roska, B., Loots, E. & Isacoff, E. Y. Tuning FlaSh: redesign of the dynamics, voltage range, and color of the genetically encoded optical sensor of membrane potential. Biophys. J. 83, 3607–3618 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Hollander, H. & Mehraein, P. On the mechanics of myelin sphere formation in Wallerian degeneration. Intravital microscopic studies of single degenerating motor fibers of the frog. Z. Zellforsch. Mikrosk. Anat. 72, 276–280 (1966).
  Article CAS PubMed Google Scholar
• Williams, P. L. & Hall, S. M. Prolonged in vivo observations of normal peripheral nerve fibres and their acute reactions to crush and deliberate trauma. J. Anat. 108, 397–408 (1971).
  CAS PubMed PubMed Central Google Scholar
• Coleman, M. Axon degeneration mechanisms: commonality amid diversity. Nature Rev. Neurosci. 6, 889–898 (2005).
  Article CAS Google Scholar
• Nguyen, Q. T., Sanes, J. R. & Lichtman, J. W. Pre-existing pathways promote precise projection patterns. Nature Neurosci. 5, 861–867 (2002).
  Article CAS PubMed Google Scholar
• Pan, Y. A., Misgeld, T., Lichtman, J. W. & Sanes, J. R. Effects of neurotoxic and neuroprotective agents on peripheral nerve regeneration assayed by time-lapse imaging in vivo. J. Neurosci. 23, 11479–11488 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Kerschensteiner, M., Schwab, M. E., Lichtman, J. W. & Misgeld, T. In vivo imaging of axonal degeneration and regeneration in the injured spinal cord. Nature Med. 11, 572–577 (2005).
  Article CAS PubMed Google Scholar
• Wang, X. et al. P2X7 receptor inhibition improves recovery after spinal cord injury. Nature Med. 10, 821–827 (2004).
  Article CAS PubMed Google Scholar
• Bhatt, D. H., Otto, S. J., Depoister, B. & Fetcho, J. R. Cyclic AMP-induced repair of zebrafish spinal circuits. Science 305, 254–258 (2004). Shows that in vivo imaging can help to document axonal regeneration and functional reconnection in the CNS of zebrafish.
  Article CAS PubMed Google Scholar
• Qiu, J. et al. Spinal axon regeneration induced by elevation of cyclic AMP. Neuron 34, 895–903 (2002).
  Article CAS PubMed Google Scholar
• Galbraith, J. A. & Terasaki, M. Controlled damage in thick specimens by multiphoton excitation. Mol. Biol. Cell 14, 1808–1817 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Yanik, M. F. et al. Neurosurgery: functional regeneration after laser axotomy. Nature 432, 822 (2004).
  Article CAS PubMed Google Scholar
• Christie, R. H. et al. Growth arrest of individual senile plaques in a model of Alzheimer's disease observed by in vivo multiphoton microscopy. J. Neurosci. 21, 858–864 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• McLellan, M. E., Kajdasz, S. T., Hyman, B. T. & Bacskai, B. J. In vivo imaging of reactive oxygen species specifically associated with thioflavine S-positive amyloid plaques by multiphoton microscopy. J. Neurosci. 23, 2212–2217 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Tsai, J., Grutzendler, J., Duff, K. & Gan, W. B. Fibrillar amyloid deposition leads to local synaptic abnormalities and breakage of neuronal branches. Nature Neurosci. 7, 1181–1183 (2004).
  Article CAS PubMed Google Scholar
• Spires, T. L. et al. Dendritic spine abnormalities in amyloid precursor protein transgenic mice demonstrated by gene transfer and intravital multiphoton microscopy. J. Neurosci. 25, 7278–7287 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Brendza, R. P. et al. Anti-Aβ antibody treatment promotes the rapid recovery of amyloid-associated neuritic dystrophy in PDAPP transgenic mice. J. Clin. Invest. 115, 428–433 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Stern, E. A. et al. Cortical synaptic integration in vivo is disrupted by amyloid-β; plaques. J. Neurosci. 24, 4535–4540 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Schaefer, A. M., Sanes, J. R. & Lichtman, J. W. A compensatory subpopulation of motor neurons in a mouse model of amyotrophic lateral sclerosis. J. Comp. Neurol. 490, 209–219 (2005).
  Article PubMed Google Scholar
• Holzbaur, E. L. Motor neurons rely on motor proteins. Trends Cell Biol. 14, 233–240 (2004).
  Article CAS PubMed Google Scholar
• Yin, X. et al. Dysmyelinated lower motor neurons retract and regenerate dysfunctional synaptic terminals. J. Neurosci. 24, 3890–3898 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Villringer, A., Them, A., Lindauer, U., Einhaupl, K. & Dirnagl, U. Capillary perfusion of the rat brain cortex. An in vivo confocal microscopy study. Circ. Res. 75, 55–62 (1994).
  Article CAS PubMed Google Scholar
• Hudetz, A. G. Blood flow in the cerebral capillary network: a review emphasizing observations with intravital microscopy. Microcirculation 4, 233–252 (1997).
  Article CAS PubMed Google Scholar
• Kleinfeld, D., Mitra, P. P., Helmchen, F. & Denk, W. Fluctuations and stimulus-induced changes in blood flow observed in individual capillaries in layers 2 through 4 of rat neocortex. Proc. Natl Acad. Sci. USA 95, 15741–15746 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Schaffer, C. B. et al. Two-photon imaging of cortical surface microvessels reveals a robust redistribution in blood flow after vascular occlusion. PLoS Biol. 4, e22 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Nishimura, N. et al. Targeted insult to subsurface cortical blood vessels using ultrashort laser pulses: three models of stroke. Nature Methods 3, 99–108 (2006). Together with reference 92, this publication introduces a new multiphoton-based toolkit to study vessel occlusion and ischaemia in the brain.
  Article CAS PubMed Google Scholar
• Zhang, Z. G. et al. A model of mini-embolic stroke offers measurements of the neurovascular unit response in the living mouse. Stroke 36, 2701–2704 (2005).
  Article PubMed Google Scholar
• Zhang, S., Boyd, J., Delaney, K. & Murphy, T. H. Rapid reversible changes in dendritic spine structure in vivo gated by the degree of ischemia. J. Neurosci. 25, 5333–5338 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Iadecola, C. Neurovascular regulation in the normal brain and in Alzheimer's disease. Nature Rev. Neurosci. 5, 347–360 (2004).
  Article CAS Google Scholar
• Takano, T. et al. Astrocyte-mediated control of cerebral blood flow. Nature Neurosci. 9, 260–267 (2006).
  Article CAS PubMed Google Scholar
• Zonta, M. et al. Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation. Nature Neurosci. 6, 43–50 (2003).
  Article CAS PubMed Google Scholar
• Mulligan, S. J. & MacVicar, B. A. Calcium transients in astrocyte endfeet cause cerebrovascular constrictions. Nature 431, 195–199 (2004).
  Article CAS PubMed Google Scholar
• Vajkoczy, P., Laschinger, M. & Engelhardt, B. α4-integrin-VCAM-1 binding mediates G protein-independent capture of encephalitogenic T cell blasts to CNS white matter microvessels. J. Clin. Invest. 108, 557–565 (2001). Introduction of a spinal cord window technique that provides a direct view of the spinal microcirculation, and that is used to study the molecular interactions underlying transmigration of encephalitogenic T cells.
  Article CAS PubMed PubMed Central Google Scholar
• Piccio, L. et al. Molecular mechanisms involved in lymphocyte recruitment in inflamed brain microvessels: critical roles for P-selectin glycoprotein ligand-1 and heterotrimeric Gi-linked receptors. J. Immunol. 168, 1940–1949 (2002).
  Article CAS PubMed Google Scholar
• dos Santos, A. C. et al. CCL2 and CCL5 mediate leukocyte adhesion in experimental autoimmune encephalomyelitis – an intravital microscopy study. J. Neuroimmunol. 162, 122–129 (2005).
  Article CAS PubMed Google Scholar
• Miller, D. H. et al. A controlled trial of natalizumab for relapsing multiple sclerosis. N. Engl. J. Med. 348, 15–23 (2003).
  Article CAS PubMed Google Scholar
• Lapointe, B. M., Herx, L. M., Gill, V., Metz, L. M. & Kubes, P. IVIg therapy in brain inflammation: etiology-dependent differential effects on leucocyte recruitment. Brain 127, 2649–2656 (2004).
  Article PubMed Google Scholar
• Nitsch, R. et al. Direct impact of T cells on neurons revealed by two-photon microscopy in living brain tissue. J. Neurosci. 24, 2458–2464 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Kawakami, N. et al. Live imaging of effector cell trafficking and autoantigen recognition within the unfolding autoimmune encephalomyelitis lesion. J. Exp. Med. 201, 1805–1814 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Rich, M. M., Colman, H. & Lichtman, J. W. In vivo imaging shows loss of synaptic sites from neuromuscular junctions in a model of myasthenia gravis. Neurology 44, 2138–2145 (1994).
  Article CAS PubMed Google Scholar
• Schwartz, T. H. & Bonhoeffer, T. In vivo optical mapping of epileptic foci and surround inhibition in ferret cerebral cortex. Nature Med. 7, 1063–1067 (2001).
  Article CAS PubMed Google Scholar
• Badea, T., Goldberg, J., Mao, B. & Yuste, R. Calcium imaging of epileptiform events with single-cell resolution. J. Neurobiol. 48, 215–227 (2001).
  Article CAS PubMed Google Scholar
• Kerr, J. N., Greenberg, D. & Helmchen, F. Imaging input and output of neocortical networks in vivo. Proc. Natl Acad. Sci. USA 102, 14063–14068 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Tian, G. F. et al. An astrocytic basis of epilepsy. Nature Med. 11, 973–981 (2005). Uses in vivo calcium imaging to reveal a potential role of astrocytic calcium signalling in epileptiform neuronal activity, and shows that antiepileptic drugs influence astrocytic calcium spikes.
  Article CAS PubMed Google Scholar
• Rensing, N. et al. In vivo imaging of dendritic spines during electrographic seizures. Ann. Neurol. 58, 888–898 (2005).
  Article PubMed Google Scholar
• Hirase, H., Creso, J. & Buzsaki, G. Capillary level imaging of local cerebral blood flow in bicuculline-induced epileptic foci. Neuroscience 128, 209–216 (2004).
  Article CAS PubMed Google Scholar
• Sullivan, M. R., Nimmerjahn, A., Sarkisov, D. V., Helmchen, F. & Wang, S. S. In vivo calcium imaging of circuit activity in cerebellar cortex. J. Neurophysiol. 94, 1636–1644 (2005).
  Article CAS PubMed Google Scholar
• Nimchinsky, E. A., Oberlander, A. M. & Svoboda, K. Abnormal development of dendritic spines in FMR1 knock-out mice. J. Neurosci. 21, 5139–5146 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Seehafer, S. S. & Pearce, D. A. You say lipofuscin, we say ceroid: defining autofluorescent storage material. Neurobiol. Aging 27, 576–588 (2006).
  Article CAS PubMed Google Scholar
• Ouardouz, M. et al. Depolarization-induced Ca2+ release in ischemic spinal cord white matter involves L-type Ca2+ channel activation of ryanodine receptors. Neuron 40, 53–63 (2003).
  Article CAS PubMed Google Scholar
• Micu, I. et al. NMDA receptors mediate calcium accumulation in myelin during chemical ischaemia. Nature 439, 988–992 (2006).
  Article CAS PubMed Google Scholar
• Laxman, B. et al. Noninvasive real-time imaging of apoptosis. Proc. Natl Acad. Sci. USA 99, 16551–16555 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Kadurugamuwa, J. L. et al. Reduction of astrogliosis by early treatment of pneumococcal meningitis measured by simultaneous imaging, in vivo, of the pathogen and host response. Infect. Immun. 73, 7836–7843 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Lin, A. H. et al. Global analysis of Smad2/3-dependent TGF-β signaling in living mice reveals prominent tissue-specific responses to injury. J. Immunol. 175, 547–554 (2005).
  Article CAS PubMed Google Scholar
• Bremer, C., Tung, C. H. & Weissleder, R. In vivo molecular target assessment of matrix metalloproteinase inhibition. Nature Med. 7, 743–748 (2001).
  Article CAS PubMed Google Scholar
• Lindsten, K., Menendez-Benito, V., Masucci, M. G. & Dantuma, N. P. A transgenic mouse model of the ubiquitin/proteasome system. Nature Biotechnol. 21, 897–902 (2003).
  Article CAS Google Scholar
• Ntziachristos, V., Ripoll, J., Wang, L. V. & Weissleder, R. Looking and listening to light: the evolution of whole-body photonic imaging. Nature Biotechnol. 23, 313–320 (2005). A comprehensive introduction to biophotonic imaging techniques and their current capabilities and limitations.
  Article CAS Google Scholar
• Michalet, X. et al. Quantum dots for live cells, in vivo imaging, and diagnostics. Science 307, 538–544 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• So, M. K., Xu, C., Loening, A. M., Gambhir, S. S. & Rao, J. Self-illuminating quantum dot conjugates for in vivo imaging. Nature Biotechnol. 24, 339–343 (2006).
  Article CAS Google Scholar
• Zipfel, W. R. et al. Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation. Proc. Natl Acad. Sci. USA 100, 7075–7080 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Kasischke, K. A., Vishwasrao, H. D., Fisher, P. J., Zipfel, W. R. & Webb, W. W. Neural activity triggers neuronal oxidative metabolism followed by astrocytic glycolysis. Science 305, 99–103 (2004).
  Article CAS PubMed Google Scholar
• Campagnola, P. J. & Loew, L. M. Second-harmonic imaging microscopy for visualizing biomolecular arrays in cells, tissues and organisms. Nature Biotechnol. 21, 1356–1360 (2003).
  Article CAS Google Scholar
• Wallrabe, H. & Periasamy, A. Imaging protein molecules using FRET and FLIM microscopy. Curr. Opin. Biotechnol. 16, 19–27 (2005).
  Article CAS PubMed Google Scholar
• Stockholm, D. et al. Imaging calpain protease activity by multiphoton FRET in living mice. J. Mol. Biol. 346, 215–222 (2005). An example of multiphoton FRET imaging in living mice to visualize the kinetics of calpain activation in muscle on the basis of a genetic sensor.
  Article CAS PubMed Google Scholar
• Yasuda, R. et al. Supersensitive Ras activation in dendrites and spines revealed by two-photon fluorescence lifetime imaging. Nature Neurosci. 9, 283–291 (2006).
  Article CAS PubMed Google Scholar
• Masters, B. R. & Bohnke, M. Three-dimensional confocal microscopy of the living human eye. Annu. Rev. Biomed. Eng. 4, 69–91 (2002).
  Article CAS PubMed Google Scholar
• Cordeiro, M. F. et al. Real-time imaging of single nerve cell apoptosis in retinal neurodegeneration. Proc. Natl Acad. Sci. USA 101, 13352–13356 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Paques, M. et al. High resolution fundus imaging by confocal scanning laser ophthalmoscopy in the mouse. Vision Res. 46, 1336–1345 (2006).
  Article PubMed Google Scholar
• Imanishi, Y., Batten, M. L., Piston, D. W., Baehr, W. & Palczewski, K. Noninvasive two-photon imaging reveals retinyl ester storage structures in the eye. J. Cell Biol. 164, 373–383 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Drexler, W. et al. Ultrahigh-resolution ophthalmic optical coherence tomography. Nature Med. 7, 502–507 (2001).
  Article CAS PubMed Google Scholar
• Zhang, J. et al. Mapping postnatal mouse brain development with diffusion tensor microimaging. Neuroimage 26, 1042–1051 (2005).
  Article PubMed Google Scholar
• Sundgren, P. C. et al. Diffusion tensor imaging of the brain: review of clinical applications. Neuroradiology 46, 339–350 (2004).
  Article CAS PubMed Google Scholar
• Pautler, R. G., Mongeau, R. & Jacobs, R. E. In vivo trans-synaptic tract tracing from the murine striatum and amygdala utilizing manganese enhanced MRI (MEMRI). Magn. Reson. Med. 50, 33–39 (2003).
  Article PubMed Google Scholar
• Caramanos, Z., Narayanan, S. & Arnold, D. L. 1H-MRS quantification of tNA and tCr in patients with multiple sclerosis: a meta-analytic review. Brain 128, 2483–2506 (2005).
  Article PubMed Google Scholar
• Natt, O. et al. High-resolution 3D MRI of mouse brain reveals small cerebral structures in vivo. J. Neurosci. Methods 120, 203–209 (2002).
  Article CAS PubMed Google Scholar
• Wang, Y., Zhang, J., Mori, S. & Nathans, J. Axonal growth and guidance defects in Frizzled3 knock-out mice: a comparison of diffusion tensor magnetic resonance imaging, neurofilament staining, and genetically directed cell labeling. J. Neurosci. 26, 355–364 (2006). An interesting comparison of non-optical and optical techniques that illustrates the recent advances of diffusion tensor imaging of axonal tracts and shows how such non-optical approaches could converge with light microscopic techniques.
  Article CAS PubMed PubMed Central Google Scholar
• Bilgen, M. et al. Electrical stimulation of cortex improves corticospinal tract tracing in rat spinal cord using manganese-enhanced MRI. J. Neurosci. Methods 9 Mar 2006 (doi:10.1016/j.jneumeth.2006.02.001).
• Bendszus, M. et al. Assessment of nerve degeneration by gadofluorine M-enhanced magnetic resonance imaging. Ann. Neurol. 57, 388–395 (2005).
  Article PubMed Google Scholar
• Jack, C. R. Jr et al. In vivo magnetic resonance microimaging of individual amyloid plaques in Alzheimer's transgenic mice. J. Neurosci. 25, 10041–10048 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Pautler, R. G. & Fraser, S. E. The year(s) of the contrast agent — micro-MRI in the new millennium. Curr. Opin. Immunol. 15, 385–392 (2003).
  Article CAS PubMed Google Scholar
• Jasanoff, A. Functional MRI using molecular imaging agents. Trends Neurosci. 28, 120–126 (2005).
  Article CAS PubMed Google Scholar
• Bendszus, M. & Stoll, G. Caught in the act: in vivo mapping of macrophage infiltration in nerve injury by magnetic resonance imaging. J. Neurosci. 23, 10892–10896 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Anderson, S. A. et al. Magnetic resonance imaging of labeled T-cells in a mouse model of multiple sclerosis. Ann. Neurol. 55, 654–659 (2004).
  Article PubMed Google Scholar
• Modo, M. et al. Tracking transplanted stem cell migration using bifunctional, contrast agent-enhanced, magnetic resonance imaging. Neuroimage 17, 803–811 (2002).
  Article PubMed Google Scholar
• Zhao, M., Beauregard, D. A., Loizou, L., Davletov, B. & Brindle, K. M. Non-invasive detection of apoptosis using magnetic resonance imaging and a targeted contrast agent. Nature Med. 7, 1241–1244 (2001).
  Article CAS PubMed Google Scholar
• Klunk, W. E. et al. Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B. Ann. Neurol. 55, 306–319 (2004).
  Article CAS PubMed Google Scholar
• Tsien, R. Y. Imagining imaging's future. Nature Rev. Mol. Cell Biol. (Suppl.), SS16–SS21 (2003).
• Weissleder, R. et al. In vivo magnetic resonance imaging of transgene expression. Nature Med. 6, 351–355 (2000).
  Article CAS PubMed Google Scholar
• Higuchi, M. et al. 19F and 1H MRI detection of amyloid-β plaques in vivo. Nature Neurosci. 8, 527–533 (2005).
  Article CAS PubMed Google Scholar
• Oweida, A. J., Dunn, E. A. & Foster, P. J. Cellular imaging at 1.5 T: detecting cells in neuroinflammation using active labeling with superparamagnetic iron oxide. Mol. Imaging 3, 85–95 (2004).
  Article PubMed Google Scholar
• Stettler, D. D., Yamahachi, H., Li, W., Denk, W. & Gilbert, C. D. Axons and synaptic boutons are highly dynamic in adult visual cortex. Neuron 49, 877–887 (2006).
  Article CAS PubMed Google Scholar
• Hell, S. W. Toward fluorescence nanoscopy. Nature Biotechnol. 21, 1347–1355 (2003).
  Article CAS Google Scholar
• Hell, S. W., Dyba, M. & Jakobs, S. Concepts for nanoscale resolution in fluorescence microscopy. Curr. Opin. Neurobiol. 14, 599–609 (2004). References 159 and 160 provide a stimulating introduction to recent technological developments towards fluorescence imaging beyond the diffraction limit.
  Article CAS PubMed Google Scholar
• Kleinfeld, D. & Griesbeck, O. From art to engineering? The rise of in vivo mammalian electrophysiology via genetically targeted labeling and nonlinear imaging. PLoS Biol. 3, e355 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Nguyen, Q. T., Callamaras, N., Hsieh, C. & Parker, I. Construction of a two-photon microscope for video-rate Ca2+ imaging. Cell Calcium 30, 383–393 (2001).
  Article CAS PubMed Google Scholar
• Majewska, A., Yiu, G. & Yuste, R. A custom-made two-photon microscope and deconvolution system. Pflugers Arch. 441, 398–408 (2000).
  Article CAS PubMed Google Scholar
• Tsai, P. S. et al. All-optical histology using ultrashort laser pulses. Neuron 39, 27–41 (2003).
  Article CAS PubMed Google Scholar
• Lichtman, J. W., Magrassi, L. & Purves, D. Visualization of neuromuscular junctions over periods of several months in living mice. J. Neurosci. 7, 1215–1222 (1987).
  Article CAS PubMed PubMed Central Google Scholar
• Sawamoto, K. et al. Visualization, direct isolation, and transplantation of midbrain dopaminergic neurons. Proc. Natl Acad. Sci. USA 98, 6423–6428 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Gong, S. et al. A gene expression atlas of the central nervous system based on bacterial artificial chromosomes. Nature 425, 917–925 (2003).
  Article CAS PubMed Google Scholar
• Tanaka, D., Nakaya, Y., Yanagawa, Y., Obata, K. & Murakami, F. Multimodal tangential migration of neocortical GABAergic neurons independent of GPI-anchored proteins. Development 130, 5803–5813 (2003).
  Article CAS PubMed Google Scholar
• Araki, R. et al. Transgenic mouse lines expressing synaptopHluorin in hippocampus and cerebellar cortex. Genesis 42, 53–60 (2005).
  Article CAS PubMed Google Scholar
• Duebel, J. et al. Two-photon imaging reveals somatodendritic chloride gradient in retinal ON-type bipolar cells expressing the biosensor Clomeleon. Neuron 49, 81–94 (2006).
  Article CAS PubMed Google Scholar
• Mallon, B. S., Shick, H. E., Kidd, G. J. & Macklin, W. B. Proteolipid promoter activity distinguishes two populations of NG2-positive cells throughout neonatal cortical development. J. Neurosci. 22, 876–885 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Motoike, T. et al. Universal GFP reporter for the study of vascular development. Genesis 28, 75–81 (2000).
  Article CAS PubMed Google Scholar