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Lessons from In Vivo Imaging

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Microglia in Health and Disease

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Abstract

The first line of defense against injury or disease in the central nervous system (CNS) is through microglia. In the adult brain, microglia were long believed to stay in a dormant/resting state, activated only in the event of an insult to the brain. This view changed dramatically with the development of modern imaging techniques that allowed the study of microglial behavior in the intact brain over time to reveal the dynamic nature of their responses. In vivo imaging studies using two-photon microscopy revealed a previously unknown function for microglia: they continuously screen the intact brain parenchyma with their fine processes on a timescale of minutes. By doing so, they contact neuronal cell bodies, axons, dendrites, and dendritic spines and are believed to play a central role in sculpting neuronal networks during development, adulthood, and the normal aging process. Following acute trauma, or in neurodegenerative or neuroinflammatory diseases, microglial responses range from protective to harmful, underscoring the need to better understand their diverse roles in different pathological conditions. In this chapter we will introduce two-photon microscopy and compare the in vivo and in vitro imaging approaches for studying microglia. We will also discuss relevant mouse models available for in vivo imaging studies of microglia and review how such studies are constantly reshaping our understanding of the multifaceted role of microglia in the healthy and diseased CNS.

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References

  • Aguzzi A, Barres BA, Bennett ML (2013) Microglia: scapegoat, saboteur, or something else? Science 339:156–161

    PubMed  CAS  Google Scholar 

  • Aloisi F (2001) Immune function of microglia. Glia 36:165–179

    PubMed  CAS  Google Scholar 

  • Barretto RP, Ko TH, Jung JC, Wang TJ, Capps G, Waters AC et al (2011) Time-lapse imaging of disease progression in deep brain areas using fluorescence microendoscopy. Nat Med 17:223–228

    PubMed  CAS  Google Scholar 

  • Bialas AR, Stevens B (2013) TGF-beta signaling regulates neuronal C1q expression and developmental synaptic refinement. Nat Neurosci 16(12):1773–1782

    PubMed  CAS  PubMed Central  Google Scholar 

  • Bolmont T, Haiss F, Eicke D, Radde R, Mathis CA, Klunk WE et al (2008) Dynamics of the microglial/amyloid interaction indicate a role in plaque maintenance. J Neurosci 28:4283–4292

    PubMed  CAS  PubMed Central  Google Scholar 

  • Booth PL, Thomas WE (1991) Dynamic features of cells expressing macrophage properties in tissue cultures of dissociated cerebral cortex from the rat. Cell Tissue Res 266:541–551

    PubMed  CAS  Google Scholar 

  • Carbonell WS, Murase S, Horwitz AF, Mandell JW (2005) Migration of perilesional microglia after focal brain injury and modulation by CC chemokine receptor 5: an in situ time-lapse confocal imaging study. J Neurosci 25:7040–7047

    PubMed  CAS  Google Scholar 

  • Carson MJ (2002) Microglia as liaisons between the immune and central nervous systems: functional implications for multiple sclerosis. Glia 40:218–231

    PubMed  PubMed Central  Google Scholar 

  • Chan WY, Kohsaka S, Rezaie P (2007) The origin and cell lineage of microglia: new concepts. Brain Res Rev 53:344–354

    PubMed  CAS  Google Scholar 

  • Chen A, Kumar SM, Sahley CL, Muller KJ (2000) Nitric oxide influences injury-induced microglial migration and accumulation in the leech CNS. J Neurosci 20:1036–1043

    PubMed  CAS  Google Scholar 

  • Czapiga M, Colton CA (1999) Function of microglia in organotypic slice cultures. J Neurosci Res 56:644–651

    PubMed  CAS  Google Scholar 

  • Dailey ME, Manders E, Soll D, Terasaki M (2006) Confocal microscopy of live cells. In: Pawley JB (ed) Handbook of biological confocal microscopy, 3rd edn. Plenum, New York

    Google Scholar 

  • Dailey ME, Waite M (1999) Confocal imaging of microglial cell dynamics in hippocampal slice cultures. Methods 18:222–230, 177

    PubMed  CAS  Google Scholar 

  • Damani MR, Zhao L, Fontainhas AM, Amaral J, Fariss RN, Wong WT (2011) Age-related alterations in the dynamic behavior of microglia. Aging Cell 10:263–276

    PubMed  CAS  PubMed Central  Google Scholar 

  • Davalos D, Akassoglou K (2008) Imaging microglia in the central nervous system: past, present and future. In: Lane TE, Carson M, Bergmann C, Wyss-Coray T (eds) Central nervous system diseases and inflammation. Springer, New York, pp 45–57

    Google Scholar 

  • Davalos D, Akassoglou K (2012) In vivo imaging of the mouse spinal cord using two-photon microscopy. J Vis Exp 59:e2760.

    Google Scholar 

  • Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S et al (2005) ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci 8:752–758

    PubMed  CAS  Google Scholar 

  • Davalos D, Lee JK, Smith WB, Brinkman B, Ellisman MH, Zheng B et al (2008) Stable in vivo imaging of densely populated glia, axons and blood vessels in the mouse spinal cord using two-photon microscopy. J Neurosci Methods 169:1–7

    PubMed  PubMed Central  Google Scholar 

  • Davalos D, Ryu JK, Merlini M, Baeten KM, Le Moan N, Petersen MA et al (2012) Fibrinogen-induced perivascular microglial clustering is required for the development of axonal damage in neuroinflammation. Nat Commun 3:1227

    PubMed  PubMed Central  Google Scholar 

  • Davis EJ, Foster TD, Thomas WE (1994) Cellular forms and functions of brain microglia. Brain Res Bull 34:73–78

    PubMed  CAS  Google Scholar 

  • Denk W, Strickler JH, Webb WW (1990) Two-photon laser scanning fluorescence microscopy. Science 248:73–76

    PubMed  CAS  Google Scholar 

  • Dibaj P, Steffens H, Zschuntzsch J, Nadrigny F, Schomburg ED, Kirchhoff F et al (2011) In vivo imaging reveals distinct inflammatory activity of CNS microglia versus PNS macrophages in a mouse model for ALS. PLoS One 6:e17910

    PubMed  CAS  PubMed Central  Google Scholar 

  • Dombeck DA, Khabbaz AN, Collman F, Adelman TL, Tank DW (2007) Imaging large-scale neural activity with cellular resolution in awake, mobile mice. Neuron 56:43–57

    PubMed  CAS  PubMed Central  Google Scholar 

  • Drew PJ, Shih AY, Driscoll JD, Knutsen PM, Blinder P, Davalos D et al (2010) Chronic optical access through a polished and reinforced thinned skull. Nat Methods 7:981–984

    PubMed  CAS  PubMed Central  Google Scholar 

  • Duffield JS, Forbes SJ, Constandinou CM, Clay S, Partolina M, Vuthoori S et al (2005) Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Invest 115:56–65

    PubMed  CAS  PubMed Central  Google Scholar 

  • Duke DC, Moran LB, Turkheimer FE, Banati R, Graeber MB (2004) Microglia in culture: what genes do they express? Dev Neurosci 26:30–37

    PubMed  CAS  Google Scholar 

  • Ebert S, Weigelt K, Walczak Y, Drobnik W, Mauerer R, Hume DA et al (2009) Docosahexaenoic acid attenuates microglial activation and delays early retinal degeneration. J Neurochem 110:1863–1875

    PubMed  CAS  Google Scholar 

  • Erblich B, Zhu L, Etgen AM, Dobrenis K, Pollard JW (2011) Absence of colony stimulation factor-1 receptor results in loss of microglia, disrupted brain development and olfactory deficits. PLoS One 6:e26317

    PubMed  CAS  PubMed Central  Google Scholar 

  • Eter N, Engel DR, Meyer L, Helb HM, Roth F, Maurer J et al (2008) In vivo visualization of dendritic cells, macrophages, and microglial cells responding to laser-induced damage in the fundus of the eye. Invest Ophthalmol Vis Sci 49:3649–3658

    PubMed  Google Scholar 

  • Farrar MJ, Bernstein IM, Schlafer DH, Cleland TA, Fetcho JR, Schaffer CB (2012) Chronic in vivo imaging in the mouse spinal cord using an implanted chamber. Nat Methods 9:297–302

    PubMed  CAS  PubMed Central  Google Scholar 

  • Feng G, Mellor RH, Bernstein M, Keller-Peck C, Nguyen QT, Wallace M et al (2000) Imaging neuronal subsets in transgenic mice expressing multiple spectral variants of GFP. Neuron 28:41–51

    PubMed  CAS  Google Scholar 

  • Flusberg BA, Cocker ED, Piyawattanametha W, Jung JC, Cheung EL, Schnitzer MJ (2005) Fiber-optic fluorescence imaging. Nat Methods 2:941–950

    PubMed  CAS  PubMed Central  Google Scholar 

  • Flusberg BA, Nimmerjahn A, Cocker ED, Mukamel EA, Barretto RP, Ko TH et al (2008) High-speed, miniaturized fluorescence microscopy in freely moving mice. Nat Methods 5:935–938

    PubMed  CAS  PubMed Central  Google Scholar 

  • Fontainhas AM, Wang M, Liang KJ, Chen S, Mettu P, Damani M et al (2011) Microglial morphology and dynamic behavior is regulated by ionotropic glutamatergic and GABAergic neurotransmission. PLoS One 6:e15973

    PubMed  CAS  PubMed Central  Google Scholar 

  • Fuhrmann M, Bittner T, Jung CK, Burgold S, Page RM, Mitteregger G et al (2010) Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer’s disease. Nat Neurosci 13:411–413

    PubMed  CAS  PubMed Central  Google Scholar 

  • Garcia-Alloza M, Ferrara BJ, Dodwell SA, Hickey GA, Hyman BT, Bacskai BJ (2007) A limited role for microglia in antibody mediated plaque clearance in APP mice. Neurobiol Dis 28:286–292

    PubMed  CAS  PubMed Central  Google Scholar 

  • Geissmann F, Manz MG, Jung S, Sieweke MH, Merad M, Ley K (2010) Development of monocytes, macrophages, and dendritic cells. Science 327:656–661

    PubMed  CAS  PubMed Central  Google Scholar 

  • Germain RN, Miller MJ, Dustin ML, Nussenzweig MC (2006) Dynamic imaging of the immune system: progress, pitfalls and promise. Nat Rev Immunol 6:497–507

    PubMed  CAS  Google Scholar 

  • Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S et al (2010) Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330:841–845

    PubMed  CAS  PubMed Central  Google Scholar 

  • Gomez-Nicola D, Fransen NL, Suzzi S, Perry VH (2013) Regulation of microglial proliferation during chronic neurodegeneration. J Neurosci 33:2481–2493

    PubMed  CAS  Google Scholar 

  • Gonzalez-Scarano F, Baltuch G (1999) Microglia as mediators of inflammatory and degenerative diseases. Annu Rev Neurosci 22:219–240

    PubMed  CAS  Google Scholar 

  • Göppert-Mayer M (1931) Über Elemtarakte mit zwei Quantensprüngen. Ann Phys 401:273–294

    Google Scholar 

  • Grutzendler J, Kasthuri N, Gan WB (2002) Long-term dendritic spine stability in the adult cortex. Nature 420:812–816

    PubMed  CAS  Google Scholar 

  • Haapaniemi H, Tomita M, Tanahashi N, Takeda H, Yokoyama M, Fukuuchi Y (1995) Non-amoeboid locomotion of cultured microglia obtained from newborn rat brain. Neurosci Lett 193:121–124

    PubMed  CAS  Google Scholar 

  • Haass C, Selkoe DJ (2007) Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer‘s amyloid beta-peptide. Nat Rev Mol Cell Biol 8:101–112

    PubMed  CAS  Google Scholar 

  • Hanisch UK, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10:1387–1394

    PubMed  CAS  Google Scholar 

  • Haynes SE, Hollopeter G, Yang G, Kurpius D, Dailey ME, Gan WB et al (2006) The P2Y12 receptor regulates microglial activation by extracellular nucleotides. Nat Neurosci 9:1512–1519

    PubMed  CAS  Google Scholar 

  • Hefendehl JK, Neher JJ, Suhs RB, Kohsaka S, Skodras A, Jucker M (2014) Homeostatic and injury-induced microglia behavior in the aging brain. Aging Cell 13:60–69

    PubMed  CAS  Google Scholar 

  • Helmchen F, Denk W (2005) Deep tissue two-photon microscopy. Nat Methods 2:932–940

    PubMed  CAS  Google Scholar 

  • Hide I, Tanaka M, Inoue A, Nakajima K, Kohsaka S, Inoue K et al (2000) Extracellular ATP triggers tumor necrosis factor-alpha release from rat microglia. J Neurochem 75:965–972

    PubMed  CAS  Google Scholar 

  • Hines DJ, Hines RM, Mulligan SJ, Macvicar BA (2009) Microglia processes block the spread of damage in the brain and require functional chloride channels. Glia 57:1610–1618

    PubMed  Google Scholar 

  • Hirasawa T, Ohsawa K, Imai Y, Ondo Y, Akazawa C, Uchino S et al (2005) Visualization of microglia in living tissues using Iba1-EGFP transgenic mice. J Neurosci Res 81:357–362

    PubMed  CAS  Google Scholar 

  • Holtmaat A, Bonhoeffer T, Chow DK, Chuckowree J, De Paola V, Hofer SB et al (2009) Long-term, high-resolution imaging in the mouse neocortex through a chronic cranial window. Nat Protoc 4:1128–1144

    PubMed  CAS  PubMed Central  Google Scholar 

  • Holtmaat AJ, Trachtenberg JT, Wilbrecht L, Shepherd GM, Zhang X, Knott GW et al (2005) Transient and persistent dendritic spines in the neocortex in vivo. Neuron 45:279–291

    PubMed  CAS  Google Scholar 

  • Honda S, Sasaki Y, Ohsawa K, Imai Y, Nakamura Y, Inoue K et al (2001) Extracellular ATP or ADP induce chemotaxis of cultured microglia through Gi/o-coupled P2Y receptors. J Neurosci 21:1975–1982

    PubMed  CAS  Google Scholar 

  • Inoue K (2008) Purinergic systems in microglia. Cell Mol Life Sci 65:3074–3080

    PubMed  CAS  Google Scholar 

  • Ishii T, Ishii M (2011) Intravital two-photon imaging: a versatile tool for dissecting the immune system. Ann Rheum Dis 70(Suppl 1):i113–i115

    PubMed  Google Scholar 

  • Jeon H, Kim JH, Kim JH, Lee WH, Lee MS, Suk K (2012) Plasminogen activator inhibitor type 1 regulates microglial motility and phagocytic activity. J Neuroinflammation 9:149

    PubMed  CAS  PubMed Central  Google Scholar 

  • Jung S, Aliberti J, Graemmel P, Sunshine MJ, Kreutzberg GW, Sher A et al (2000) Analysis of fractalkine receptor CX3CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Mol Cell Biol 20:4106–4114

    PubMed  CAS  PubMed Central  Google Scholar 

  • Kaur C, Hao AJ, Wu CH, Ling EA (2001) Origin of microglia. Microsc Res Tech 54:2–9

    PubMed  CAS  Google Scholar 

  • Kawakami N, Bartholomaus I, Pesic M, Mues M (2012) An autoimmunity odyssey: how autoreactive T cells infiltrate into the CNS. Immunol Rev 248:140–155

    PubMed  Google Scholar 

  • Kerschensteiner M, Schwab ME, Lichtman JW, Misgeld T (2005) In vivo imaging of axonal degeneration and regeneration in the injured spinal cord. Nat Med 11:572–577

    PubMed  CAS  Google Scholar 

  • Kettenmann H, Hanisch UK, Noda M, Verkhratsky A (2011) Physiology of microglia. Physiol Rev 91:461–553

    PubMed  CAS  Google Scholar 

  • Kierdorf K, Erny D, Goldmann T, Sander V, Schulz C, Perdiguero EG et al (2013) Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways. Nat Neurosci 16:273–280

    PubMed  CAS  Google Scholar 

  • Kim JV, Dustin ML (2006) Innate response to focal necrotic injury inside the blood-brain barrier. J Immunol 177:5269–5277

    PubMed  CAS  Google Scholar 

  • Koenigsknecht-Talboo J, Meyer-Luehmann M, Parsadanian M, Garcia-Alloza M, Finn MB, Hyman BT et al (2008) Rapid microglial response around amyloid pathology after systemic anti-Abeta antibody administration in PDAPP mice. J Neurosci 28:14156–14164

    PubMed  CAS  PubMed Central  Google Scholar 

  • Koizumi S, Ohsawa K, Inoue K, Kohsaka S (2013) Purinergic receptors in microglia: functional modal shifts of microglia mediated by P2 and P1 receptors. Glia 61:47–54

    PubMed  Google Scholar 

  • Krabbe G, Halle A, Matyash V, Rinnenthal JL, Eom GD, Bernhardt U et al (2013) Functional impairment of microglia coincides with beta-amyloid deposition in mice with Alzheimer-like pathology. PLoS One 8:e60921

    PubMed  CAS  PubMed Central  Google Scholar 

  • Kreutzberg GW (1996) Microglia: a sensor for pathological events in the CNS. Trends Neurosci 19:312–318

    PubMed  CAS  Google Scholar 

  • Lalancette-Hebert M, Phaneuf D, Soucy G, Weng YC, Kriz J (2009) Live imaging of Toll-like receptor 2 response in cerebral ischaemia reveals a role of olfactory bulb microglia as modulators of inflammation. Brain 132:940–954

    PubMed  CAS  Google Scholar 

  • Lawson LJ, Perry VH, Dri P, Gordon S (1990) Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience 39:151–170

    PubMed  CAS  Google Scholar 

  • Lee JE, Liang KJ, Fariss RN, Wong WT (2008) Ex vivo dynamic imaging of retinal microglia using time-lapse confocal microscopy. Invest Ophthalmol Vis Sci 49:4169–4176

    PubMed  PubMed Central  Google Scholar 

  • Liang KJ, Lee JE, Wang YD, Ma W, Fontainhas AM, Fariss RN et al (2009) Regulation of dynamic behavior of retinal microglia by CX3CR1 signaling. Invest Ophthalmol Vis Sci 50:4444–4451

    PubMed  PubMed Central  Google Scholar 

  • Liu S, Li ZW, Weinreb RN, Xu G, Lindsey JD, Ye C et al (2012) Tracking retinal microgliosis in models of retinal ganglion cell damage. Invest Ophthalmol Vis Sci 53:6254–6262

    PubMed  Google Scholar 

  • Liu Z, Condello C, Schain A, Harb R, Grutzendler J (2010) CX3CR1 in microglia regulates brain amyloid deposition through selective protofibrillar amyloid-beta phagocytosis. J Neurosci 30:17091–17101

    PubMed  CAS  PubMed Central  Google Scholar 

  • Lohmann C, Finski A, Bonhoeffer T (2005) Local calcium transients regulate the spontaneous motility of dendritic filopodia. Nat Neurosci 8:305–312

    PubMed  CAS  Google Scholar 

  • Lossi L, Alasia S, Salio C, Merighi A (2009) Cell death and proliferation in acute slices and organotypic cultures of mammalian CNS. Prog Neurobiol 88:221–245

    PubMed  Google Scholar 

  • Lovett-Barron M, Kaifosh P, Kheirbek MA, Danielson N, Zaremba JD, Reardon TR et al (2014) Dendritic inhibition in the hippocampus supports fear learning. Science 343:857–863

    PubMed  CAS  PubMed Central  Google Scholar 

  • Lund S, Christensen KV, Hedtjarn M, Mortensen AL, Hagberg H, Falsig J et al (2006) The dynamics of the LPS triggered inflammatory response of murine microglia under different culture and in vivo conditions. J Neuroimmunol 180:71–87

    PubMed  CAS  Google Scholar 

  • Maggi L, Scianni M, Branchi I, D’Andrea I, Lauro C, Limatola C (2011) CX(3)CR1 deficiency alters hippocampal-dependent plasticity phenomena blunting the effects of enriched environment. Front Cell Neurosci 5:22

    PubMed  CAS  PubMed Central  Google Scholar 

  • Marin-Teva JL, Dusart I, Colin C, Gervais A, van Rooijen N, Mallat M (2004) Microglia promote the death of developing Purkinje cells. Neuron 41:535–547

    PubMed  CAS  Google Scholar 

  • Marker DF, Tremblay ME, Lu SM, Majewska AK, Gelbard HA (2010) A thin-skull window technique for chronic two-photon in vivo imaging of murine microglia in models of neuroinflammation. J Vis Exp 43

    Google Scholar 

  • Mayevsky A (1978) Ischemia in the brain: the effects of carotid artery ligation and decapitation on the energy state of the awake and anesthetized rat. Brain Res 140:217–230

    PubMed  CAS  Google Scholar 

  • McGlade-McCulloh E, Morrissey AM, Norona F, Muller KJ (1989) Individual microglia move rapidly and directly to nerve lesions in the leech central nervous system. Proc Natl Acad Sci U S A 86:1093–1097

    PubMed  CAS  PubMed Central  Google Scholar 

  • Meyer-Luehmann M, Spires-Jones TL, Prada C, Garcia-Alloza M, de Calignon A, Rozkalne A et al (2008) Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer’s disease. Nature 451:720–724

    PubMed  CAS  PubMed Central  Google Scholar 

  • Misgeld T, Kerschensteiner M (2006) In vivo imaging of the diseased nervous system. Nat Rev Neurosci 7:449–463

    PubMed  CAS  Google Scholar 

  • Misgeld T, Nikic I, Kerschensteiner M (2007) In vivo imaging of single axons in the mouse spinal cord. Nat Protoc 2:263–268

    PubMed  CAS  Google Scholar 

  • Muller C, Beck H, Coulter D, Remy S (2012) Inhibitory control of linear and supralinear dendritic excitation in CA1 pyramidal neurons. Neuron 75:851–864

    PubMed  Google Scholar 

  • Nagerl UV, Eberhorn N, Cambridge SB, Bonhoeffer T (2004) Bidirectional activity-dependent morphological plasticity in hippocampal neurons. Neuron 44:759–767

    PubMed  Google Scholar 

  • Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308:1314–1318

    PubMed  CAS  Google Scholar 

  • Ohsawa K, Irino Y, Nakamura Y, Akazawa C, Inoue K, Kohsaka S (2007) Involvement of P2X4 and P2Y12 receptors in ATP-induced microglial chemotaxis. Glia 55:604–616

    PubMed  Google Scholar 

  • Ohsawa K, Irino Y, Sanagi T, Nakamura Y, Suzuki E, Inoue K et al (2010) P2Y12 receptor-mediated integrin-beta1 activation regulates microglial process extension induced by ATP. Glia 58:790–801

    PubMed  Google Scholar 

  • Palop JJ, Mucke L (2010) Amyloid-beta-induced neuronal dysfunction in Alzheimer’s disease: from synapses toward neural networks. Nat Neurosci 13:812–818

    PubMed  CAS  PubMed Central  Google Scholar 

  • Paolicelli RC, Bolasco G, Pagani F, Maggi L, Scianni M, Panzanelli P et al (2011) Synaptic pruning by microglia is necessary for normal brain development. Science 333:1456–1458

    PubMed  CAS  Google Scholar 

  • Paques M, Simonutti M, Augustin S, Goupille O, El Mathari B, Sahel JA (2010) In vivo observation of the locomotion of microglial cells in the retina. Glia 58:1663–1668

    PubMed  Google Scholar 

  • Parkhurst CN, Yang G, Ninan I, Savas JN, Yates JR 3rd, Lafaille JJ et al (2013) Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 155:1596–1609

    PubMed  CAS  PubMed Central  Google Scholar 

  • Peri F, Nusslein-Volhard C (2008) Live imaging of neuronal degradation by microglia reveals a role for v0-ATPase a1 in phagosomal fusion in vivo. Cell 133:916–927

    PubMed  CAS  Google Scholar 

  • Perry VH, Nicoll JA, Holmes C (2010) Microglia in neurodegenerative disease. Nat Rev Neurol 6:193–201

    PubMed  Google Scholar 

  • Petersen MA, Dailey ME (2004) Diverse microglial motility behaviors during clearance of dead cells in hippocampal slices. Glia 46:195–206

    PubMed  Google Scholar 

  • Prinz M, Priller J, Sisodia SS, Ransohoff RM (2011) Heterogeneity of CNS myeloid cells and their roles in neurodegeneration. Nat Neurosci 14:1227–1235

    PubMed  CAS  Google Scholar 

  • Raivich G, Bohatschek M, Kloss CU, Werner A, Jones LL, Kreutzberg GW (1999) Neuroglial activation repertoire in the injured brain: graded response, molecular mechanisms and cues to physiological function. Brain Res Brain Res Rev 30:77–105

    PubMed  CAS  Google Scholar 

  • Ransohoff RM, Brown MA (2012) Innate immunity in the central nervous system. J Clin Invest 122:1164–1171

    PubMed  CAS  PubMed Central  Google Scholar 

  • Rodhe J (2013) Cell culturing of human and murine microglia cell lines. Methods Mol Biol 1041:11–16

    PubMed  Google Scholar 

  • Rogers JT, Morganti JM, Bachstetter AD, Hudson CE, Peters MM, Grimmig BA et al (2011) CX3CR1 deficiency leads to impairment of hippocampal cognitive function and synaptic plasticity. J Neurosci 31:16241–16250

    PubMed  CAS  Google Scholar 

  • Saijo K, Glass CK (2011) Microglial cell origin and phenotypes in health and disease. Nat Rev Immunol 11:775–787

    PubMed  CAS  Google Scholar 

  • Sasmono RT, Oceandy D, Pollard JW, Tong W, Pavli P, Wainwright BJ et al (2003) A macrophage colony-stimulating factor receptor-green fluorescent protein transgene is expressed throughout the mononuclear phagocyte system of the mouse. Blood 101:1155–1163

    PubMed  CAS  Google Scholar 

  • Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R et al (2012) Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74:691–705

    PubMed  CAS  PubMed Central  Google Scholar 

  • Seshadri S, Fitzpatrick AL, Ikram MA, DeStefano AL, Gudnason V, Boada M et al (2010) Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA 303:1832–1840

    PubMed  CAS  PubMed Central  Google Scholar 

  • Shigemoto-Mogami Y, Koizumi S, Tsuda M, Ohsawa K, Kohsaka S, Inoue K (2001) Mechanisms underlying extracellular ATP-evoked interleukin-6 release in mouse microglial cell line, MG-5. J Neurochem 78:1339–1349

    PubMed  CAS  Google Scholar 

  • Sierra A, Encinas JM, Deudero JJ, Chancey JH, Enikolopov G, Overstreet-Wadiche LS et al (2010) Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis. Cell Stem Cell 7:483–495

    PubMed  CAS  PubMed Central  Google Scholar 

  • Sierra A, Gottfried-Blackmore AC, McEwen BS, Bulloch K (2007) Microglia derived from aging mice exhibit an altered inflammatory profile. Glia 55:412–424

    PubMed  Google Scholar 

  • Smith ME, van der Maesen K, Somera FP (1998) Macrophage and microglial responses to cytokines in vitro: phagocytic activity, proteolytic enzyme release, and free radical production. J Neurosci Res 54:68–78

    PubMed  CAS  Google Scholar 

  • Stence N, Waite M, Dailey ME (2001) Dynamics of microglial activation: a confocal time-lapse analysis in hippocampal slices. Glia 33:256–266

    PubMed  CAS  Google Scholar 

  • Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS, Nouri N et al (2007) The classical complement cascade mediates CNS synapse elimination. Cell 131:1164–1178

    PubMed  CAS  Google Scholar 

  • Stoll G, Jander S (1999) The role of microglia and macrophages in the pathophysiology of the CNS. Prog Neurobiol 58:233–247

    PubMed  CAS  Google Scholar 

  • Streit WJ (2013) Microglial cells. In: Kettenmann H, Ransom BR (eds) Neuroglia, 3rd edn. Oxford University Press, New York

    Google Scholar 

  • Streit WJ, Graeber MB, Kreutzberg GW (1988) Functional plasticity of microglia: a review. Glia 1:301–307

    PubMed  CAS  Google Scholar 

  • Suzumura A, Marunouchi T, Yamamoto H (1991) Morphological transformation of microglia in vitro. Brain Res 545:301–306

    PubMed  CAS  Google Scholar 

  • Svoboda K, Denk W, Kleinfeld D, Tank DW (1997) In vivo dendritic calcium dynamics in neocortical pyramidal neurons. Nature 385:161–165

    PubMed  CAS  Google Scholar 

  • Svoboda K, Yasuda R (2006) Principles of two-photon excitation microscopy and its applications to neuroscience. Neuron 50:823–839

    PubMed  CAS  Google Scholar 

  • Synofzik M, Fernandez-Santiago R, Maetzler W, Schols L, Andersen PM (2010) The human G93A SOD1 phenotype closely resembles sporadic amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 81:764–767

    PubMed  Google Scholar 

  • Takeda H, Tomita M, Tanahashi N, Kobari M, Yokoyama M, Takao M et al (1998) Hydrogen peroxide enhances phagocytic activity of ameboid microglia. Neurosci Lett 240:5–8

    PubMed  CAS  Google Scholar 

  • Thomas WE (1992) Brain macrophages: evaluation of microglia and their functions. Brain Res Brain Res Rev 17:61–74

    PubMed  CAS  Google Scholar 

  • Tomita M, Fukuuchi Y, Tanahashi N, Kobari M, Takeda H, Yokoyama M et al (1996) Swift transformation and locomotion of polymorphonuclear leukocytes and microglia as observed by VEC-DIC microscopy (video microscopy). Keio J Med 45:213–224

    PubMed  CAS  Google Scholar 

  • Tremblay ME, Lowery RL, Majewska AK (2010) Microglial interactions with synapses are modulated by visual experience. PLoS Biol 8:e1000527

    PubMed  PubMed Central  Google Scholar 

  • Tremblay ME, Zettel ML, Ison JR, Allen PD, Majewska AK (2012) Effects of aging and sensory loss on glial cells in mouse visual and auditory cortices. Glia 60:541–558

    PubMed  PubMed Central  Google Scholar 

  • Tsien RY (1998) The green fluorescent protein. Annu Rev Biochem 67:509–544

    PubMed  CAS  Google Scholar 

  • Ueno M, Fujita Y, Tanaka T, Nakamura Y, Kikuta J, Ishii M et al (2013) Layer V cortical neurons require microglial support for survival during postnatal development. Nat Neurosci 16:543–551

    PubMed  CAS  Google Scholar 

  • Venneti S, Lopresti BJ, Wiley CA (2013) Molecular imaging of microglia/macrophages in the brain. Glia 61:10–23

    PubMed  PubMed Central  Google Scholar 

  • Wake H, Moorhouse AJ, Jinno S, Kohsaka S, Nabekura J (2009) Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J Neurosci 29:3974–3980

    PubMed  CAS  Google Scholar 

  • Wang T, Kass IS (1997) Preparation of brain slices. Methods Mol Biol 72:1–14

    PubMed  CAS  Google Scholar 

  • Ward SA, Ransom PA, Booth PL, Thomas WE (1991) Characterization of ramified microglia in tissue culture: pinocytosis and motility. J Neurosci Res 29:13–28

    PubMed  CAS  Google Scholar 

  • Wollmer MA, Lucius R, Wilms H, Held-Feindt J, Sievers J, Mentlein R (2001) ATP and adenosine induce ramification of microglia in vitro. J Neuroimmunol 115:19–27

    PubMed  CAS  Google Scholar 

  • Wu LJ, Vadakkan KI, Zhuo M (2007) ATP-induced chemotaxis of microglial processes requires P2Y receptor-activated initiation of outward potassium currents. Glia 55:810–821

    PubMed  Google Scholar 

  • Wu LJ, Zhuo M (2008) Resting microglial motility is independent of synaptic plasticity in mammalian brain. J Neurophysiol 99:2026–2032

    PubMed  Google Scholar 

  • Xiang Z, Chen M, Ping J, Dunn P, Lv J, Jiao B et al (2006) Microglial morphology and its transformation after challenge by extracellular ATP in vitro. J Neurosci Res 83:91–101

    PubMed  CAS  Google Scholar 

  • Xu HT, Pan F, Yang G, Gan WB (2007) Choice of cranial window type for in vivo imaging affects dendritic spine turnover in the cortex. Nat Neurosci 10:549–551

    PubMed  CAS  Google Scholar 

  • Yasuda R, Harvey CD, Zhong H, Sobczyk A, van Aelst L, Svoboda K (2006) Supersensitive Ras activation in dendrites and spines revealed by two-photon fluorescence lifetime imaging. Nat Neurosci 9:283–291

    PubMed  CAS  Google Scholar 

  • Yona S, Kim KW, Wolf Y, Mildner A, Varol D, Breker M et al (2013) Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 38:79–91

    PubMed  CAS  PubMed Central  Google Scholar 

  • Ziv Y, Burns LD, Cocker ED, Hamel EO, Ghosh KK, Kitch LJ et al (2013) Long-term dynamics of CA1 hippocampal place codes. Nat Neurosci 16:264–266

    PubMed  CAS  PubMed Central  Google Scholar 

  • Zusso M, Methot L, Lo R, Greenhalgh AD, David S, Stifani S (2012) Regulation of postnatal forebrain amoeboid microglial cell proliferation and development by the transcription factor Runx1. J Neurosci 32:11285–11298

    PubMed  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Gladstone Institute of Neurological Disease, University of California, San Francisco, 1650 Owens Street, San Francisco, CA, 94158, USA

    Dimitrios Davalos Ph.D.

  2. Department of Neuroimmunology and Imaging, German Center for Neurodegenerative diseases (DZNE), c/o Biomedical Center, Sigmund-Freud-Str. 25, Bonn, 53175, Germany

    Martin Fuhrmann Ph.D.

Authors
  1. Dimitrios Davalos Ph.D.
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  2. Martin Fuhrmann Ph.D.
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Correspondence to Dimitrios Davalos Ph.D. .

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Editors and Affiliations

  1. Axe Neurosciences, Centre de recherche du, CHU de Québec, and Department of Molecular Medicine, Université Laval, Québec, Québec, Canada

    Marie-Ève Tremblay

  2. Achucarro Basque Center for Neuroscience, University of the Basque Country, EHU/UPV, Ikerbasque Foundation, Zamudio, Bizkaia, Spain

    Amanda Sierra

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Davalos, D., Fuhrmann, M. (2014). Lessons from In Vivo Imaging. In: Tremblay, MÈ., Sierra, A. (eds) Microglia in Health and Disease. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1429-6_4

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