Quantitative microglia analyses reveal diverse morphologic responses in the rat cortex after diffuse brain injury
Open accessAbstract
Determining regions of altered brain physiology after diffuse brain injury is challenging. Microglia, brain immune cells with ramified and dynamically moving processes, constantly surveil the parenchyma for dysfunction which, when present, results in a changed morphology. Our purpose was to define the spatiotemporal changes in microglia morphology over 28 days following rat midline fluid percussion injury (mFPI) as a first step in exploiting microglia morphology to reflect altered brain physiology. Microglia morphology was quantified from histological sections using Image J skeleton and fractal analysis procedures at three time points and in three regions post-mFPI: impact site, primary somatosensory cortex barrel field (S1BF), and a remote region. Microglia ramification (process length/cell and endpoints/cell) decreased in the impact and S1BF but not the remote region (p < 0.05). Microglia complexity was decreased in the S1BF (p = 0.003) and increased in the remote region (p < 0.02). Rod-shaped microglia were present in the S1BF and had a 1.8:1.0 length:width ratio. An in-depth quantitative morphologic analysis revealed diverse and widespread changes to microglia morphology in the cortex post-mFPI. Due to their close link to neuronal function, changes in microglia morphology, summarized in this study, likely reflect altered physiology with diverse and widespread impact on neuronal and circuit function.
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Microglial ramifications are typically indicative of resting state microglia, which play an active role in the surveillance and monitoring of the brain parenchyma.
“Microglial ramifications are typically indicative of resting state microglia, which play an active role in the surveillance and monitoring of the brain parenchyma, with studies showing that insults such as injury result in reduced ramification [23].”
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Cites
Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo
Nimmerjahn, A., Kirchhoff, F., & Helmchen, F. (2005) · Science · doi:10.1126/science.1110647 · Cited by 5,827 · see citing works
ATP mediates rapid microglial response to local brain injury in vivo
Davalos, D., Grutzendler, J., Yang, G., Kim, J. V., Zuo, Y., Jung, S., Littman, D. R., Dustin, M. L., & Gan, W.-B. (2005) · Nature Neuroscience · doi:10.1038/nn1472 · Cited by 3,913 · see citing works
Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain
Lawson, L. J., Perry, V. H., Dri, P., & Gordon, S. (1990) · Neuroscience · doi:10.1016/0306-4522(90)90229-w · Cited by 2,045 · see citing works
Microglial cell origin and phenotypes in health and disease
Saijo, K., & Glass, C. K. (2011) · Nature Reviews Immunology · doi:10.1038/nri3086 · Cited by 1,100 · see citing works
Differential Regulation of AMPA Receptor and GABA Receptor Trafficking by Tumor Necrosis Factor-α
Stellwagen, D., Beattie, E. C., Seo, J. Y., & Malenka, R. C. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.4486-04.2005 · Cited by 985 · see citing works
Fontainhas, A. M., Wang, M., Liang, K. J., Chen, S., Mettu, P., Damani, M., Fariss, R. N., Li, W., & Wong, W. T. (2011) · PLoS ONE · doi:10.1371/journal.pone.0015973 · Cited by 334 · see citing works
Hellwig, S., Brioschi, S., Dieni, S., Frings, L., Masuch, A., Blank, T., & Biber, K. (2016) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2015.11.008 · Cited by 252 · see citing works
Kumar, A., Stoica, B. A., Sabirzhanov, B., Burns, M. P., Faden, A. I., & Loane, D. J. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.11.013 · Cited by 244 · see citing works
Flagged first, then by citations
Research works printed but not linked: 43
- [2]Leo, P. & McCrea, M. Frontiers in Neuroscience: Epidemiology. In Translational Research in Traumatic Brain Injury (eds Laskowitz, D. & Grant, G.) (CRC Press/Taylor and Francis Group, Boca Raton (FL), 2016). 26583170
- [3]LaPlaca MC Simon CM Prado GR Cullen DK CNS injury biomechanics and experimental models Prog Brain Res 2007 161 13 26 10.1016/S0079-6123(06)61002-9 17618967 · DOI
- [4]Wolf JA Stys PK Lusardi T Meaney D Smith DH Traumatic axonal injury induces calcium influx modulated by tetrodotoxin-sensitive sodium channels J Neurosci 2001 21 1923 1930 11245677 PMC6762603
- [5]Barkhoudarian G Hovda DA Giza CC The Molecular Pathophysiology of Concussive Brain Injury - an Update Phys Med Rehabil Clin N Am 2016 27 373 393 10.1016/j.pmr.2016.01.003 27154851 · DOI
- [6]Choe MC The Pathophysiology of Concussion Curr Pain Headache Rep 2016 20 42 10.1007/s11916-016-0573-9 27184060 · DOI
- [7]Johnson VE SNTF immunostaining reveals previously undetected axonal pathology in traumatic brain injury Acta Neuropathol 2016 131 115 135 10.1007/s00401-015-1506-0 26589592 PMC4780426 · DOI
- [8]Lifshitz J Kelley BJ Povlishock JT Perisomatic thalamic axotomy after diffuse traumatic brain injury is associated with atrophy rather than cell death J Neuropathol Exp Neurol 2007 66 218 229 10.1097/01.jnen.0000248558.75950.4d 17356383 · DOI
- [9]Hall KD Lifshitz J Diffuse traumatic brain injury initially attenuates and later expands activation of the rat somatosensory whisker circuit concomitant with neuroplastic responses Brain Res 2010 1323 161 173 10.1016/j.brainres.2010.01.067 20122903 PMC2888803 · DOI
- [11]Bianchi R Giambanco I Donato R S100B/RAGE-dependent activation of microglia via NF-kappaB and AP-1 Co-regulation of COX-2 expression by S100B, IL-1beta and TNF-alpha Neurobiol Aging 2010 31 665 677 10.1016/j.neurobiolaging.2008.05.017 18599158 · DOI
- [14]Orr, A. G., Orr, A. L., Li, X. J., Gross, R. E. & Traynelis, S. F. Adenosine A(2A) receptor mediates microglial process retraction. in Nat Neurosci 872–878 (United States, 2009). PMC2712729 19525944
- [15]Dissing-Olesen L Activation of neuronal NMDA receptors triggers transient ATP-mediated microglial process outgrowth J Neurosci 2014 34 10511 10527 10.1523/JNEUROSCI.0405-14.2014 25100586 PMC6802598 · DOI · Paper page
- [16]Stellwagen D Malenka RC Synaptic scaling mediated by glial TNF-alpha Nature 2006 440 1054 1059 10.1038/nature04671 16547515 · DOI · Paper page
- [19]Wohleb ES Neuron-Microglia Interactions in Mental Health Disorders: “For Better, and For Worse” Front Immunol 2016 7 544 10.3389/fimmu.2016.00544 27965671 PMC5126117 · DOI
- [20]Yirmiya R Goshen I Immune modulation of learning, memory, neural plasticity and neurogenesis Brain Behav Immun 2011 25 181 213 10.1016/j.bbi.2010.10.015 20970492 · DOI · Paper page
- [21]Tremblay, M. E. et al. The Role of Microglia in the Healthy Brain. in J Neurosci 16064–16069 (2011). PMC6633221 22072657
- [22]Morrison, H. W. & Filosa, J. A. A quantitative spatiotemporal analysis of microglia morphology during ischemic stroke and reperfusion. in J Neuroinflammation 4 (2013). PMC3570327 23311642
- [23]Ziebell JM Taylor SE Cao T Harrison JL Lifshitz J Rod microglia: elongation, alignment, and coupling to form trains across the somatosensory cortex after experimental diffuse brain injury J Neuroinflammation 2012 9 247 10.1186/1742-2094-9-247 23111107 PMC3526458 · DOI
- [24]Bachstetter AD Rod-shaped microglia morphology is associated with aging in 2 human autopsy series Neurobiol Aging 2017 52 98 105 10.1016/j.neurobiolaging.2016.12.028 28131016 PMC5359029 · DOI
- [25]Tam WY Ma CH Bipolar/rod-shaped microglia are proliferating microglia with distinct M1/M2 phenotypes Sci Rep 2014 4 7279 10.1038/srep07279 25452009 PMC4250916 · DOI
- [26]Taylor SE Morganti-Kossmann C Lifshitz J Ziebell JM Rod microglia: a morphological definition PLoS One 2014 9 e97096 10.1371/journal.pone.0097096 24830807 PMC4022629 · DOI
- [27]Cao T Thomas TC Ziebell JM Pauly JR Lifshitz J Morphological and genetic activation of microglia after diffuse traumatic brain injury in the rat Neuroscience 2012 225 65 75 10.1016/j.neuroscience.2012.08.058 22960311 PMC3489473 · DOI
- [28]Lifshitz J Lisembee AM Neurodegeneration in the somatosensory cortex after experimental diffuse brain injury Brain Struct Funct 2012 217 49 61 10.1007/s00429-011-0323-z 21597967 PMC3536493 · DOI
- [30]Morrison, H. W. & Filosa, J. A. Sex differences in astrocyte and microglia responses immediately following middle cerebral artery occlusion in adult mice. Neuroscience (2016). PMC5118180 27717807
- [31]Soltys Z Quantitative morphological study of microglial cells in the ischemic rat brain using principal component analysis J Neurosci Methods 2005 146 50 60 10.1016/j.jneumeth.2005.01.009 15935220 · DOI
- [32]Soltys Z Ziaja M Pawlinski R Setkowicz Z Janeczko K Morphology of reactive microglia in the injured cerebral cortex Fractal analysis and complementary quantitative methods. J Neurosci Res 2001 63 90 97 11169618
- [33]Hosseini AH Lifshitz J Brain injury forces of moderate magnitude elicit the fencing response Med Sci Sports Exerc 2009 41 1687 1697 10.1249/MSS.0b013e31819fcd1b 19657303 PMC11421656 · DOI
- [34]Arganda-Carreras I Fernandez-Gonzalez R Munoz-Barrutia A Ortiz-De-Solorzano C 3D reconstruction of histological sections: Application to mammary gland tissue Microsc Res Tech 2010 73 1019 1029 10.1002/jemt.20829 20232465 · DOI
- [35]Gundersen HJ The new stereological tools: disector, fractionator, nucleator and point sampled intercepts and their use in pathological research and diagnosis Apmis 1988 96 857 881 10.1111/j.1699-0463.1988.tb00954.x 3056461 · DOI
- [36]Karperien, A., Ahammer, H. & Jelinek, H. F. Quantitating the subtleties of microglial morphology with fractal analysis. Front Cell Neurosci7 (2013). PMC3558688 23386810
- [37]Karperien, A. L. & Jelinek, H. F. Fractal, Multifractal, and Lacunarity Analysis of Microglia in Tissue Engineering. Front Bioeng Biotechnol3 (2015). PMC4396415 25927064
- [39]Kumar A Loane DJ Neuroinflammation after traumatic brain injury: opportunities for therapeutic intervention Brain Behav Immun 2012 26 1191 1201 10.1016/j.bbi.2012.06.008 22728326 · DOI · Paper page
- [40]Loane DJ Kumar A Microglia in the TBI brain: The good, the bad, and the dysregulated Exp Neurol 2016 275 Pt 3 316 327 10.1016/j.expneurol.2015.08.018 26342753 PMC4689601 · DOI
- [41]Lenz, K. M., Nugent, B. M., Haliyur, R. & McCarthy, M. M. Microglia are essential to masculinization of brain and behavior. In J Neurosci 2761–2772 (United States, 2013). PMC3727162 23407936
- [42]Orlowski D Soltys Z Janeczko K Morphological development of microglia in the postnatal rat brain. A quantitative study Int J Dev Neurosci 2003 21 445 450 10.1016/j.ijdevneu.2003.09.001 14659995 · DOI
- [44]Hinwood M Chronic stress induced remodeling of the prefrontal cortex: structural re-organization of microglia and the inhibitory effect of minocycline Cereb Cortex 2013 23 1784 1797 10.1093/cercor/bhs151 22710611 · DOI
- [45]Rowson SA Neuroinflammation and Behavior in HIV-1 Transgenic Rats Exposed to Chronic Adolescent Stress Front Psychiatry 2016 7 102 10.3389/fpsyt.2016.00102 27378953 PMC4913326 · DOI
- [46]Streit WJ Walter SA Pennell NA Reactive microgliosis Prog Neurobiol 1999 57 563 581 10.1016/S0301-0082(98)00069-0 10221782 · DOI · Paper page
- [47]Ohsawa K Adenosine A3 receptor is involved in ADP-induced microglial process extension and migration J Neurochem 2012 121 217 227 10.1111/j.1471-4159.2012.07693.x 22335470 · DOI
- [48]Namjoshi DR Merging pathology with biomechanics using CHIMERA (Closed-Head Impact Model of Engineered Rotational Acceleration): a novel, surgery-free model of traumatic brain injury Mol Neurodegener 2014 9 55 10.1186/1750-1326-9-55 25443413 PMC4269957 · DOI · Paper page
- [49]Kumar A NOX2 drives M1-like microglial/macrophage activation and neurodegeneration following experimental traumatic brain injury Brain Behav Immun 2016 58 291 309 10.1016/j.bbi.2016.07.158 27477920 PMC5067217 · DOI · Paper page
- [51]Byrnes KR Loane DJ Stoica BA Zhang J Faden AI Delayed mGluR5 activation limits neuroinflammation and neurodegeneration after traumatic brain injury J Neuroinflammation 2012 9 43 10.1186/1742-2094-9-43 22373400 PMC3308916 · DOI
- [52]Eakin, K., Rowe, R. K. & Lifshitz, J. Frontiers in Neuroengineering Modeling Fluid Percussion Injury: Relevance to Human Traumatic Brain Injury. in Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects (ed. Kobeissy, F. H.) (CRC Press/Taylor & Francis(c) 2015 by Taylor & Francis Group, LLC., Boca Raton (FL), 2015). 26269911
- [53]Lifshitz J Clinical relevance of midline fluid percussion brain injury: Acute deficits, chronic morbidities and the utility of biomarkers Brain Inj 2016 30 1293 1301 10.1080/02699052.2016.1193628 27712117 PMC5303557 · DOI
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“monitoring of the brain parenchyma, with studies showing that insults such as injury result in reduced ramification [23].”
BackgroundGuadalupi, L., Mandolesi, G., Vanni, V., Balletta, S., Caioli, S., Pavlovic, A., De Vito, F., Fresegna, D., Sanna, K., Vitiello, L., et al. (2024) · Neuropharmacology · doi:10.1016/j.neuropharm.2024.109940 · Cited by 22 · see citing works
- Authors
- Morrison, H., Young, K., Qureshi, M., Rowe, R. K., & Lifshitz, J.
- Affiliations
- University of Arizona (US)
- Arizona State University (US)
- Barrow Neurological Institute (US)
- Corresponding author
- Morrison, Helena
- Venue
- Scientific Reports
- Published
- 2017-10-16
- Volume
- 7
- Issue
- 1
- Pages
- 13211-13211
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC5643511
- OpenAlex
- W2761242880
- Cited by
- 276
- References
- 8
- Citations by year
- 2026: 19 · 2025: 42 · 2024: 39 · 2023: 41 · 2022: 45 · 2021: 43 · 2020: 22 · 2019: 18 · 2018: 7
- FWCI
- 6.40
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UA Campus Repository (The University of Arizona) (acceptedVersion, cc-by)
- Funders
- Science Foundation Arizona
- University of Arizona
- Diane and Bruce Halle Foundation
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (R03NS090013, R21NS096515)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
- Keywords
- microglial morphology, diffuse brain injury, fluid percussion injury, primary somatosensory cortex, barrel cortex, microglial ramification, fractal analysis, neuroinflammation
- MeSH terms
- Brain Injuries, Diffuse, Animals, Male, Percussion, Somatosensory Cortex, Rats, Sprague-Dawley, Microglia, Fractals, Rats
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