Microglia and sexual differentiation of the developing brain: A focus on ontogeny and intrinsic factors
Abstract
Sexual differentiation of the brain during early development likely underlies the strong sex biases prevalent in many neurological conditions. Mounting evidence indicates that microglia, the innate immune cells of the central nervous system, are intricately involved in these sex‐specific processes of differentiation. In this review, we synthesize literature demonstrating sex differences in microglial number, morphology, transcriptional state, and functionality throughout spatiotemporal development as well as highlight current literature regarding ontogeny of microglia. Along with vanRyzin et al. in this issue, we explore the idea that differences in microglia imparted by chromosomal or ontogeny‐related programming can influence microglial‐driven sexual differentiation of the brain, as well as the idea that extrinsic differences in the male and female brain microenvironment may in turn impart sex differences in microglia.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Sex hormones influence the developmental trajectories of male and female microglia, manifesting in differential regional densities, morphology, phagocytic capacity and metabolic influx.
“There is growing evidence to suggest that sex hormones influence the developmental trajectories of male and female microglia manifesting in differential regional densities, morphology, phagocytic capacity and metabolic influx67.”
From Mouse microglia express unique miRNA-mRNA networks to facilitate age-specific functions in the developing central nervous system (2023) · cites this paper as [67]
Functional and structural differences between male and female microglia have been consistently observed, but transcriptomic results are less congruent.
“Interestingly, while functional and structural differences between male and female microglia have been consistently observed, transcriptomic results are less congruent67.”
From Mouse microglia express unique miRNA-mRNA networks to facilitate age-specific functions in the developing central nervous system (2023) · cites this paper as [67]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease
Keren-Shaul, H., Spinrad, A., Weiner, A., Matcovitch-Natan, O., Dvir-Szternfeld, R., Ulland, T. K., David, E., Baruch, K., Lara-Astaiso, D., Toth, B., et al. (2017) · Cell · doi:10.1016/j.cell.2017.05.018 · Cited by 5,493 · see citing works
Fate Mapping Analysis Reveals That Adult Microglia Derive from Primitive Macrophages
Ginhoux, F., Greter, M., Leboeuf, M., Nandi, S., See, P., Gokhan, S., Mehler, M. F., Conway, S. J., Ng, L. G., Stanley, E. R., et al. (2010) · Science · doi:10.1126/science.1194637 · Cited by 5,175 · see citing works
Synaptic Pruning by Microglia Is Necessary for Normal Brain Development
Paolicelli, R. C., Bolasco, G., Pagani, F., Maggi, L., Scianni, M., Panzanelli, P., Giustetto, M., Ferreira, T. A., Guiducci, E., Dumas, L., et al. (2011) · Science · doi:10.1126/science.1202529 · Cited by 4,244 · see citing works
Microglia Sculpt Postnatal Neural Circuits in an Activity and Complement-Dependent Manner
Schafer, D. P., Lehrman, E. K., Kautzman, A. G., Koyama, R., Mardinly, A. R., Yamasaki, R., Ransohoff, R. M., Greenberg, M. E., Barres, B. A., & Stevens, B. (2012) · Neuron · doi:10.1016/j.neuron.2012.03.026 · Cited by 4,089 · 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
Hammond, T. R., Dufort, C., Dissing-Olesen, L., Giera, S., Young, A., Wysoker, A., Walker, A. J., Segel, M., Nemesh, J., Saunders, A., et al. (2018) · doi:10.1101/406140 · Cited by 2,225 · see citing works
Microglial <scp>M1/M2</scp> polarization and metabolic states
Orihuela, R., McPherson, C. A., & Harry, G. J. (2016) · British Journal of Pharmacology · doi:10.1111/bph.13139 · Cited by 2,070 · see citing works
Adult mouse cortical cell taxonomy revealed by single cell transcriptomics
Tasic, B., Menon, V., Nguyen, T. N., Kim, T. K., Jarsky, T., Yao, Z., Levi, B., Gray, L. T., Sorensen, S. A., Dolbeare, T., et al. (2016) · Nature Neuroscience · doi:10.1038/nn.4216 · Cited by 1,714 · see citing works
Oxidative metabolism and PGC-1β attenuate macrophage-mediated inflammation
Vats, D., Mukundan, L., Odegaard, J. I., Zhang, L., Smith, K. L., Morel, C. R., Greaves, D. R., Murray, P. J., & Chawla, A. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.05.011 · Cited by 1,369 · cited 2× · see citing works
“Whereas classically defined anti-inflammatory macrophages activated by IL-4 upregulate fatty acid metabolism, glucose uptake, and mitochondrial biogenesis (Vats et al., 2006), mouse microglia in vitro showed decreased lactate production and glucose consumption in response to IL-4 (Orihuela et al.”
BackgroundMicroglia development follows a stepwise program to regulate brain homeostasis
Matcovitch-Natan, O., Winter, D. R., Giladi, A., Vargas Aguilar, S., Spinrad, A., Sarrazin, S., Ben-Yehuda, H., David, E., Zelada González, F., Perrin, P., et al. (2016) · Science · doi:10.1126/science.aad8670 · Cited by 1,180 · see citing works
Li, Q., Cheng, Z., Zhou, L., Darmanis, S., Neff, N. F., Okamoto, J., Gulati, G., Bennett, M. L., Sun, L. O., Clarke, L. E., et al. (2019) · Neuron · doi:10.1016/j.neuron.2018.12.006 · Cited by 1,129 · see citing works
Estradiol and the Developing Brain
McCARTHY, M. M. (2008) · Physiological Reviews · doi:10.1152/physrev.00010.2007 · Cited by 885 · see citing works
The Sedoheptulose Kinase CARKL Directs Macrophage Polarization through Control of Glucose Metabolism
Haschemi, A., Kosma, P., Gille, L., Evans, C. R., Burant, C. F., Starkl, P., Knapp, B., Haas, R., Schmid, J. A., Jandl, C., et al. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.04.023 · Cited by 635 · see citing works
Herbomel, P., Thisse, B., & Thisse, C. (2001) · Developmental Biology · doi:10.1006/dbio.2001.0393 · Cited by 574 · see citing works
Transcriptional and Translational Differences of Microglia from Male and Female Brains
Guneykaya, D., Ivanov, A., Hernandez, D. P., Haage, V., Wojtas, B., Meyer, N., Maricos, M., Jordan, P., Buonfiglioli, A., Gielniewski, B., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.08.001 · Cited by 477 · see citing works
Epigenetic regulation of brain region-specific microglia clearance activity
Ayata, P., Badimon, A., Strasburger, H. J., Duff, M. K., Montgomery, S. E., Loh, Y.-H. E., Ebert, A., Pimenova, A. A., Ramirez, B. R., Chan, A. T., et al. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0192-3 · Cited by 460 · see citing works
Local cues establish and maintain region-specific phenotypes of basal ganglia microglia
De Biase, L. M., Schuebel, K. E., Fusfeld, Z. H., Jair, K., Hawes, I. A., Cimbro, R., Zhang, H.-Y., Liu, Q.-R., Shen, H., Xi, Z.-X., et al. (2017) · Neuron · doi:10.1016/j.neuron.2017.06.020 · Cited by 432 · see citing works
Cronk, J. C., Filiano, A. J., Louveau, A., Marin, I., Marsh, R., Ji, E., Goldman, D. H., Smirnov, I., Geraci, N., Acton, S., et al. (2018) · Journal of Experimental Medicine · doi:10.1084/jem.20180247 · Cited by 412 · see citing works
Hoxb8 Is Required for Normal Grooming Behavior in Mice
Greer, J. M., & Capecchi, M. R. (2002) · Neuron · doi:10.1016/s0896-6273(01)00564-5 · Cited by 401 · cited 1× · see citing works
“…idea that microglia may traffic via alternative routes from the fetal yolk sac to the brain gained support from the finding that a proportion of microglia in the brain are derived from fetal yolk sac cells expressing the homeobox 8 (Hoxb8) gene (Chen et al., 2010; Greer & Capecchi, 2002).”
BackgroundHanamsagar, R., Alter, M. D., Block, C. S., Sullivan, H., Bolton, J. L., & Bilbo, S. D. (2017) · Glia · doi:10.1002/glia.23176 · Cited by 384 · see citing works
Highly multiplexed simultaneous detection of RNAs and proteins in single cells
Frei, A. P., Bava, F.-A., Zunder, E. R., Hsieh, E. W. Y., Chen, S.-Y., Nolan, G. P., & Gherardini, P. F. (2016) · Nature Methods · doi:10.1038/nmeth.3742 · Cited by 330 · see citing works
VanRyzin, J. W., Marquardt, A. E., Argue, K. J., Vecchiarelli, H. A., Ashton, S. E., Arambula, S. E., Hill, M. N., & McCarthy, M. M. (2019) · Neuron · doi:10.1016/j.neuron.2019.02.006 · Cited by 272 · see citing works
Zuloaga, D. G., Puts, D. A., Jordan, C. L., & Breedlove, S. M. (2008) · Hormones and Behavior · doi:10.1016/j.yhbeh.2008.01.013 · Cited by 236 · see citing works
Elmore, M. R. P., Lee, R. J., West, B. L., & Green, K. N. (2015) · PLoS ONE · doi:10.1371/journal.pone.0122912 · Cited by 228 · see citing works
Sex and Gender Differences in Central Nervous System-Related Disorders
Zagni, E., Simoni, L., & Colombo, D. (2016) · Neuroscience Journal · doi:10.1155/2016/2827090 · Cited by 173 · see citing works
Gaignard, P., Savouroux, S., Liere, P., Pianos, A., Thérond, P., Schumacher, M., Slama, A., & Guennoun, R. (2015) · Endocrinology · doi:10.1210/en.2014-1913 · Cited by 150 · see citing works
The response of the sexes to nutritional stress
Widdowson, E. M. (1976) · Proceedings of the Nutrition Society · doi:10.1079/pns19760030 · Cited by 115 · cited 1× · see citing works
“While there are few studies into mitochondrial metabolism within microglia themselves, there are many examples of sex differences in overall metabolism (reviewed by Widdowson (1976)) and total brain metabolic outcomes.”
BackgroundSexual dimorphism of microglia and synapses during mouse postnatal development
Weinhard, L., Neniskyte, U., Vadisiute, A., di Bartolomei, G., Aygün, N., Riviere, L., Zonfrillo, F., Dymecki, S., & Gross, C. (2018) · Developmental Neurobiology · doi:10.1002/dneu.22568 · Cited by 107 · see citing works
Yoshizawa, H., Gazes, Y., Stern, Y., Miyata, Y., & Uchiyama, S. (2014) · Psychiatry Research: Neuroimaging · doi:10.1016/j.pscychresns.2013.10.009 · Cited by 100 · see citing works
Age and sex-related changes in rat brain mitochondrial oxidative status
Guevara, R., Gianotti, M., Oliver, J., & Roca, P. (2011) · Experimental Gerontology · doi:10.1016/j.exger.2011.08.003 · Cited by 63 · see citing works
Jaber, S. M., Bordt, E. A., Bhatt, N. M., Lewis, D. M., Gerecht, S., Fiskum, G., & Polster, B. M. (2018) · Neurochemistry International · doi:10.1016/j.neuint.2017.09.003 · Cited by 40 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 89
- Aanerud Joel, Borghammer Per, Rodell Anders, Jónsdottir Kristjana Y., and Gjedde Albert. 2017 “ Sex Differences of Human Cortical Blood Flow and Energy Metabolism.” Journal of Cerebral Blood Flow and Metabolism: Official Journal of the International Society of Cerebral Blood Flow and Metabolism 37 (7): 2433– 40. PMC5531342 27629099
- Ajami Bahareh, Samusik Nikolay, Wieghofer Peter, Ho Peggy P., Crotti Andrea, Bjornson Zach, Prinz Marco, Fantl Wendy J., Nolan Garry P., and Steinman Lawrence. 2018 “ Single-Cell Mass Cytometry Reveals Distinct Populations of Brain Myeloid Cells in Mouse Neuroinflammation and Neurodegeneration Models.” Nature Neuroscience 21 (4): 541– 51. 29507414 PMC8629134
- Amen Daniel G., Trujillo Manuel, Keator David, Taylor Derek V., Willeumier Kristen, Meysami Somayeh, and Raji Cyrus A.. 2017 “ Gender-Based Cerebral Perfusion Differences in 46,034 Functional Neuroimaging Scans.” Journal of Alzheimer’s Disease: JAD 60 (2): 605– 14. 28777753
- Arnò Benedetta, Grassivaro Francesca, Rossi Chiara, Bergamaschi Andrea, Castiglioni Valentina, Furlan Roberto, Greter Melanie, 2014 “ Neural Progenitor Cells Orchestrate Microglia Migration and Positioning into the Developing Cortex.” Nature Communications 5 (11): 5611. 25425146
- Baxter LR Jr, Mazziotta JC, Phelps ME, Selin CE, Guze BH, and Fairbanks L. 1987 “ Cerebral Glucose Metabolic Rates in Normal Human Females versus Normal Males.” Psychiatry Research 21 (3): 237– 45. 3498176
- Bendall Sean C., Nolan Garry P., Roederer Mario, and Chattopadhyay Pratip K.. 2012 “ A Deep Profiler’s Guide to Cytometry.” Trends in Immunology 33 (7): 323– 32. 22476049 PMC3383392
- Bennett Mariko L., Bennett F. Chris, Liddelow Shane A., Ajami Bahareh, Zamanian Jennifer L., Fernhoff Nathaniel B., Mulinyawe Sara B., 2016 “ New Tools for Studying Microglia in the Mouse and Human CNS.” Proceedings of the National Academy of Sciences of the United States of America 113 (12): E1738– 46. 26884166 PMC4812770
- Böttcher Chotima, Schlickeiser Stephan, Sneeboer Marjolein A. M., Kunkel Desiree, Knop Anniki, Paza Evdokia, Fidzinski Pawel, 2019 “ Human Microglia Regional Heterogeneity and Phenotypes Determined by Multiplexed Single-Cell Mass Cytometry.” Nature Neuroscience 22 (1): 78– 90. 30559476
- Brink, van den Susanne C., Sage Fanny, Vértesy Ábel, Spanjaard Bastiaan, Peterson-Maduro Josi, Baron Chloé S., Robin Catherine, and van Oudenaarden Alexander. 2017 “ Single-Cell Sequencing Reveals Dissociation-Induced Gene Expression in Tissue Subpopulations.” Nature Methods 14 (10): 935– 36. 28960196
- Camus M. Florencia, Clancy David J., and Dowling Damian K.. 2012 “ Mitochondria, Maternal Inheritance, and Male Aging.” Current Biology: CB 22 (18): 1717– 21. 22863313
- Case Laure K., Wall Emma H., Dragon Julie A., Saligrama Naresha, Krementsov Dimitry N., Moussawi Mohamad, Zachary James F., Huber Sally A., Blankenhorn Elizabeth P., and Teuscher Cory. 2013 “ The Y Chromosome as a Regulatory Element Shaping Immune Cell Transcriptomes and Susceptibility to Autoimmune Disease.” Genome Research 23 (9): 1474– 85. 23800453 PMC3759723
- Cheng Mimi K., and Disteche Christine M.. 2004 “ Silence of the Fathers: Early X Inactivation.” BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology 26 (8): 821– 24. 15273983
- Chen Shau-Kwaun, Tvrdik Petr, Peden Erik, Cho Scott, Wu Sen, Spangrude Gerald, and Capecchi Mario R.. 2010 “ Hematopoietic Origin of Pathological Grooming in Hoxb8 Mutant Mice.” Cell 141 (5): 775– 85. 20510925 PMC2894573
- Crain Jessica M., Nikodemova Maria, and Watters Jyoti J.. 2013 “ Microglia Express Distinct M1 and M2 Phenotypic Markers in the Postnatal and Adult Central Nervous System in Male and Female Mice.” Journal of Neuroscience Research 91 (9): 1143– 51. 23686747 PMC3715560
- Cunningham Christopher L., Martínez-Cerdeño Verónica, and Noctor Stephen C.. 2013 “ Microglia Regulate the Number of Neural Precursor Cells in the Developing Cerebral Cortex.” The Journal of Neuroscience: The Official Journal of the Society for Neuroscience 33 (10): 4216– 33. 23467340 PMC3711552
- Demarest Tyler G., Schuh Rosemary A., Waddell Jaylyn, McKenna Mary C., and Fiskum Gary. 2016 “ Sex-Dependent Mitochondrial Respiratory Impairment and Oxidative Stress in a Rat Model of Neonatal Hypoxic-Ischemic Encephalopathy.” Journal of Neurochemistry 137 (5): 714– 29. 27197831 PMC4876982
- De Shrutokirti, Donn Van Deren Eric Peden, Hockin Matt, Boulet Anne, Titen Simon, and Capecchi Mario R.. 2018 “ Two Distinct Ontogenies Confer Heterogeneity to Mouse Brain Microglia.” Development 145 (13). 10.1242/dev.152306. PMC6053660 29973370 · DOI
- Dorfman Mauricio D., Krull Jordan E., Douglass John D., Fasnacht Rachael, Fernando Lara-Lince Thomas H. Meek, Shi Xiaogang, 2017 “ Sex Differences in Microglial CX3CR1 Signalling Determine Obesity Susceptibility in Mice.” Nature Communications 8 (2): 14556. PMC5322503 28223698
- Esposito G, Van Horn JD, Weinberger DR, and Berman KF. 1996 “ Gender Differences in Cerebral Blood Flow as a Function of Cognitive State with PET.” Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine 37 (4): 559– 64. 8691239
- Fish Eleanor N. 2008 “ The X-Files in Immunity: Sex-Based Differences Predispose Immune Responses.” Nature Reviews. Immunology 8 (9): 737– 44. PMC7097214 18728636
- Ford AL, Goodsall AL, Hickey WF, and Sedgwick JD. 1995 “ Normal Adult Ramified Microglia Separated from Other Central Nervous System Macrophages by Flow Cytometric Sorting. Phenotypic Differences Defined and Direct Ex Vivo Antigen Presentation to Myelin Basic Protein-Reactive CD4+ T Cells Compared.” Journal of Immunology 154 (9): 4309– 21. 7722289
- Galloway Dylan A., Blandford Stephanie N., Berry Tangyne, Williams John B., Stefanelli Mark, Ploughman Michelle, and Moore Craig S.. 2018 “ miR‐223 Promotes Regenerative Myeloid Cell Phenotype and Function in the Demyelinated Central Nervous System.” Glia, 12 10.1002/glia.23576. 30548333 · DOI · Paper page
- Galván-Peña Silvia, and O’Neill Luke A. J.. 2014 “ Metabolic Reprograming in Macrophage Polarization.” Frontiers in Immunology 5 (9): 420. 25228902 PMC4151090
- Giedd Jay N. 2004 “ Structural Magnetic Resonance Imaging of the Adolescent Brain.” Annals of the New York Academy of Sciences 1021 (6): 77– 85. 15251877
- Guevara Rocío, Gianotti Magdalena, Roca Pilar, and Oliver Jordi. 2011 “ Age and Sex-Related Changes in Rat Brain Mitochondrial Function.” Cellular Physiology and Biochemistry: International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology 27 (3–4): 201– 6. 21471708
- Gur RC, Mozley LH, Mozley PD, Resnick SM, Karp JS, Alavi A, Arnold SE, and Gur RE. 1995 “ Sex Differences in Regional Cerebral Glucose Metabolism during a Resting State.” Science 267 (5197): 528– 31. 7824953
- Gur RE, and Gur RC. 1990 “ Gender Differences in Regional Cerebral Blood Flow.” Schizophrenia Bulletin 16 (2): 247– 54. 2374883
- Haas, de Alexander H., Boddeke Hendrikus W. G. M., and Biber Knut. 2008 “ Region-Specific Expression of Immunoregulatory Proteins on Microglia in the Healthy CNS.” Glia 56 (8): 888– 94. 18338796
- Haimon Zhana, Volaski Alon, Orthgiess Johannes, Sigalit Boura-Halfon Diana Varol, Shemer Anat, Yona Simon, 2018 “ Re-Evaluating Microglia Expression Profiles Using RiboTag and Cell Isolation Strategies.” Nature Immunology 19 (6): 636– 44. 29777220 PMC5986066
- Hanisch Uwe-Karsten, and Kettenmann Helmut. 2007 “ Microglia: Active Sensor and Versatile Effector Cells in the Normal and Pathologic Brain.” Nature Neuroscience 10 (11): 1387– 94. 17965659
- Harbo Hanne F., Gold Ralf, and Tintoré Mar. 2013 “ Sex and Gender Issues in Multiple Sclerosis.” Therapeutic Advances in Neurological Disorders 6 (4): 237– 48. 23858327 PMC3707353
- Heard Edith, and Disteche Christine M.. 2006 “ Dosage Compensation in Mammals: Fine-Tuning the Expression of the X Chromosome.” Genes & Development 20 (14): 1848– 67. 16847345
- Hoeffel Guillaume, and Ginhoux Florent. 2015 “ Ontogeny of Tissue-Resident Macrophages.” Frontiers in Immunology 6 (9): 486. 26441990 PMC4585135
- Kaiser Tobias, and Feng Guoping. 2019 “ Tmem119-EGFP and Tmem119-CreERT2 Transgenic Mice for Labeling and Manipulating Microglia.” eNeuro 6 (4). 10.1523/ENEURO.0448-18.2019. PMC6712208 31371457 · DOI · Paper page
- Konkle Anne T. M., and McCarthy Margaret M.. 2011 “ Developmental Time Course of Estradiol, Testosterone, and Dihydrotestosterone Levels in Discrete Regions of Male and Female Rat Brain.” Endocrinology 152 (1): 223– 35. 21068160 PMC3033055
- Kopec Ashley M., Smith Caroline J., Ayre Nathan R., Sweat Sean C., and Bilbo Staci D.. 2018 “ Microglial Dopamine Receptor Elimination Defines Sex-Specific Nucleus Accumbens Development and Social Behavior in Adolescent Rats.” Nature Communications 9 (1): 3769. PMC6156594 30254300
- Lehmann Sabrina M., Christina Krüger Boyoun Park, Derkow Katja, Rosenberger Karen, Baumgart Jan, Trimbuch Thorsten, 6/ 2012 “ An Unconventional Role for miRNA: Let-7 Activates Toll-like Receptor 7 and Causes Neurodegeneration.” Nature Neuroscience 15 (6): 827– 35. 22610069
- Lenz Kathryn M., Nugent Bridget M., Haliyur Rachana, and McCarthy Margaret M.. 2013 “ Microglia Are Essential to Masculinization of Brain and Behavior.” The Journal of Neuroscience: The Official Journal of the Society for Neuroscience 33 (7): 2761– 72. 23407936 PMC3727162
- Lenz Kathryn M., Pickett Lindsay A., Wright Christopher L., Davis Katherine T., Joshi Aarohi, and McCarthy Margaret M.. 2018 “ Mast Cells in the Developing Brain Determine Adult Sexual Behavior.” The Journal of Neuroscience: The Official Journal of the Society for Neuroscience 38 (37): 8044– 59. 30093566 PMC6136154
- Liu Zhaoyuan, Gu Yaqi, Chakarov Svetoslav, Bleriot Camille, Chen Xin, Shin Amanda, Huang Weijie, 2019 “ Fate Mapping via Ms4a3 Expression History Traces Monocyte-Derived Cells.” bioRxiv. 10.1101/652032. 31491389 · DOI
- Lyck Lise, Ishar Dalmau Santamaria Bente Pakkenberg, Chemnitz John, Henrik Daa Schrøder Bente Finsen, and Hans Jørgen G. Gundersen. 2009 “ An Empirical Analysis of the Precision of Estimating the Numbers of Neurons and Glia in Human Neocortex Using a Fractionator-Design with Sub-Sampling.” Journal of Neuroscience Methods 182 (2): 143– 56. 19520115
- McBride Devin W., and Zhang John H.. 2017 “ Precision Stroke Animal Models: The Permanent MCAO Model Should Be the Primary Model, Not Transient MCAO.” Translational Stroke Research, 7 10.1007/s12975-017-0554-2. PMC5772000 28718030 · DOI
- McCarthy Margaret M., Pickett Lindsay A., VanRyzin Jonathan W., and Kight Katherine E.. 2015 “ Surprising Origins of Sex Differences in the Brain.” Hormones and Behavior 76 (11): 3– 10. 25917865 PMC4620061
- Mills Evanna L., Kelly Beth, and O’Neil Luke A. J.. 2017 “ Mitochondria Are the Powerhouses of Immunity.” Nature Immunology 18 (5): 488– 98. 28418387
- Moreira Ana C., Silva Ana M., Santos Maria S., and Sardão Vilma A.. 2013 “ Resveratrol Affects Differently Rat Liver and Brain Mitochondrial Bioenergetics and Oxidative Stress in Vitro: Investigation of the Role of Gender.” Food and Chemical Toxicology: An International Journal Published for the British Industrial Biological Research Association 53 (3): 18– 26. 23200887
- Mrdjen Dunja, Pavlovic Anto, Hartmann Felix J., Schreiner Bettina, Utz Sebastian G., Leung Brian P., Lelios Iva, 2018 “ High-Dimensional Single-Cell Mapping of Central Nervous System Immune Cells Reveals Distinct Myeloid Subsets in Health, Aging, and Disease.” Immunity 48 (2): 380– 95.e6. 29426702
- Nagy Csörsz, and Haschemi Arvand. 2015 “ Time and Demand Are Two Critical Dimensions of Immunometabolism: The Process of Macrophage Activation and the Pentose Phosphate Pathway.” Frontiers in Immunology 6 (4): 164. 25904920 PMC4389563
- Nelson Lars H., Warden Spencer, and Lenz Kathryn M.. 2017 “ Sex Differences in Microglial Phagocytosis in the Neonatal Hippocampus.” Brain, Behavior, and Immunity 64 (8): 11– 22. PMC5512447 28341582
- Nimmerjahn Axel, Kirchhoff Frank, and Helmchen Fritjof. 2005 “ Resting Microglial Cells Are Highly Dynamic Surveillants of Brain Parenchyma in Vivo.” Science 308 (5726): 1314– 18. 15831717
- Olenchock Benjamin A., Rathmell Jeffrey C., and Vander Heiden. 2017 “ Biochemical Underpinnings of Immune Cell Metabolic Phenotypes.” Immunity 46 (5): 703– 13. 28514672 PMC5660630
- O’Neill Luke A. J., Kishton Rigel J., and Rathmell Jeff. 2016 “ A Guide to Immunometabolism for Immunologists.” Nature Reviews. Immunology 16 (9): 553– 65. PMC5001910 27396447
- O’Shaughnessy Peter J., Monteiro Ana, Bhattacharya Siladitya, and Fowler Paul A.. 2011 “ Maternal Smoking and Fetal Sex Significantly Affect Metabolic Enzyme Expression in the Human Fetal Liver.” The Journal of Clinical Endocrinology and Metabolism 96 (9): 2851– 60. 21715529
- Parkhurst Christopher N., Yang Guang, Ninan Ipe, Savas Jeffrey N., Yates John R. 3rd, Lafaille Juan J., Hempstead Barbara L., Littman Dan R., and Gan Wen-Biao. 2013 “ Microglia Promote Learning-Dependent Synapse Formation through Brain-Derived Neurotrophic Factor.” Cell 155 (7): 1596– 1609. 24360280 PMC4033691
- Pearce Erika L., and Pearce Edward J.. 2013 “ Metabolic Pathways in Immune Cell Activation and Quiescence.” Immunity 38 (4): 633– 43. 23601682 PMC3654249
- Pelvig DP, Pakkenberg H, Stark AK, and Pakkenberg B. 2008 “ Neocortical Glial Cell Numbers in Human Brains.” Neurobiology of Aging 29 (11): 1754– 62. 17544173
- Pinheiro Iris, Dejager Lien, and Libert Claude. 2011 “ X-Chromosome-Located microRNAs in Immunity: Might They Explain Male/female Differences? The X Chromosome-Genomic Context May Affect X-Located miRNAs and Downstream Signaling, Thereby Contributing to the Enhanced Immune Response of Females.” BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology 33 (11): 791– 802. 21953569
- Pont-Lezica Lorena, Beumer Wouter, Colasse Sabrina, Drexhage Hemmo, Versnel Marjan, and Bessis Alain. 2014 “ Microglia Shape Corpus Callosum Axon Tract Fasciculation: Functional Impact of Prenatal Inflammation.” The European Journal of Neuroscience 39 (10): 1551– 57. 24593277
- Qian Bin-Zhi, Li Jiufeng, Zhang Hui, Kitamura Takanori, Zhang Jinghang, Campion Liam R., Kaiser Elizabeth A., Snyder Linda A., and Pollard Jeffrey W.. 2011 “ CCL2 Recruits Inflammatory Monocytes to Facilitate Breast-Tumour Metastasis.” Nature 475 (7355): 222– 25. 21654748 PMC3208506
- Ransohoff Richard M. 2016 “ A Polarizing Question: Do M1 and M2 Microglia Exist?” Nature Neuroscience 19 (8): 987– 91. 27459405
- Rodriguez G, Warkentin S, Risberg J, and Rosadini G. 1988 “ Sex Differences in Regional Cerebral Blood Flow.” Journal of Cerebral Blood Flow and Metabolism: Official Journal of the International Society of Cerebral Blood Flow and Metabolism 8 (6): 783– 89. 3192645
- Rothhammer Veit, Borucki Davis M., Tjon Emily C., Takenaka Maisa C., Chao Chun-Cheih, Ardura-Fabregat Alberto, Alves de Lima Kalil, 2018 “ Microglial Control of Astrocytes in Response to Microbial Metabolites.” Nature 557 (7707): 724– 28. 29769726 PMC6422159
- Samokhvalov Igor M., Samokhvalova Natalia I., and Nishikawa Shin-Ichi. 2007 “ Cell Tracing Shows the Contribution of the Yolk Sac to Adult Haematopoiesis.” Nature 446 (7139): 1056– 61. 17377529
- Sato Miyuki, and Sato Ken. 2013 “ Maternal Inheritance of Mitochondrial DNA by Diverse Mechanisms to Eliminate Paternal Mitochondrial DNA.” Biochimica et Biophysica Acta 1833 (8): 1979– 84. 23524114
- Satterthwaite Theodore D., Shinohara Russell T., Wolf Daniel H., Hopson Ryan D., Elliott Mark A., Vandekar Simon N., Ruparel Kosha, 2014 “ Impact of Puberty on the Evolution of Cerebral Perfusion during Adolescence.” Proceedings of the National Academy of Sciences of the United States of America 111 (23): 8643– 48. 24912164 PMC4060665
- Schafer Dorothy P., Lehrman Emily K., and Stevens Beth. 2013 “ The ‘Quad-Partite’ Synapse: Microglia-Synapse Interactions in the Developing and Mature CNS.” Glia 61 (1): 24– 36. 22829357 PMC4082974
- Schlegelmilch Timm, Henke Katrin, and Peri Francesca. 2011 “ Microglia in the Developing Brain: From Immunity to Behaviour.” Current Opinion in Neurobiology 21 (1): 5– 10. 20817438
- Schwarz Jaclyn M., Sholar Paige W., and Bilbo Staci D.. 2012 “ Sex Differences in Microglial Colonization of the Developing Rat Brain.” Journal of Neurochemistry 120 (6): 948– 63. 22182318 PMC3296888
- Sedgwick JD, Schwender S, Imrich H, Dörries R, Butcher GW, and ter Meulen V. 1991 “ Isolation and Direct Characterization of Resident Microglial Cells from the Normal and Inflamed Central Nervous System.” Proceedings of the National Academy of Sciences of the United States of America 88 (16): 7438– 42. 1651506 PMC52311
- Seki Scott M., and Gaultier Alban. 2017 “ Exploring Non-Metabolic Functions of Glycolytic Enzymes in Immunity.” Frontiers in Immunology 8 (11): 1549. 29213268 PMC5702622
- Silvin Aymeric, and Ginhoux Florent. 2018 “ Microglia Heterogeneity along a Spatio-Temporal Axis: More Questions than Answers.” Glia 66 (10): 2045– 57. 30144321
- Smith Amanda L., Alexander Michelle, Rosenkrantz Ted S., Lisa Sadek Mona, and Fitch R. Holly. 2014 “ Sex Differences in Behavioral Outcome Following Neonatal Hypoxia Ischemia: Insights from a Clinical Meta-Analysis and a Rodent Model of Induced Hypoxic Ischemic Brain Injury.” Experimental Neurology 254 (4): 54– 67. 24434477
- Souyris Mélanie, Cenac Claire, Azar Pascal, Daviaud Danièle, Canivet Astrid, Grunenwald Solange, Pienkowski Catherine, Chaumeil Julie, Mejía José E., and Guéry Jean-Charles. 2018 “ TLR7 Escapes X Chromosome Inactivation in Immune Cells.” Science Immunology 3 (19): eaap8855. 29374079
- Spach Karen M., Blake Melissa, Bunn Janice Y., Ben McElvany Rajkumar Noubade, Blankenhorn Elizabeth P., and Teuscher Cory. 2009 “ Cutting Edge: The Y Chromosome Controls the Age-Dependent Experimental Allergic Encephalomyelitis Sexual Dimorphism in SJL/J Mice.” Journal of Immunology 182 (4): 1789– 93. PMC2658649 19201829
- Squarzoni Paola, Oller Guillaume, Hoeffel Guillaume, Lorena Pont-Lezica Philippe Rostaing, Low Donovan, Bessis Alain, Ginhoux Florent, and Garel Sonia. 2014 “ Microglia Modulate Wiring of the Embryonic Forebrain.” Cell Reports 8 (5): 1271– 79. 25159150
- Stremmel C, Schuchert R, Wagner F, Thaler R, Weinberger T, Pick R, Mass E, 2018 “ Yolk Sac Macrophage Progenitors Traffic to the Embryo during Defined Stages of Development.” Nature Communications 9 (1): 75. PMC5758709 29311541
- Swinnen Nina, Smolders Sophie, Avila Ariel, Notelaers Kristof, Paesen Rik, Ameloot Marcel, Bert Brône Pascal Legendre, and Rigo Jean-Michel. 2013 “ Complex Invasion Pattern of the Cerebral Cortex Bymicroglial Cells during Development of the Mouse Embryo.” Glia 61 (2): 150– 63. 23001583
- Teuscher Cory, Noubade Rajkumar, Spach Karen, Benjamin McElvany Janice Y. Bunn, Fillmore Parley D., Zachary James F., and Blankenhorn Elizabeth P.. 2006 “ Evidence That the Y Chromosome Influences Autoimmune Disease in Male and Female Mice.” Proceedings of the National Academy of Sciences of the United States of America 103 (21): 8024– 29. 16702550 PMC1472423
- Thibaut Florence. 2016 “ The Role of Sex and Gender in Neuropsychiatric Disorders.” Dialogues in Clinical Neuroscience 18 (4): 351– 52. 28179806 PMC5286720
- Thion Morgane S., Ginhoux Florent, and Garel Sonia. 2018 “ Microglia and Early Brain Development: An Intimate Journey.” Science 362 (6411): 185– 89. 30309946
- Thion Morgane Sonia, Low Donovan, Silvin Aymeric, Chen Jinmiao, Grisel Pauline, Jonas Schulte-Schrepping Ronnie Blecher, 2018 “ Microbiome Influences Prenatal and Adult Microglia in a Sex-Specific Manner.” Cell 172 (3): 500– 516.e16. 29275859 PMC5786503
- Van den Bossche Jan, O’Neill Luke A., and Menon Deepthi. 2017 “Macrophage Immunometabolism: Where Are We (Going)?” Trends in Immunology 38 (6): 395– 406. 28396078
- VanRyzin Jonathan W., Pickett Lindsay A., and McCarthy Margaret M.. 2018 “ Microglia: Driving Critical Periods and Sexual Differentiation of the Brain.” Developmental Neurobiology 78 (6): 580– 92. 29243403 PMC5980665
- Verney Catherine, Monier Anne, Fallet-Bianco Catherine, and Gressens Pierre. 2010 “ Early Microglial Colonization of the Human Forebrain and Possible Involvement in Periventricular White-Matter Injury of Preterm Infants.” Journal of Anatomy 217 (4): 436– 48. 20557401 PMC2992419
- Villa Alessandro, Gelosa Paolo, Castiglioni Laura, Cimino Mauro, Rizzi Nicoletta, Pepe Giovanna, Lolli Federica, 2018 “ Sex-Specific Features of Microglia from Adult Mice.” Cell Reports 23 (12): 3501– 11. 29924994 PMC6024879
- Voloboueva Ludmila A., Emery John F., Sun Xiaoyun, and Giffard Rona G.. 2013 “ Inflammatory Response of Microglial BV-2 Cells Includes a Glycolytic Shift and Is Modulated by Mitochondrial Glucose-Regulated Protein 75/mortalin.” FEBS Letters 587 (6): 756– 62. 23395614 PMC3603371
- Wang Luxi, Pavlou Sofia, Du Xuan, Bhuckory Mohajeet, Xu Heping, and Chen Mei. 2019 “ Glucose Transporter 1 Critically Controls Microglial Activation through Facilitating Glycolysis.” Molecular Neurodegeneration 14 (1): 2. 30634998 PMC6329071
- Wang Xu, Soloway Paul D., and Clark Andrew G.. 2010 “ Paternally Biased X Inactivation in Mouse Neonatal Brain.” Genome Biology 11 (7): R79. 20663224 PMC2926790
- Weisz J, and Ward IL. 1980 “ Plasma Testosterone and Progesterone Titers of Pregnant Rats, Their Male and Female Fetuses, and Neonatal Offspring.” Endocrinology 106 (1): 306– 16. 7349961
- Zeisel Amit, Muñoz-Manchado Ana B., Codeluppi Simone, Lönnerberg Peter, La Manno Gioele, Juréus Anna, Marques Sueli, 2015 “ Brain Structure. Cell Types in the Mouse Cortex and Hippocampus Revealed by Single-Cell RNA-Seq.” Science 347 (6226): 1138– 42. 25700174
Cited by
Sorted by citations
Uncovering sex differences of rodent microglia
Han, J., Fan, Y., Zhou, K., Blomgren, K., & Harris, R. A. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02124-z · Cited by 224 · see citing works
Dysregulated phosphoinositide 3-kinase signaling in microglia: shaping chronic neuroinflammation
Chu, E., Mychasiuk, R., Hibbs, M. L., & Semple, B. D. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02325-6 · Cited by 152 · see citing works
Exploring Sex-Related Differences in Microglia May Be a Game-Changer in Precision Medicine
Lynch, M. A. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.868448 · Cited by 146 · see citing works
Brain macrophage development, diversity and dysregulation in health and disease
Silvin, A., Qian, J., & Ginhoux, F. (2023) · Cellular & Molecular Immunology · doi:10.1038/s41423-023-01053-6 · Cited by 137 · see citing works
Mesocorticolimbic Dopamine Pathways Across Adolescence: Diversity in Development
Reynolds, L. M., & Flores, C. (2021) · Frontiers in Neural Circuits · doi:10.3389/fncir.2021.735625 · Cited by 137 · see citing works
Bosch, M. E., Dodiya, H. B., Michalkiewicz, J., Lee, C., Shaik, S. M., Weigle, I. Q., Zhang, C., Osborn, J., Nambiar, A., Patel, P., et al. (2024) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00700-w · Cited by 70 · see citing works
Microglia and Sensitive Periods in Brain Development
Dziabis, J. E., & Bilbo, S. D. (2021) · Current Topics in Behavioral Neurosciences · doi:10.1007/7854_2021_242 · Cited by 42 · see citing works
Self-citationWalsh, A. D., Stone, S., Freytag, S., Aprico, A., Kilpatrick, T. J., Ansell, B. R. E., & Binder, M. D. (2023) · Communications Biology · doi:10.1038/s42003-023-04926-8 · Cited by 9 · see citing works
- Authors
- Bordt, E. A., Ceasrine, A. M., & Bilbo, S. D.
- Venue
- Glia
- Publisher
- Wiley
- Published
- 2019-11-19
- Volume
- 68
- Issue
- 6
- Pages
- 1085-1099
- ISSN
- 0894-1491
- 1098-1136
- PMC
- PMC7148120
- Cited by
- 118
- References
- 31
- Language
- en
- Funders
- National Institute of Environmental Health Sciences (R01 ES025549)
- National Institute of Mental Health (F32 MH116604, R01 MH101183)
- National Institute on Drug Abuse (R01 DA034185)
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
