Sex differences in microglial phagocytosis in the neonatal hippocampus
Open accessAbstract
Microglia regulate brain development through many processes, such as promoting neurogenesis, supporting cell survival, and phagocytizing progenitor, newly-born, and dying cells. Many of these same developmental processes show robust sex differences, yet very few studies have assessed sex differences in microglia function during development. Hormonally-induced sexual differentiation of the brain occurs during the perinatal period, thus we examined sex differences in microglial morphology, phagocytosis, and proliferation in the hippocampus during the early postnatal period. We found that the neonatal female hippocampus had significantly more microglia with phagocytic cups than the male hippocampus. We subsequently found that female microglia phagocytized more neural progenitor cells and healthy cells compared to males, but there were no sex differences in the number of newly-born or dying cells targeted by microglial phagocytosis. We found that the number of phagocytic microglia in females was reduced to male-typical levels by treatment with estradiol, the hormone responsible for masculinizing the rodent brain. Females also had higher expression of several phagocytic pathway genes in the hippocampus compared to males. In contrast to robust sex differences in phagocytic microglia, we found no sex differences in the number of microglia with amoeboid, transitioning, or ramified morphologies or differences in three-dimensional reconstructions of microglial morphology. While we did not find a baseline sex difference in microglial proliferation during or following the prenatal gonadal hormone surge in males, we found that estradiol treatment increased microglia proliferation in females. Overall, these data show that there are important sex differences in microglia function in the hippocampus during the early neonatal period.
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Cites
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
Zhang, Y., Chen, K., Sloan, S. A., Bennett, M. L., Scholze, A. R., O'Keeffe, S., Phatnani, H. P., Guarnieri, P., Caneda, C., Ruderisch, N., et al. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.1860-14.2014 · Cited by 4,875 · 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
Altman, J., & Bayer, S. A. (1990) · Journal of Comparative Neurology · doi:10.1002/cne.903010304 · Cited by 819 · see citing works
Layer V cortical neurons require microglial support for survival during postnatal development
Ueno, M., Fujita, Y., Tanaka, T., Nakamura, Y., Kikuta, J., Ishii, M., & Yamashita, T. (2013) · Nature Neuroscience · doi:10.1038/nn.3358 · Cited by 781 · see citing works
Induction of PGE2 by estradiol mediates developmental masculinization of sex behavior
Amateau, S. K., & McCarthy, M. M. (2004) · Nature Neuroscience · doi:10.1038/nn1254 · Cited by 340 · see citing works
Flagged first, then by citations
Research works printed but not linked: 46
- Ahern TH Krug S Carr AV Murray EK Fitzpatrick E Bengston L McCutcheon J De Vries GJ Forger NG 2013 Cell death atlas of the postnatal mouse ventral forebrain and hypothalamus: Effects of age and sex: Cell Death Atlas, Hypothalamus and Forebrain J Comp Neurol 521 2551 2569 10.1002/cne.23298 23296992 PMC4968939 · DOI
- Alliot F Godin I Pessac B 1999 Microglia derive from progenitors, originating from the yolk sac, and which proliferate in the brain Dev Brain Res 117 145 152 10567732
- Amateau SK Alt JJ Stamps CL McCarthy MM 2004 Brain Estradiol Content in Newborn Rats: Sex Differences, Regional Heterogeneity, and Possible de No vo Synthesis by the Female Telencephalon Endocrinology 145 2906 2917 10.1210/en.2003-1363 14988386 · DOI
- Arnò B Grassivaro F Rossi C Bergamaschi A Castiglioni V Furlan R Greter M Favaro R Comi G Becher B Martino G Muzio L 2014 Neural progenitor cells orchestrate microglia migration and positioning into the developing cortex Nat Commun 5 5611 10.1038/ncomms6611 25425146 · DOI
- Bowers JM Waddell J McCarthy MM 2010 A developmental sex difference in hippocampal neurogenesis is mediated by endogenous oestradiol Biol Sex Differ 1 10 1186 PMC3016241 21208470
- Brown GC Neher JJ 2014 Microglial phagocytosis of live neurons Nat Rev Neurosci 15 209 216 24646669
- Cannon JP O’Driscoll M Litman GW 2012 Specific lipid recognition is a general feature of CD300 and TREM molecules Immunogenetics 64 39 47 10.1007/s00251-011-0562-4 21800138 · DOI
- Chertoff M Shrivastava K Gonzalez B Acarin L Giménez-Llort L 2013 Differential Modulation of TREM2 Protein during Postnatal Brain Development in Mice PLoS ONE 8 e72083 10.1371/journal.pone.0072083 23977213 PMC3747061 · DOI
- Crain JM Nikodemova M Watters JJ 2013 Microglia express distinct M1 and M2 phenotypic markers in the postnatal and adult central nervous system in male and female mice: Microglial Gene Expression in Healthy Brain J Neurosci Res 91 1143 1151 10.1002/jnr.23242 23686747 PMC3715560 · DOI
- Cunningham CL Martinez-Cerdeno V Noctor SC 2013 Microglia Regulate the Number of Neural Precursor Cells in the Developing Cerebral Cortex J Neurosci 33 4216 4233 10.1523/JNEUROSCI.3441-12.2013 23467340 PMC3711552 · DOI · Paper page
- Dalmau I Finsen B Tønder N Zimmer J Gonzalez B Castellano B 1997 Development of microglia in the prenatal rat hippocampus J Comp Neurol 377 70 84 8986873
- Dalmau I Finsen B Zimmer J González B Castellano B 1998 Development of microglia in the postnatal rat hippocampus Hippocampus 8 458 474 9825958
- Eyo UB Miner SA Weiner JA Dailey ME 2016 Developmental changes in microglial mobilization are independent of apoptosis in the neonatal mouse hippocampus Brain Behav Immun 55 49 59 10.1016/j.bbi.2015.11.009 26576723 PMC4864211 · DOI
- Forger NG Strahan JA Castillo-Ruiz A 2016 Cellular and molecular mechanisms of sexual differentiation in the mammalian nervous system Front Neuroendocrinol 40 67 86 10.1016/j.yfrne.2016.01.001 26790970 PMC4897775 · DOI
- Guadagno J Swan P Shaikh R Cregan SP 2015 Microglia-derived IL-1β triggers p53-mediated cell cycle arrest and apoptosis in neural precursor cells Cell Death Dis 6 e1779 10.1038/cddis.2015.151 26043079 PMC4669832 · DOI
- Hodge RD Garcia AJ Elsen GE Nelson BR Mussar KE Reiner SL Ramirez JM Hevner RF 2013 Tbr2 Expression in Cajal-Retzius Cells and Intermediate Neuronal Progenitors Is Required for Morphogenesis of the Dentate Gyrus J Neurosci 33 4165 4180 10.1523/JNEUROSCI.4185-12.2013 23447624 PMC3623668 · DOI
- Hsieh CL Koike M Spusta SC Niemi EC Yenari M Nakamura MC Seaman WE 2009 A role for TREM2 ligands in the phagocytosis of apoptotic neuronal cells by microglia Journal of Neurochemistry 109 1144 1156 10.1111/j.1471-4159.2009.06042.x 19302484 PMC3087597 · DOI · Paper page
- Ivanova T Beyer C 2000 Ontogenetic expression and sex differences of aromatase and estrogen receptor- αβ; mRNA in the mouse hippocampus Cell Tissue Res 300 231 237 10.1007/s004410000199 10867819 · DOI
- Khalaf-Nazzal R Francis F 2013 Hippocampal development — Old and new findings Neuroscience 248 225 242 10.1016/j.neuroscience.2013.05.061 23756184 · DOI
- Konkle ATM McCarthy MM 2011 Developmental Time Course of Estradiol, Testosterone, and Dihydrotestosterone Levels in Discrete Regions of Male and Female Rat Brain Endocrinology 152 223 235 10.1210/en.2010-0607 21068160 PMC3033055 · DOI
- Krebs-Kraft DL Hill MN Hillard CJ McCarthy MM 2010 Sex difference in cell proliferation in developing rat amygdala mediated by endocannabinoids has implications for social behavior Proc Natl Acad Sci 107 20535 20540 10.1073/pnas.1005003107 21059913 PMC2996668 · DOI · Paper page
- Lelli A Gervais A Colin C Chéret C de Almodovar CR Carmeliet P Krause KH Boillée S Mallat M 2013 The NADPH oxidase Nox2 regulates VEGFR1/CSF-1R-mediated microglial chemotaxis and promotes early postnatal infiltration of phagocytes in the subventricular zone of the mouse cerebral cortex: Microglial Nox2 in Development Glia 61 1542 1555 10.1002/glia.22540 23836548 · DOI
- Lenz KM Nugent BM Haliyur R McCarthy MM 2013 Microglia Are Essential to Masculinization of Brain and Behavior J Neurosci 33 2761 2772 10.1523/JNEUROSCI.1268-12.2013 23407936 PMC3727162 · DOI · Paper page
- McArthur S Cristante E Paterno M Christian H Roncaroli F Gillies GE Solito E 2010 Annexin A1: A Central Player in the Anti-Inflammatory and Neuroprotective Role of Microglia J Immunol 185 6317 6328 10.4049/jimmunol.1001095 20962261 PMC3145124 · DOI
- McCarthy MM Schwarz JM Wright CL Dean SL 2008 Mechanisms Mediating Oestradiol Modulation of the Developing Brain J Neuroendocrinol 20 777 783 10.1111/j.1365-2826.2008.01723.x 18601700 PMC2570052 · DOI
- Mosher KI Andres RH Fukuhara T Bieri G Hasegawa-Moriyama M He Y Guzman R Wyss-Coray T 2012 Neural progenitor cells regulate microglia functions and activity Nat Neurosci 15 1485 1487 23086334 PMC3495979
- Mosley M Shah C Morse KA Miloro SA Holmes MM Ahern TH Forger NG 2016 Patterns of cell death in the perinatal mouse forebrain: Cell death in the perinatal mouse brain J Comp Neurol 10.1002/cne.24041 PMC5116296 27199256 · DOI
- Neher JJ Neniskyte U Hornik T Brown GC 2014 Inhibition of UDP/P2Y6 purinergic signaling prevents phagocytosis of viable neurons by activated microglia in vitro and in vivo: P2Y6 Purinergic Signaling in Phagoptosis Glia 62 1463 1475 10.1002/glia.22693 24838858 PMC4336556 · DOI
- Norden DM Trojanowski PJ Villanueva E Navarro E Godbout JP 2016 Sequential activation of microglia and astrocyte cytokine expression precedes increased iba-1 or GFAP immunoreactivity following systemic immune challenge: Iba1 and GFAP Are Unreliable Activation Markers Glia 64 300 316 10.1002/glia.22930 26470014 PMC4707977 · DOI
- Nugent BM Wright CL Shetty AC Hodes GE Lenz KM Mahurkar A Russo SJ Devine SE McCarthy MM 2015 Brain feminization requires active repression of masculinization via DNA methylation Nat Neurosci 18 690 697 10.1038/nn.3988 25821913 PMC4519828 · DOI
- Perez-Pouchoulen M VanRyzin JW McCarthy MM 2015 Morphological and Phagocytic Profile of Microglia in the Developing Rat Cerebellum eNeuro 2 10.1523/ENEURO.0036-15.2015 PMC4596010 26464992 · DOI
- Preissler J Grosche A Lede V Le Duc D Krügel K Matyash V Szulzewsky F Kallendrusch S Immig K Kettenmann H Bechmann I Schöneberg T Schulz A 2015 Altered microglial phagocytosis in GPR34-deficient mice: Microglial Phagocytosis in GPR34−/− Mice Glia 63 206 215 10.1002/glia.22744 25142016 · DOI
- Rhoda J Corbier P Roffi J 1984 Gonadal steroid concentrations in serum and hypothalamus of the rat at birth: aromatization of testosterone to 17 beta-estradiol Endocrinology 114 1754 1760 10.1210/endo-114-5-1754 6714163 · DOI
- Russell DG VanderVen BC Glennie S Mwandumba H Heyderman RS 2009 The macrophage marches on its phagosome: dynamic assays of phagosome function Nature Reviews Immunology 9 594 600 PMC2776640 19590530
- Schwarz JM Sholar PW Bilbo SD 2012 Sex differences in microglial colonization of the developing rat brain: Sex differences in microglial colonization J Neurochem no–no 10.1111/j.1471-4159.2011.07630.x PMC3296888 22182318 · DOI · Paper page
- Scotland RS Stables MJ Madalli S Watson P Gilroy DW 2011 Sex differences in resident immune cell phenotype underlie more efficient acute inflammatory responses in female mice Blood 118 5918 5927 10.1182/blood-2011-03-340281 21911834 PMC5363818 · DOI
- Shigemoto-Mogami Y Hoshikawa K Goldman JE Sekino Y Sato K 2014 Microglia Enhance Neurogenesis and Oligodendrogenesis in the Early Postnatal Subventricular Zone J Neurosci 34 2231 2243 10.1523/JNEUROSCI.1619-13.2014. 24501362 PMC3913870 · DOI
- Solum DT Handa RJ 2001 Localization of estrogen receptor alpha (ERa) in pyramidal neurons of the developing rat hippocampus Dev Brain Res 165 175 11412902
- Spittau B Rilka J Steinfath E Zöller T Krieglstein K 2015 TGFβ1 increases microglia-mediated engulfment of apoptotic cells via upregulation of the milk fat globule-EGF factor 8: TGFβ1 Upregulates Mfge8 Expression Glia 63 142 153 10.1002/glia.22740 25130376 · DOI
- Surace MJ Block ML 2012 Targeting microglia-mediated neurotoxicity: the potential of NOX2 inhibitors Cellular and Molecular Life Sciences 69 2409 2427 10.1007/s00018-012-1015-4. 22581365 PMC3677079 · DOI
- Waddell J Bowers JM Edwards NS Jordan CL McCarthy MM 2013 Dysregulation of neonatal hippocampal cell genesis in the androgen insensitive Tfm rat Horm Behav 64 144 152 10.1016/j.yhbeh.2013.05.009 23747829 PMC3753588 · DOI
- Wakselman S Bechade C Roumier A Bernard D Triller A Bessis A 2008 Developmental Neuronal Death in Hippocampus Requires the Microglial CD11b Integrin and DAP12 Immunoreceptor J Neurosci 28 8138 8143 10.1523/JNEUROSCI.1006-08.2008 18685038 PMC6670768 · DOI · Paper page
- Wang Y Cella M Mallinson K Ulrich JD Young KL Robinette ML Gilfillan S Krishnan GM Sudhakar S Zinselmeyer BH Holtzman DM Cirrito JR Colonna M 2015 TREM2 Lipid Sensing Sustains the Microglial Response in an Alzheimer’s Disease Model Cell 160 1061 1071 10.1016/j.cell.2015.01.049 25728668 PMC4477963 · DOI · Paper page
- Weisz J Ward IL 1980 Plasma testosterone and progesterone titers of pregnant rats, their male and female fetuses, and neonatal offspring Endocrinology 106 306 316 10.1210/endo-106-1-306 7349961 · DOI · Paper page
- Zhang JM Konkle ATM Zup SL McCarthy MM 2008 Impact of sex and hormones on new cells in the developing rat hippocampus: a novel source of sex dimorphism? Eur J Neurosci 27 791 800 10.1111/j.1460-9568.2008.06073.x 18333959 PMC2735768 · DOI · Paper page
- Zuloaga DG Zuloaga KL Hinds LR Carbone DL Handa RJ 2014 Estrogen receptor β expression in the mouse forebrain: Age and sex differences: Estrogen receptor β forebrain distribution J Comp Neurol 522 358 371 10.1002/cne.23400 23818057 PMC4815281 · DOI
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- Authors
- Nelson, L. H., Warden, S., & Lenz, K. M.
- Affiliations
- The Ohio State University (US)
- Corresponding author
- Nelson, Lars H.
- Venue
- Brain, Behavior, and Immunity
- Publisher
- Elsevier BV
- Published
- 2017-08
- Volume
- 64
- Pages
- 11-22
- ISSN
- 0889-1591 (ISSN-L)
- PMC
- PMC5512447
- OpenAlex
- W2600475754
- Cited by
- 189
- References
- 6
- Citations by year
- 2026: 13 · 2025: 13 · 2024: 25 · 2023: 24 · 2022: 25 · 2021: 21 · 2020: 18 · 2019: 23 · 2018: 18 · 2017: 8
- FWCI
- 8.94
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- Locations
- Brain Behavior and Immunity (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- OSU
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Sex and Gender in Healthcare
- Keywords
- sex differences, microglia, phagocytosis, neonatal hippocampus, neural progenitor cells, estradiol, gonadal hormones, microglial morphology, microglial proliferation, sexual differentiation of the brain, postnatal development
- MeSH terms
- Animals, Animals, Newborn, Female, Hippocampus, Male, Phagocytosis, Sex Characteristics, Gene Expression, Rats, Sprague-Dawley, Microglia, Cell Proliferation
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