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Journal of neuroinflammation
Jan 24, 2025;22 (1): 18.

Sex chromosomes and sex hormones differently shape microglial properties during normal physiological conditions in the adult mouse hippocampus.

Bianca Caroline Bobotis, Mohammadparsa Khakpour, Olivia Braniff, Elisa Gonçalves de Andrade, Makenna Gargus, Micah Allen, Micaël Carrier, Joanie Baillargeon, Manu Rangachari, Marie-Ève Tremblay
Author Information
  1. Bianca Caroline Bobotis: Division of Medical Sciences, University of Victoria, Victoria, BC, Canada.
  2. Mohammadparsa Khakpour: Division of Medical Sciences, University of Victoria, Victoria, BC, Canada.
  3. Olivia Braniff: Division of Medical Sciences, University of Victoria, Victoria, BC, Canada.
  4. Elisa Gonçalves de Andrade: Division of Medical Sciences, University of Victoria, Victoria, BC, Canada.
  5. Makenna Gargus: Division of Medical Sciences, University of Victoria, Victoria, BC, Canada.
  6. Micah Allen: Division of Medical Sciences, University of Victoria, Victoria, BC, Canada.
  7. Micaël Carrier: Division of Medical Sciences, University of Victoria, Victoria, BC, Canada.
  8. Joanie Baillargeon: Axe neurosciences, Centre de recherche du CHU de Québec-Université Laval, Québec City, QC, Canada.
  9. Manu Rangachari: Axe neurosciences, Centre de recherche du CHU de Québec-Université Laval, Québec City, QC, Canada.
  10. Marie-Ève Tremblay: Division of Medical Sciences, University of Victoria, Victoria, BC, Canada. evetremblay@uvic.ca.
PMID: 39856696 DOI: 10.1186/s12974-025-03341-6

Abstract

The brain presents various structural and functional sex differences, for which multiple factors are attributed: genetic, epigenetic, metabolic, and hormonal. While biological sex is determined by both sex chromosomes and sex hormones, little is known about how these two factors interact to establish this dimorphism. Sex differences in the brain also affect its resident immune cells, microglia, which actively survey the brain parenchyma and interact with sex hormones throughout life. However, microglial differences in density and distribution, morphology and ultrastructural patterns in physiological conditions during adulthood are largely unknown. Here, we investigated these aforementioned properties of microglia using the Four Core Genotypes (FCG) model, which allows for an independent assessment of gonadal hormones and sex chromosomal effects in four conditions: FCG XX and Tg XY (both ovaries); Tg XX and Tg XY (both testes). We also compared the FCG results with XX and XY wild-type (WT) mice. In adult mice, we focused our investigation on the ventral hippocampus across different layers: CA1 stratum radiatum (Rad) and CA1 stratum lacunosum-moleculare (LMol), as well as the dentate gyrus polymorphic layer (PoDG). Double immunostaining for Iba1 and TMEM119 revealed that microglial density is influenced by both sex chromosomes and sex hormones. We show in the Rad and LMol that microglia are denser in FCG XX compared to Tg XY mice, however, microglia were densest in WT XX mice. In the PoDG, ovarian animals had increased microglial density compared to testes animals. Additionally, microglial morphology was modulated by a complex interaction between hormones and chromosomes, affecting both their cellular soma and arborization across the hippocampal layers. Moreover, ultrastructural analysis showed that microglia in WT animals make overall more contacts with pre- and post-synaptic elements than in FCG animals. Lastly, microglial markers of cellular stress, including mitochondrion elongation, and dilation of the endoplasmic reticulum and Golgi apparatus, were mostly chromosomally driven. Overall, we characterized different aspects of microglial properties during normal physiological conditions that were found to be shaped by sex chromosomes and sex hormones, shading more light onto how sex differences affect the brain immunity at steady-state.

Keywords

Density Distribution Four core genotypes Hippocampus Microglia Morphology Mouse Scanning Electron Microscopy Sex differences Ultrastructure

References

  1. DeCasien AR, Guma E, Liu S, Raznahan A. Sex differences in the human brain: a roadmap for more careful analysis and interpretation of a biological reality. Biology Sex Differences. 2022;13:43.
  2. Nojima T, Rings A, Allen AM, Otto N, Verschut TA, Billeter J-C, et al. A sex-specific switch between visual and olfactory inputs underlies adaptive sex differences in behavior. Curr Biol. 2021;31:1175–e11916. [PMID: 33508219]
  3. Alfano V, Cavaliere C, Di Cecca A, Ciccarelli G, Salvatore M, Aiello M, et al. Sex differences in functional brain networks involved in interoception: an fMRI study. Front Neurosci. 2023;17:1130025. [PMID: 36998736]
  4. Ratnu VS, Emami MR, Bredy TW. Genetic and epigenetic factors underlying sex differences in the regulation of gene expression in the brain. J Neurosci Res. 2017;95:301–10. [PMID: 27870402]
  5. Weber CM, Clyne AM. Sex differences in the blood–brain barrier and neurodegenerative diseases. APL Bioeng. 2021;5:011509. [PMID: 33758788]
  6. Westergaard D, Moseley P, Sørup FKH, Baldi P, Brunak S. Population-wide analysis of differences in disease progression patterns in men and women. Nat Commun. 2019;10:666. [PMID: 30737381]
  7. Park J-C, Lim H, Byun MS, Yi D, Byeon G, Jung G, et al. Sex differences in the progression of glucose metabolism dysfunction in Alzheimer’s disease. Exp Mol Med. 2023;55:1023–32. [PMID: 37121979]
  8. Harley R, Goodfellow VN. The biochemical role of SRY in sex determination. Mol Reprod Dev. 1994;39:184–93. [PMID: 7826621]
  9. Corre C, Friedel M, Vousden DA, Metcalf A, Spring S, Qiu LR, et al. Separate effects of sex hormones and sex chromosomes on brain structure and function revealed by high-resolution magnetic resonance imaging and spatial navigation assessment of the four core genotype mouse model. Brain Struct Funct. 2016;221:997–1016. [PMID: 25445841]
  10. Bobotis BC, Braniff O, Gargus M, Akinluyi ET, Awogbindin IO, Tremblay M-È. Sex differences of microglia in the healthy brain from embryonic development to adulthood and across lifestyle influences. Brain Res Bull. 2023;202:110752. [PMID: 37652267]
  11. Bramble MS, Lipson A, Vashist N, Vilain E. Effects of chromosomal sex and hormonal influences on shaping sex differences in brain and behavior: lessons from cases of disorders of sex development. J Neurosci Res. 2017;95:65–74. [PMID: 27841933]
  12. Hiort O. The differential role of androgens in early human sex development. BMC Med. 2013;11:152. [PMID: 23800242]
  13. Spritzer MD, Galea LAM. Testosterone and dihydrotestosterone, but not estradiol, enhance survival of new hippocampal neurons in adult male rats. Dev Neurobiol. 2007;67:1321–33. [PMID: 17638384]
  14. Hui CW, Vecchiarelli HA, Gervais É, Luo X, Michaud F, Scheefhals L, et al. Sex differences of Microglia and synapses in the hippocampal dentate gyrus of adult mouse offspring exposed to maternal Immune activation. Front Cell Neurosci. 2020;14:558181. [PMID: 33192308]
  15. Loiola RA, Wickstead ES, Solito E, McArthur S. Estrogen promotes pro-resolving microglial behavior and phagocytic cell clearance through the actions of annexin A1. Front Endocrinol (Lausanne). 2019;10:420.
  16. Bordeleau M, Lacabanne C, Fernández de Cossío L, Vernoux N, Savage JC, González-Ibáñez F, et al. Microglial and peripheral immune priming is partially sexually dimorphic in adolescent mouse offspring exposed to maternal high-fat diet. J Neuroinflamm. 2020;17:264.
  17. Schwarz JM, Sholar PW, Bilbo SD. Sex differences in microglial colonization of the developing rat brain. J Neurochem. 2012;120:948–63. [PMID: 22182318]
  18. Lenz KM, Nugent BM, Haliyur R, McCarthy MM. Microglia are essential to masculinization of Brain and Behavior. J Neurosci. 2013;33:2761–72. [PMID: 23407936]
  19. Doyle HH, Eidson LN, Sinkiewicz DM, Murphy AZ. Sex differences in Microglia Activity within the Periaqueductal Gray of the rat: a potential mechanism driving the Dimorphic effects of Morphine. J Neurosci. 2017;37:3202–14. [PMID: 28219988]
  20. Weinhard L, Neniskyte U, Vadisiute A, di Bartolomei G, Aygün N, Riviere L, et al. Sexual dimorphism of microglia and synapses during mouse postnatal development. Dev Neurobiol. 2018;78:618–26. [PMID: 29239126]
  21. Tremblay M-È. Microglial functional alteration and increased diversity in the challenged brain: insights into novel targets for intervention. Brain Behav Immun - Health. 2021;16:100301.
  22. Tremblay M-È, Majewska AK. Ultrastructural Analyses of Microglial Interactions with synapses. Methods Mol Biol. 2019;2034:83–95. [PMID: 31392679]
  23. Venturino A, Schulz R, De Jesús-Cortés H, Maes ME, Nagy B, Reilly-Andújar F, et al. Microglia enable mature perineuronal nets disassembly upon anesthetic ketamine exposure or 60-Hz light entrainment in the healthy brain. Cell Rep. 2021;36:109313. [PMID: 34233180]
  24. Nguyen PT, Dorman LC, Pan S, Vainchtein ID, Han RT, Nakao-Inoue H, et al. Microglial remodeling of the Extracellular Matrix promotes synapse plasticity. Cell. 2020;182:388–e40315. [PMID: 32615087]
  25. Filipello F, Morini R, Corradini I, Zerbi V, Canzi A, Michalski B, et al. The Microglial Innate Immune receptor TREM2 is required for synapse elimination and normal brain connectivity. Immunity. 2018;48:979–e9918. [PMID: 29752066]
  26. Jiang T, Zhang Y-D, Gao Q, Zhou J-S, Zhu X-C, Lu H, et al. TREM1 facilitates microglial phagocytosis of amyloid beta. Acta Neuropathol. 2016;132:667–83. [PMID: 27670763]
  27. St-Pierre M-K, Bordeleau M, Tremblay M-È. Visualizing dark microglia. Methods Mol Biol. 2019;2034:97–110. https://doi.org/10.1007/978-1-4939-9658-2_8 .
  28. St-Pierre M-K, Carrier M, Lau V, Tremblay M-È. Investigating microglial ultrastructural alterations and intimate relationships with neuronal stress, dystrophy, and degeneration in mouse models of Alzheimer’s Disease. Methods Mol Biol. 2022;2515:29–58. [PMID: 35776344]
  29. Juraska JM, Sisk CL, DonCarlos LL. Sexual differentiation of the adolescent rodent brain: hormonal influences and developmental mechanisms. Horm Behav. 2013;64:203–10. [PMID: 23998664]
  30. Alliot F, Godin I, Pessac B. Microglia derive from progenitors, originating from the yolk sac, and which proliferate in the brain. Brain Res Dev Brain Res. 1999;117:145–52. [PMID: 10567732]
  31. Welsh M, Saunders PTK, Fisken M, Scott HM, Hutchison GR, Smith LB, et al. Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism. J Clin Invest. 2008;118:1479–90. [PMID: 18340380]
  32. Habert R, Picon R. Testosterone, dihydrotestosterone and estradiol-17 beta levels in maternal and fetal plasma and in fetal testes in the rat. J Steroid Biochem. 1984;21:193–8. [PMID: 6482429]
  33. Keller D, Erö C, Markram H. Cell densities in the mouse brain: a systematic review. Front Neuroanat. 2018;12:83.
  34. Sauer J-F, Bartos M. The role of the dentate gyrus in mnemonic functions. Neuroforum. 2020;26:247–54.
  35. García-Ovejero D, Veiga S, García-Segura LM, Doncarlos LL. Glial expression of estrogen and androgen receptors after rat brain injury. J Comp Neurol. 2002;450:256–71. [PMID: 12209854]
  36. Habib P, Dreymueller D, Ludwig A, Beyer C, Dang J. Sex steroid hormone-mediated functional regulation of microglia-like BV-2 cells during hypoxia. J Steroid Biochem Mol Biol. 2013;138:195–205. [PMID: 23792783]
  37. Wu W, Tan X, Dai Y, Krishnan V, Warner M, Gustafsson J-Å. Targeting estrogen receptor β in microglia and T cells to treat experimental autoimmune encephalomyelitis. Proc Natl Acad Sci. 2013;110:3543–8. [PMID: 23401502]
  38. Bisht K, Sharma KP, Lecours C, Sánchez MG, El Hajj H, Milior G, et al. Dark microglia: a new phenotype predominantly associated with pathological states. Glia. 2016;64:826–39. [PMID: 26847266]
  39. Anderson AG, Rogers BB, Loupe JM, Rodriguez-Nunez I, Roberts SC, White LM, et al. Single nucleus multiomics identifies ZEB1 and MAFB as candidate regulators of Alzheimer’s disease-specific cis-regulatory elements. Cell Genomics. 2023;3:100263. [PMID: 36950385]
  40. Lavisse S, Goutal S, Wimberley C, Tonietto M, Bottlaender M, Gervais P, et al. Increased microglial activation in patients with Parkinson disease using [18F]-DPA714 TSPO PET imaging. Parkinsonism Relat Disord. 2021;82:29–36. [PMID: 33242662]
  41. Bovenzi R, Sancesario GM, Conti M, Grillo P, Cerroni R, Bissacco J, et al. Sex hormones differentially contribute to Parkinson disease in males: a multimodal biomarker study. Eur J Neurol. 2023;30:1983–90. [PMID: 36971787]
  42. Lopez-Lee C, Torres ERS, Carling G, Gan L. Mechanisms of sex differences in Alzheimer’s disease. Neuron. 2024;112:1208–21. [PMID: 38402606]
  43. Doss PMIA, Umair M, Baillargeon J, Fazazi R, Fudge N, Akbar I, et al. Male sex chromosomal complement exacerbates the pathogenicity of Th17 cells in a chronic model of central nervous system autoimmunity. Cell Rep. 2021;34:108833. [PMID: 33691111]
  44. Guneykaya D, Ivanov A, Hernandez DP, Haage V, Wojtas B, Meyer N, et al. Transcriptional and Translational Differences of Microglia from male and female brains. Cell Rep. 2018;24:2773–e27836. [PMID: 30184509]
  45. Villa A, Gelosa P, Castiglioni L, Cimino M, Rizzi N, Pepe G, et al. Sex-specific features of Microglia from Adult mice. Cell Rep. 2018;23:3501–11. [PMID: 29924994]
  46. Gildawie KR, Orso R, Peterzell S, Thompson V, Brenhouse HC. Sex differences in prefrontal cortex microglia morphology: impact of a two-hit model of adversity throughout development. Neurosci Lett. 2020;738:135381. [PMID: 32927000]
  47. Itoh Y, Mackie R, Kampf K, Domadia S, Brown JD, O’Neill R, et al. Four core genotypes mouse model: localization of the sry transgene and bioassay for testicular hormone levels. BMC Res Notes. 2015;8:69. [PMID: 25870930]
  48. Lovell-Badge R, Robertson E. XY female mice resulting from a heritable mutation in the primary testis determining gene, Tdy. Development. 1990;109:635–46. [PMID: 2401216]
  49. De Vries GJ, Rissman EF, Simerly RB, Yang L-Y, Scordalakes EM, Auger CJ, et al. A model system for study of sex chromosome effects on sexually dimorphic neural and behavioral traits. J Neurosci. 2002;22:9005–14. [PMID: 12388607]
  50. Bordeleau M, Carrier M, Luheshi GN, Tremblay M-È. Microglia along sex lines: from brain colonization, maturation and function, to implication in neurodevelopmental disorders. Semin Cell Dev Biol. 2019;94:152–63. [PMID: 31201858]
  51. Hojo Y, Higo S, Kawato S, Hatanaka Y, Ooishi Y, Murakami G, et al. Hippocampal synthesis of sex steroids and corticosteroids: essential for modulation of synaptic plasticity. Front Endocrinol (Lausanne). 2011;2:43. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3356120/
  52. Hojo Y, Murakami G, Mukai H, Higo S, Hatanaka Y, Ogiue-Ikeda M, et al. Estrogen synthesis in the brain—role in synaptic plasticity and memory. Mol Cell Endocrinol. 2008;290:31–43. [PMID: 18541362]
  53. Ooishi Y, Kawato S, Hojo Y, Hatanaka Y, Higo S, Murakami G, et al. Modulation of synaptic plasticity in the hippocampus by hippocampus-derived estrogen and androgen. J Steroid Biochem Mol Biol. 2012;131:37–51. [PMID: 22075082]
  54. Fanselow MS, Dong H-W. Are the dorsal and ventral Hippocampus functionally distinct structures? Neuron. 2010;65:7–19. [PMID: 20152109]
  55. Jinno S, Klausberger T, Marton LF, Dalezios Y, Roberts JDB, Fuentealba P, et al. Neuronal diversity in GABAergic Long-Range projections from the Hippocampus. J Neurosci. 2007;27:8790–804. [PMID: 17699661]
  56. De Felice E, Gonçalves de Andrade E, Golia MT, González Ibáñez F, Khakpour M, Di Castro MA, et al. Microglial diversity along the hippocampal longitudinal axis impacts synaptic plasticity in adult male mice under homeostatic conditions. J Neuroinflamm. 2022;19:292.
  57. González Ibáñez F, Halvorson T, Sharma K, McKee CG, Carrier M, Picard K, et al. Ketogenic diet changes microglial morphology and the hippocampal lipidomic profile differently in stress susceptible versus resistant male mice upon repeated social defeat. Brain Behav Immun. 2023;114:383–406. [PMID: 37689276]
  58. Khakpour M, Ibáñez FG, Bordeleau M, Picard K, Mckee-Reid L, Ben-Azu B, et al. Manual versus automatic analysis of microglial density and distribution: a comparison in the hippocampus of healthy and lipopolysaccharide-challenged mature male mice. Micron. 2022;161:103334. [PMID: 35970079]
  59. Sharon A, Erez H, Spira ME. Significant sex differences in the efficacy of the CSF1R Inhibitor-PLX5622 on rat brain Microglia Elimination. Pharmaceuticals. 2022;15:569. [PMID: 35631395]
  60. Bender RA, Zhou L, Vierk R, Brandt N, Keller A, Gee CE, et al. Sex-dependent regulation of aromatase-mediated synaptic plasticity in the Basolateral Amygdala. J Neurosci. 2017;37:1532–45. [PMID: 28028198]
  61. Bakker J, Baum MJ. Role for estradiol in female-typical brain and behavioral sexual differentiation. Front Neuroendocrinol. 2008;29:1–16. [PMID: 17720235]
  62. Vousden DA, Corre C, Spring S, Qiu LR, Metcalf A, Cox E, et al. Impact of X/Y genes and sex hormones on mouse neuroanatomy. NeuroImage. 2018;173:551–63. [PMID: 29501873]
  63. Arnold AP. X chromosome agents of sexual differentiation. Nat Rev Endocrinol. 2022;18:574–83. [PMID: 35705742]
  64. González Ibanez F, Picard K, Bordeleau M, Sharma K, Bisht K, Tremblay M-È. Immunofluorescence staining using IBA1 and TMEM119 for microglial density, morphology and peripheral myeloid cell infiltration analysis in mouse brain. J Vis Exp. 2019.
  65. Bobotis BC, Halvorson T, Carrier M, Tremblay M-È. Established and emerging techniques for the study of microglia: visualization, depletion, and fate mapping. Front Cell Neurosci. 2024;18:1317125. [PMID: 38425429]
  66. Carrier M, Robert M-È, St-Pierre M-K, Ibáñez FG, Gonçalves de Andrade E, Laroche A, et al. Bone marrow-derived myeloid cells transiently colonize the brain during postnatal development and interact with glutamatergic synapses. iScience. 2024;27:110037. [PMID: 39021809]
  67. Vankriekelsvenne E, Chrzanowski U, Manzhula K, Greiner T, Wree A, Hawlitschka A, et al. Transmembrane protein 119 is neither a specific nor a reliable marker for microglia. Glia. 2022;70:1170–90. [PMID: 35246882]
  68. Franklin KBJ, Paxinos G. Paxinos and Franklin’s The mouse brain in stereotaxic coordinates. Fourth edition. Amsterdam: Academic Press, an imprint of Elsevier; 2013.
  69. Picard K, Corsi G, Decoeur F, Di Castro MA, Bordeleau M, Persillet M, et al. Microglial homeostasis disruption modulates non-rapid eye movement sleep duration and neuronal activity in adult female mice. Brain Behav Immun. 2023;107:153–64. [PMID: 36202169]
  70. Leyh J, Paeschke S, Mages B, Michalski D, Nowicki M, Bechmann I, et al. Classification of microglial morphological phenotypes using machine learning. Front Cell Neurosci. 2021;15:701673.
  71. Bankhead P, Loughrey MB, Fernández JA, Dombrowski Y, McArt DG, Dunne PD, et al. QuPath: open source software for digital pathology image analysis. Sci Rep. 2017;7:16878. [PMID: 29203879]
  72. Savage JC, Picard K, González-Ibáñez F, Tremblay M-È. A brief history of microglial ultrastructure: distinctive features, phenotypes, and functions discovered over the past 60 years by electron microscopy. Front Immunol. 2018;9:803.
  73. Nahirney PC, Tremblay M-E. Brain ultrastructure: putting the Pieces together. Front Cell Dev Biol. 2021;9:629503. [PMID: 33681208]
  74. Steinfeld N, Ma C-IJ, Maxfield FR. Signaling pathways regulating the extracellular digestion of lipoprotein aggregates by macrophages. Mol Biol Cell. 2024;35:ar5. [PMID: 37910189]
  75. Digestive exophagy. Phagocyte digestion of objects too large for phagocytosis - Maxfield – 2020 - Traffic - Wiley Online Library [Internet]. [cited 2024 Dec 5]. Available from: https://onlinelibrary.wiley.com/doi/ https://doi.org/10.1111/tra.12712
  76. Bordeleau M, Fernández de Cossío L, Lacabanne C, Savage JC, Vernoux N, Chakravarty M, et al. Maternal high-fat diet modifies myelin organization, microglial interactions, and results in social memory and sensorimotor gating deficits in adolescent mouse offspring. Brain Behav Immun Health. 2021;15:100281. [PMID: 34589781]
  77. St-Pierre M-K, Carrier M, González Ibáñez F, Šimončičová E, Wallman M-J, Vallières L, et al. Ultrastructural characterization of dark microglia during aging in a mouse model of Alzheimer’s disease pathology and in human post-mortem brain samples. J Neuroinflammation. 2022;19:235. [PMID: 36167544]
  78. Iovino L, VanderZwaag J, Kaur G, Khakpour M, Giusti V, Donadon M, et al. Investigation of microglial diversity in a LRRK2 G2019S mouse model of Parkinson’s disease. Neurobiol Dis. 2024;195:106481. [PMID: 38527708]
  79. Rodríguez JJ, Witton J, Olabarria M, Noristani HN, Verkhratsky A. Increase in the density of resting microglia precedes neuritic plaque formation and microglial activation in a transgenic model of Alzheimer’s disease. Cell Death Dis. 2010;1:e1–1. [PMID: 21364611]
  80. Ju H, Park KW, Kim I, Cave JW, Cho S. Phagocytosis converts infiltrated monocytes to microglia-like phenotype in experimental brain ischemia. J Neuroinflamm. 2022;19:190.
  81. Vidal-Itriago A, Radford RAW, Aramideh JA, Maurel C, Scherer NM, Don EK, et al. Microglia morphophysiological diversity and its implications for the CNS. Front Immunol. 2022;13:997786. [PMID: 36341385]
  82. Savage JC, Carrier M, Tremblay M-È. Morphology of Microglia Across Contexts of Health and Disease. Methods Mol Biol. 2019;2034:13–26. [PMID: 31392674]
  83. Paolicelli RC, Sierra A, Stevens B, Tremblay M-E, Aguzzi A, Ajami B, et al. Microglia states and nomenclature: a field at its crossroads. Neuron. 2022;110:3458–83. [PMID: 36327895]
  84. Colombo G, Cubero RJA, Kanari L, Venturino A, Schulz R, Scolamiero M, et al. A tool for mapping microglial morphology, morphOMICs, reveals brain-region and sex-dependent phenotypes. Nat Neurosci. 2022;25:1379–93. [PMID: 36180790]
  85. Zanier ER, Fumagalli S, Perego C, Pischiutta F, De Simoni M-G. Shape descriptors of the never resting microglia in three different acute brain injury models in mice. Intensive Care Med Experimental. 2015;3:7.
  86. Maras PM, Hebda-Bauer EK, Hagenauer MH, Hilde KL, Blandino P, Watson SJ, et al. Differences in microglia morphological profiles reflect divergent emotional temperaments: insights from a selective breeding model. Transl Psychiatry. 2022;12:1–11.
  87. Šišková Z, Tremblay M-È. Microglia and synapse: interactions in health and neurodegeneration. Neural Plast. 2013;2013:425845. [PMID: 24392228]
  88. Fujikawa R, Jinno S. Identification of hyper-ramified microglia in the CA1 region of the mouse hippocampus potentially associated with stress resilience. Eur J Neurosci. 2022;56:5137–53. [PMID: 36017697]
  89. Streit WJ, Braak H, Xue Q-S, Bechmann I. Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer’s disease. Acta Neuropathol. 2009;118:475–85. [PMID: 19513731]
  90. Bisht K, Sharma KP, Lecours C, Gabriela Sánchez M, El Hajj H, Milior G, et al. Dark microglia: a new phenotype predominantly associated with pathological states. Glia. 2016;64:826–39. [PMID: 26847266]
  91. El Hajj H, Savage JC, Bisht K, Parent M, Vallières L, Rivest S, et al. Ultrastructural evidence of microglial heterogeneity in Alzheimer’s disease amyloid pathology. J Neuroinflammation. 2019;16:87. [PMID: 30992040]
  92. She Z-Y, Yang W-X. Sry and SoxE genes: how they participate in mammalian sex determination and gonadal development? Semin Cell Dev Biol. 2017;63:13–22. [PMID: 27481580]
  93. Kenchappa RS, Diwakar L, Annepu J, Ravindranath V. Estrogen and neuroprotection: higher constitutive expression of glutaredoxin in female mice offers protection against MPTP-mediated neurodegeneration. FASEB J. 2004;18:1102–4. [PMID: 15132975]
  94. Tukiainen T, Villani A-C, Yen A, Rivas MA, Marshall JL, Satija R, et al. Landscape of X chromosome inactivation across human tissues. Nature. 2017;550:244–8. [PMID: 29022598]
  95. Tharp ME, Han CZ, Balak CD, Fitzpatrick C, O’Connor C, Preissl S et al. The inactive X chromosome drives sex differences in microglial inflammatory activity in human glioblastoma. bioRxiv. 2024;2024.06.06.597433.
  96. Ocañas SR, Pham KD, Cox JEJ, Keck AW, Ko S, Ampadu FA, et al. Microglial senescence contributes to female-biased neuroinflammation in the aging mouse hippocampus: implications for Alzheimer’s disease. J Neuroinflamm. 2023;20:188.
  97. Christine Knickmeyer R, Baron-Cohen S. Fetal testosterone and sex differences. Early Hum Dev. 2006;82:755–60. [PMID: 17084045]
  98. Isgor C, Watson SJ. Estrogen receptor alpha and beta mRNA expressions by proliferating and differentiating cells in the adult rat dentate gyrus and subventricular zone. Neuroscience. 2005;134:847–56. [PMID: 15994024]
  99. Arnold AP, Chen X. What does the four core genotypes mouse model tell us about sex differences in the brain and other tissues? Front Neuroendocrinol. 2009;30:1–9. [PMID: 19028515]
  100. Markham JA, Jurgens HA, Auger CJ, De Vries GJ, Arnold AP, Juraska JM. Sex differences in mouse cortical thickness are independent of the complement of sex chromosomes. Neuroscience. 2003;116:71–5. [PMID: 12535939]
  101. Wagner CK, Xu J, Pfau JL, Quadros PS, De Vries GJ, Arnold AP. Neonatal mice possessing an sry transgene show a masculinized pattern of progesterone receptor expression in the brain independent of sex chromosome status. Endocrinology. 2004;145:1046–9. [PMID: 14645115]
  102. Acaz-Fonseca E, Duran JC, Carrero P, Garcia-Segura LM, Arevalo MA. Sex differences in glia reactivity after cortical brain injury. Glia. 2015;63:1966–81. [PMID: 26037411]
  103. De Felice E, Bobotis BC, Rigillo G, Khakpour M, Gonçalves de Andrade E, Benatti C, et al. Female mice exhibit similar long-term plasticity and microglial properties between the dorsal and ventral hippocampal poles. Brain Behav Immun. 2025;124:192–204. https://www.sciencedirect.com/science/article/pii/S0889159124007232
  104. Bennett A, Baker C, Alward T, Vanner S, Reed D, Lomax A. The impact of the Estrous Cycle on Abdominal Pain. Physiology. 2024;39:1202.
  105. Velez-Perez A, Holder MK, Fountain S, Blaustein JD. Estradiol increases microglial response to lipopolysaccharide in the ventromedial hpothalamus during the peripubertal sensitive period in female mice. eNeuro. 2020;7:ENEURO.0505-19.2020.
  106. Ghosh MK, Chen K-HE, Dill-Garlow R, Ma LJ, Yonezawa T, Itoh Y, et al. Sex differences in the immune system become evident in the perinatal period in the four core genotypes mouse. Front Endocrinol (Lausanne). 2021;12:582614.
  107. Qi S, Mamun AA, Ngwa C, Romana S, Ritzel R, Arnold AP, et al. X chromosome escapee genes are involved in ischemic sexual dimorphism through epigenetic modification of inflammatory signals. J Neuroinflamm. 2021;18:70.
  108. Panten J, Del Prete S, Cleland JP, Saunders LM, van Riet J, Schneider A, et al. Four core genotypes mice harbour a 3.2 MB X-Y translocation that perturbs Tlr7 dosage. Nat Commun. 2024;15:8814. [PMID: 39394207]
  109. Schilling S, Chausse B, Dikmen HO, Almouhanna F, Hollnagel J-O, Lewen A, et al. TLR2- and TLR3-activated microglia induce different levels of neuronal network dysfunction in a context-dependent manner. Brain Behav Immun. 2021;96:80–91. [PMID: 34015428]
  110. Michaelis KA, Norgard MA, Levasseur PR, Olson B, Burfeind KG, Buenafe AC, et al. Persistent toll-like receptor 7 stimulation induces behavioral and molecular innate immune tolerance. Brain Behav Immun. 2019;82:338–53. [PMID: 31499172]
  111. Perkins AE, Piazza MK, Deak T. Stereological analysis of microglia in aged male and female Fischer 344 rats in socially-relevant brain regions. Neuroscience. 2018;377:40–52. [PMID: 29496632]
  112. Cooke PS, Nanjappa MK, Ko C, Prins GS, Hess RA. Estrogens in male physiology. Physiol Rev. 2017;97:995–1043. [PMID: 28539434]
  113. Ärnlöv J, Pencina MJ, Amin S, Nam B-H, Benjamin EJ, Murabito JM, et al. Endogenous sex hormones and Cardiovascular Disease incidence in men. Ann Intern Med. 2006;145:176–84. [PMID: 16880459]
  114. Khalil RA, Estrogen. Vascular estrogen receptor and hormone therapy in Postmenopausal Vascular Disease. Biochem Pharmacol. 2013;86. https://doi.org/10.1016/j.bcp.2013.09.024 .
  115. Maggioli E, McArthur S, Mauro C, Kieswich J, Kusters DHM, Reutelingsperger CPM, et al. Estrogen protects the blood-brain barrier from inflammation-induced disruption and increased lymphocyte trafficking. Brain Behav Immun. 2016;51:212–22. [PMID: 26321046]
  116. Bake S, Sohrabji F. 17β-Estradiol differentially regulates blood-brain barrier permeability in Young and Aging Female rats. Endocrinology. 2004;145:5471–5. [PMID: 15471968]
  117. Bohnert S, Seiffert A, Trella S, Bohnert M, Distel L, Ondruschka B, et al. TMEM119 as a specific marker of microglia reaction in traumatic brain injury in postmortem examination. Int J Legal Med. 2020;134:2167–76. [PMID: 32719959]
  118. Kaiser T, Feng G. Tmem119-EGFP and Tmem119-CreERT2 Transgenic Mice for Labeling and Manipulating Microglia. eNeuro. 2019;6:ENEURO.0448-18.2019.
  119. Ma W, Oswald J, Rios Angulo A, Chen Q. Tmem119 expression is downregulated in a subset of brain metastasis-associated microglia. BMC Neurosci. 2024;25:6. [PMID: 38308250]
  120. Ruan C, Elyaman W. A New understanding of TMEM119 as a marker of Microglia. Front Cell Neurosci. 2022;16:902372. [PMID: 35769325]
  121. Kenkhuis B, Somarakis A, Kleindouwel LRT, van Roon-Mom WMC, Höllt T, van der Weerd L. Co-expression patterns of microglia markers Iba1, TMEM119 and P2RY12 in Alzheimer’s disease. Neurobiol Dis. 2022;167:105684. [PMID: 35247551]
  122. Young K, Rothers J, Castaneda S, Ritchie J, Pottenger AE, Morrison HW. Sex and regional differences in microglia morphology and complement receptor 3 are independent of constitutive neuroinflammatory protein concentrations in healthy mice [Internet]. PeerJ Inc.; 2018 May. Report No.: e26937v1. Available from: https://peerj.com/preprints/26937
  123. Mitran SI, Burada E, Tănasie CA, Manea NC, Ciorbagiu MC, Mirea CS, et al. Microglial morphology determined with confocal and two-photon laser scanning microscopy. Rom J Morphol Embryol. 2018;59:485–90. [PMID: 30173252]
  124. Davies DS, Ma J, Jegathees T, Goldsbury C. Microglia show altered morphology and reduced arborization in human brain during aging and Alzheimer’s disease. Brain Pathol. 2017;27:795–808. [PMID: 27862631]
  125. Moisan M-P. Sexual dimorphism in glucocorticoid stress response. Int J Mol Sci. 2021;22:3139. [PMID: 33808655]
  126. Moench KM, Breach MR, Wellman CL. Chronic stress produces enduring sex- and region-specific alterations in novel stress-induced c-Fos expression. Neurobiol Stress. 2019;10:100147. [PMID: 30937353]
  127. Herman J, Parikh R, Herman JP. Sex and stress: Corticocolimbic Glucocorticoid Signaling Dynamics. Psychoneuroendocrinology. 2024;160:106739.
  128. Matarrese P, Colasanti T, Ascione B, Margutti P, Franconi F, Alessandri C, et al. Gender disparity in susceptibility to oxidative stress and apoptosis induced by autoantibodies specific to RLIP76 in vascular cells. Antioxid Redox Signal. 2011;15:2825–36. [PMID: 21671802]
  129. Massaad CA, Klann E. Reactive oxygen species in the regulation of synaptic plasticity and memory. Antioxid Redox Signal. 2011;14:2013–54. [PMID: 20649473]
  130. Dash UC, Bhol NK, Swain SK, Samal RR, Nayak PK, Raina V et al. Oxidative stress and inflammation in the pathogenesis of neurological disorders: Mechanisms and implications. Acta Pharmaceutica Sinica B [Internet]. 2024 [cited 2024 Dec 13]; Available from: https://www.sciencedirect.com/science/article/pii/S2211383524004040
  131. Esteras N, Kopach O, Maiolino M, Lariccia V, Amoroso S, Qamar S, et al. Mitochondrial ROS control neuronal excitability and cell fate in frontotemporal dementia. Alzheimer’s Dement. 2022;18:318–38.
  132. Houldsworth A. Role of oxidative stress in neurodegenerative disorders: a review of reactive oxygen species and prevention by antioxidants. Brain Commun. 2024;6:fcad356. [PMID: 38214013]
  133. Paolicelli RC, Bolasco G, Pagani F, Maggi L, Scianni M, Panzanelli P, et al. Synaptic pruning by microglia is necessary for normal brain development. Science. 2011;333:1456–8. [PMID: 21778362]
  134. Prengel TM, Brunne B, Habiballa M, Rune GM. Sexually differentiated microglia and CA1 hippocampal synaptic connectivity. J Neuroendocrinol. 2023;35:e13276. [PMID: 37170708]
  135. Bernier L-P, Bohlen CJ, York EM, Choi HB, Kamyabi A, Dissing-Olesen L, et al. Nanoscale Surveillance of the brain by Microglia via cAMP-Regulated Filopodia. Cell Rep. 2019;27:2895–e29084. [PMID: 31167136]
  136. Sierra A, Encinas JM, Deudero JJ, Chancey JH, Enikolopov G, Overstreet-Wadiche LS, et al. Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis. Cell Stem Cell. 2010;7:483–95. [PMID: 20887954]

Grants

  1. #PJT191944/CIHR
  2. #PJT191944/CIHR
  3. #PJT461831/CIHR
  4. #39965/Canada Foundation for Innovation John R. Evans Leaders
  5. RGPIN-2024-06043/Natural Sciences and Engineering Research Council of Canada Discovery grant

MeSH Term

Animals
Microglia
Mice
Male
Female
Hippocampus
Sex Chromosomes
Gonadal Steroid Hormones
Sex Characteristics
Mice, Transgenic
Mice, Inbred C57BL
Calcium-Binding Proteins

Chemicals

Gonadal Steroid Hormones
Calcium-Binding Proteins
Journal Article
Article has an altmetric score of 11

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