Abstract
The hypothalamus is a key component of the limbic system that plays an essential role in regulating physiological homeostasis via the release of trophic hormones that serve to connect the nervous and endocrine systems. The organization and function of the discrete nuclei that comprise the hypothalamus have been well studied, yet the programs that govern their development remain poorly described. This paucity of understanding is especially true for the microglial-neuronal interactions that occur during hypothalamic development and are important for the generation of a fully functioning hypothalamus. Recent scientific advancements have begun to elucidate the intricate programs that drive the invasion and maturation of these specialized glial cells, especially within the embryonic hypothalamus. Broadly, during neurogenesis, macrophages travel from the yolk sac to invade the brain parenchyma, where they transition to become microglia, the first and only glial cell present in the early embryonic central nervous system. These phagocytic immune cells are crucial during embryogenesis for the proper establishment of hypothalamic metabolic circuitry and have been shown to be both sexually dimorphic themselves, as well as contribute to the sexual dimorphism that exists within the hypothalamus. Thus, understanding the molecular nature of microglial-neuronal interactions in the developing hypothalamus is essential to having a comprehensive appreciation for the establishment of this important neuroendocrine region.
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References
Amit I, Winter DR, Jung S (2016) The role of the local environment and epigenetics in shaping macrophage identity and their effect on tissue homeostasis. Nat Immunol 17(1):18–25. https://doi.org/10.1038/ni.3325
Bennett FC, Bennett ML, Yaqoob F, Mulinyawe SB, Grant GA, Hayden Gephart M et al (2018) A combination of ontogeny and CNS environment establishes microglial identity. Neuron 98(6):1170–1183 e1178. https://doi.org/10.1016/j.neuron.2018.05.014
Bolos M, Perea JR, Terreros-Roncal J, Pallas-Bazarra N, Jurado-Arjona J, Avila J, Llorens-Martin M (2018) Absence of microglial CX3CR1 impairs the synaptic integration of adult-born hippocampal granule neurons. Brain Behav Immun 68:76–89. https://doi.org/10.1016/j.bbi.2017.10.002
Bolton JL, Auten RL, Bilbo SD (2014) Prenatal air pollution exposure induces sexually dimorphic fetal programming of metabolic and neuroinflammatory outcomes in adult offspring. Brain Behav Immun 37:30–44. https://doi.org/10.1016/j.bbi.2013.10.029
Boyadjieva NI, Sarkar DK (2013) Microglia play a role in ethanol-induced oxidative stress and apoptosis in developing hypothalamic neurons. Alcohol Clin Exp Res 37(2):252–262. https://doi.org/10.1111/j.1530-0277.2012.01889.x
Butovsky O, Jedrychowski MP, Moore CS, Cialic R, Lanser AJ, Gabriely G et al (2014) Identification of a unique TGF-beta-dependent molecular and functional signature in microglia. Nat Neurosci 17(1):131–143. https://doi.org/10.1038/nn.3599
Caetano L, Pinheiro H, Patricio P, Mateus-Pinheiro A, Alves ND, Coimbra B et al (2017) Adenosine A2A receptor regulation of microglia morphological remodeling-gender bias in physiology and in a model of chronic anxiety. Mol Psychiatry 22(7):1035–1043. https://doi.org/10.1038/mp.2016.173
Castillo-Ruiz A, Mosley M, George AJ, Mussaji LF, Fullerton EF, Ruszkowski EM et al (2018) The microbiota influences cell death and microglial colonization in the perinatal mouse brain. Brain Behav Immun 67:218–229. https://doi.org/10.1016/j.bbi.2017.08.027
Cunningham CL, Martinez-Cerdeno V, Noctor SC (2013) Microglia regulate the number of neural precursor cells in the developing cerebral cortex. J Neurosci 33(10):4216–4233. https://doi.org/10.1523/JNEUROSCI.3441-12.2013
De S, Van Deren D, Peden E, Hockin M, Boulet A, Titen S, Capecchi MR (2018) Two distinct ontogenies confer heterogeneity to mouse brain microglia. Development 145(13). https://doi.org/10.1242/dev.152306
Dzierzak E, Speck NA (2008) Of lineage and legacy: the development of mammalian hematopoietic stem cells. Nat Immunol 9(2):129–136. https://doi.org/10.1038/ni1560
Elmore MR, Najafi AR, Koike MA, Dagher NN, Spangenberg EE, Rice RA et al (2014) Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron 82(2):380–397. https://doi.org/10.1016/j.neuron.2014.02.040
Elmore MR, Lee RJ, West BL, Green KN (2015) Characterizing newly repopulated microglia in the adult mouse: impacts on animal behavior, cell morphology, and neuroinflammation. PLoS One 10(4):e0122912. https://doi.org/10.1371/journal.pone.0122912
Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S et al (2010) Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330(6005):841–845. https://doi.org/10.1126/science.1194637
Goldmann T, Wieghofer P, Jordao MJ, Prutek F, Hagemeyer N, Frenzel K et al (2016) Origin, fate and dynamics of macrophages at central nervous system interfaces. Nat Immunol 17(7):797–805. https://doi.org/10.1038/ni.3423
Gomez Perdiguero E, Klapproth K, Schulz C, Busch K, Azzoni E, Crozet L et al (2015) Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 518(7540):547–551. https://doi.org/10.1038/nature13989
Grayson BE, Levasseur PR, Williams SM, Smith MS, Marks DL, Grove KL (2010) Changes in melanocortin expression and inflammatory pathways in fetal offspring of nonhuman primates fed a high-fat diet. Endocrinology 151(4):1622–1632. https://doi.org/10.1210/en.2009-1019
Hammond TR, Dufort C, Dissing-Olesen L, Giera S, Young A, Wysoker A et al (2019) Single-cell RNA sequencing of microglia throughout the mouse lifespan and in the injured brain reveals complex cell-state changes. Immunity 50(1):253–271 e256. https://doi.org/10.1016/j.immuni.2018.11.004
Hoeffel G, Ginhoux F (2018) Fetal monocytes and the origins of tissue-resident macrophages. Cell Immunol 330:5–15. https://doi.org/10.1016/j.cellimm.2018.01.001
Hoeffel G, Chen J, Lavin Y, Low D, Almeida FF, See P et al (2015) C-Myb(+) erythro-myeloid progenitor-derived fetal monocytes give rise to adult tissue-resident macrophages. Immunity 42(4):665–678. https://doi.org/10.1016/j.immuni.2015.03.011
Huang Y, Xu Z, Xiong S, Sun F, Qin G, Hu G et al (2018) Repopulated microglia are solely derived from the proliferation of residual microglia after acute depletion. Nat Neurosci 21(4):530–540. https://doi.org/10.1038/s41593-018-0090-8
Kieusseian A, Brunet de la Grange P, Burlen-Defranoux O, Godin I, Cumano A (2012) Immature hematopoietic stem cells undergo maturation in the fetal liver. Development 139(19):3521–3530. https://doi.org/10.1242/dev.079210
Lawson LJ, Perry VH, Dri P, Gordon S (1990) Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience 39(1):151–170. https://doi.org/10.1016/0306-4522(90)90229-w
Lenz KM, Nugent BM, Haliyur R, McCarthy MM (2013) Microglia are essential to masculinization of brain and behavior. J Neurosci 33(7):2761–2772. https://doi.org/10.1523/JNEUROSCI.1268-12.2013
Lenz KM, Pickett LA, Wright CL, Davis KT, Joshi A, McCarthy MM (2018) Mast cells in the developing brain determine adult sexual behavior. J Neurosci 38(37):8044–8059. https://doi.org/10.1523/JNEUROSCI.1176-18.2018
Lenz KM, Pickett LA, Wright CL, Galan A, McCarthy MM (2019) Prenatal allergen exposure perturbs sexual differentiation and programs lifelong changes in adult social and sexual behavior. Sci Rep 9(1):4837. https://doi.org/10.1038/s41598-019-41258-2
Lutz TA, Le Foll C (2019) Endogenous amylin contributes to birth of microglial cells in arcuate nucleus of hypothalamus and area postrema during fetal development. Am J Physiol Regul Integr Comp Physiol 316(6):R791–R801. https://doi.org/10.1152/ajpregu.00004.2019
Marsters CM, Rosin JM, Thornton HF, Aslanpour S, Klenin N, Wilkinson G et al (2016) Oligodendrocyte development in the embryonic tuberal hypothalamus and the influence of Ascl1. Neural Dev 11(1):20. https://doi.org/10.1186/s13064-016-0075-9
Mirza MA, Ritzel R, Xu Y, McCullough LD, Liu F (2015) Sexually dimorphic outcomes and inflammatory responses in hypoxic-ischemic encephalopathy. J Neuroinflamm 12:32. https://doi.org/10.1186/s12974-015-0251-6
Norsted E, Gomuc B, Meister B (2008) Protein components of the blood-brain barrier (BBB) in the mediobasal hypothalamus. J Chem Neuroanat 36(2):107–121. https://doi.org/10.1016/j.jchemneu.2008.06.002
Rosin JM, Kurrasch DM (2019) Emerging roles for hypothalamic microglia as regulators of physiological homeostasis. Front Neuroendocrinol. https://doi.org/10.1016/j.yfrne.2019.100748
Rosin JM, Vora SR, Kurrasch DM (2018) Depletion of embryonic microglia using the CSF1R inhibitor PLX5622 has adverse sex-specific effects on mice, including accelerated weight gain, hyperactivity and anxiolytic-like behaviour. Brain Behav Immun 73:682–697. https://doi.org/10.1016/j.bbi.2018.07.023
Rutzel H, Schiebler TH (1980) Prenatal and early postnatal development of the glial cells in the median eminence of the rat. Cell Tissue Res 211(1):117–137. https://doi.org/10.1007/bf00233728
Schwarz JM, Sholar PW, Bilbo SD (2012) Sex differences in microglial colonization of the developing rat brain. J Neurochem 120(6):948–963. https://doi.org/10.1111/j.1471-4159.2011.07630.x
Spangenberg E, Severson PL, Hohsfield LA, Crapser J, Zhang J, Burton EA et al (2019) Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model. Nat Commun 10(1):3758. https://doi.org/10.1038/s41467-019-11674-z
Takahashi M, Komada M, Miyazawa K, Goto S, Ikeda Y (2018) Bisphenol A exposure induces increased microglia and microglial related factors in the murine embryonic dorsal telencephalon and hypothalamus. Toxicol Lett 284:113–119. https://doi.org/10.1016/j.toxlet.2017.12.010
VanRyzin JW, Yu SJ, Perez-Pouchoulen M, McCarthy MM (2016) Temporary depletion of microglia during the early postnatal period induces lasting sex-dependent and sex-independent effects on behavior in rats. eNeuro 3(6). https://doi.org/10.1523/ENEURO.0297-16.2016
Wang Y, Szretter KJ, Vermi W, Gilfillan S, Rossini C, Cella M et al (2012) IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia. Nat Immunol 13(8):753–760. https://doi.org/10.1038/ni.2360
Xu J, Zhu L, He S, Wu Y, Jin W, Yu T et al (2015) Temporal-spatial resolution fate mapping reveals distinct origins for embryonic and adult microglia in zebrafish. Dev Cell 34(6):632–641. https://doi.org/10.1016/j.devcel.2015.08.018
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Rosin, J.M., Kurrasch, D.M. (2021). The Role of Microglia in the Developing Hypothalamus. In: Tasker, J.G., Bains, J.S., Chowen, J.A. (eds) Glial-Neuronal Signaling in Neuroendocrine Systems. Masterclass in Neuroendocrinology, vol 11. Springer, Cham. https://doi.org/10.1007/978-3-030-62383-8_1
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