{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T06:34:14Z","timestamp":1789194854028,"version":"build-2803163510"},"reference-count":39,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2022,5,2]],"date-time":"2022-05-02T00:00:00Z","timestamp":1651449600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003977","name":"Israel Science Foundation","doi-asserted-by":"publisher","award":["1808\/19"],"award-info":[{"award-number":["1808\/19"]}],"id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Microglia play pivotal roles in central nervous system development, homeostasis, responses to trauma, and neurodegenerative and neuropsychiatric disorders with significant sex-bias in their symptoms and prevalence. Survival of the microglia in adult brains depends on the expression of the colony-stimulating factor 1 receptor (CSF1R). The inhibition of CSF1R by brain-permeant PLX5622 in the chow eliminates, within 5\u201310 days, ~90% of the microglia in female and male mice, thereby enabling the investigation of the roles of the microglia in health and pathological mice models. Because of a prevailing \u201cimpression\u201d that PLX5622 is ineffective in rats, it has hardly been used in studies of adult rats. Here, we report that effective microglia elimination by PLX5622-chow in rats is highly sex-dependent. Our observations provide missing information for the limited use and interpretation of PLX5622 in biomedical studies of the microglia in rat models. The sex differences that are too often overlooked must be carefully considered and clearly emphasized.<\/jats:p>","DOI":"10.3390\/ph15050569","type":"journal-article","created":{"date-parts":[[2022,5,2]],"date-time":"2022-05-02T07:08:58Z","timestamp":1651475338000},"page":"569","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Significant Sex Differences in the Efficacy of the CSF1R Inhibitor-PLX5622 on Rat Brain Microglia Elimination"],"prefix":"10.3390","volume":"15","author":[{"given":"Aviv","family":"Sharon","sequence":"first","affiliation":[{"name":"Department of Neurobiology, Alexander Silberman Institute of Life Science, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel"},{"name":"The Charles E. Smith Family and Joel Elkes Laboratory for Collaborative Research in Psychobiology, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0726-3041","authenticated-orcid":false,"given":"Hadas","family":"Erez","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Alexander Silberman Institute of Life Science, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel"},{"name":"The Charles E. Smith Family and Joel Elkes Laboratory for Collaborative Research in Psychobiology, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Micha E.","family":"Spira","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Alexander Silberman Institute of Life Science, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel"},{"name":"The Charles E. Smith Family and Joel Elkes Laboratory for Collaborative Research in Psychobiology, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.yhbeh.2012.02.018","article-title":"Sex, glia, and development: Interactions in health and disease","volume":"62","author":"Schwarz","year":"2012","journal-title":"Horm. Behav."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1504","DOI":"10.1002\/glia.23176","article-title":"Generation of a microglial developmental index in mice and in humans reveals a sex difference in maturation and immune reactivity","volume":"65","author":"Hanamsagar","year":"2017","journal-title":"Glia"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.conb.2017.10.004","article-title":"On place and time: Microglia in embryonic and perinatal brain development","volume":"47","author":"Thion","year":"2017","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1146\/annurev-physiol-022516-034406","article-title":"Microglia in Physiology and Disease","volume":"79","author":"Wolf","year":"2017","journal-title":"Annu. Rev. Physiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2576","DOI":"10.3389\/fimmu.2018.02576","article-title":"Microglia: Immune Regulators of Neurodevelopment","volume":"9","author":"Cowan","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.yfrne.2018.11.003","article-title":"Sexual differentiation of microglia","volume":"52","author":"Villa","year":"2019","journal-title":"Front. Neuroendocrinol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1002\/glia.23753","article-title":"Microglia and sexual differentiation of the developing brain: A focus on ontogeny and intrinsic factors","volume":"68","author":"Bordt","year":"2020","journal-title":"Glia"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1186\/s40035-020-00221-2","article-title":"Neuroinflammation in neurodegenerative disorders: The roles of microglia and astrocytes","volume":"9","author":"Kwon","year":"2020","journal-title":"Transl. Neurodegener."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1186\/s12974-016-0614-7","article-title":"Phenotypic clustering: A novel method for microglial morphology analysis","volume":"13","author":"Verdonk","year":"2016","journal-title":"J. Neuroinflamm."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1038\/nn.4631","article-title":"Microglia turnover with aging and in an Alzheimer\u2019s model via long-term in vivo single-cell imaging","volume":"20","author":"Fuger","year":"2017","journal-title":"Nat. Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1038\/nn.4547","article-title":"A new fate mapping system reveals context-dependent random or clonal expansion of microglia","volume":"20","author":"Sagar","year":"2017","journal-title":"Nat. Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Zhan, L., Krabbe, G., Du, F., Jones, I., Reichert, M.C., Telpoukhovskaia, M., Kodama, L., Wang, C., Cho, S.H., and Sayed, F. (2019). Proximal recolonization by self-renewing microglia re-establishes microglial homeostasis in the adult mouse brain. PLoS Biol., 17.","DOI":"10.1371\/journal.pbio.3000134"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/j.immuni.2018.11.004","article-title":"Single-Cell RNA Sequencing of Microglia throughout the Mouse Lifespan and in the Injured Brain Reveals Complex Cell-State Changes","volume":"50","author":"Hammond","year":"2019","journal-title":"Immunity"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1002\/JLB.MR0519-143R","article-title":"Phenotypic impacts of CSF1R deficiencies in humans and model organisms","volume":"107","author":"Hume","year":"2020","journal-title":"J. Leukoc. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1016\/j.it.2020.07.001","article-title":"To Kill a Microglia: A Case for CSF1R Inhibitors","volume":"41","author":"Green","year":"2020","journal-title":"Trends Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"583647","DOI":"10.3389\/fimmu.2020.583647","article-title":"Tools and Approaches for Studying Microglia In vivo","volume":"11","author":"Dando","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1016\/j.neuron.2014.02.040","article-title":"Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain","volume":"82","author":"Elmore","year":"2014","journal-title":"Neuron"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Elmore, M.R., Lee, R.J., West, B.L., and Green, K.N. (2015). Characterizing newly repopulated microglia in the adult mouse: Impacts on animal behavior, cell morphology, and neuroinflammation. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0122912"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3758","DOI":"10.1038\/s41467-019-11674-z","article-title":"Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer\u2019s disease model","volume":"10","author":"Spangenberg","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1186\/s12974-015-0366-9","article-title":"Colony-stimulating factor 1 receptor inhibition prevents microglial plaque association and improves cognition in 3xTg-AD mice","volume":"12","author":"Dagher","year":"2015","journal-title":"J. Neuroinflamm."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2385","DOI":"10.1002\/glia.23477","article-title":"A limited capacity for microglial repopulation in the adult brain","volume":"66","author":"Najafi","year":"2018","journal-title":"Glia"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.expneurol.2019.04.011","article-title":"Concentration-dependent effects of CSF1R inhibitors on oligodendrocyte progenitor cells ex vivo and in vivo","volume":"318","author":"Liu","year":"2019","journal-title":"Exp. Neurol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2199","DOI":"10.3389\/fimmu.2019.02199","article-title":"CSF1R Ligands IL-34 and CSF1 Are Differentially Required for Microglia Development and Maintenance in White and Gray Matter Brain Regions","volume":"10","author":"Foreman","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1242\/dmm.026120","article-title":"Rodent models in neuroscience research: Is it a rat race?","volume":"9","author":"Ellenbroek","year":"2016","journal-title":"Dis. Models Mech."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1021\/acschemneuro.6b00415","article-title":"Comeback of the Rat in Biomedical Research","volume":"8","author":"Homberg","year":"2017","journal-title":"ACS Chem. Neurosci."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Sehgal, A., Irvine, K.M., and Hume, D.A. (2021). Functions of macrophage colony-stimulating factor (CSF1) in development, homeostasis, and tissue repair. Seminars in Immunology, Academic Press.","DOI":"10.1016\/j.smim.2021.101509"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"100010","DOI":"10.1016\/j.bbih.2019.100010","article-title":"Astrocytic response to neural injury is larger during development than inadulthood and is not predicated upon the presence of microglia","volume":"1","author":"Riquier","year":"2020","journal-title":"Brain Behav. Immun. Health"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1097\/j.pain.0000000000002376","article-title":"Microglial ablation does not affect opioid-induced hyperalgesia in rodents","volume":"163","author":"Liu","year":"2021","journal-title":"Pain"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"646914","DOI":"10.3389\/fnins.2021.646914","article-title":"Inflammatory Foreign Body Response Induced by Neuro-Implants in Rat Cortices Depleted of Resident Microglia by a CSF1R Inhibitor and Its Implications","volume":"15","author":"Sharon","year":"2021","journal-title":"Front. Neurosci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"926","DOI":"10.3389\/fnins.2020.00926","article-title":"Immunohistological and Ultrastructural Study of the Inflammatory Response to Perforated Polyimide Cortical Implants: Mechanisms Underlying Deterioration of Electrophysiological Recording Quality","volume":"14","author":"Huang","year":"2020","journal-title":"Front. Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1038\/s41380-019-0609-8","article-title":"Microglial regional heterogeneity and its role in the brain","volume":"25","author":"Tan","year":"2020","journal-title":"Mol. Psychiatry"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2773","DOI":"10.1016\/j.celrep.2018.08.001","article-title":"Transcriptional and Translational Differences of Microglia from Male and Female Brains","volume":"24","author":"Guneykaya","year":"2018","journal-title":"Cell Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"235","DOI":"10.3389\/fncel.2017.00235","article-title":"Microglia Morphological Categorization in a Rat Model of Neuroinflammation by Hierarchical Cluster and Principal Components Analysis","volume":"11","author":"Grondona","year":"2017","journal-title":"Front. Cell. Neurosci."},{"key":"ref_34","first-page":"314","article-title":"Region-Specific Phenotypes of Microglia: The Role of Local Regulatory Cues","volume":"25","author":"Bonci","year":"2019","journal-title":"Neurosci. A Rev. J. Bringing Neurobiol. Neurol. Psychiatry"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Patkar, O.L., Caruso, M., Teakle, N., Keshvari, S., Bush, S.J., Pridans, C., Belmer, A., Summers, K.M., Irvine, K.M., and Hume, D.A. (2021). Analysis of homozygous and heterozygous Csf1r knockout in the rat as a model for understanding microglial function in brain development and the impacts of human CSF1R mutations. Neurobiol. Dis., 151.","DOI":"10.1016\/j.nbd.2021.105268"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: An open-source platform for biological-image analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/nmeth.2089","article-title":"NIH Image to ImageJ: 25 years of image analysis","volume":"9","author":"Schneider","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1002\/cyto.a.20462","article-title":"Automated analysis of neurite branching in cultured cortical neurons using HCA-Vision","volume":"71","author":"Vallotton","year":"2007","journal-title":"Cytom. Part A J. Int. Soc. Anal. Cytol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1177\/1087057110382894","article-title":"HCA-vision: Automated neurite outgrowth analysis","volume":"15","author":"Wang","year":"2010","journal-title":"J. Biomol. 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