@article{ddefa46b0f8e4a3eb9ad06e514fa478c,
title = "The Influence of Microglial Elimination and Repopulation on Stress Sensitization Induced by Repeated Social Defeat",
abstract = "Background: Stress is associated with an increased prevalence of anxiety and depression. Repeated social defeat (RSD) stress in mice increases the release of monocytes from the bone marrow that are recruited to the brain by microglia. These monocytes enhance inflammatory signaling and augment anxiety. Moreover, RSD promotes stress sensitization, in which exposure to acute stress 24 days after cessation of RSD causes anxiety recurrence. The purpose of this study was to determine whether microglia were critical to stress sensitization and exhibited increased reactivity to subsequent acute stress or immune challenge. Methods: Mice were exposed to RSD, microglia were eliminated by colony-stimulating factor 1 receptor antagonism (PLX5622) and allowed to repopulate, and responses to acute stress or immune challenge (lipopolysaccharide) were determined 24 days after RSD sensitization. Results: Microglia maintained a unique messenger RNA signature 24 days after RSD. Moreover, elimination of RSD-sensitized microglia prevented monocyte accumulation in the brain and blocked anxiety recurrence following acute stress (24 days). When microglia were eliminated prior to RSD and repopulated and mice were subjected to acute stress, there was monocyte accumulation in the brain and anxiety in RSD-sensitized mice. These responses were unaffected by microglial elimination/repopulation. This may be related to neuronal sensitization that persisted 24 days after RSD. Following immune challenge, there was robust microglial reactivity in RSD-sensitized mice associated with prolonged sickness behavior. Here, microglial elimination/repopulation prevented the amplified immune reactivity ex vivo and in vivo in RSD-sensitized mice. Conclusions: Microglia and neurons remain sensitized weeks after RSD, and only the immune reactivity component of RSD-sensitized microglia was prevented by elimination/repopulation.",
keywords = "Anxiety, CSF1R antagonist, Microglia, Monocytes, Repeated social defeat, Stress",
author = "Weber, {Michael D.} and McKim, {Daniel B.} and Anzela Niraula and Witcher, {Kristina G.} and Wenyuan Yin and Sobol, {Carly G.} and Yufen Wang and Sawicki, {Caroline M.} and Sheridan, {John F.} and Godbout, {Jonathan P.}",
note = "Funding Information: This research was supported by National Institutes of Health Grant Nos. R01-MH-093473 and R01-MH093472 (to JFS) and Grant No. R01-AG051902 (to JPG). MDW, CMS, and KGW were supported by National Institute of Dental and Craniofacial Research (NIDCR) Training Grant No. T32-DE014320. DBM was supported by National Institute of Mental Health Grant No. F31-MH109234, and CMS was supported by NIDCR Grant No. F30-DE026075. WY and KGW were supported by The Ohio State University fellowships.We thank Plexxikon Inc. for the use of PLX5622. We also thank The Ohio State University Comprehensive Cancer Center's Analytical Cytometry and Nucleic Acid Shared Resources. In addition, we thank the Campus Microscopy and Imaging Facility, supported in part by National Cancer Institute Grant No. P30-CA016058, for the instruments and services to generate confocal images presented in this article. We acknowledge the Genomic Shared Resources and the Center for Genome Technology at the University of Miami for their help with the RNA sequencing. Last, we acknowledge an allocation of computing time from the Ohio Supercomputing Center in support of this work. Funding Information: We thank Plexxikon Inc. for the use of PLX5622. We also thank The Ohio State University Comprehensive Cancer Center{\textquoteright}s Analytical Cytometry and Nucleic Acid Shared Resources. In addition, we thank the Campus Microscopy and Imaging Facility, supported in part by National Cancer Institute Grant No. P30-CA016058 , for the instruments and services to generate confocal images presented in this article. We acknowledge the Genomic Shared Resources and the Center for Genome Technology at the University of Miami for their help with the RNA sequencing. Last, we acknowledge an allocation of computing time from the Ohio Supercomputing Center in support of this work. Funding Information: This research was supported by National Institutes of Health Grant Nos. R01-MH-093473 and R01-MH093472 (to JFS) and Grant No. R01-AG051902 (to JPG). MDW, CMS , and KGW were supported by National Institute of Dental and Craniofacial Research (NIDCR) Training Grant No. T32-DE014320 . DBM was supported by National Institute of Mental Health Grant No. F31-MH109234 , and CMS was supported by NIDCR Grant No. F30-DE026075 . WY and KGW were supported by The Ohio State University fellowships. Publisher Copyright: {\textcopyright} 2018 Society of Biological Psychiatry",
year = "2019",
month = apr,
day = "15",
doi = "10.1016/j.biopsych.2018.10.009",
language = "English (US)",
volume = "85",
pages = "667--678",
journal = "Biological Psychiatry",
issn = "0006-3223",
publisher = "Elsevier USA",
number = "8",
}