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The Influence of Microglial Elimination and Repopulation on Stress Sensitization Induced by Repeated Social Defeat

  • Michael D. Weber
    Affiliations
    Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, Ohio

    Division of Biosciences, The Ohio State University College of Dentistry, Columbus, Ohio
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  • Daniel B. McKim
    Affiliations
    Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, Ohio

    Division of Biosciences, The Ohio State University College of Dentistry, Columbus, Ohio
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  • Anzela Niraula
    Affiliations
    Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, Ohio

    Division of Biosciences, The Ohio State University College of Dentistry, Columbus, Ohio
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  • Kristina G. Witcher
    Affiliations
    Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, Ohio
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  • Wenyuan Yin
    Affiliations
    Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, Ohio

    Division of Biosciences, The Ohio State University College of Dentistry, Columbus, Ohio
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  • Carly G. Sobol
    Affiliations
    Division of Biosciences, The Ohio State University College of Dentistry, Columbus, Ohio
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  • Yufen Wang
    Affiliations
    Division of Biosciences, The Ohio State University College of Dentistry, Columbus, Ohio
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  • Caroline M. Sawicki
    Affiliations
    Division of Biosciences, The Ohio State University College of Dentistry, Columbus, Ohio
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  • John F. Sheridan
    Correspondence
    John Sheridan, Ph.D., 120c IMBR Building, 460 Medical Center Drive, Columbus, OH 43210.
    Affiliations
    Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, Ohio

    Institute for Behavioral Medicine Research, The Ohio State University Wexner Medical Center, Columbus, Ohio

    Division of Biosciences, The Ohio State University College of Dentistry, Columbus, Ohio
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  • Jonathan P. Godbout
    Correspondence
    Address correspondence to Jonathan Godbout, Ph.D., 231 IBMR Building, 460 Medical Center Drive, Columbus, OH 43210.
    Affiliations
    Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, Ohio

    Institute for Behavioral Medicine Research, The Ohio State University Wexner Medical Center, Columbus, Ohio
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      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

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      Linked Article

      • From Stress Sensitization to Microglial Priming and Vice Versa: A New Era of Research in Biological Psychiatry
        Biological PsychiatryVol. 85Issue 8
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          The world of stress-related research used to be quite straightforward. Based on animal models of stress, it was commonly accepted that anxiety- and depression-like behavior induced by acute or repeated exposure to inescapable stressors could be explained by the interaction between peripherally released stress mediators, represented mainly by glucocorticoids and catecholamines, and brain neurotransmitters. We also knew that stressors could affect immune responses at the periphery, not only because of the sensitivity of immune cells to stress hormones but also because of the innervation of the lymphoid organs by the sympathetic nervous system.
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      • Microglia, Monocytes, and the Recurrence of Anxiety in Stress-Sensitized Mice
        Biological PsychiatryVol. 85Issue 12
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          We read with great interest the article by Weber et al. (1) in Biological Psychiatry describing the effects of microglia elimination and repopulation on stress sensitization induced by repeated social defeat (RSD). The article highlights brain-immune interactions and, in particular, the importance of stress-primed microglia for monocyte accumulation in the brain of RSD-sensitized mice following acute stress. The transcriptomic analysis of microglia 24 days after RSD could be very useful to other researchers, so the authors may wish to make this information accessible to the community by depositing it to an appropriate data repository.
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