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Re-establishment of Anxiety in Stress-Sensitized Mice Is Caused by Monocyte Trafficking from the Spleen to the Brain

Published:December 11, 2013DOI:https://doi.org/10.1016/j.biopsych.2013.11.029

      Background

      Persistent anxiety-like symptoms may have an inflammatory-related pathophysiology. Our previous work using repeated social defeat (RSD) in mice showed that recruitment of peripheral myeloid cells to the brain is required for the development of anxiety. Here, we aimed to determine if 1) RSD promotes prolonged anxiety through redistribution of myeloid cells and 2) prior exposure to RSD sensitizes the neuroimmune axis to secondary subthreshold stress.

      Methods

      Mice were subjected to RSD and several immune and behavioral parameters were determined .5, 8, or 24 days later. In follow-up studies, control and RSD mice were subjected to subthreshold stress at 24 days.

      Results

      Repeated social defeat-induced macrophage recruitment to the brain corresponded with development and maintenance of anxiety-like behavior 8 days after RSD, but neither remained at 24 days. Nonetheless, social avoidance and an elevated neuroinflammatory profile were maintained at 24 days. Subthreshold social defeat in RSD-sensitized mice increased peripheral macrophage trafficking to the brain that promoted re-establishment of anxiety. Moreover, subthreshold social defeat increased social avoidance in RSD-sensitized mice compared with naïve mice. Stress-induced monocyte trafficking was linked to redistribution of myeloid progenitor cells in the spleen. Splenectomy before subthreshold stress attenuated macrophage recruitment to the brain and prevented anxiety-like behavior in RSD-sensitized mice.

      Conclusions

      These data indicate that monocyte trafficking from the spleen to the brain contributes re-establishment of anxiety in stress-sensitized mice. These findings show that neuroinflammatory mechanisms promote mood disturbances following stress-sensitization and outline novel neuroimmune interactions that underlie recurring anxiety disorders such as posttraumatic stress disorder.

      Key Words

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      References

        • Kendler K.S.
        • Karkowski L.M.
        • Prescott C.A.
        Causal relationship between stressful life events and the onset of major depression.
        Am J Psychiatry. 1999; 156: 837-841
        • Gilman S.E.
        • Trinh N.H.
        • Smoller J.W.
        • Fava M.
        • Murphy J.M.
        • Breslau J.
        Psychosocial stressors and the prognosis of major depression: A test of Axis IV.
        Psychol Med. 2013; 43: 303-316
        • Charney D.S.
        Psychobiological mechanisms of resilience and vulnerability: Implications for successful adaptation to extreme stress.
        Am J Psychiatry. 2004; 161: 195-216
        • Mathew S.J.
        • Price R.B.
        • Charney D.S.
        Recent advances in the neurobiology of anxiety disorders: Implications for novel therapeutics.
        Am J Med Genet C Semin Med Genet. 2008; 148C: 89-98
        • Dantzer R.
        • O′Connor J.C.
        • Freund G.G.
        • Johnson R.W.
        • Kelley K.W.
        From inflammation to sickness and depression: When the immune system subjugates the brain.
        Nat Rev Neurosci. 2008; 9: 46-56
        • Haroon E.
        • Raison C.L.
        • Miller A.H.
        Psychoneuroimmunology meets neuropsychopharmacology: Translational implications of the impact of inflammation on behavior.
        Neuropsychopharmacology. 2012; 37: 137-162
        • Beumer W.
        • Gibney S.M.
        • Drexhage R.C.
        • Pont-Lezica L.
        • Doorduin J.
        • Klein H.C.
        • et al.
        The immune theory of psychiatric diseases: A key role for activated microglia and circulating monocytes.
        J Leukoc Biol. 2012; 92: 959-975
        • Miller A.H.
        • Maletic V.
        • Raison C.L.
        Inflammation and its discontents: The role of cytokines in the pathophysiology of major depression.
        Biol Psychiatry. 2009; 65: 732-741
        • Tanaka K.
        • Furuyashiki T.
        • Kitaoka S.
        • Senzai Y.
        • Imoto Y.
        • Segi-Nishida E.
        • et al.
        Prostaglandin E2-mediated attenuation of mesocortical dopaminergic pathway is critical for susceptibility to repeated social defeat stress in mice.
        J Neurosci. 2012; 32: 4319-4329
        • Christoffel D.J.
        • Golden S.A.
        • Dumitriu D.
        • Robison A.J.
        • Janssen W.G.
        • Ahn H.F.
        • et al.
        IkappaB kinase regulates social defeat stress-induced synaptic and behavioral plasticity.
        J Neurosci. 2011; 31: 314-321
        • Koo J.W.
        • Russo S.J.
        • Ferguson D.
        • Nestler E.J.
        • Duman R.S.
        Nuclear factor-kappaB is a critical mediator of stress-impaired neurogenesis and depressive behavior.
        Proc Natl Acad Sci U S A. 2010; 107: 2669-2674
        • Koo J.W.
        • Duman R.S.
        IL-1beta is an essential mediator of the antineurogenic and anhedonic effects of stress.
        Proc Natl Acad Sci U S A. 2008; 105: 751-756
        • Andrews J.A.
        • Neises K.D.
        Cells, biomarkers, and post-traumatic stress disorder: Evidence for peripheral involvement in a central disease.
        J Neurochem. 2012; 120: 26-36
        • Pace T.W.
        • Heim C.M.
        A short review on the psychoneuroimmunology of posttraumatic stress disorder: From risk factors to medical comorbidities.
        Brain Behav Immun. 2012; 25: 6-13
        • Wohleb E.S.
        • Powell N.D.
        • Godbout J.P.
        • Sheridan J.F.
        Stress-induced recruitment of bone marrow-derived monocytes to the brain promotes anxiety-like behavior.
        J Neurosci. 2013; 33: 13820-13833
        • Wohleb E.S.
        • Hanke M.L.
        • Corona A.W.
        • Powell N.D.
        • Stiner L.M.
        • Bailey M.T.
        • et al.
        β-Adrenergic receptor antagonism prevents anxiety-like behavior and microglial reactivity induced by repeated social defeat.
        J Neurosci. 2011; 31: 6277-6288
        • Hanke M.L.
        • Powell N.D.
        • Stiner L.M.
        • Bailey M.T.
        • Sheridan J.F.
        β-adrenergic blockade decreases the immunomodulatory effects of social disruption stress.
        Brain Behav Immun. 2012; 26: 1150-1159
        • Kinsey S.G.
        • Bailey M.T.
        • Sheridan J.F.
        • Padgett D.A.
        • Avitsur R.
        Repeated social defeat causes increased anxiety-like behavior and alters splenocyte function in C57BL/6 and CD-1 mice.
        Brain Behav Immun. 2007; 21: 458-466
        • Bailey M.T.
        • Kinsey S.G.
        • Padgett D.A.
        • Sheridan J.F.
        • Leblebicioglu B.
        Social stress enhances IL-1beta and TNF-alpha production by Porphyromonas gingivalis lipopolysaccharide-stimulated CD11b+ cells.
        Physiol Behav. 2009; 98: 351-358
        • Engler H.
        • Engler A.
        • Bailey M.T.
        • Sheridan J.F.
        Tissue-specific alterations in the glucocorticoid sensitivity of immune cells following repeated social defeat in mice.
        J Neuroimmunol. 2005; 163: 110-119
        • Engler H.
        • Bailey M.T.
        • Engler A.
        • Sheridan J.F.
        Effects of repeated social stress on leukocyte distribution in bone marrow, peripheral blood and spleen.
        J Neuroimmunol. 2004; 148: 106-115
        • Avitsur R.
        • Kavelaars A.
        • Heijnen C.
        • Sheridan J.F.
        Social stress and the regulation of tumor necrosis factor-alpha secretion.
        Brain Behav Immun. 2005; 19: 311-317
        • Wohleb E.S.
        • Fenn A.M.
        • Pacenta A.M.
        • Powell N.D.
        • Sheridan J.F.
        • Godbout J.P.
        Peripheral innate immune challenge exaggerated microglia activation, increased the number of inflammatory CNS macrophages, and prolonged social withdrawal in socially defeated mice.
        Psychoneuroendocrinology. 2012; 37: 1491-1505
        • Krishnan V.
        • Han M.H.
        • Graham D.H.
        • Berton O.
        • Renthal W.
        • Russo S.J.
        • et al.
        Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions.
        Cell. 2007; 131: 391-404
        • Berton O.
        • McClung C.A.
        • Dileone R.J.
        • Krishnan V.
        • Renthal W.
        • Russo S.J.
        • et al.
        Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress.
        Science. 2006; 311: 864-868
        • Vallieres L.
        • Sawchenko P.E.
        Bone marrow-derived cells that populate the adult mouse brain preserve their hematopoietic identity.
        J Neurosci. 2003; 23: 5197-5207
        • Donnelly D.J.
        • Gensel J.C.
        • Ankeny D.P.
        • van Rooijen N.
        • Popovich P.G.
        An efficient and reproducible method for quantifying macrophages in different experimental models of central nervous system pathology.
        J Neurosci Methods. 2009; 181: 36-44
        • Livak K.J.
        • Schmittgen T.D.
        Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.
        Methods. 2001; 25: 402-408
        • Stark J.L.
        • Avitsur R.
        • Padgett D.A.
        • Campbell K.A.
        • Beck F.M.
        • Sheridan J.F.
        Social stress induces glucocorticoid resistance in macrophages.
        Am J Physiol Regul Integr Comp Physiol. 2001; 280: R1799-R1805
        • Powell N.D.
        • Sloan E.K.
        • Bailey M.T.
        • Arevalo J.M.
        • Miller G.E.
        • Chen E.
        • et al.
        Social stress up-regulates inflammatory gene expression in the leukocyte transcriptome via beta-adrenergic induction of myelopoiesis.
        Proc Natl Acad Sci U S A. 2013; 110: 16574-16579
        • Kierdorf K.
        • Katzmarski N.
        • Haas C.A.
        • Prinz M.
        Bone marrow cell recruitment to the brain in the absence of irradiation or parabiosis bias.
        PLoS One. 2013; 8: e58544
        • Lampron A.
        • Lessard M.
        • Rivest S.
        Effects of myeloablation, peripheral chimerism, and whole-body irradiation on the entry of bone marrow-derived cells into the brain.
        Cell Transplant. 2012; 21: 1149-1159
        • Mildner A.
        • Schmidt H.
        • Nitsche M.
        • Merkler D.
        • Hanisch U.K.
        • Mack M.
        • et al.
        Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions.
        Nat Neurosci. 2007; 10: 1544-1553
        • Brevet M.
        • Kojima H.
        • Asakawa A.
        • Atsuchi K.
        • Ushikai M.
        • Ataka K.
        • et al.
        Chronic foot-shock stress potentiates the influx of bone marrow-derived microglia into hippocampus.
        J Neurosci Res. 2010; 88: 1890-1897
        • Ajami B.
        • Bennett J.L.
        • Krieger C.
        • McNagny K.M.
        • Rossi F.M.
        Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool.
        Nat Neurosci. 2011; 14: 1142-1149
        • Schulz C.
        • Gomez Perdiguero E.
        • Chorro L.
        • Szabo-Rogers H.
        • Cagnard N.
        • Kierdorf K.
        • et al.
        A lineage of myeloid cells independent of Myb and hematopoietic stem cells.
        Science. 2012; 336: 86-90
        • Ginhoux F.
        • Greter M.
        • Leboeuf M.
        • Nandi S.
        • See P.
        • Gokhan S.
        • et al.
        Fate mapping analysis reveals that adult microglia derive from primitive macrophages.
        Science. 2010; 330: 841-845
        • Corona A.W.
        • Huang Y.
        • O′Connor J.C.
        • Dantzer R.
        • Kelley K.W.
        • Popovich P.G.
        • Godbout J.P.
        Fractalkine receptor (CX3CR1) deficiency sensitizes mice to the behavioral changes induced by lipopolysaccharide.
        J Neuroinflammation. 2010; 7: 93
        • Henry C.J.
        • Huang Y.
        • Wynne A.M.
        • Godbout J.P.
        Peripheral lipopolysaccharide (LPS) challenge promotes microglial hyperactivity in aged mice that is associated with exaggerated induction of both pro-inflammatory IL-1beta and anti-inflammatory IL-10 cytokines.
        Brain Behav Immun. 2009; 23: 309-317
        • Godbout J.P.
        • Moreau M.
        • Lestage J.
        • Chen J.
        • Sparkman N.L.
        • O′Connor J.
        • et al.
        Aging exacerbates depressive-like behavior in mice in response to activation of the peripheral innate immune system.
        Neuropsychopharmacology. 2008; 33: 2341-2351
        • Godbout J.P.
        • Johnson R.W.
        Age and neuroinflammation: A lifetime of psychoneuroimmune consequences.
        Neurol Clin. 2006; 24: 521-538
        • Iwata M.
        • Ota K.T.
        • Duman R.S.
        The inflammasome: Pathways linking psychological stress, depression, and systemic illnesses.
        Brain Behav Immun. 2012; 31: 105-114
        • Koo J.W.
        • Duman R.S.
        Evidence for IL-1 receptor blockade as a therapeutic strategy for the treatment of depression.
        Curr Opin Investig Drugs. 2009; 10: 664-671
        • Duman R.S.
        Neuronal damage and protection in the pathophysiology and treatment of psychiatric illness: Stress and depression.
        Dialogues Clin Neurosci. 2009; 11: 239-255
        • Seifert H.A.
        • Hall A.A.
        • Chapman C.B.
        • Collier L.A.
        • Willing A.E.
        • Pennypacker K.R.
        A transient decrease in spleen size following stroke corresponds to splenocyte release into systemic circulation.
        J Neuroimmune Pharmacol. 2012; 7: 1017-1024
        • Dutta P.
        • Courties G.
        • Wei Y.
        • Leuschner F.
        • Gorbatov R.
        • Robbins C.S.
        • et al.
        Myocardial infarction accelerates atherosclerosis.
        Nature. 2012; 487: 325-329
        • Swirski F.K.
        • Nahrendorf M.
        • Etzrodt M.
        • Wildgruber M.
        • Cortez-Retamozo V.
        • Panizzi P.
        • et al.
        Identification of splenic reservoir monocytes and their deployment to inflammatory sites.
        Science. 2009; 325: 612-616
        • Sloan E.K.
        • Capitanio J.P.
        • Tarara R.P.
        • Cole S.W.
        Social temperament and lymph node innervation.
        Brain Behav Immun. 2008; 22: 717-726
        • Cole S.W.
        • Arevalo J.M.
        • Takahashi R.
        • Sloan E.K.
        • Lutgendorf S.K.
        • Sood K.
        • et al.
        Computational identification of gene-social environment interaction at the human IL6 locus.
        Proc Natl Acad Sci U S A. 2010; 107: 5681-5686
        • Mehta D.
        • Klengel T.
        • Conneely K.N.
        • Smith A.K.
        • Altmann A.
        • Pace T.W.
        • et al.
        Childhood maltreatment is associated with distinct genomic and epigenetic profiles in posttraumatic stress disorder.
        Proc Natl Acad Sci U S A. 2013; 110: 8302-8307
        • Miller G.E.
        • Chen E.
        • Sze J.
        • Marin T.
        • Arevalo J.M.
        • Doll R.
        • et al.
        A functional genomic fingerprint of chronic stress in humans: Blunted glucocorticoid and increased NF-kappaB signaling.
        Biol Psychiatry. 2008; 64: 266-272
        • Dhabhar F.S.
        Enhancing versus suppressive effects of stress on immune function: Implications for immunoprotection and immunopathology.
        Neuroimmunomodulation. 2009; 16: 300-317
        • D′Mello C.
        • Le T.
        • Swain M.G.
        Cerebral microglia recruit monocytes into the brain in response to tumor necrosis factoralpha signaling during peripheral organ inflammation.
        J Neurosci. 2009; 29: 2089-2102
        • Olson V.G.
        • Rockett H.R.
        • Reh R.K.
        • Redila V.A.
        • Tran P.M.
        • Venkov H.A.
        • et al.
        The role of norepinephrine in differential response to stress in an animal model of posttraumatic stress disorder.
        Biol Psychiatry. 2011; 70: 441-448
        • Qian J.
        • Zhu L.
        • Li Q.
        • Belevych N.
        • Chen Q.
        • Zhao F.
        • et al.
        Interleukin-1R3 mediates interleukin-1-induced potassium current increase through fast activation of Akt kinase.
        Proc Natl Acad Sci U S A. 2012; 109: 12189-12194
        • Stellwagen D.
        • Malenka R.C.
        Synaptic scaling mediated by glial TNF-alpha.
        Nature. 2006; 440: 1054-1059
        • Gruol D.L.
        • Nelson T.E.
        Purkinje neuron physiology is altered by the inflammatory factor interleukin-6.
        Cerebellum. 2005; 4: 198-205
        • Serrats J.
        • Schiltz J.C.
        • Garcia-Bueno B.
        • van Rooijen N.
        • Reyes T.M.
        • Sawchenko P.E.
        Dual roles for perivascular macrophages in immune-to-brain signaling.
        Neuron. 2010; 65: 94-106
        • Derecki N.C.
        • Quinnies K.M.
        • Kipnis J.
        Alternatively activated myeloid (M2) cells enhance cognitive function in immune compromised mice.
        Brain Behav Immun. 2011; 25: 379-385
        • Dantzer R.
        • Kelley K.W.
        Twenty years of research on cytokine-induced sickness behavior.
        Brain Behav Immun. 2007; 21: 153-160
        • Anisman H.
        Cascading effects of stressors and inflammatory immune system activation: Implications for major depressive disorder.
        J Psychiatry Neurosci. 2009; 34: 4-20
        • McLaughlin K.A.
        • Conron K.J.
        • Koenen K.C.
        • Gilman S.E.
        Childhood adversity, adult stressful life events, and risk of past-year psychiatric disorder: A test of the stress sensitization hypothesis in a population-based sample of adults.
        Psychol Med. 2010; 40: 1647-1658
        • Pace T.W.
        • Mletzko T.C.
        • Alagbe O.
        • Musselman D.L.
        • Nemeroff C.B.
        • Miller A.H.
        • Heim C.M.
        Increased stress-induced inflammatory responses in male patients with major depression and increased early life stress.
        Am J Psychiatry. 2006; 163: 1630-1633
        • Sidman R.L.
        • Kosaras B.
        • Misra B.M.
        • Senft S.L.
        High Resolution Mouse Brain Atlas. 1999; (Available at) (Accessed September 2012)