Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Integrating neuroimmune systems in the neurobiology of depression

Key Points

  • The neurobiology of depression features dichotomous alterations in corticolimbic brain regions. For example, the prefrontal cortex and hippocampus exhibit neuronal atrophy and synaptic dysfunction, whereas the nucleus accumbens and amygdala exhibit neuronal hypertrophy and increased synaptic activity.

  • In subsets of depressed individuals, there is dysregulation of peripheral and central immune systems that are implicated in the neurobiology of depression. Rodents exposed to environmental and psychosocial stress recapitulate immune dysfunction observed in clinical populations.

  • Microglia, the brain-resident macrophages, integrate neuroimmune signals and mediate neuroplasticity in physiological and pathological conditions. Neurons provide soluble and contact-dependent signals that modulate the function and activation of microglia.

  • Typical antidepressant agents improve mood by regulating the levels of the monoamines serotonin and noradrenaline, but also partially through attenuation of immune dysregulation. Other antidepressant therapies that limit neuroimmune activation and promote anti-inflammatory pathways may provide alternative treatment options for subsets of depressed individuals.

  • Further studies of the dynamic role of microglia in the neurobiology of depression and synapse function may reveal novel molecular pathways that can be therapeutically targeted.

Abstract

Data from clinical and preclinical studies indicate that immune dysregulation, specifically of inflammatory processes, is associated with symptoms of major depressive disorder (MDD). In particular, increased levels of circulating pro-inflammatory cytokines and concomitant activation of brain-resident microglia can lead to depressive behavioural symptoms. Repeated exposure to psychological stress has a profound impact on peripheral immune responses and perturbs the function of brain microglia, which may contribute to neurobiological changes underlying MDD. Here, we review these findings and discuss ongoing studies examining neuroimmune mechanisms that influence neuronal activity as well as synaptic plasticity. Interventions targeting immune-related cellular and molecular pathways may benefit subsets of MDD patients with immune dysregulation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Neurobiology of depression.
Figure 2: Stress-associated changes in neuroimmune function.
Figure 3: Microglia–neuron interactions in the naive, homeostatic brain and in the stressed or depressed brain.
Figure 4: Neuroimmune mechanisms in the pathophysiology and treatment of depression.

Similar content being viewed by others

References

  1. Kessler, R. C., Chiu, W. T., Demler, O., Merikangas, K. R. & Walters, E. E. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch. Gen. Psychiatry 62, 617–627 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Kessler, R. C. Epidemiology of women and depression. J. Affect. Disord. 74, 5–13 (2003).

    Article  PubMed  Google Scholar 

  3. Murray, C. J. et al. The state of US health, 1990–2010: burden of diseases, injuries, and risk factors. JAMA 310, 591–608 (2013).

    Article  CAS  PubMed  Google Scholar 

  4. Russo, S. J. & Nestler, E. J. The brain reward circuitry in mood disorders. Nat. Rev. Neurosci. 14, 609–625 (2013).

    Article  CAS  PubMed  Google Scholar 

  5. Krishnan, V. & Nestler, E. J. The molecular neurobiology of depression. Nature 455, 894–902 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Duman, R. S. & Aghajanian, G. K. Synaptic dysfunction in depression: potential therapeutic targets. Science 338, 68–72 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Duman, R. S. & Li, N. A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists. Phil. Trans. R. Soc. B 367, 2475–2484 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Schmidt, H. D., Shelton, R. C. & Duman, R. S. Functional biomarkers of depression: diagnosis, treatment, and pathophysiology. Neuropsychopharmacology 36, 2375–2394 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Foley, D. L. et al. Major depression and associated impairment: same or different genetic and environmental risk factors? Am. J. Psychiatry 160, 2128–2133 (2003).

    Article  PubMed  Google Scholar 

  10. Sullivan, P. F., Neale, M. C. & Kendler, K. S. Genetic epidemiology of major depression: review and meta-analysis. Am. J. Psychiatry 157, 1552–1562 (2000).

    Article  CAS  PubMed  Google Scholar 

  11. Gilman, S. E. et al. Psychosocial stressors and the prognosis of major depression: a test of Axis IV. Psychol. Med. 43, 303–316 (2013).

    Article  CAS  PubMed  Google Scholar 

  12. 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. 40, 1647–1658 (2010).

    Article  CAS  PubMed  Google Scholar 

  13. Kendler, K. S. & Halberstadt, L. J. The road not taken: life experiences in monozygotic twin pairs discordant for major depression. Mol. Psychiatry 18, 975–984 (2013).

    Article  CAS  PubMed  Google Scholar 

  14. Duman, R. S. Neuronal damage and protection in the pathophysiology and treatment of psychiatric illness: stress and depression. Dialogues Clin. Neurosci. 11, 239–255 (2009).

    PubMed  PubMed Central  Google Scholar 

  15. Christoffel, D. J., Golden, S. A. & Russo, S. J. Structural and synaptic plasticity in stress-related disorders. Rev. Neurosci. 22, 535–549 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hodes, G. E., Kana, V., Menard, C., Merad, M. & Russo, S. J. Neuroimmune mechanisms of depression. Nat. Neurosci. 18, 1386–1393 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wohleb, E. S., McKim, D. B., Sheridan, J. F. & Godbout, J. P. Monocyte trafficking to the brain with stress and inflammation: a novel axis of immune-to-brain communication that influences mood and behavior. Front. Neurosci. 8, 447 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Maes, M. Evidence for an immune response in major depression: a review and hypothesis. Prog. Neuropsychopharmacol. Biol. Psychiatry 19, 11–38 (1995).

    Article  CAS  PubMed  Google Scholar 

  19. Howren, M. B., Lamkin, D. M. & Suls, J. Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom. Med. 71, 171–186 (2009).

    Article  CAS  PubMed  Google Scholar 

  20. Dowlati, Y. et al. A meta-analysis of cytokines in major depression. Biol. Psychiatry 67, 446–457 (2010).

    Article  CAS  PubMed  Google Scholar 

  21. Capuron, L. & Dantzer, R. Cytokines and depression: the need for a new paradigm. Brain Behav. Immun. 17 (Suppl. 1), 119–124 (2003).

    Article  Google Scholar 

  22. 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. 9, 46–56 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Miller, A. H., Maletic, V. & Raison, C. L. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol. Psychiatry 65, 732–741 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Iwata, M., Ota, K. T. & Duman, R. S. The inflammasome: pathways linking psychological stress, depression, and systemic illnesses. Brain Behav. Immun. 31, 105–114 (2013).

    Article  CAS  PubMed  Google Scholar 

  25. Ridker, P. M., Thuren, T., Zalewski, A. & Libby, P. Interleukin-1β inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). Am. Heart J. 162, 597–605 (2011).

    Article  CAS  PubMed  Google Scholar 

  26. Dunn, J. H., Ellis, L. Z. & Fujita, M. Inflammasomes as molecular mediators of inflammation and cancer: potential role in melanoma. Cancer Lett. 314, 24–33 (2012).

    Article  CAS  PubMed  Google Scholar 

  27. da Silva, J., Goncalves-Pereira, M., Xavier, M. & Mukaetova-Ladinska, E. B. Affective disorders and risk of developing dementia: systematic review. Br. J. Psychiatry 202, 177–186 (2013).

    Article  PubMed  Google Scholar 

  28. Leonard, B. E. Inflammation, depression and dementia: are they connected? Neurochem. Res. 32, 1749–1756 (2007).

    Article  CAS  PubMed  Google Scholar 

  29. Ownby, R. L., Crocco, E., Acevedo, A., John, V. & Loewenstein, D. Depression and risk for Alzheimer disease: systematic review, meta-analysis, and metaregression analysis. Arch. Gen. Psychiatry 63, 530–538 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Goodman, W. K. & Charney, D. S. Therapeutic applications and mechanisms of action of monoamine oxidase inhibitor and heterocyclic antidepressant drugs. J. Clin. Psychiatry 46, 6–24 (1985).

    CAS  PubMed  Google Scholar 

  31. Heninger, G. R., Delgado, P. L. & Charney, D. S. The revised monoamine theory of depression: a modulatory role for monoamines, based on new findings from monoamine depletion experiments in humans. Pharmacopsychiatry 29, 2–11 (1996).

    Article  CAS  PubMed  Google Scholar 

  32. Maas, J. W. Biogenic amines and depression. Biochemical and pharmacological separation of two types of depression. Arch. Gen. Psychiatry 32, 1357–1361 (1975).

    Article  CAS  PubMed  Google Scholar 

  33. Kendell, S. F., Krystal, J. H. & Sanacora, G. GABA and glutamate systems as therapeutic targets in depression and mood disorders. Expert Opin. Ther. Targets 9, 153–168 (2005).

    Article  CAS  PubMed  Google Scholar 

  34. Northoff, G. & Sibille, E. Why are cortical GABA neurons relevant to internal focus in depression? A cross-level model linking cellular, biochemical and neural network findings. Mol. Psychiatry 19, 966–977 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Sanacora, G. & Saricicek, A. GABAergic contributions to the pathophysiology of depression and the mechanism of antidepressant action. CNS Neurol. Disord. Drug Targets 6, 127–140 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Butler, P. W. & Besser, G. M. Pituitary–adrenal function in severe depressive illness. Lancet 1, 1234–1236 (1968).

    Article  CAS  PubMed  Google Scholar 

  37. Dinan, T. G. Glucocorticoids and the genesis of depressive illness. A psychobiological model. Br. J. Psychiatry 164, 365–371 (1994).

    Article  CAS  PubMed  Google Scholar 

  38. Price, J. L. & Drevets, W. C. Neural circuits underlying the pathophysiology of mood disorders. Trends Cogn. Sci. 16, 61–71 (2010).

    Article  Google Scholar 

  39. Ressler, K. J. & Mayberg, H. S. Targeting abnormal neural circuits in mood and anxiety disorders: from the laboratory to the clinic. Nat. Neurosci. 10, 1116–1124 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Shin, L. M. & Liberzon, I. The neurocircuitry of fear, stress, and anxiety disorders. Neuropsychopharmacology 35, 169–191 (2010).

    Article  PubMed  Google Scholar 

  41. Magarinos, A. M., McEwen, B. S., Flugge, G. & Fuchs, E. Chronic psychosocial stress causes apical dendritic atrophy of hippocampal CA3 pyramidal neurons in subordinate tree shrews. J. Neurosci. 16, 3534–3540 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Radley, J. J. et al. Chronic behavioral stress induces apical dendritic reorganization in pyramidal neurons of the medial prefrontal cortex. Neuroscience 125, 1–6 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Kang, H. J. et al. Decreased expression of synapse-related genes and loss of synapses in major depressive disorder. Nat. Med. 18, 1413–1417 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Duric, V. et al. Altered expression of synapse and glutamate related genes in post-mortem hippocampus of depressed subjects. Int. J. Neuropsychopharmacol. 16, 69–82 (2012).

    Article  PubMed  CAS  Google Scholar 

  45. Gould, E., Tanapat, P., McEwen, B. S., Flugge, G. & Fuchs, E. Proliferation of granule cell precursors in the dentate gyrus of adult monkeys is diminished by stress. Proc. Natl Acad. Sci. USA 95, 3168–3171 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Gould, E., McEwen, B. S., Tanapat, P., Galea, L. A. & Fuchs, E. Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation. J. Neurosci. 17, 2492–2498 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Magarinos, A. M. & McEwen, B. S. Stress-induced atrophy of apical dendrites of hippocampal CA3c neurons: involvement of glucocorticoid secretion and excitatory amino acid receptors. Neuroscience 69, 89–98 (1995).

    Article  CAS  PubMed  Google Scholar 

  48. Wellman, C. L. Dendritic reorganization in pyramidal neurons in medial prefrontal cortex after chronic corticosterone administration. J. Neurobiol. 49, 245–253 (2001).

    Article  CAS  PubMed  Google Scholar 

  49. Vyas, A., Mitra, R., Shankaranarayana Rao, B. S. & Chattarji, S. Chronic stress induces contrasting patterns of dendritic remodeling in hippocampal and amygdaloid neurons. J. Neurosci. 22, 6810–6818 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Roozendaal, B., McEwen, B. S. & Chattarji, S. Stress, memory and the amygdala. Nat. Rev. Neurosci. 10, 423–433 (2009).

    Article  CAS  PubMed  Google Scholar 

  51. Krishnan, V. et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell 131, 391–404 (2007).

    Article  CAS  PubMed  Google Scholar 

  52. Malberg, J. E., Eisch, A. J., Nestler, E. J. & Duman, R. S. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J. Neurosci. 20, 9104–9110 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Santarelli, L. et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301, 805–809 (2003).

    Article  CAS  PubMed  Google Scholar 

  54. Navarria, A. et al. Rapid antidepressant actions of scopolamine: role of medial prefrontal cortex and M1-subtype muscarinic acetylcholine receptors. Neurobiol. Dis. 82, 254–261 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Voleti, B. et al. Scopolamine rapidly increases Mammalian target of rapamycin complex 1 signaling, synaptogenesis, and antidepressant behavioral responses. Biol. Psychiatry 74, 742–749 (2013).

    Article  CAS  PubMed  Google Scholar 

  56. Li, N. et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329, 959–964 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Dantzer, R., O'Connor, J. C., Lawson, M. A. & Kelley, K. W. Inflammation-associated depression: from serotonin to kynurenine. Psychoneuroendocrinology 36, 426–436 (2011).

    Article  CAS  PubMed  Google Scholar 

  58. DellaGioia, N. & Hannestad, J. A critical review of human endotoxin administration as an experimental paradigm of depression. Neurosci. Biobehav. Rev. 34, 130–143 (2010).

    Article  CAS  PubMed  Google Scholar 

  59. Steptoe, A., Hamer, M. & Chida, Y. The effects of acute psychological stress on circulating inflammatory factors in humans: a review and meta-analysis. Brain Behav. Immun. 21, 901–912 (2007).

    Article  CAS  PubMed  Google Scholar 

  60. Felger, J. C. et al. Inflammation is associated with decreased functional connectivity within corticostriatal reward circuitry in depression. Mol. Psychiatry http://dx.doi.org/10.1038/mp.2015.168 (2015). This paper provides initial clinical evidence linking elevated peripheral markers of inflammation with decreases in the functional connectivity of PFC–striatum pathways, which correlate with depressive symptom severity.

  61. Lamers, F. et al. Evidence for a differential role of HPA-axis function, inflammation and metabolic syndrome in melancholic versus atypical depression. Mol. Psychiatry 18, 692–699 (2013). A clinical study showing that subtypes of depression have characteristic immune and hormone biomarkers, potentially reflecting varied pathophysiological mechanisms.

    Article  CAS  PubMed  Google Scholar 

  62. Gold, P. W. The organization of the stress system and its dysregulation in depressive illness. Mol. Psychiatry 20, 32–47 (2015).

    Article  CAS  PubMed  Google Scholar 

  63. Torres-Platas, S. G., Cruceanu, C., Chen, G. G., Turecki, G. & Mechawar, N. Evidence for increased microglial priming and macrophage recruitment in the dorsal anterior cingulate white matter of depressed suicides. Brain Behav. Immun. 42, 50–59 (2014).

    Article  CAS  PubMed  Google Scholar 

  64. Steiner, J. et al. Immunological aspects in the neurobiology of suicide: elevated microglial density in schizophrenia and depression is associated with suicide. J. Psychiatr. Res. 42, 151–157 (2008).

    Article  PubMed  Google Scholar 

  65. Setiawan, E. et al. Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes. JAMA Psychiatry 72, 268–275 2015).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Martinez, J. M., Garakani, A., Yehuda, R. & Gorman, J. M. Proinflammatory and “resiliency” proteins in the CSF of patients with major depression. Depress. Anxiety 29, 32–38 (2012).

    Article  CAS  PubMed  Google Scholar 

  67. Carpenter, L. L., Heninger, G. R., Malison, R. T., Tyrka, A. R. & Price, L. H. Cerebrospinal fluid interleukin (IL)-6 in unipolar major depression. J. Affect. Disord. 79, 285–289 (2004).

    Article  CAS  PubMed  Google Scholar 

  68. Hampel, H., Kotter, H. U. & Moller, H. J. Blood–cerebrospinal fluid barrier dysfunction for high molecular weight proteins in Alzheimer disease and major depression: indication for disease subsets. Alzheimer Dis. Assoc. Disord. 11, 78–87 (1997).

    Article  CAS  PubMed  Google Scholar 

  69. Haroon, E. et al. Conceptual convergence: increased inflammation is associated with increased basal ganglia glutamate in patients with major depression. Mol. Psychiatry http://dx.doi.org/10.1038/mp.2015.206 (2016).

  70. Shelton, R. C. et al. Altered expression of genes involved in inflammation and apoptosis in frontal cortex in major depression. Mol. Psychiatry 16, 751–762 (2011).

    Article  CAS  PubMed  Google Scholar 

  71. Kim, S., Hwang, Y., Webster, M. J. & Lee, D. Differential activation of immune/inflammatory response-related co-expression modules in the hippocampus across the major psychiatric disorders. Mol. Psychiatry 21, 376–385 (2016).

    Article  CAS  PubMed  Google Scholar 

  72. Beumer, W. et al. The immune theory of psychiatric diseases: a key role for activated microglia and circulating monocytes. J. Leukoc. Biol. 92, 959–975 (2012).

    Article  CAS  PubMed  Google Scholar 

  73. Sternberg, E. M. Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens. Nat. Rev. Immunol. 6, 318–328 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Irwin, M. R. & Cole, S. W. Reciprocal regulation of the neural and innate immune systems. Nat. Rev. Immunol. 11, 625–632 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Erickson, M. A., Dohi, K. & Banks, W. A. Neuroinflammation: a common pathway in CNS diseases as mediated at the blood–brain barrier. Neuroimmunomodulation 19, 121–130 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Quan, N. Immune-to-brain signaling: how important are the blood–brain barrier-independent pathways? Mol. Neurobiol. 37, 142–152 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Schwartz, M., Kipnis, J., Rivest, S. & Prat, A. How do immune cells support and shape the brain in health, disease, and aging? J. Neurosci. 33, 17587–17596 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Prinz, M., Priller, J., Sisodia, S. S. & Ransohoff, R. M. Heterogeneity of CNS myeloid cells and their roles in neurodegeneration. Nat. Neurosci. 14, 1227–1235 (2011).

    Article  CAS  PubMed  Google Scholar 

  79. Schiltz, J. C. & Sawchenko, P. E. Signaling the brain in systemic inflammation: the role of perivascular cells. Front. Biosci. 8, s1321–s1329 (2003).

    Article  CAS  PubMed  Google Scholar 

  80. Serrats, J. et al. Dual roles for perivascular macrophages in immune-to-brain signaling. Neuron 65, 94–106 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Schwartz, M., London, A. & Shechter, R. Boosting T-cell immunity as a therapeutic approach for neurodegenerative conditions: the role of innate immunity. Neuroscience 158, 1133–1142 (2009).

    Article  CAS  PubMed  Google Scholar 

  82. Kipnis, J., Gadani, S. & Derecki, N. C. Pro-cognitive properties of T cells. Nat. Rev. Immunol. 12, 663–669 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Dhabhar, F. S., Malarkey, W. B., Neri, E. & McEwen, B. S. Stress-induced redistribution of immune cells — from barracks to boulevards to battlefields: a tale of three hormones — Curt Richter Award winner. Psychoneuroendocrinology 37, 1345–1368 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Dhabhar, F. S. Enhancing versus suppressive effects of stress on immune function: implications for immunoprotection and immunopathology. Neuroimmunomodulation 16, 300–317 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Trottier, M. D., Newsted, M. M., King, L. E. & Fraker, P. J. Natural glucocorticoids induce expansion of all developmental stages of murine bone marrow granulocytes without inhibiting function. Proc. Natl Acad. Sci. USA 105, 2028–2033 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Engler, H. et al. Interleukin-1 receptor type 1-deficient mice fail to develop social stress-associated glucocorticoid resistance in the spleen. Psychoneuroendocrinology 33, 108–117 (2008).

    Article  CAS  PubMed  Google Scholar 

  87. 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. 163, 110–119 (2005).

    Article  CAS  PubMed  Google Scholar 

  88. Stark, J. L., Avitsur, R., Hunzeker, J., Padgett, D. A. & Sheridan, J. F. Interleukin-6 and the development of social disruption-induced glucocorticoid resistance. J. Neuroimmunol. 124, 9–15 (2002).

    Article  CAS  PubMed  Google Scholar 

  89. Stark, J. L. et al. Social stress induces glucocorticoid resistance in macrophages. Am. J. Physiol. Regul. Integr. Comp. Physiol. 280, R1799–R1805 (2001).

    Article  CAS  PubMed  Google Scholar 

  90. Felten, D. L., Felten, S. Y., Carlson, S. L., Olschowka, J. A. & Livnat, S. Noradrenergic and peptidergic innervation of lymphoid tissue. J. Immunol. 135, 755s–765s (1985).

    CAS  PubMed  Google Scholar 

  91. Nance, D. M. & Sanders, V. M. Autonomic innervation and regulation of the immune system (1987–2007). Brain Behav. Immun. 21, 736–745 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Hanke, M. L., Powell, N. D., Stiner, L. M., Bailey, M. T. & Sheridan, J. F. Beta adrenergic blockade decreases the immunomodulatory effects of social disruption stress. Brain Behav. Immun. 26, 1150–1159 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Grisanti, L. A. et al. Pro-inflammatory responses in human monocytes are β1-adrenergic receptor subtype dependent. Mol. Immunol. 47, 1244–1254 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Spiegel, A. et al. Catecholaminergic neurotransmitters regulate migration and repopulation of immature human CD34+ cells through Wnt signaling. Nat. Immunol. 8, 1123–1131 (2007).

    Article  CAS  PubMed  Google Scholar 

  95. Katayama, Y. et al. Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell 124, 407–421 (2006).

    Article  CAS  PubMed  Google Scholar 

  96. Powell, N. D. et al. Social stress up-regulates inflammatory gene expression in the leukocyte transcriptome via β-adrenergic induction of myelopoiesis. Proc. Natl Acad. Sci. USA 110, 16574–16579 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Heidt, T. et al. Chronic variable stress activates hematopoietic stem cells. Nat. Med. 20, 754–758 (2014). A preclinical study showing that psychological stress can induce the proliferation and mobilization of haematopoietic immune cells through SNS signalling, resulting in increased numbers of circulating monocytes and granulocytes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Swirski, F. K. et al. Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science 325, 612–616 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Johnson, J. D. et al. Catecholamines mediate stress-induced increases in peripheral and central inflammatory cytokines. Neuroscience 135, 1295–1307 (2005).

    Article  CAS  PubMed  Google Scholar 

  100. Miller, G. E. et al. A functional genomic fingerprint of chronic stress in humans: blunted glucocorticoid and increased NF-κB signaling. Biol. Psychiatry 64, 266–272 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Pace, T. W. et al. Increased stress-induced inflammatory responses in male patients with major depression and increased early life stress. Am. J. Psychiatry 163, 1630–1633 (2006).

    Article  PubMed  Google Scholar 

  102. Wohleb, E. S. et al. Knockdown of interleukin-1 receptor type-1 on endothelial cells attenuated stress-induced neuroinflammation and prevented anxiety-like behavior. J. Neurosci. 34, 2583–2591 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. 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. 33, 13820–13833 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Wohleb, E. S. et al. Peripheral innate immune challenge exaggerated microglia activation, increased the number of inflammatory CNS macrophages, and prolonged social withdrawal in socially defeated mice. Psychoneuroendocrinology 37, 1491–1505 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Wohleb, E. S. et al. β-adrenergic receptor antagonism prevents anxiety-like behavior and microglial reactivity induced by repeated social defeat. J. Neurosci. 31, 6277–6288 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Hodes, G. E. et al. Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress. Proc. Natl Acad. Sci. USA 111, 16136–16141 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. McKim, D. B. et al. Sympathetic release of splenic monocytes promotes recurring anxiety following repeated social defeat. Biol. Psychiatry 79, 803–813 (2016).

    Article  CAS  PubMed  Google Scholar 

  108. Wohleb, E. S. et al. Re-establishment of anxiety in stress-sensitized mice is caused by monocyte trafficking from the spleen to the brain. Biol. Psychiatry 75, 970–981 (2014).

    Article  CAS  PubMed  Google Scholar 

  109. Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010). Using transgenic mice, this study provides direct evidence that microglia populate the brain early during neurodevelopment and do not undergo renewal from blood-derived myeloid cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Davalos, D. et al. ATP mediates rapid microglial response to local brain injury in vivo. Nat. Neurosci. 8, 752–758 (2005).

    CAS  PubMed  Google Scholar 

  111. Kettenmann, H., Hanisch, U. K., Noda, M. & Verkhratsky, A. Physiology of microglia. Physiol. Rev. 91, 461–553 (2011).

    Article  CAS  PubMed  Google Scholar 

  112. Ransohoff, R. M. & Perry, V. H. Microglial physiology: unique stimuli, specialized responses. Annu. Rev. Immunol. 27, 119–145 (2009).

    Article  CAS  PubMed  Google Scholar 

  113. Kierdorf, K. & Prinz, M. Factors regulating microglia activation. Front. Cell. Neurosci. 7, 44 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Butovsky, O. et al. Identification of a unique TGF-β-dependent molecular and functional signature in microglia. Nat. Neurosci. 17, 131–143 (2014). This preclinical work reveals that gene expression and function in microglia are driven by brain-specific signals, such as TGFβ, that can contribute to deleterious microglial function.

    Article  CAS  PubMed  Google Scholar 

  115. Elmore, M. R. et al. Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron 82, 380–397 (2014). This study uncovers a requirement for CSF1 signalling in maintaining microglial function under physiological conditions, and shows that repopulation of microglia occurs via amplification of intrinsic progenitor cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Wang, Y. et al. IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia. Nat. Immunol. 13, 753–760 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Biber, K., Neumann, H., Inoue, K. & Boddeke, H. W. Neuronal 'On' and 'Off' signals control microglia. Trends Neurosci. 30, 596–602 (2007).

    Article  CAS  PubMed  Google Scholar 

  118. Jurgens, H. A. & Johnson, R. W. Dysregulated neuronal-microglial cross-talk during aging, stress and inflammation. Exp. Neurol. 233, 40–48 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  119. Paolicelli, R. C. et al. Synaptic pruning by microglia is necessary for normal brain development. Science 333, 1456–1458 (2011). Seminal findings showing that microglia contribute to synaptic refinement of hippocampal neurons during development and that reduced microglial function leads to persistence of immature synapses and altered neurodevelopment.

    Article  CAS  PubMed  Google Scholar 

  120. Zhan, Y. et al. Deficient neuron–microglia signaling results in impaired functional brain connectivity and social behavior. Nat. Neurosci. 17, 400–406 (2014).

    Article  CAS  PubMed  Google Scholar 

  121. Rogers, J. T. et al. CX3CR1 deficiency leads to impairment of hippocampal cognitive function and synaptic plasticity. J. Neurosci. 31, 16241–16250 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Tremblay, M. E. et al. The role of microglia in the healthy brain. J. Neurosci. 31, 16064–16069 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Gyoneva, S. & Traynelis, S. F. Norepinephrine modulates the motility of resting and activated microglia via different adrenergic receptors. J. Biol. Chem. 288, 15291–15302 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Fontainhas, A. M. et al. Microglial morphology and dynamic behavior is regulated by ionotropic glutamatergic and GABAergic neurotransmission. PLoS ONE 6, e15973 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Pocock, J. M. & Kettenmann, H. Neurotransmitter receptors on microglia. Trends Neurosci. 30, 527–535 (2007).

    Article  CAS  PubMed  Google Scholar 

  126. Tremblay, M. E., Lowery, R. L. & Majewska, A. K. Microglial interactions with synapses are modulated by visual experience. PLoS Biol. 8, e1000527 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Wake, H., Moorhouse, A. J., Jinno, S., Kohsaka, S. & Nabekura, J. Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J. Neurosci. 29, 3974–3980 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Schafer, D. P. et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74, 691–705 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Davies, L. C., Jenkins, S. J., Allen, J. E. & Taylor, P. R. Tissue-resident macrophages. Nat. Immunol. 14, 986–995 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Frank, M. G., Thompson, B. M., Watkins, L. R. & Maier, S. F. Glucocorticoids mediate stress-induced priming of microglial pro-inflammatory responses. Brain Behav. Immun. 26, 337–345 (2012).

    Article  CAS  PubMed  Google Scholar 

  131. Frank, M. G., Miguel, Z. D., Watkins, L. R. & Maier, S. F. Prior exposure to glucocorticoids sensitizes the neuroinflammatory and peripheral inflammatory responses to E. coli lipopolysaccharide. Brain Behav. Immun. 24, 19–30 (2010).

    Article  CAS  PubMed  Google Scholar 

  132. Frank, M. G., Baratta, M. V., Sprunger, D. B., Watkins, L. R. & Maier, S. F. Microglia serve as a neuroimmune substrate for stress-induced potentiation of CNS pro-inflammatory cytokine responses. Brain Behav. Immun. 21, 47–59 (2007).

    Article  CAS  PubMed  Google Scholar 

  133. Chang, Y. et al. Inhibitory effects of ketamine on lipopolysaccharide-induced microglial activation. Mediators Inflamm. 2009, 705379 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  134. Nair, A. & Bonneau, R. H. Stress-induced elevation of glucocorticoids increases microglia proliferation through NMDA receptor activation. J. Neuroimmunol. 171, 72–85 (2006).

    Article  CAS  PubMed  Google Scholar 

  135. Glezer, I. & Rivest, S. Glucocorticoids: protectors of the brain during innate immune responses. Neuroscientist 10, 538–552 (2004).

    Article  CAS  PubMed  Google Scholar 

  136. Sorrells, S. F. & Sapolsky, R. M. An inflammatory review of glucocorticoid actions in the CNS. Brain Behav. Immun. 21, 259–272 (2007).

    Article  CAS  PubMed  Google Scholar 

  137. Weber, M. D., Frank, M. G., Sobesky, J. L., Watkins, L. R. & Maier, S. F. Blocking toll-like receptor 2 and 4 signaling during a stressor prevents stress-induced priming of neuroinflammatory responses to a subsequent immune challenge. Brain Behav. Immun. 32, 112–121 (2013).

    Article  CAS  PubMed  Google Scholar 

  138. Pereira, D. B. et al. Life stress, negative mood states, and antibodies to heat shock protein 70 in endometrial cancer. Brain Behav. Immun. 24, 210–214 (2010).

    Article  CAS  PubMed  Google Scholar 

  139. Sriram, K., Rodriguez-Fernandez, M. & Doyle, F. J. III . A detailed modular analysis of heat-shock protein dynamics under acute and chronic stress and its implication in anxiety disorders. PLoS ONE 7, e42958 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Zlatkovic, J., Bernardi, R. E. & Filipovic, D. Protective effect of Hsp70i against chronic social isolation stress in the rat hippocampus. J. Neural Transm. 121, 3–14 (2014).

    Article  CAS  PubMed  Google Scholar 

  141. Weber, M. D., Frank, M. G., Tracey, K. J., Watkins, L. R. & Maier, S. F. Stress induces the danger-associated molecular pattern HMGB-1 in the hippocampus of male Sprague Dawley rats: a priming stimulus of microglia and the NLRP3 inflammasome. J. Neurosci. 35, 316–324 (2015). Primary findings showing that stress-induced HMGB1 release in the hippocampus causes priming of microglia through increased NLRP3 activation, leading to amplified pro-inflammatory cytokine responses to stimulation by endotoxin.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  142. Wu, T. Y. et al. High-mobility group box-1 was released actively and involved in LPS induced depressive-like behavior. J. Psychiatr. Res. 64, 99–106 (2015).

    Article  PubMed  Google Scholar 

  143. Emanuele, E. et al. Serum levels of soluble receptor for advanced glycation endproducts (sRAGE) in patients with different psychiatric disorders. Neurosci. Lett. 487, 99–102 (2011).

    Article  CAS  PubMed  Google Scholar 

  144. Aguirre, A., Maturana, C. J., Harcha, P. A. & Saez, J. C. Possible involvement of TLRs and hemichannels in stress-induced CNS dysfunction via mastocytes, and glia activation. Mediators Inflamm. 2013, 893521 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  145. Verkhratsky, A., Krishtal, O. A. & Burnstock, G. Purinoceptors on neuroglia. Mol. Neurobiol. 39, 190–208 (2009).

    Article  CAS  PubMed  Google Scholar 

  146. Boucsein, C. et al. Purinergic receptors on microglial cells: functional expression in acute brain slices and modulation of microglial activation in vitro. Eur. J. Neurosci. 17, 2267–2276 (2003).

    Article  PubMed  Google Scholar 

  147. Ogata, T. et al. Adenosine triphosphate inhibits cytokine release from lipopolysaccharide-activated microglia via P2y receptors. Brain Res. 981, 174–183 (2003).

    Article  CAS  PubMed  Google Scholar 

  148. Seo, D. R. et al. Cross talk between P2 purinergic receptors modulates extracellular ATP-mediated interleukin-10 production in rat microglial cells. Exp. Mol. Med. 40, 19–26 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Harry, G. J. Microglia during development and aging. Pharmacol. Ther. 139, 313–326 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Basso, A. M. et al. Behavioral profile of P2X7 receptor knockout mice in animal models of depression and anxiety: relevance for neuropsychiatric disorders. Behav. Brain Res. 198, 83–90 (2009).

    Article  CAS  PubMed  Google Scholar 

  151. Halmai, Z. et al. Associations between depression severity and purinergic receptor P2RX7 gene polymorphisms. J. Affect. Disord. 150, 104–109 (2013).

    Article  CAS  PubMed  Google Scholar 

  152. Lucae, S. et al. P2RX7, a gene coding for a purinergic ligand-gated ion channel, is associated with major depressive disorder. Hum. Mol. Genet. 15, 2438–2445 (2006).

    Article  CAS  PubMed  Google Scholar 

  153. McQuillin, A. et al. Case–control studies show that a non-conservative amino-acid change from a glutamine to arginine in the P2RX7 purinergic receptor protein is associated with both bipolar- and unipolar-affective disorders. Mol. Psychiatry 14, 614–620 (2009).

    Article  CAS  PubMed  Google Scholar 

  154. Stokes, L. et al. Two haplotypes of the P2X7 receptor containing the Ala-348 to Thr polymorphism exhibit a gain-of-function effect and enhanced interleukin-1β secretion. FASEB J. 24, 2916–2927 (2010).

    Article  CAS  PubMed  Google Scholar 

  155. Li, Y., Du, X. F., Liu, C. S., Wen, Z. L. & Du, J. L. Reciprocal regulation between resting microglial dynamics and neuronal activity in vivo. Dev. Cell 23, 1189–1202 (2012).

    Article  CAS  PubMed  Google Scholar 

  156. Perrotti, L. I. et al. Induction of ΔFosB in reward-related brain structures after chronic stress. J. Neurosci. 24, 10594–10602 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Walker, F. R., Nilsson, M. & Jones, K. Acute and chronic stress-induced disturbances of microglial plasticity, phenotype and function. Curr. Drug Targets 14, 1262–1276 (2013).

    Article  CAS  PubMed  Google Scholar 

  158. Yirmiya, R., Rimmerman, N. & Reshef, R. Depression as a microglial disease. Trends Neurosci. 38, 637–658 (2015).

    Article  CAS  PubMed  Google Scholar 

  159. Grabert, K. et al. Microglial brain region-dependent diversity and selective regional sensitivities to aging. Nat. Neurosci. 19, 504–516 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Hinwood, M., Morandini, J., Day, T. A. & Walker, F. R. Evidence that microglia mediate the neurobiological effects of chronic psychological stress on the medial prefrontal cortex. Cereb. Cortex 22, 1442–1454 (2012).

    Article  CAS  PubMed  Google Scholar 

  161. Wood, S. K. et al. Inflammatory factors mediate vulnerability to a social stress-induced depressive-like phenotype in passive coping rats. Biol. Psychiatry 78, 38–48 (2015).

    Article  CAS  PubMed  Google Scholar 

  162. Kreisel, T. et al. Dynamic microglial alterations underlie stress-induced depressive-like behavior and suppressed neurogenesis. Mol. Psychiatry 19, 699–709 (2014). This study provides compelling findings showing that short-term stress causes microglial activation and that chronic stress exposure promotes dystrophic microglial responses in the hippocampus, both contributing to the development of depressive-like behaviours.

    Article  CAS  PubMed  Google Scholar 

  163. Delpech, J. C. et al. Microglia in neuronal plasticity: influence of stress. Neuropharmacology 96, 19–28 (2015).

    Article  CAS  PubMed  Google Scholar 

  164. Boersma, M. C. et al. A requirement for nuclear factor-κB in developmental and plasticity-associated synaptogenesis. J. Neurosci. 31, 5414–5425 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Christoffel, D. J. et al. IκB kinase regulates social defeat stress-induced synaptic and behavioral plasticity. J. Neurosci. 31, 314–321 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Koo, J. W., Russo, S. J., Ferguson, D., Nestler, E. J. & Duman, R. S. Nuclear factor-κB is a critical mediator of stress-impaired neurogenesis and depressive behavior. Proc. Natl Acad. Sci. USA 107, 2669–2674 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Tanaka, K. et al. Prostaglandin E2-mediated attenuation of mesocortical dopaminergic pathway is critical for susceptibility to repeated social defeat stress in mice. J. Neurosci. 32, 4319–4329 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Goshen, I. et al. Brain interleukin-1 mediates chronic stress-induced depression in mice via adrenocortical activation and hippocampal neurogenesis suppression. Mol. Psychiatry 13, 717–728 (2008).

    Article  CAS  PubMed  Google Scholar 

  169. Goshen, I. & Yirmiya, R. Interleukin-1 (IL-1): a central regulator of stress responses. Front. Neuroendocrinol. 30, 30–45 (2009).

    Article  CAS  PubMed  Google Scholar 

  170. Koo, J. W. & Duman, R. S. IL-1β is an essential mediator of the antineurogenic and anhedonic effects of stress. Proc. Natl Acad. Sci. USA 105, 751–756 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. McKim, D. B. et al. Neuroinflammatory dynamics underlie memory impairments after repeated social defeat. J. Neurosci. 36, 2590–2604 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Liu, M. et al. Microglia activation regulates GluR1 phosphorylation in chronic unpredictable stress-induced cognitive dysfunction. Stress 18, 96–106 (2015).

    Article  CAS  PubMed  Google Scholar 

  173. Warner-Schmidt, J. L., Vanover, K. E., Chen, E. Y., Marshall, J. J. & Greengard, P. Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) are attenuated by antiinflammatory drugs in mice and humans. Proc. Natl Acad. Sci. USA 108, 9262–9267 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Yirmiya, R. & Goshen, I. Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain Behav. Immun. 25, 181–213 (2011).

    Article  CAS  PubMed  Google Scholar 

  175. Yu, H. et al. Variant brain-derived neurotrophic factor Val66Met polymorphism alters vulnerability to stress and response to antidepressants. J. Neurosci. 32, 4092–4101 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Berton, O. et al. Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science 311, 864–868 (2006).

    Article  CAS  PubMed  Google Scholar 

  177. Parkhurst, C. N. et al. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 155, 1596–1609 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Banasr, M. et al. Glial pathology in an animal model of depression: reversal of stress-induced cellular, metabolic and behavioral deficits by the glutamate-modulating drug riluzole. Mol. Psychiatry 15, 501–511 (2010).

    Article  CAS  PubMed  Google Scholar 

  179. Guloksuz, S., Rutten, B. P., Arts, B., van Os, J. & Kenis, G. The immune system and electroconvulsive therapy for depression. J. ECT 30, 132–137 (2014).

    Article  CAS  PubMed  Google Scholar 

  180. Perez-Caballero, L. et al. Early responses to deep brain stimulation in depression are modulated by anti-inflammatory drugs. Mol. Psychiatry 19, 607–614 (2014).

    Article  CAS  PubMed  Google Scholar 

  181. Beattie, E. C. et al. Control of synaptic strength by glial TNFα. Science 295, 2282–2285 (2002). A fundamental study elucidating the mechanisms by which glial-derived TNF modulates baseline levels of synaptic plasticity by trafficking of AMPA receptors.

    Article  CAS  PubMed  Google Scholar 

  182. Stellwagen, D. & Malenka, R. C. Synaptic scaling mediated by glial TNF-α. Nature 440, 1054–1059 (2006).

    Article  CAS  PubMed  Google Scholar 

  183. Stellwagen, D., Beattie, E. C., Seo, J. Y. & Malenka, R. C. Differential regulation of AMPA receptor and GABA receptor trafficking by tumor necrosis factor-α. J. Neurosci. 25, 3219–3228 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Qiu, Z., Sweeney, D. D., Netzeband, J. G. & Gruol, D. L. Chronic interleukin-6 alters NMDA receptor-mediated membrane responses and enhances neurotoxicity in developing CNS neurons. J. Neurosci. 18, 10445–10456 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Gruol, D. L. & Nelson, T. E. Purkinje neuron physiology is altered by the inflammatory factor interleukin-6. Cerebellum 4, 198–205 (2005).

    Article  CAS  PubMed  Google Scholar 

  186. Qian, J. et al. Interleukin-1R3 mediates interleukin-1-induced potassium current increase through fast activation of Akt kinase. Proc. Natl Acad. Sci. USA 109, 12189–12194 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Milior, G. et al. Fractalkine receptor deficiency impairs microglial and neuronal responsiveness to chronic stress. Brain Behav. Immun. http://dx.doi.org/10.1016/j.bbi.2015.07.024 (2015). An initial report showing that hippocampal microglial processes have increased dendritic and synaptic elements following chronic stress, and that CX 3 CR1 mediates these synaptic as well as behavioural (anhedonia) deficits.

  188. Walsh, J. G., Muruve, D. A. & Power, C. Inflammasomes in the CNS. Nat. Rev. Neurosci. 15, 84–97 (2014).

    Article  CAS  PubMed  Google Scholar 

  189. Guo, H., Callaway, J. B. & Ting, J. P. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat. Med. 21, 677–687 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  190. Schroder, K. & Tschopp, J. The inflammasomes. Cell 140, 821–832 (2010).

    Article  CAS  PubMed  Google Scholar 

  191. Mariathasan, S. et al. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 440, 228–232 (2006).

    Article  CAS  PubMed  Google Scholar 

  192. Alcocer-Gomez, E. et al. NLRP3 inflammasome is activated in mononuclear blood cells from patients with major depressive disorder. Brain Behav. Immun. 36, 111–117 (2014). Clinical work reporting that depressed individuals have elevated levels of NLRP3 inflammasome proteins in peripheral mononuclear immune cells, suggesting that this is a common molecular pathway leading to enhanced inflammation.

    Article  CAS  PubMed  Google Scholar 

  193. Zhang, Y. et al. NLRP3 inflammasome mediates chronic mild stress-induced depression in mice via neuroinflammation. Int. J. Neuropsychopharmacol. 18, pyv006 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  194. Alcocer-Gomez, E. et al. Stress-induced depressive behaviors require a functional NLRP3 inflammasome. Mol. Neurobiol. http://dx.doi.org/10.1007/s12035-015-9408-7 (2015).

  195. Iwata, M. et al. Psychological stress activates the inflammasome via release of adenosine triphosphate and stimulation of the purinergic type 2X7 receptor. Biol. Psychiatry http://dx.doi.org/10.1016/j.biopsych.2015.11.026 (2015).

  196. Krishnan, V. & Nestler, E. J. Linking molecules to mood: new insight into the biology of depression. Am. J. Psychiatry 167, 1305–1320 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  197. Walker, F. R. A critical review of the mechanism of action for the selective serotonin reuptake inhibitors: do these drugs possess anti-inflammatory properties and how relevant is this in the treatment of depression? Neuropharmacology 67, 304–317 (2013).

    Article  CAS  PubMed  Google Scholar 

  198. Baune, B. T. & Eyre, H. Anti-inflammatory effects of antidepressant and atypical antipsychotic medication for the treatment of major depression and comorbid arthritis: a case report. J. Med. Case Rep. 4, 6 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  199. O'Brien, S. M., Scott, L. V. & Dinan, T. G. Antidepressant therapy and C-reactive protein levels. Br. J. Psychiatry 188, 449–452 (2006).

    Article  PubMed  Google Scholar 

  200. Hannestad, J., DellaGioia, N. & Bloch, M. The effect of antidepressant medication treatment on serum levels of inflammatory cytokines: a meta-analysis. Neuropsychopharmacology 36, 2452–2459 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Hannestad, J., DellaGioia, N., Ortiz, N., Pittman, B. & Bhagwagar, Z. Citalopram reduces endotoxin-induced fatigue. Brain Behav. Immun. 25, 256–259 (2011).

    Article  CAS  PubMed  Google Scholar 

  202. Tynan, R. J. et al. A comparative examination of the anti-inflammatory effects of SSRI and SNRI antidepressants on LPS stimulated microglia. Brain Behav. Immun. 26, 469–479 (2012).

    Article  CAS  PubMed  Google Scholar 

  203. Ramirez, K., Shea, D. T., McKim, D. B., Reader, B. F. & Sheridan, J. F. Imipramine attenuates neuroinflammatory signaling and reverses stress-induced social avoidance. Brain Behav. Immun. 46, 212–220 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Maes, M., Song, C. & Yirmiya, R. Targeting IL-1 in depression. Expert Opin. Ther. Targets 16, 1097–1112 (2012).

    Article  CAS  PubMed  Google Scholar 

  205. Raison, C. L. et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry 70, 31–41 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Krishnan, R. et al. Effects of etanercept therapy on fatigue and symptoms of depression in subjects treated for moderate to severe plaque psoriasis for up to 96 weeks. Br. J. Dermatol. 157, 1275–1277 (2007).

    Article  CAS  PubMed  Google Scholar 

  207. Tyring, S. et al. Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase III trial. Lancet 367, 29–35 (2006).

    Article  CAS  PubMed  Google Scholar 

  208. Akhondzadeh, S. et al. Clinical trial of adjunctive celecoxib treatment in patients with major depression: a double blind and placebo controlled trial. Depress. Anxiety 26, 607–611 (2009).

    Article  CAS  PubMed  Google Scholar 

  209. Muller, N. et al. The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine. Mol. Psychiatry 11, 680–684 (2006).

    Article  CAS  PubMed  Google Scholar 

  210. Na, K. S., Lee, K. J., Lee, J. S., Cho, Y. S. & Jung, H. Y. Efficacy of adjunctive celecoxib treatment for patients with major depressive disorder: a meta-analysis. Prog. Neuropsychopharmacol. Biol. Psychiatry 48, 79–85 (2014).

    Article  CAS  PubMed  Google Scholar 

  211. Eyre, H. A., Air, T., Proctor, S., Rositano, S. & Baune, B. T. A critical review of the efficacy of non-steroidal anti-inflammatory drugs in depression. Prog. Neuropsychopharmacol. Biol. Psychiatry 57, 11–16 (2015).

    Article  CAS  PubMed  Google Scholar 

  212. Fleshner, M. Stress-evoked sterile inflammation, danger associated molecular patterns (DAMPs), microbial associated molecular patterns (MAMPs) and the inflammasome. Brain Behav. Immun. 27, 1–7 (2013).

    Article  CAS  PubMed  Google Scholar 

  213. Yamanashi, T. et al. NLRP3 inflammasome is activated by psychological stress: a potential role of NLRP3 inhibitor β-hydroxybutyrate's antidepressant effect. Program No. 775.05/G34. 2015 Neuroscience Meeting Planner (Society for Neuroscience, Washington, DC, 2015).

  214. Ota, K. T. & Duman, R. S. Environmental and pharmacological modulations of cellular plasticity: role in the pathophysiology and treatment of depression. Neurobiol. Dis. 57, 28–37 (2012).

    Article  PubMed  CAS  Google Scholar 

  215. Eyre, H. A., Papps, E. & Baune, B. T. Treating depression and depression-like behavior with physical activity: an immune perspective. Front. Psychiatry 4, 3 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  216. Vukovic, J., Colditz, M. J., Blackmore, D. G., Ruitenberg, M. J. & Bartlett, P. F. Microglia modulate hippocampal neural precursor activity in response to exercise and aging. J. Neurosci. 32, 6435–6443 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Schloesser, R. J., Lehmann, M., Martinowich, K., Manji, H. K. & Herkenham, M. Environmental enrichment requires adult neurogenesis to facilitate the recovery from psychosocial stress. Mol. Psychiatry 15, 1152–1163 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Lehmann, M. L., Brachman, R. A., Martinowich, K., Schloesser, R. J. & Herkenham, M. Glucocorticoids orchestrate divergent effects on mood through adult neurogenesis. J. Neurosci. 33, 2961–2972 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Goshen, I. et al. Environmental enrichment restores memory functioning in mice with impaired IL-1 signaling via reinstatement of long-term potentiation and spine size enlargement. J. Neurosci. 29, 3395–3403 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. DeVries, A. C., Craft, T. K., Glasper, E. R., Neigh, G. N. & Alexander, J. K. 2006 Curt P. Richter award winner: social influences on stress responses and health. Psychoneuroendocrinology 32, 587–603 (2007).

    Article  PubMed  Google Scholar 

  221. Bailey, M. T. Influence of stressor-induced nervous system activation on the intestinal microbiota and the importance for immunomodulation. Adv. Exp. Med. Biol. 817, 255–276 (2014).

    Article  CAS  PubMed  Google Scholar 

  222. Galley, J. D. & Bailey, M. T. Impact of stressor exposure on the interplay between commensal microbiota and host inflammation. Gut Microbes 5, 390–396 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  223. Miller, A. H. & Raison, C. L. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat. Rev. Immunol. 16, 22–34 (2015).

    Article  CAS  Google Scholar 

  224. Dantzer, R. & Kelley, K. W. Twenty years of research on cytokine-induced sickness behavior. Brain Behav. Immun. 21, 153–160 (2007).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by endowment funds from Yale University, New Haven, Connecticut, USA, and by the State of Connecticut, USA.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ronald S. Duman.

Ethics declarations

Competing interests

R.S.D. has received consulting fees, speaking fees and/or grant support from Naurex, Taisho Pharmaceutical, Johnson & Johnson, Eli Lilly and Company, Lundbeck, Sunovion Pharmaceuticals, and Forest Laboratories. E.S.W., T.F. and M.I. declare no competing interests.

PowerPoint slides

Glossary

Endotoxin

A component of the bacterial cell wall that binds to pattern recognition receptors on host immune cells and elicits inflammatory responses without persistent infection.

Sickness behaviour

Reductions in locomotor activity, food intake and social interaction that are induced by inflammatory factors to facilitate pathogen clearance and recovery, and to prevent spread of infection.

Anhedonia

A core symptom of depression that manifests as an inability to experience pleasure during usually enjoyable activities.

Melancholic depression

A subtype of major depressive disorder that is characterized by anhedonia and diminished affect, leading to impaired mood in response to positive events.

Atypical depression

A subtype of major depressive disorder that is characterized by general fatigue, increased sleep and weight gain, as well as intense changes in mood based on extraneous circumstances and factors.

Neurovegetative

A cluster of depression symptoms, including but not limited to significant changes in weight and eating patterns, sleep patterns and sensitivity to interpersonal issues.

Social defeat

A standardized rodent model of psychosocial stress induced by losing a confrontation with a conspecific.

Minocycline

A brain-penetrating tetracycline antibiotic that exerts anti-inflammatory and neuroprotective effects by putatively directly inhibiting microglia.

Tricyclic antidepressant

An early chemical class of antidepressant drug that acts primarily by inhibiting serotonin and noradrenaline reuptake; however, therapeutic effects lag by several weeks, suggesting a role for adaptive changes.

Monoamine oxidase inhibitors

A class of antidepressant drugs that prevent enzymatic breakdown of monoamines, typically used when other drugs are ineffective.

β-hydroxybutyrate

A ketone metabolite recently reported to selectively block activation of the NLRP3 (NOD-, LRR- and pyrin domain-containing 3) inflammasome, an effect that could underlie the anti-inflammatory effects of ketogenic diets.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wohleb, E., Franklin, T., Iwata, M. et al. Integrating neuroimmune systems in the neurobiology of depression. Nat Rev Neurosci 17, 497–511 (2016). https://doi.org/10.1038/nrn.2016.69

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn.2016.69

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing