Integrating neuroimmune systems in the neurobiology of depression

Nature Reviews Neuroscience

Volumn 17, Issue 8, 2016, Pages 497-511

  Wohleb, Eric S ^a   Franklin, Tina ^a   Iwata, Masaaki ^b   Duman, Ronald S ^a  

^a YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b TOTTORI UNIVERSITY   (Japan)

Author keywords

[No Author keywords available]

Indexed keywords

INFLAMMASOME; CYTOKINE;

CELL FUNCTION; CELL INTERACTION; CYTOKINE PRODUCTION; HUMAN; IMMUNE DYSREGULATION; IMMUNOCOMPETENT CELL; INTRACELLULAR SIGNALING; MAJOR DEPRESSION; MICROGLIA; NERVE CELL; NERVE CELL PLASTICITY; NERVOUS SYSTEM INFLAMMATION; NEUROBIOLOGY; NEUROIMMUNOLOGY; NONHUMAN; PATHOPHYSIOLOGY; PRIORITY JOURNAL; REVIEW; STRESS; ANIMAL; BRAIN; IMMUNOLOGY; IMMUNOMODULATION; METABOLISM; PHYSIOLOGY; PROCEDURES;

ANIMALS; BRAIN; CYTOKINES; DEPRESSIVE DISORDER, MAJOR; HUMANS; NEUROBIOLOGY; NEUROIMMUNOMODULATION; NEURONAL PLASTICITY;

EID: 84973595854     PISSN: 1471003X     EISSN: 14710048     Source Type: Journal    
DOI: 10.1038/nrn.2016.69     Document Type: Review

References (224)

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
2. Kessler R. C. Epidemiology of women and depression. J. Affect. Disord. 74, 5-13 (2003
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
4. Russo S. J., & Nestler E. J. The brain reward circuitry in mood disorders. Nat. Rev. Neurosci. 14, 609-625 (2013
5. Krishnan V., & Nestler E. J. The molecular neurobiology of depression. Nature 455, 894-902 (2008
6. Duman R. S., & Aghajanian G. K. Synaptic dysfunction in depression: potential therapeutic targets. Science 338, 68-72 (2012
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
8. Schmidt H. D., Shelton R. C., & Duman R. S. Functional biomarkers of depression: diagnosis, treatment, and pathophysiology. Neuropsychopharmacology 36, 2375-2394 (2011
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
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
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
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
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
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
15. Christoffel D. J., Golden S. A., & Russo S. J. Structural and synaptic plasticity in stress-related disorders. Rev. Neurosci. 22, 535-549 (2011
16. Hodes G. E., Kana V., Menard C., Merad M., & Russo S. J. Neuroimmune mechanisms of depression. Nat. Neurosci. 18, 1386-1393 (2015
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
18. Maes M. Evidence for an immune response in major depression: a review and hypothesis. Prog. Neuropsychopharmacol. Biol. Psychiatry 19, 11-38 (1995
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
20. Dowlati Y., et al. A meta-analysis of cytokines in major depression. Biol. Psychiatry 67, 446-457 (2010
21. Capuron L., & Dantzer R. Cytokines and depression: the need for a new paradigm. Brain Behav. Immun. 17 (Suppl. 1), 119-124 (2003
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
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
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
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
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
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
28. Leonard B. E. Inflammation, depression and dementia: are they connected?. Neurochem. Res. 32, 1749-1756 (2007
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
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
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
32. Maas J. W. Biogenic amines and depression. Biochemical and pharmacological separation of two types of depression. Arch. Gen. Psychiatry 32, 1357-1361 (1975
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
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
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
36. Butler P. W., & Besser G. M. Pituitary-adrenal function in severe depressive illness. Lancet 1, 1234-1236 (1968
37. Dinan T. G. Glucocorticoids and the genesis of depressive illness. A psychobiological model. Br. J. Psychiatry 164, 365-371 (1994
38. Price J. L., & Drevets W. C. Neural circuits underlying the pathophysiology of mood disorders. Trends Cogn. Sci. 16, 61-71 (2010
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
40. Shin L. M., & Liberzon I. The neurocircuitry of fear, stress, and anxiety disorders. Neuropsychopharmacology 35, 169-191 (2010
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
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
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
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
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
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
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
48. Wellman C. L. Dendritic reorganization in pyramidal neurons in medial prefrontal cortex after chronic corticosterone administration. J. Neurobiol. 49, 245-253 (2001
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
50. Roozendaal B., McEwen B. S., & Chattarji S. Stress, memory and the amygdala. Nat. Rev. Neurosci. 10, 423-433 (2009
51. Krishnan V., et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell 131, 391-404 (2007
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
53. Santarelli L., et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301, 805-809 (2003
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
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
56. Li N., et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329, 959-964 (2010
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
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
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
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
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
62. Gold P. W. The organization of the stress system and its dysregulation in depressive illness. Mol. Psychiatry 20, 32-47 (2015
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
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
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
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
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
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
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
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
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
73. Sternberg E. M. Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens. Nat. Rev. Immunol. 6, 318-328 (2006
74. Irwin M. R., & Cole S. W. Reciprocal regulation of the neural and innate immune systems. Nat. Rev. Immunol. 11, 625-632 (2011
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
76. Quan N. Immune-to brain signaling: how important are the blood-brain barrier-independent pathways?. Mol. Neurobiol. 37, 142-152 (2008
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
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
79. Schiltz J. C., & Sawchenko P. E. Signaling the brain in systemic inflammation: the role of perivascular cells. Front. Biosci. 8, s1321-s1329 (2003
80. Serrats J., et al. Dual roles for perivascular macrophages in immune-to brain signaling. Neuron 65, 94-106 (2010
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
82. Kipnis J., Gadani S., & Derecki N. C. Pro-cognitive properties of T cells. Nat. Rev. Immunol. 12, 663-669 (2012
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
84. Dhabhar F. S. Enhancing versus suppressive effects of stress on immune function: implications for immunoprotection and immunopathology. Neuroimmunomodulation 16, 300-317 (2009
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
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
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
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
89. Stark J. L., et al. Social stress induces glucocorticoid resistance in macrophages. Am. J. Physiol. Regul. Integr. Comp. Physiol. 280, R1799-R1805 (2001
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
91. Nance D. M., & Sanders V. M. Autonomic innervation and regulation of the immune system (1987-2007). Brain Behav. Immun. 21, 736-745 (2007
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
93. Grisanti L. A., et al. Pro-inflammatory responses in human monocytes are β1 adrenergic receptor subtype dependent. Mol. Immunol. 47, 1244-1254 (2010
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
95. Katayama Y., et al. Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell 124, 407-421 (2006
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
97. Heidt T., et al. Chronic variable stress activates hematopoietic stem cells. Nat. Med. 20, 754-758 (2014
98. Swirski F. K., et al. Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science 325, 612-616 (2009
99. Johnson J. D., et al. Catecholamines mediate stress-induced increases in peripheral and central inflammatory cytokines. Neuroscience 135, 1295-1307 (2005
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
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
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
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
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
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
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
107. McKim D. B., et al. Sympathetic release of splenic monocytes promotes recurring anxiety following repeated social defeat. Biol. Psychiatry 79, 803-813 (2016
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
109. Ginhoux F., et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841-845 (2010
110. Davalos D., et al. ATP mediates rapid microglial response to local brain injury in vivo. Nat. Neurosci. 8, 752-758 (2005
111. Kettenmann H., Hanisch U. K., Noda M., & Verkhratsky A. Physiology of microglia. Physiol. Rev. 91, 461-553 (2011
112. Ransohoff R. M., & Perry V. H. Microglial physiology: unique stimuli, specialized responses. Annu. Rev. Immunol. 27, 119-145 (2009
113. Kierdorf K., & Prinz M. Factors regulating microglia activation. Front. Cell. Neurosci. 7, 44 (2013
114. Butovsky O., et al. Identification of a unique TGF-β-dependent molecular and functional signature in microglia. Nat. Neurosci. 17, 131-143 (2014
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
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
117. Biber K., Neumann H., Inoue K., & Boddeke H. W. Neuronal 'On' and 'Off' signals control microglia. Trends Neurosci. 30, 596-602 (2007
118. Jurgens H. A., & Johnson R. W. Dysregulated neuronal-microglial cross-talk during aging, stress and inflammation. Exp. Neurol. 233, 40-48 (2010
119. Paolicelli R. C., et al. Synaptic pruning by microglia is necessary for normal brain development. Science 333, 1456-1458 (2011
120. Zhan Y., et al. Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior. Nat. Neurosci. 17, 400-406 (2014
121. Rogers J. T., et al. CX3CR1 deficiency leads to impairment of hippocampal cognitive function and synaptic plasticity. J. Neurosci. 31, 16241-16250 (2011
122. Tremblay M. E., et al. The role of microglia in the healthy brain. J. Neurosci. 31, 16064-16069 (2011
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
124. Fontainhas A. M., et al. Microglial morphology and dynamic behavior is regulated by ionotropic glutamatergic and GABAergic neurotransmission. PLoS ONE 6, e15973 (2011
125. Pocock J. M., & Kettenmann H. Neurotransmitter receptors on microglia. Trends Neurosci. 30, 527-535 (2007
126. Tremblay M. E., Lowery R. L., & Majewska A. K. Microglial interactions with synapses are modulated by visual experience. PLoS Biol. 8, e1000527 (2010
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
128. Schafer D. P., et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74, 691-705 (2012
129. Davies L. C., Jenkins S. J., Allen J. E., & Taylor P. R. Tissue-resident macrophages. Nat. Immunol. 14, 986-995 (2013
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
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
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
133. Chang Y., et al. Inhibitory effects of ketamine on lipopolysaccharide-induced microglial activation. Mediators Inflamm. 2009, 705379 (2009
134. Nair A., & Bonneau R. H. Stress-induced elevation of glucocorticoids increases microglia proliferation through NMDA receptor activation. J. Neuroimmunol. 171, 72-85 (2006
135. Glezer I., & Rivest S. Glucocorticoids: protectors of the brain during innate immune responses. Neuroscientist 10, 538-552 (2004
136. Sorrells S. F., & Sapolsky R. M. An inflammatory review of glucocorticoid actions in the CNS. Brain Behav. Immun. 21, 259-272 (2007
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
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
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
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
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
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
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
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
145. Verkhratsky A., Krishtal O. A., & Burnstock G. Purinoceptors on neuroglia. Mol. Neurobiol. 39, 190-208 (2009
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
147. Ogata T., et al. Adenosine triphosphate inhibits cytokine release from lipopolysaccharide-activated microglia via P2y receptors. Brain Res. 981, 174-183 (2003
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
149. Harry G. J. Microglia during development and aging. Pharmacol. Ther. 139, 313-326 (2013
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
151. Halmai Z., et al. Associations between depression severity and purinergic receptor P2RX7 gene polymorphisms. J. Affect. Disord. 150, 104-109 (2013
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
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
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
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
156. Perrotti L. I., et al. Induction of δFosB in reward-related brain structures after chronic stress. J. Neurosci. 24, 10594-10602 (2004
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
158. Yirmiya R., Rimmerman N., & Reshef R. Depression as a microglial disease. Trends Neurosci. 38, 637-658 (2015
159. Grabert K., et al. Microglial brain region-dependent diversity and selective regional sensitivities to aging. Nat. Neurosci. 19, 504-516 (2016
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
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
162. Kreisel T., et al. Dynamic microglial alterations underlie stress-induced depressive-like behavior and suppressed neurogenesis. Mol. Psychiatry 19, 699-709 (2014
163. Delpech J. C., et al. Microglia in neuronal plasticity: influence of stress. Neuropharmacology 96, 19-28 (2015
164. Boersma M. C., et al. A requirement for nuclear factor κB in developmental and plasticity-associated synaptogenesis. J. Neurosci. 31, 5414-5425 (2011
165. Christoffel D. J., et al. IκB kinase regulates social defeat stress-induced synaptic and behavioral plasticity. J. Neurosci. 31, 314-321 (2011
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
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
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
169. Goshen I., & Yirmiya R. Interleukin 1 (IL 1): a central regulator of stress responses. Front. Neuroendocrinol. 30, 30-45 (2009
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
171. McKim D. B., et al. Neuroinflammatory dynamics underlie memory impairments after repeated social defeat. J. Neurosci. 36, 2590-2604 (2016
172. Liu M., et al. Microglia activation regulates GluR1 phosphorylation in chronic unpredictable stress-induced cognitive dysfunction. Stress 18, 96-106 (2015
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
174. Yirmiya R., & Goshen I. Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain Behav. Immun. 25, 181-213 (2011
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
176. Berton O., et al. Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science 311, 864-868 (2006
177. Parkhurst C. N., et al. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 155, 1596-1609 (2013
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
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
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
181. Beattie E. C., et al. Control of synaptic strength by glial TNFα. Science 295, 2282-2285 (2002
182. Stellwagen D., & Malenka R. C. Synaptic scaling mediated by glial TNF-α. Nature 440, 1054-1059 (2006
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
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
185. Gruol D. L., & Nelson T. E. Purkinje neuron physiology is altered by the inflammatory factor interleukin 6. Cerebellum 4, 198-205 (2005
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
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
188. Walsh J. G., Muruve D. A., & Power C. Inflammasomes in the CNS. Nat. Rev. Neurosci. 15, 84-97 (2014
189. Guo H., Callaway J. B., & Ting J. P. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat. Med. 21, 677-687 (2015
190. Schroder K., & Tschopp J. The inflammasomes. Cell 140, 821-832 (2010
191. Mariathasan S., et al. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 440, 228-232 (2006
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
193. Zhang Y., et al. NLRP3 inflammasome mediates chronic mild stress-induced depression in mice via neuroinflammation. Int. J. Neuropsychopharmacol. 18, pyv006 (2015
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
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
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
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
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
201. Hannestad J., DellaGioia N., Ortiz N., Pittman B., & Bhagwagar Z. Citalopram reduces endotoxin-induced fatigue. Brain Behav. Immun. 25, 256-259 (2011
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
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
204. Maes M., Song C., & Yirmiya R. Targeting IL 1 in depression. Expert Opin. Ther. Targets 16, 1097-1112 (2012
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
224. Dantzer R., & Kelley K. W. Twenty years of research on cytokine-induced sickness behavior. Brain Behav. Immun. 21, 153-160 (2007