Chronic stress is a major risk factor in the pathophysiology of many neuropsychiatric disorders. Further, chronic stress conditions can promote neuroinflammation and inflammatory responses in both humans and animal models. Type I interferons (IFN-I) are critical mediators of the inflammatory response in the periphery and responsible for the altered mood and behavior. However, the underlying mechanisms are not well understood. In the present study, we investigated the role of IFN-I signaling in chronic stress-induced changes in neuroinflammation and behavior. Using the chronic restraint stress model, we found that chronic stress induces a significant increase in serum IFNβ levels in mice, and systemic blockade of IFN-I signaling attenuated chronic stress-induced infiltration of macrophages into prefrontal cortex and behavioral abnormalities. Furthermore, complement component 3 (C3) mediates systemic IFNβ-induced changes in neuroinflammation and behavior. Also, we found significant increases in the mRNA expression levels of IFN-I stimulated genes in the prefrontal cortex of depressed suicide subjects and significant correlation with C3 and inflammatory markers. Together, these findings from animal and human postmortem brain studies identify a crucial role of C3 in IFN-I-mediated changes in neuroinflammation and behavior under chronic stress conditions.
Subscribe to Journal
Get full journal access for 1 year
only $9.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Marshall PS, Watson D, Steinberg P, Cornblatt B, Peterson PK, Callies A, et al. An assessment of cognitive function and mood in chronic fatigue syndrome. Biol Psychiatry. 1996;39:199–206.
Beck AT. Depression: clinical, experimental, and theoretical aspects.1967.
Enns MW, Bernstein CN, Kroeker K, Graff L, Walker JR, Lix LM, et al. The association of fatigue, pain, depression and anxiety with work and activity impairment in immune mediated inflammatory diseases. PLoS One. 2018;13:e0198975.
Feinstein A, Brochet B, Sumowski J. The cognitive effects of anxiety and depression in immune-mediated inflammatory diseases. Neurology. 2019;92:211–2.
Whitehouse CE, Fisk JD, Bernstein CN, Berrigan LI, Bolton JM, Graff LA, et al. Comorbid anxiety, depression, and cognition in MS and other immune-mediated disorders. Neurology. 2019;92:e406–17.
Slavich GM, Irwin MR. From stress to inflammation and major depressive disorder: a social signal transduction theory of depression. Psychol Bull. 2014;140:774–815.
Schedlowski M, Engler H, Grigoleit JS. Endotoxin-induced experimental systemic inflammation in humans: a model to disentangle immune-to-brain communication. Brain Behav Immun. 2014;35:1–8.
Eisenberger NI, Inagaki TK, Mashal NM, Irwin MR. Inflammation and social experience: an inflammatory challenge induces feelings of social disconnection in addition to depressed mood. Brain Behav Immun. 2010;24:558–63.
Brydon L, Harrison NA, Walker C, Steptoe A, Critchley HD. Peripheral inflammation is associated with altered substantia nigra activity and psychomotor slowing in humans. Biol Psychiatry. 2008;63:1022–9.
Corona AW, Fenn AM, Godbout JP. Cognitive and behavioral consequences of impaired immunoregulation in aging. J Neuroimmune Pharm. 2012;7:7–23.
Munhoz CD, Lepsch LB, Kawamoto EM, Malta MB, Lima Lde S, Avellar MC, et al. Chronic unpredictable stress exacerbates lipopolysaccharide-induced activation of nuclear factor-kappaB in the frontal cortex and hippocampus via glucocorticoid secretion. J Neurosci. 2006;26:3813–20.
Crider A, Feng T, Pandya CD, Davis T, Nair A, Ahmed AO, et al. Complement component 3a receptor deficiency attenuates chronic stress-induced monocyte infiltration and depressive-like behavior. Brain Behav Immun. 2018;70:246–56.
Pyter LM, Kelly SD, Harrell CS, Neigh GN. Sex differences in the effects of adolescent stress on adult brain inflammatory markers in rats. Brain Behav Immun. 2013;30:88–94.
Wohleb ES, Hanke ML, Corona AW, Powell ND, Stiner LM, Bailey MT, et al. beta-Adrenergic receptor antagonism prevents anxiety-like behavior and microglial reactivity induced by repeated social defeat. J Neurosci. 2011;31:6277–88.
Kreisel T, Frank MG, Licht T, Reshef R, Ben-Menachem-Zidon O, Baratta MV, et al. Dynamic microglial alterations underlie stress-induced depressive-like behavior and suppressed neurogenesis. Mol Psychiatry. 2014;19:699–709.
McKim DB, Patterson JM, Wohleb ES, Jarrett BL, Reader BF, Godbout JP, et al. Sympathetic release of splenic monocytes promotes recurring anxiety following repeated social defeat. Biol Psychiatry. 2016;79:803–13.
Wohleb ES, Patterson JM, Sharma V, Quan N, Godbout JP, Sheridan JF. Knockdown of interleukin-1 receptor type-1 on endothelial cells attenuated stress-induced neuroinflammation and prevented anxiety-like behavior. J Neurosci. 2014;34:2583–91.
Schreiber G, Piehler J. The molecular basis for functional plasticity in type I interferon signaling. Trends Immunol. 2015;36:139–49.
Kawai T, Akira S. Innate immune recognition of viral infection. Nat Immunol. 2006;7:131–7.
de Weerd NA, Samarajiwa SA, Hertzog PJ. Type I interferon receptors: biochemistry and biological functions. J Biol Chem. 2007;282:20053–7.
Blank T, Prinz M. Type I interferon pathway in CNS homeostasis and neurological disorders. Glia. 2017;65:1397–406.
Mendoza-Fernandez V, Andrew RD, Barajas-Lopez C. Interferon-alpha inhibits long-term potentiation and unmasks a long-term depression in the rat hippocampus. Brain Res. 2000;885:14–24.
Schrott LM, Crnic LS. Increased anxiety behaviors in autoimmune mice. Behav Neurosci. 1996;110:492–502.
Prinz M, Knobeloch KP. Type I interferons as ambiguous modulators of chronic inflammation in the central nervous system. Front Immunol. 2012;3:67.
Vattakatuchery JJ, Rickards H, Cavanna AE. Pathogenic mechanisms of depression in multiple sclerosis. J Neuropsychiatry Clin Neurosci. 2011;23:261–76.
Dowell NG, Cooper EA, Tibble J, Voon V, Critchley HD, Cercignani M, et al. Acute changes in striatal microstructure predict the development of interferon-alpha induced fatigue. Biol Psychiatry. 2016;79:320–8.
McNutt MD, Liu S, Manatunga A, Royster EB, Raison CL, Woolwine BJ, et al. Neurobehavioral effects of interferon-alpha in patients with hepatitis-C: symptom dimensions and responsiveness to paroxetine. Neuropsychopharmacology 2012;37:1444–54.
Alba Pale L, Leon Caballero J, Samso Buxareu B, Salgado Serrano P, Perez Sola V. Systematic review of depression in patients with multiple sclerosis and its relationship to interferonbeta treatment. Mult Scler Relat Disord. 2017;17:138–43.
Hoyo-Becerra C, Schlaak JF, Hermann DM. Insights from interferon-alpha-related depression for the pathogenesis of depression associated with inflammation. Brain Behav Immun. 2014;42:222–31.
Coch C, Viviani R, Breitfeld J, Munzer K, Dassler-Plencker J, Holdenrieder S, et al. Interferon-beta-induced changes in neuroimaging phenotypes of appetitive motivation and reactivity to emotional salience. Neuroimage Clin. 2019;24:102020.
Mostafavi S, Battle A, Zhu X, Potash JB, Weissman MM, Shi J, et al. Type I interferon signaling genes in recurrent major depression: increased expression detected by whole-blood RNA sequencing. Mol Psychiatry. 2014;19:1267–74.
Zheng LS, Hitoshi S, Kaneko N, Takao K, Miyakawa T, Tanaka Y, et al. Mechanisms for interferon-alpha-induced depression and neural stem cell dysfunction. Stem Cell Rep. 2014;3:73–84.
Wang J, Campbell IL, Zhang H. Systemic interferon-alpha regulates interferon-stimulated genes in the central nervous system. Mol Psychiatry. 2008;13:293–301.
Bian Y, Pan Z, Hou Z, Huang C, Li W, Zhao B. Learning, memory, and glial cell changes following recovery from chronic unpredictable stress. Brain Res Bull. 2012;88:471–6.
Kopp BL, Wick D, Herman JP. Differential effects of homotypic vs. heterotypic chronic stress regimens on microglial activation in the prefrontal cortex. Physiol Behav. 2013;122:246–52.
London A, Cohen M, Schwartz M. Microglia and monocyte-derived macrophages: functionally distinct populations that act in concert in CNS plasticity and repair. Front Cell Neurosci. 2013;7:34.
Ransohoff RM, Engelhardt B. The anatomical and cellular basis of immune surveillance in the central nervous system. Nat Rev Immunol. 2012;12:623–35.
Goldmann T, Zeller N, Raasch J, Kierdorf K, Frenzel K, Ketscher L, et al. USP18 lack in microglia causes destructive interferonopathy of the mouse brain. EMBO J. 2015;34:1612–29.
Bialas AR, Presumey J, Das A, van der Poel CE, Lapchak PH, Mesin L, et al. Microglia-dependent synapse loss in type I interferon-mediated lupus. Nature. 2017;546:539–43.
Lynch MA. The multifaceted profile of activated microglia. Mol Neurobiol. 2009;40:139–56.
Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS, Nouri N, et al. The classical complement cascade mediates CNS synapse elimination. Cell. 2007;131:1164–78.
Krugers HJ, Lucassen PJ, Karst H, Joels M. Chronic stress effects on hippocampal structure and synaptic function: relevance for depression and normalization by anti-glucocorticoid treatment. Front Synaptic Neurosci. 2010;2:24.
Csabai D, Wiborg O, Czeh B. Reduced synapse and axon numbers in the prefrontal cortex of rats subjected to a chronic stress model for depression. Front Cell Neurosci. 2018;12:24.
Suvrathan A, Tomar A, Chattarji S. Effects of chronic and acute stress on rat behaviour in the forced-swim test. Stress. 2010;13:533–40.
Ulloa JL, Castaneda P, Berrios C, Diaz-Veliz G, Mora S, Bravo JA, et al. Comparison of the antidepressant sertraline on differential depression-like behaviors elicited by restraint stress and repeated corticosterone administration. Pharm Biochem Behav. 2010;97:213–21.
Chiba S, Numakawa T, Ninomiya M, Richards MC, Wakabayashi C, Kunugi H. Chronic restraint stress causes anxiety- and depression-like behaviors, downregulates glucocorticoid receptor expression, and attenuates glutamate release induced by brain-derived neurotrophic factor in the prefrontal cortex. Prog Neuropsychopharmacol Biol Psychiatry. 2012;39:112–9.
Bogdanova OV, Kanekar S, D’Anci KE, Renshaw PF. Factors influencing behavior in the forced swim test. Physiol Behav. 2013;118:227–39.
Henckens MJ, van der Marel K, van der Toorn A, Pillai AG, Fernandez G, Dijkhuizen RM, et al. Stress-induced alterations in large-scale functional networks of the rodent brain. Neuroimage. 2015;105:312–22.
Seewoo BJ, Hennessy LA, Feindel KW, Etherington SJ, Croarkin PE, Rodger J. Validation of chronic restraint stress model in young adult rats for the study of depression using longitudinal multimodal MR imaging. eNeuro. 2020;7:ENEURO.0113-20.2020.
Alemu JL, Elberling F, Azam B, Pakkenberg B, Olesen MV. Electroconvulsive treatment prevents chronic restraint stress-induced atrophy of the hippocampal formation—a stereological study. Brain Behav. 2019;9:e01195.
Park MJ, Seo BA, Lee B, Shin HS, Kang MG. Stress-induced changes in social dominance are scaled by AMPA-type glutamate receptor phosphorylation in the medial prefrontal cortex. Sci Rep. 2018;8:15008.
Liu Y, Zhuang X, Gou L, Ling X, Tian X, Liu L, et al. Protective effects of nizofenone administration on the cognitive impairments induced by chronic restraint stress in mice. Pharm Biochem Behav. 2013;103:474–80.
Bowman RE, Beck KD, Luine VN. Chronic stress effects on memory: sex differences in performance and monoaminergic activity. Horm Behav. 2003;43:48–59.
Wang Y, Kan H, Yin Y, Wu W, Hu W, Wang M, et al. Protective effects of ginsenoside Rg1 on chronic restraint stress induced learning and memory impairments in male mice. Pharm Biochem Behav. 2014;120:73–81.
Huang P, Li C, Fu T, Zhao D, Yi Z, Lu Q, et al. Flupirtine attenuates chronic restraint stress-induced cognitive deficits and hippocampal apoptosis in male mice. Behav Brain Res. 2015;288:1–10.
Woo H, Hong CJ, Jung S, Choe S, Yu SW. Chronic restraint stress induces hippocampal memory deficits by impairing insulin signaling. Mol Brain. 2018;11:37.
Lee T, Jarome T, Li SJ, Kim JJ, Helmstetter FJ. Chronic stress selectively reduces hippocampal volume in rats: a longitudinal magnetic resonance imaging study. Neuroreport. 2009;20:1554–8.
Chen Y, Mao Y, Zhou D, Hu X, Wang J, Ma Y. Environmental enrichment and chronic restraint stress in ICR mice: effects on prepulse inhibition of startle and Y-maze spatial recognition memory. Behav Brain Res. 2010;212:49–55.
Sanz H, Aponte JJ, Harezlak J, Dong Y, Ayestaran A, Nhabomba A, et al. drLumi: An open-source package to manage data, calibrate, and conduct quality control of multiplex bead-based immunoassays data analysis. PLoS One. 2017;12:e0187901.
Pandya CD, Hoda N, Crider A, Peter D, Kutiyanawalla A, Kumar S, et al. Transglutaminase 2 overexpression induces depressive-like behavior and impaired TrkB signaling in mice. Mol Psychiatry. 2017;22:745–53.
Conrad CD, Galea LA, Kuroda Y, McEwen BS. Chronic stress impairs rat spatial memory on the Y maze, and this effect is blocked by tianeptine pretreatment. Behav Neurosci. 1996;110:1321–34.
Wright RL, Conrad CD. Chronic stress leaves novelty-seeking behavior intact while impairing spatial recognition memory in the Y-maze. Stress. 2005;8:151–4.
Soper A, Kimura I, Nagaoka S, Konno Y, Yamamoto K, Koyanagi Y, et al. Type I interferon responses by HIV-1 infection: association with disease progression and control. Front Immunol. 2017;8:1823.
Dantzer R, Kelley KW. Twenty years of research on cytokine-induced sickness behavior. Brain Behav Immun. 2007;21:153–60.
Miller AH, Maletic V, Raison CL. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry. 2009;65:732–41.
Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, et al. A meta-analysis of cytokines in major depression. Biol Psychiatry. 2010;67:446–57.
Liu Y, Ho RC, Mak A. Interleukin (IL)-6, tumour necrosis factor alpha (TNF-alpha) and soluble interleukin-2 receptors (sIL-2R) are elevated in patients with major depressive disorder: a meta-analysis and meta-regression. J Affect Disord. 2012;139:230–9.
Pace TW, Mletzko TC, Alagbe O, Musselman DL, Nemeroff CB, Miller AH, et al. Increased stress-induced inflammatory responses in male patients with major depression and increased early life stress. Am J Psychiatry. 2006;163:1630–3.
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. 2007;21:901–12.
Manikowska K, Mikolajczyk M, Mikolajczak PL, Bobkiewicz-Kozlowska T. The influence of mianserin on TNF-alpha, IL-6 and IL-10 serum levels in rats under chronic mild stress. Pharm Rep. 2014;66:22–7.
Martinez FO, Helming L, Gordon S. Alternative activation of macrophages: an immunologic functional perspective. Annu Rev Immunol. 2009;27:451–83.
Fernandes A, Miller-Fleming L, Pais TF. Microglia and inflammation: conspiracy, controversy or control? Cell Mol Life Sci. 2014;71:3969–85.
Gordon S. Alternative activation of macrophages. Nat Rev Immunol. 2003;3:23–35.
Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017;541:481–7.
Zamanian JL, Xu L, Foo LC, Nouri N, Zhou L, Giffard RG, et al. Genomic analysis of reactive astrogliosis. J Neurosci. 2012;32:6391–410.
Presumey J, Bialas AR, Carroll MC. Complement system in neural synapse elimination in development and disease. Adv Immunol. 2017;135:53–79.
Ricklin D, Lambris JD. Complement in immune and inflammatory disorders: pathophysiological mechanisms. J Immunol. 2013;190:3831–8.
Wang Q, Timberlake MA 2nd, Prall K, Dwivedi Y. The recent progress in animal models of depression. Prog Neuropsychopharmacol Biol Psychiatry. 2017;77:99–109.
Miller ES, Apple CG, Kannan KB, Funk ZM, Plazas JM, Efron PA, et al. Chronic stress induces persistent low-grade inflammation. Am J Surg. 2019;218:677–83.
Zhu Y, Klomparens EA, Guo S, Geng X. Neuroinflammation caused by mental stress: the effect of chronic restraint stress and acute repeated social defeat stress in mice. Neurol Res. 2019;41:762–9.
Walker FR, Nilsson M, Jones K. Acute and chronic stress-induced disturbances of microglial plasticity, phenotype and function. Curr Drug Targets. 2013;14:1262–76.
Lehmann ML, Weigel TK, Poffenberger CN, Herkenham M. The behavioral sequelae of social defeat require microglia and are driven by oxidative stress in mice. J Neurosci. 2019;39:5594–605.
Hinwood M, Morandini J, Day TA, Walker FR. Evidence that microglia mediate the neurobiological effects of chronic psychological stress on the medial prefrontal cortex. Cereb Cortex. 2012;22:1442–54.
O’Connell RM, Taganov KD, Boldin MP, Cheng G, Baltimore D. MicroRNA-155 is induced during the macrophage inflammatory response. Proc Natl Acad Sci USA. 2007;104:1604–9.
Molnarfi N, Gruaz L, Dayer JM, Burger D. Opposite effects of IFN beta on cytokine homeostasis in LPS- and T cell contact-activated human monocytes. J Neuroimmunol. 2004;146:76–83.
Taniguchi T, Takaoka A. A weak signal for strong responses: interferon-alpha/beta revisited. Nat Rev Mol Cell Biol. 2001;2:378–86.
Santha P, Veszelka S, Hoyk Z, Meszaros M, Walter FR, Toth AE, et al. Restraint stress-induced morphological changes at the blood-brain barrier in adult rats. Front Mol Neurosci. 2015;8:88.
Blank T, Detje CN, Spiess A, Hagemeyer N, Brendecke SM, Wolfart J, et al. Brain endothelial- and epithelial-specific interferon receptor chain 1 drives virus-induced sickness behavior and cognitive impairment. Immunity. 2016;44:901–12.
Barner MMM, Brombacher F, Kopf M. Differences between IL-4R alpha-deficient and IL-4-deficient mice reveal a role for IL-13 in the regulation of Th2 responses. Curr Biol. 1998;8:669–72.
Daley JM, Brancato SK, Thomay AA, Reichner JS, Albina JE. The phenotype of murine wound macrophages. J Leukoc Biol. 2010;87:59–67.
Ferrante CJ, Pinhal-Enfield G, Elson G, Cronstein BN, Hasko G, Outram S, et al. The adenosine-dependent angiogenic switch of macrophages to an M2-like phenotype is independent of interleukin-4 receptor alpha (IL-4Ralpha) signaling. Inflammation. 2013;36:921–31.
Yamasaki R, Lu H, Butovsky O, Ohno N, Rietsch AM, Cialic R, et al. Differential roles of microglia and monocytes in the inflamed central nervous system. J Exp Med. 2014;211:1533–49.
Butovsky O, Jedrychowski MP, Moore CS, Cialic R, Lanser AJ, Gabriely G, et al. Identification of a unique TGF-beta-dependent molecular and functional signature in microglia. Nat Neurosci. 2014;17:131–43.
Wu T, Dejanovic B, Gandham VD, Gogineni A, Edmonds R, Schauer S, et al. Complement C3 is activated in human AD brain and is required for neurodegeneration in mouse models of amyloidosis and tauopathy. Cell Rep. 2019;28:2111–23 e6.
Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S, Ramakrishnan S, et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science. 2016;352:712–6.
Tenner AJ, Stevens B, Woodruff TM. New tricks for an ancient system: physiological and pathological roles of complement in the CNS. Mol Immunol. 2018;102:3–13.
Morgan BP. Complement in the pathogenesis of Alzheimer’s disease. Semin Immunopathol. 2018;40:113–24.
Hajishengallis G, Reis ES, Mastellos DC, Ricklin D, Lambris JD. Novel mechanisms and functions of complement. Nat Immunol. 2017;18:1288–98.
Whalley K. Neurodegenerative disease: complement mediates pathological pruning. Nat Rev Neurosci. 2016;17:336.
Owens T, Khorooshi R, Wlodarczyk A, Asgari N. Interferons in the central nervous system: a few instruments play many tunes. Glia. 2014;62:339–55.
Gough DJ, Messina NL, Clarke CJ, Johnstone RW, Levy DE. Constitutive type I interferon modulates homeostatic balance through tonic signaling. Immunity. 2012;36:166–74.
Deczkowska A, Baruch K, Schwartz M. Type I/II interferon balance in the regulation of brain physiology and pathology. Trends Immunol. 2016;37:181–92.
Arscott WT, Soltys J, Knight J, Mao-Draayer Y. Interferon beta-1b directly modulates human neural stem/progenitor cell fate. Brain Res. 2011;1413:1–8.
Ejlerskov P, Hultberg JG, Wang J, Carlsson R, Ambjorn M, Kuss M, et al. Lack of Neuronal IFN-beta-IFNAR causes lewy body- and parkinson’s disease-like dementia. Cell. 2015;163:324–39.
Lacy M, Hauser M, Pliskin N, Assuras S, Valentine MO, Reder A. The effects of long-term interferon-beta-1b treatment on cognitive functioning in multiple sclerosis: a 16-year longitudinal study. Mult Scler. 2013;19:1765–72.
Reder AT, Feng X. How type I interferons work in multiple sclerosis and other diseases: some unexpected mechanisms. J Interferon Cytokine Res. 2014;34:589–99.
Kremenchutzky M, Morrow S, Rush C. The safety and efficacy of IFN-beta products for the treatment of multiple sclerosis. Expert Opin Drug Saf. 2007;6:279–88.
Lugaresi A, Rottoli MR, Patti F. Fostering adherence to injectable disease-modifying therapies in multiple sclerosis. Expert Rev Neurother. 2014;14:1029–42.
Reder AT, Oger JF, Kappos L, O’Connor P, Rametta M. Short-term and long-term safety and tolerability of interferon beta-1b in multiple sclerosis. Mult Scler Relat Disord. 2014;3:294–302.
Ziemssen T. Multiple sclerosis beyond EDSS: depression and fatigue. J Neurol Sci. 2009;277:S37–41.
Ben-Yehuda H, Matcovitch-Natan O, Kertser A, Spinrad A, Prinz M, Amit I, et al. Maternal Type-I interferon signaling adversely affects the microglia and the behavior of the offspring accompanied by increased sensitivity to stress. Mol Psychiatry. 2020;25:1050–67.
Goodbourn S. The regulation of beta-interferon gene expression. Semin Cancer Biol. 1990;1:89–95.
Tamura T, Yanai H, Savitsky D, Taniguchi T. The IRF family transcription factors in immunity and oncogenesis. Annu Rev Immunol. 2008;26:535–84.
Koo JW, Russo SJ, Ferguson D, Nestler EJ, Duman RS. Nuclear factor-kappaB is a critical mediator of stress-impaired neurogenesis and depressive behavior. Proc Natl Acad Sci USA. 2010;107:2669–74.
Rosenkranz JA, Venheim ER, Padival M. Chronic stress causes amygdala hyperexcitability in rodents. Biol Psychiatry. 2010;67:1128–36.
Zhang W, Rosenkranz JA. Repeated restraint stress increases basolateral amygdala neuronal activity in an age-dependent manner. Neuroscience. 2012;226:459–74.
Munshi S, Rosenkranz JA. Effects of peripheral immune challenge on in vivo firing of basolateral amygdala neurons in adult male rats. Neuroscience. 2018;390:174–86.
Munshi S, Loh MK, Ferrara N, DeJoseph MR, Ritger A, Padival M, et al. Repeated stress induces a pro-inflammatory state, increases amygdala neuronal and microglial activation, and causes anxiety in adult male rats. Brain Behav Immun. 2020;84:180–99.
Wohleb ES, Fenn AM, Pacenta AM, Powell ND, Sheridan JF, Godbout JP. Peripheral innate immune challenge exaggerated microglia activation, increased the number of inflammatory CNS macrophages, and prolonged social withdrawal in socially defeated mice. Psychoneuroendocrinology. 2012;37:1491–505.
Azzinnari D, Sigrist H, Staehli S, Palme R, Hildebrandt T, Leparc G, et al. Mouse social stress induces increased fear conditioning, helplessness and fatigue to physical challenge together with markers of altered immune and dopamine function. Neuropharmacology. 2014;85:328–41.
Ray B, Gaskins DL, Sajdyk TJ, Spence JP, Fitz SD, Shekhar A, et al. Restraint stress and repeated corticotrophin-releasing factor receptor activation in the amygdala both increase amyloid-beta precursor protein and amyloid-beta peptide but have divergent effects on brain-derived neurotrophic factor and pre-synaptic proteins in the prefrontal cortex of rats. Neuroscience. 2011;184:139–50.
The authors acknowledge the funding support from US National Institute of Health/National Institute of Mental Health (NIMH) grants (MH120876 and MH121959), and the Merit Review Award (BX004758) from the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development to AP. The contents do not represent the views of the Department of Veterans Affairs or the United States Government. The research funding support from Augusta University is acknowledged. The authors would like to acknowledge Quebec Suicide Brain Bank for human postmortem tissue samples.
Conflict of interest
The authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Tripathi, A., Whitehead, C., Surrao, K. et al. Type 1 interferon mediates chronic stress-induced neuroinflammation and behavioral deficits via complement component 3-dependent pathway. Mol Psychiatry 26, 3043–3059 (2021). https://doi.org/10.1038/s41380-021-01065-6