Neurochemical Research

, Volume 41, Issue 1–2, pp 144–155 | Cite as

Cerebral Response to Peripheral Challenge with a Viral Mimetic

Original Paper


It has been well established that peripheral inflammation resulting from microbial infections profoundly alters brain function. This review focuses on experimental systems that model cerebral effects of peripheral viral challenge. The most common models employ the induction of the acute phase response via intraperitoneal injection of a viral mimetic, polyinosinic-polycytidylic acid (PIC). The ensuing transient surge of blood-borne inflammatory mediators induces a “mirror” inflammatory response in the brain characterized by the upregulated expression of a plethora of genes encoding cytokines, chemokines and other inflammatory/stress proteins. These inflammatory mediators modify the activity of neuronal networks leading to a constellation of behavioral traits collectively categorized as the sickness behavior. Sickness behavior is an important protective response of the host that has evolved to enhance survival and limit the spread of infections within a population. However, a growing body of clinical data indicates that the activation of inflammatory pathways in the brain may constitute a serious comorbidity factor for neuropathological conditions. Such comorbidity has been demonstrated using the PIC paradigm in experimental models of Alzheimer’s disease, prion disease and seizures. Also, prenatal or perinatal PIC challenge has been shown to disrupt normal cerebral development of the offspring resulting in phenotypes consistent with neuropsychiatric disorders, such as schizophrenia and autism. Remarkably, recent studies indicate that mild peripheral PIC challenge may be neuroprotective in stroke. Altogether, the PIC challenge paradigm represents a unique heuristic model to elucidate the immune-to-brain communication pathways and to explore preventive strategies for neuropathological disorders.


Inflammation Sickness behavior Neuropathologies Viral infections Comorbidity Neuroprotection 



This work was partly supported by a research grant from the National Institutes of Health/National Institute of General Medical Sciences, U54GM104942. The content is solely the responsibility of the author and does not necessarily represent the official views of the NIH. The author would like to thank Mr. Brent Lally for proofreading this manuscript.


  1. 1.
    Dantzer R (2006) Cytokine, sickness behavior, and depression. Neurol Clin 24:441–460PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Dantzer R, Kelley KW (2007) Twenty years of research on cytokine-induced sickness behavior. Brain Behav Immun 21:153–160PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Quan N, Banks WA (2007) Brain-immune communication pathways. Brain Behav Immun 21:727–735PubMedCrossRefGoogle Scholar
  4. 4.
    Jacobs BL, Langland JO (1996) When two strands are better than one: the mediators and modulators of the cellular responses to double-stranded RNA. Virology 219:339–349PubMedCrossRefGoogle Scholar
  5. 5.
    Weber F, Wagner V, Rasmussen SB, Hartmann R, Paludan SR (2006) Double-stranded RNA is produced by positive-strand RNA viruses and DNA viruses but not in detectable amounts by negative-strand RNA viruses. J Virol 80:5059–5064PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Berke IC, Li Y, Modis Y (2013) Structural basis of innate immune recognition of viral RNA. Cell Microbiol 15:386–394PubMedCrossRefGoogle Scholar
  7. 7.
    Guha-Thakurta N, Majde JA (1997) Early induction of proinflammatory cytokine and type I interferon mRNAs following Newcastle disease virus, poly [rI:rC], or low-dose LPS challenge of the mouse. J Interferon Cytokine Res 17:197–204PubMedCrossRefGoogle Scholar
  8. 8.
    Muller U, Steinhoff U, Reis LF, Hemmi S, Pavlovic J, Zinkernagel RM, Aguet M (1994) Functional role of type I and type II interferons in antiviral defense. Science 264:1918–1921PubMedCrossRefGoogle Scholar
  9. 9.
    Traynor TR, Majde JA, Bohnet SG, Krueger JM (2004) Intratracheal double-stranded RNA plus interferon-gamma: a model for analysis of the acute phase response to respiratory viral infections. Life Sci 74:2563–2576PubMedCrossRefGoogle Scholar
  10. 10.
    Fortier ME, Kent S, Ashdown H, Poole S, Boksa P, Luheshi GN (2004) The viral mimic, polyinosinic: polycytidylic acid, induces fever in rats via an interleukin-1-dependent mechanism. Am J Physiol Regul Integr Comp Physiol 287:R759–R766PubMedCrossRefGoogle Scholar
  11. 11.
    Katafuchi T, Kondo T, Take S, Yoshimura M (2005) Enhanced expression of brain interferon-alpha and serotonin transporter in immunologically induced fatigue in rats. Eur J Neurosci 22:2817–2826PubMedCrossRefGoogle Scholar
  12. 12.
    Fang J, Bredow S, Taishi P, Majde JA, Krueger JM (1999) Synthetic influenza viral double-stranded RNA induces an acute-phase response in rabbits. J Med Virol 57:198–203PubMedCrossRefGoogle Scholar
  13. 13.
    Kimura-Takeuchi M, Majde JA, Toth LA, Krueger JM (1992) Influenza virus-induced changes in rabbit sleep and acute phase responses. Am J Physiol 263:R1115–R1121PubMedGoogle Scholar
  14. 14.
    Carter WA, De CE (1974) Viral infection and host defense. Science 186:1172–1178PubMedCrossRefGoogle Scholar
  15. 15.
    Dunn AJ, Vickers SL (1994) Neurochemical and neuroendocrine responses to Newcastle disease virus administration in mice. Brain Res 645:103–112PubMedCrossRefGoogle Scholar
  16. 16.
    Majde JA (2000) Viral double-stranded RNA, cytokines, and the flu. J Interferon Cytokine Res 20:259–272PubMedCrossRefGoogle Scholar
  17. 17.
    Loftis JM, Huckans M, Ruimy S, Hinrichs DJ, Hauser P (2008) Depressive symptoms in patients with chronic hepatitis C are correlated with elevated plasma levels of interleukin-1beta and tumor necrosis factor-alpha. Neurosci Lett 430:264–268PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Huckans M, Seelye A, Parcel T, Mull L, Woodhouse J, Bjornson D, Fuller BE, Loftis JM, Morasco BJ, Sasaki AW, Storzbach D, Hauser P (2009) The cognitive effects of hepatitis C in the presence and absence of a history of substance use disorder. J Int Neuropsychol Soc 15:69–82PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Nelligan JA, Loftis JM, Matthews AM, Zucker BL, Linke AM, Hauser P (2008) Depression comorbidity and antidepressant use in veterans with chronic hepatitis C: results from a retrospective chart review. J Clin Psychiatry 69:810–816PubMedCrossRefGoogle Scholar
  20. 20.
    Lenczowski MJ, Van Dam AM, Poole S, Larrick JW, Tilders FJ (1997) Role of circulating endotoxin and interleukin-6 in the ACTH and corticosterone response to intraperitoneal LPS. Am J Physiol 273:R1870–R1877PubMedGoogle Scholar
  21. 21.
    Romanovsky AA, Ivanov AI, Lenczowski MJ, Kulchitsky VA, Van Dam AM, Poole S, Homer LD, Tilders FJ (2000) Lipopolysaccharide transport from the peritoneal cavity to the blood: is it controlled by the vagus nerve? Auton Neurosci 85:133–140PubMedCrossRefGoogle Scholar
  22. 22.
    Krasowska-Zoladek A, Banaszewska M, Kraszpulski M, Konat GW (2007) Kinetics of inflammatory response of astrocytes induced by TLR 3 and TLR4 ligation. J Neurosci Res 85:205–212PubMedCrossRefGoogle Scholar
  23. 23.
    Fil D, Borysiewicz E, Konat GW (2011) A broad upregulation of cerebral chemokine genes by peripherally generated inflammatory mediators. Metab Brain Dis 26:49–59PubMedCrossRefGoogle Scholar
  24. 24.
    Hopwood N, Maswanganyi T, Harden LM (2009) Comparison of anorexia, lethargy, and fever induced by bacterial and viral mimetics in rats. Can J Physiol Pharmacol 87:211–220PubMedCrossRefGoogle Scholar
  25. 25.
    Thomson CA, McColl A, Cavanagh J, Graham GJ (2014) Peripheral inflammation is associated with remote global gene expression changes in the brain. J Neuroinflammation 11:73PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Michalovicz LT, Konat GW (2014) Peripherally restricted acute phase response to a viral mimic alters hippocampal gene expression. Metab Brain Dis 29:75–86PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Cunningham C, Campion S, Teeling J, Felton L, Perry VH (2007) The sickness behaviour and CNS inflammatory mediator profile induced by systemic challenge of mice with synthetic double-stranded RNA (poly I:C). Brain Behav Immun 21:490–502PubMedCrossRefGoogle Scholar
  28. 28.
    Weintraub MK, Kranjac D, Eimerbrink MJ, Pearson SJ, Vinson BT, Patel J, Summers WM, Parnell TB, Boehm GW, Chumley MJ (2014) Peripheral administration of poly I: C leads to increased hippocampal amyloid-beta and cognitive deficits in a non-transgenic mouse. Behav Brain Res 266:183–187PubMedCrossRefGoogle Scholar
  29. 29.
    Milton NG, Hillhouse EW, Milton AS (1992) Activation of the hypothalamo-pituitary-adrenocortical axis in the conscious rabbit by the pyrogen polyinosinic: polycytidylic acid is dependent on corticotrophin-releasing factor-41. J Endocrinol 135:69–75PubMedCrossRefGoogle Scholar
  30. 30.
    Deacon RM (2006) Burrowing in rodents: a sensitive method for detecting behavioral dysfunction. Nat Protoc 1:118–121PubMedCrossRefGoogle Scholar
  31. 31.
    Konat GW, Borysiewicz E, Fil D, James I (2009) Peripheral challenge with double-stranded RNA elicits global up-regulation of cytokine gene expression in the brain. J Neurosci Res 87:1381–1388PubMedCrossRefGoogle Scholar
  32. 32.
    Konat GW, Borysiewicz E (2009) Cerebellar expression of inflammatory genes triggered by peripheral challenge with dsRNA. J Neurochem 108(Suppl. 1):133Google Scholar
  33. 33.
    Michalovicz LT, Lally BE, Konat GW (2015) Peripheral challenge with a viral mimic upregulates expression of the complement genes in the hippocampus. J Neuroimmunol 285:137–142PubMedCrossRefGoogle Scholar
  34. 34.
    Plata-Salaman CR (1994) Meal patterns in response to the intracerebroventricular administration of interleukin-1 beta in rats. Physiol Behav 55:727–733PubMedCrossRefGoogle Scholar
  35. 35.
    Plata-Salaman CR, Borkoski JP (1994) Chemokines/intercrines and central regulation of feeding. Am J Physiol 266:R1711–R1715PubMedGoogle Scholar
  36. 36.
    MacManus A, Ramsden M, Murray M, Henderson Z, Pearson HA, Campbell VA (2000) Enhancement of (45)Ca(2 +) influx and voltage-dependent Ca(2 +) channel activity by beta-amyloid-(1-40) in rat cortical synaptosomes and cultured cortical neurons. Modulation by the proinflammatory cytokine interleukin-1beta. J Biol Chem 275:4713–4718PubMedCrossRefGoogle Scholar
  37. 37.
    Murray CA, McGahon B, McBennett S, Lynch MA (1997) Interleukin-1 beta inhibits glutamate release in hippocampus of young, but not aged, rats. Neurobiol Aging 18:343–348PubMedCrossRefGoogle Scholar
  38. 38.
    Cunningham AJ, Murray CA, O’Neill LA, Lynch MA, O’Connor JJ (1996) Interleukin-1 beta (IL-1 beta) and tumour necrosis factor (TNF) inhibit long-term potentiation in the rat dentate gyrus in vitro. Neurosci Lett 203:17–20PubMedCrossRefGoogle Scholar
  39. 39.
    Schneider H, Pitossi F, Balschun D, Wagner A, del Rey A, Besedovsky HO (1998) A neuromodulatory role of interleukin-1beta in the hippocampus. Proc Natl Acad Sci USA 95:7778–7783PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Viviani B, Bartesaghi S, Gardoni F, Vezzani A, Behrens MM, Bartfai T, Binaglia M, Corsini E, Di Luca M, Galli CL, Marinovich M (2003) Interleukin-1beta enhances NMDA receptor-mediated intracellular calcium increase through activation of the Src family of kinases. J Neurosci 23:8692–8700PubMedGoogle Scholar
  41. 41.
    Yang S, Liu ZW, Wen L, Qiao HF, Zhou WX, Zhang YX (2005) Interleukin-1beta enhances NMDA receptor-mediated current but inhibits excitatory synaptic transmission. Brain Res 1034:172–179PubMedCrossRefGoogle Scholar
  42. 42.
    Viviani B, Gardoni F, Marinovich M (2007) Cytokines and neuronal ion channels in health and disease. Int Rev Neurobiol 82:247–263PubMedCrossRefGoogle Scholar
  43. 43.
    Bellinger FP, Madamba S, Siggins GR (1993) Interleukin 1 beta inhibits synaptic strength and long-term potentiation in the rat CA1 hippocampus. Brain Res 628:227–234PubMedCrossRefGoogle Scholar
  44. 44.
    Wang S, Cheng Q, Malik S, Yang J (2000) Interleukin-1beta inhibits gamma-aminobutyric acid type A (GABA(A)) receptor current in cultured hippocampal neurons. J Pharmacol Exp Ther 292:497–504PubMedGoogle Scholar
  45. 45.
    Hu S, Sheng WS, Ehrlich LC, Peterson PK, Chao CC (2000) Cytokine effects on glutamate uptake by human astrocytes. Neuroimmunomodulation 7:153–159PubMedCrossRefGoogle Scholar
  46. 46.
    Xiaoqin Z, Zhengli L, Changgeng Z, Xiaojing W, Li L (2005) Changes in behavior and amino acid neurotransmitters in the brain of rats with seizure induced by IL-1beta or IL-6. J Huazhong Univ Sci Technol Med Sci 25:236–239PubMedCrossRefGoogle Scholar
  47. 47.
    Samland H, Huitron-Resendiz S, Masliah E, Criado J, Henriksen SJ, Campbell IL (2003) Profound increase in sensitivity to glutamatergic-but not cholinergic agonist-induced seizures in transgenic mice with astrocyte production of IL-6. J Neurosci Res 73:176–187PubMedCrossRefGoogle Scholar
  48. 48.
    De Sarro G, Russo E, Ferreri G, Giuseppe B, Flocco MA, Di Paola ED, De Sarro A (2004) Seizure susceptibility to various convulsant stimuli of knockout interleukin-6 mice. Pharmacol Biochem Behav 77:761–766PubMedCrossRefGoogle Scholar
  49. 49.
    Balschun D, Wetzel W, del Rey A, Pitossi F, Schneider H, Zuschratter W, Besedovsky HO (2004) Interleukin-6: a cytokine to forget. FASEB J 18:1788–1790PubMedGoogle Scholar
  50. 50.
    Wei H, Chadman KK, McCloskey DP, Sheikh AM, Malik M, Brown WT, Li X (2012) Brain IL-6 elevation causes neuronal circuitry imbalances and mediates autism-like behaviors. Biochim Biophys Acta 1822:831–842PubMedCrossRefGoogle Scholar
  51. 51.
    Song C, Merali Z, Anisman H (1999) Variations of nucleus accumbens dopamine and serotonin following systemic interleukin-1, interleukin-2 or interleukin-6 treatment. Neuroscience 88:823–836PubMedCrossRefGoogle Scholar
  52. 52.
    Beattie EC, Stellwagen D, Morishita W, Bresnahan JC, Ha BK, Von ZM, Beattie MS, Malenka RC (2002) Control of synaptic strength by glial TNFalpha. Science 295:2282–2285PubMedCrossRefGoogle Scholar
  53. 53.
    Stellwagen D, Beattie EC, Seo JY, Malenka RC (2005) Differential regulation of AMPA receptor and GABA receptor trafficking by tumor necrosis factor-alpha. J Neurosci 25:3219–3228PubMedCrossRefGoogle Scholar
  54. 54.
    Houzen H, Kikuchi S, Kanno M, Shinpo K, Tashiro K (1997) Tumor necrosis factor enhancement of transient outward potassium currents in cultured rat cortical neurons. J Neurosci Res 50:990–999PubMedCrossRefGoogle Scholar
  55. 55.
    Stellwagen D, Malenka RC (2006) Synaptic scaling mediated by glial TNF-alpha. Nature 440:1054–1059PubMedCrossRefGoogle Scholar
  56. 56.
    Bezzi P, Domercq M, Brambilla L, Galli R, Schols D, De CE, Vescovi A, Bagetta G, Kollias G, Meldolesi J, Volterra A (2001) CXCR4-activated astrocyte glutamate release via TNFalpha: amplification by microglia triggers neurotoxicity. Nat Neurosci 4:702–710PubMedCrossRefGoogle Scholar
  57. 57.
    Koller H, Allert N, Oel D, Stoll G, Siebler M (1998) TNF alpha induces a protein kinase C-dependent reduction in astroglial K+ conductance. Neuroreport 9:1375–1378PubMedCrossRefGoogle Scholar
  58. 58.
    Murray C, Griffin EW, O’Loughlin E, Lyons A, Sherwin E, Ahmed S, Stevenson NJ, Harkin A, Cunningham C (2015) Interdependent and independent roles of type I interferons and IL-6 in innate immune, neuroinflammatory and sickness behaviour responses to systemic poly I:C. Brain Behav Immun 48:274–286PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Hadjilambreva G, Mix E, Rolfs A, Muller J, Strauss U (2005) Neuromodulation by a cytokine: interferon-beta differentially augments neocortical neuronal activity and excitability. J Neurophysiol 93:843–852PubMedCrossRefGoogle Scholar
  60. 60.
    Muller M, Fontana A, Zbinden G, Gahwiler BH (1993) Effects of interferons and hydrogen peroxide on CA3 pyramidal cells in rat hippocampal slice cultures. Brain Res 619:157–162PubMedCrossRefGoogle Scholar
  61. 61.
    Costello DA, Lynch MA (2013) Toll-like receptor 3 activation modulates hippocampal network excitability, via glial production of interferon-beta. Hippocampus 23:696–707PubMedCrossRefGoogle Scholar
  62. 62.
    Di Filippo M, Tozzi A, Arcangeli S, de Iure A, Durante V, Di Gregorio M, Gardoni F, Calabresi P (2016) Interferon-beta1a modulates glutamate neurotransmission in the CNS through CaMKII and GluN2A-containing NMDA receptors. Neuropharmacology 100:98–105PubMedCrossRefGoogle Scholar
  63. 63.
    Vlkolinsky R, Siggins GR, Campbell IL, Krucker T (2004) Acute exposure to CXC chemokine ligand 10, but not its chronic astroglial production, alters synaptic plasticity in mouse hippocampal slices. J Neuroimmunol 150:37–47PubMedCrossRefGoogle Scholar
  64. 64.
    Nelson TE, Gruol DL (2004) The chemokine CXCL10 modulates excitatory activity and intracellular calcium signaling in cultured hippocampal neurons. J Neuroimmunol 156:74–87PubMedCrossRefGoogle Scholar
  65. 65.
    Cho J, Nelson TE, Bajova H, Gruol DL (2009) Chronic CXCL10 alters neuronal properties in rat hippocampal culture. J Neuroimmunol 207:92–100PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Lax P, Limatola C, Fucile S, Trettel F, Di BS, Renzi M, Ragozzino D, Eusebi F (2002) Chemokine receptor CXCR2 regulates the functional properties of AMPA-type glutamate receptor GluR1 in HEK cells. J Neuroimmunol 129:66–73PubMedCrossRefGoogle Scholar
  67. 67.
    Giovannelli A, Limatola C, Ragozzino D, Mileo AM, Ruggieri A, Ciotti MT, Mercanti D, Santoni A, Eusebi F (1998) CXC chemokines interleukin-8 (IL-8) and growth-related gene product alpha (GROalpha) modulate Purkinje neuron activity in mouse cerebellum. J Neuroimmunol 92:122–132PubMedCrossRefGoogle Scholar
  68. 68.
    Ragozzino D, Giovannelli A, Mileo AM, Limatola C, Santoni A, Eusebi F (1998) Modulation of the neurotransmitter release in rat cerebellar neurons by GRO beta. Neuroreport 9:3601–3606PubMedCrossRefGoogle Scholar
  69. 69.
    Puma C, Danik M, Quirion R, Ramon F, Williams S (2001) The chemokine interleukin-8 acutely reduces Ca(2+) currents in identified cholinergic septal neurons expressing CXCR1 and CXCR2 receptor mRNAs. J Neurochem 78:960–971PubMedCrossRefGoogle Scholar
  70. 70.
    Gosselin RD, Varela C, Banisadr G, Mechighel P, Rostene W, Kitabgi P, Melik-Parsadaniantz S (2005) Constitutive expression of CCR2 chemokine receptor and inhibition by MCP-1/CCL2 of GABA-induced currents in spinal cord neurones. J Neurochem 95:1023–1034PubMedCrossRefGoogle Scholar
  71. 71.
    Guyon A, Skrzydelski D, De Giry I, Rovère C, Conductier G, Trocello JM, Daugé V, Kitabgi P, Rostène W, Nahon JL, Mélik Parsadaniantz S (2009) Long term exposure to the chemokine CCL2 activates the nigrostriatal dopamine system: a novel mechanism for the control of dopamine release. Neuroscience 162:1072–1080PubMedCrossRefGoogle Scholar
  72. 72.
    Kuijpers M, van Gassen KL, de Graan PN, Gruol D (2010) Chronic exposure to the chemokine CCL3 enhances neuronal network activity in rat hippocampal cultures. J Neuroimmunol 229:73–80PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Minano FJ, Fernandez-Alonso A, Myers RD, Sancibrian M (1996) Hypothalamic interaction between macrophage inflammatory protein-1 alpha (MIP-1 alpha) and MIP-1 beta in rats: a new level for fever control? J Physiol 491(Pt 1):209–217PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Tavares E, Minano FJ (2004) Differential sensitivities of pyrogenic chemokine fevers to CC chemokine receptor 5 antibodies. Fundam Clin Pharmacol 18:163–169PubMedCrossRefGoogle Scholar
  75. 75.
    Machado RR, Soares DM, Proudfoot AE, Souza GE (2007) CCR1 and CCR5 chemokine receptors are involved in fever induced by LPS (E. coli) and RANTES in rats. Brain Res 1161:21–31PubMedCrossRefGoogle Scholar
  76. 76.
    Myers RD, Paez X, Roscoe AK, Sherry B, Cerami A (1993) Fever and feeding: differential actions of macrophage inflammatory protein-1 (MIP-1), MIP-1 alpha and MIP-1 beta on rat hypothalamus. Neurochem Res 18:667–673PubMedCrossRefGoogle Scholar
  77. 77.
    Minano FJ, Myers RD (1991) Anorexia and adipsia: dissociation from fever after MIP-1 injection in ventromedial hypothalamus and preoptic area of rats. Brain Res Bull 27:273–278PubMedCrossRefGoogle Scholar
  78. 78.
    Adler MW, Geller EB, Chen X, Rogers TJ (2005) Viewing chemokines as a third major system of communication in the brain. AAPS. J 7:E865–E870PubMedCentralCrossRefGoogle Scholar
  79. 79.
    Melik-Parsadaniantz S, Rostene W (2008) Chemokines and neuromodulation. J Neuroimmunol 198:62–68PubMedCrossRefGoogle Scholar
  80. 80.
    Voss T, Barth SW, Rummel C, Gerstberger R, Hubschle T, Roth J (2007) STAT3 and COX-2 activation in the guinea-pig brain during fever induced by the Toll-like receptor-3 agonist polyinosinic: polycytidylic acid. Cell Tissue Res 328:549–561PubMedCrossRefGoogle Scholar
  81. 81.
    Hein AM, O’Banion MK (2009) Neuroinflammation and memory: the role of prostaglandins. Mol Neurobiol 40:15–32PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Chen C, Bazan NG (2005) Endogenous PGE2 regulates membrane excitability and synaptic transmission in hippocampal CA1 pyramidal neurons. J Neurophysiol 93:929–941PubMedCrossRefGoogle Scholar
  83. 83.
    Dawson VL, Dawson TM (1996) Nitric oxide in neuronal degeneration. Proc Soc Exp Biol Med 211:33–40PubMedCrossRefGoogle Scholar
  84. 84.
    Tang Z, Gan Y, Liu Q, Yin JX, Liu Q, Shi J, Shi FD (2014) CX3CR1 deficiency suppresses activation and neurotoxicity of microglia/macrophage in experimental ischemic stroke. J Neuroinflammation 11:26PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    George J, Bleasdale S, Singleton SJ (1997) Causes and prognosis of delirium in elderly patients admitted to a district general hospital. Age Ageing 26:423–427PubMedCrossRefGoogle Scholar
  86. 86.
    Holmes C, El-Okl M, Williams AL, Cunningham C, Wilcockson D, Perry VH (2003) Systemic infection, interleukin 1beta, and cognitive decline in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 74:788–789PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Holmes C (2013) Review: systemic inflammation and Alzheimer’s disease. Neuropathol Appl Neurobiol 39:51–68PubMedCrossRefGoogle Scholar
  88. 88.
    Murray AM, Levkoff SE, Wetle TT, Beckett L, Cleary PD, Schor JD, Lipsitz LA, Rowe JW, Evans DA (1993) Acute delirium and functional decline in the hospitalized elderly patient. J Gerontol 48:M181–M186PubMedCrossRefGoogle Scholar
  89. 89.
    Nee LE, Lippa CF (1999) Alzheimer’s disease in 22 twin pairs—13-year follow-up: hormonal, infectious and traumatic factors. Dement Geriatr Cogn Disord 10:148–151PubMedCrossRefGoogle Scholar
  90. 90.
    Katan M, Moon YP, Paik MC, Sacco RL, Wright CB, Elkind MS (2013) Infectious burden and cognitive function: the Northern Manhattan Study. Neurology 80:1209–1215PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Kranjac D, McLinden KA, Koster KM, Kaldenbach DL, Chumley MJ, Boehm GW (2012) Peripheral administration of poly I: C disrupts contextual fear memory consolidation and BDNF expression in mice. Behav Brain Res 228:452–457PubMedCrossRefGoogle Scholar
  92. 92.
    McLinden KA, Kranjac D, Deodati LE, Kahn M, Chumley MJ, Boehm GW (2012) Age exacerbates sickness behavior following exposure to a viral mimetic. Physiol Behav 105:1219–1225PubMedCrossRefGoogle Scholar
  93. 93.
    Field R, Campion S, Warren C, Murray C, Cunningham C (2010) Systemic challenge with the TLR3 agonist poly I: C induces amplified IFNalpha/beta and IL-1beta responses in the diseased brain and exacerbates chronic neurodegeneration. Brain Behav Immun 24:996–1007PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Kirschman LT, Borysiewicz E, Fil D, Konat GW (2011) Peripheral immune challenge with dsRNA enhances kainic acid-induced status epilepticus. Metab Brain Dis 26:91–93PubMedCrossRefGoogle Scholar
  95. 95.
    Tellez-Zenteno JF, Matijevic S, Wiebe S (2005) Somatic comorbidity of epilepsy in the general population in Canada. Epilepsia 46:1955–1962PubMedCrossRefGoogle Scholar
  96. 96.
    Ben-Ari Y, Cossart R (2000) Kainate, a double agent that generates seizures: two decades of progress. Trends Neurosci 23:580–587PubMedCrossRefGoogle Scholar
  97. 97.
    Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, Ransohoff RM, Greenberg ME, Barres BA, Stevens B (2012) Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74:691–705PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Stephan AH, Madison DV, Mateos JM, Fraser DA, Lovelett EA, Coutellier L, Kim L, Tsai HH, Huang EJ, Rowitch DH, Berns DS, Tenner AJ, Shamloo M, Barres BA (2013) A dramatic increase of C1q protein in the CNS during normal aging. J Neurosci 33:13460–13474PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS, Nouri N, Micheva KD, Mehalow AK, Huberman AD, Stafford B, Sher A, Litke AM, Lambris JD, Smith SJ, John SW, Barres BA (2007) The classical complement cascade mediates CNS synapse elimination. Cell 131:1164–1178PubMedCrossRefGoogle Scholar
  100. 100.
    Xiong ZQ, Qian W, Suzuki K, McNamara JO (2003) Formation of complement membrane attack complex in mammalian cerebral cortex evokes seizures and neurodegeneration. J Neurosci 23:955–960PubMedGoogle Scholar
  101. 101.
    Vezzani A, Balosso S, Ravizza T (2008) The role of cytokines in the pathophysiology of epilepsy. Brain Behav Immun 22:797–803PubMedCrossRefGoogle Scholar
  102. 102.
    Vezzani A, Ravizza T, Balosso S, Aronica E (2008) Glia as a source of cytokines: implications for neuronal excitability and survival. Epilepsia 49(Suppl 2):24–32PubMedCrossRefGoogle Scholar
  103. 103.
    Bookheimer SY, Strojwas MH, Cohen MS, Saunders AM, Pericak-Vance MA, Mazziotta JC, Small GW (2000) Patterns of brain activation in people at risk for Alzheimer’s disease. N Engl J Med 343:450–456PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Miller SL, Fenstermacher E, Bates J, Blacker D, Sperling RA, Dickerson BC (2008) Hippocampal activation in adults with mild cognitive impairment predicts subsequent cognitive decline. J Neurol Neurosurg Psychiatry 79:630–635PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Meyer U, Feldon J (2010) Epidemiology-driven neurodevelopmental animal models of schizophrenia. Prog Neurobiol 90:285–326PubMedCrossRefGoogle Scholar
  106. 106.
    Meyer U, Feldon J (2011) To poly(I:C) or not to poly(I:C): advancing preclinical schizophrenia research through the use of prenatal immune activation models. Neuropharmacology 62:1308–1321PubMedCrossRefGoogle Scholar
  107. 107.
    Meyer U, Feldon J, Dammann O (2011) Schizophrenia and autism: both shared and disorder-specific pathogenesis via perinatal inflammation? Pediatr Res 69:26R–33RPubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Meyer U, Feldon J (2009) Prenatal exposure to infection: a primary mechanism for abnormal dopaminergic development in schizophrenia. Psychopharmacology 206:587–602PubMedCrossRefGoogle Scholar
  109. 109.
    Makinodan M, Yamauchi T, Tatsumi K, Okuda H, Noriyama Y, Sadamatsu M, Kishimoto T, Wanaka A (2009) Yi-gan san restores behavioral alterations and a decrease of brain glutathione level in a mouse model of schizophrenia. J Brain Dis 1:1–6PubMedPubMedCentralGoogle Scholar
  110. 110.
    De Miranda J, Yaddanapudi K, Hornig M, Villar G, Serge R, Lipkin WI (2010) Induction of Toll-like receptor 3-mediated immunity during gestation inhibits cortical neurogenesis and causes behavioral disturbances. MBio 1:1–10CrossRefGoogle Scholar
  111. 111.
    Yee N, Ribic A, de Roo CC, Fuchs E (2011) Differential effects of maternal immune activation and juvenile stress on anxiety-like behaviour and physiology in adult rats: no evidence for the “double-hit hypothesis”. Behav Brain Res 224:180–188PubMedCrossRefGoogle Scholar
  112. 112.
    Song X, Li W, Yang Y, Zhao J, Jiang C, Li W, Lv L (2011) The nuclear factor-kappaB inhibitor pyrrolidine dithiocarbamate reduces polyinosinic-polycytidylic acid-induced immune response in pregnant rats and the behavioral defects of their adult offspring. Behav Brain Funct 7:50PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Mattei D, Djodari-Irani A, Hadar R, Pelz A, de Cossio LF, Goetz T, Matyash M, Kettenmann H, Winter C, Wolf SA (2014) Minocycline rescues decrease in neurogenesis, increase in microglia cytokines and deficits in sensorimotor gating in an animal model of schizophrenia. Brain Behav Immun 38:175–184PubMedCrossRefGoogle Scholar
  114. 114.
    Pineda E, Shin D, You SJ, Auvin S, Sankar R, Mazarati A (2013) Maternal immune activation promotes hippocampal kindling epileptogenesis in mice. Ann Neurol 74:11–19PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Khan D, Fernando P, Cicvaric A, Berger A, Pollak A, Monje FJ, Pollak DD (2014) Long-term effects of maternal immune activation on depression-like behavior in the mouse. Transl Psychiatry 4:e363PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Dickerson DD, Overeem KA, Wolff AR, Williams JM, Abraham WC, Bilkey DK (2014) Association of aberrant neural synchrony and altered GAD67 expression following exposure to maternal immune activation, a risk factor for schizophrenia. Transl Psychiatry 4:e418PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Bauman MD, Iosif AM, Smith SE, Bregere C, Amaral DG, Patterson PH (2014) Activation of the maternal immune system during pregnancy alters behavioral development of rhesus monkey offspring. Biol Psychiatry 75:332–341PubMedCrossRefGoogle Scholar
  118. 118.
    Machado CJ, Whitaker AM, Smith SE, Patterson PH, Bauman MD (2015) Maternal immune activation in nonhuman primates alters social attention in juvenile offspring. Biol Psychiatry 77:823–832PubMedCrossRefGoogle Scholar
  119. 119.
    Liu YH, Lai WS, Tsay HJ, Wang TW, Yu JY (2013) Effects of maternal immune activation on adult neurogenesis in the subventricular zone-olfactory bulb pathway and olfactory discrimination. Schizophr Res 151:1–11PubMedCrossRefGoogle Scholar
  120. 120.
    Forrest CM, Khalil OS, Pisar M, Smith RA, Darlington LG, Stone TW (2012) Prenatal activation of Toll-like receptors-3 by administration of the viral mimetic poly(I:C) changes synaptic proteins, N-methyl-d-aspartate receptors and neurogenesis markers in offspring. Mol Brain 5:22PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Weir RK, Forghany R, Smith SE, Patterson PH, McAllister AK, Schumann CM, Bauman MD (2015) Preliminary evidence of neuropathology in nonhuman primates prenatally exposed to maternal immune activation. Brain Behav Immun 48:139–146PubMedCrossRefGoogle Scholar
  122. 122.
    Makinodan M, Tatsumi K, Manabe T, Yamauchi T, Makinodan E, Matsuyoshi H, Shimoda S, Noriyama Y, Kishimoto T, Wanaka A (2008) Maternal immune activation in mice delays myelination and axonal development in the hippocampus of the offspring. J Neurosci Res 86:2190–2200PubMedCrossRefGoogle Scholar
  123. 123.
    Li Q, Cheung C, Wei R, Cheung V, Hui ES, You Y, Wong P, Chua SE, McAlonan GM, Wu EX (2010) Voxel-based analysis of postnatal white matter microstructure in mice exposed to immune challenge in early or late pregnancy. Neuroimage 52:1–8PubMedCrossRefGoogle Scholar
  124. 124.
    Rowland LM, Spieker EA, Francis A, Barker PB, Carpenter WT, Buchanan RW (2009) White matter alterations in deficit schizophrenia. Neuropsychopharmacology 34:1514–1522PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Arsenault D, St-Amour I, Cisbani G, Rousseau LS, Cicchetti F (2014) The different effects of LPS and poly I: C prenatal immune challenges on the behavior, development and inflammatory responses in pregnant mice and their offspring. Brain Behav Immun 38:77–90PubMedCrossRefGoogle Scholar
  126. 126.
    Pratt L, Ni L, Ponzio NM, Jonakait GM (2013) Maternal inflammation promotes fetal microglial activation and increased cholinergic expression in the fetal basal forebrain: role of interleukin-6. Pediatr Res 74:393–401PubMedCrossRefGoogle Scholar
  127. 127.
    Roenker NL, Gudelsky G, Ahlbrand R, Bronson SL, Kern JR, Waterman H, Richtand NM (2011) Effect of paliperidone and risperidone on extracellular glutamate in the prefrontal cortex of rats exposed to prenatal immune activation or MK-801. Neurosci Lett 500:167–171PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Jing Y, Zhang H, Wolff AR, Bilkey DK, Liu P (2013) Altered arginine metabolism in the hippocampus and prefrontal cortex of maternal immune activation rat offspring. Schizophr Res 148:151–156PubMedCrossRefGoogle Scholar
  129. 129.
    Ibi D, Nagai T, Kitahara Y, Mizoguchi H, Koike H, Shiraki A, Takuma K, Kamei H, Noda Y, Nitta A, Nabeshima T, Yoneda Y, Yamada K (2009) Neonatal polyI: C treatment in mice results in schizophrenia-like behavioral and neurochemical abnormalities in adulthood. Neurosci Res 64:297–305PubMedCrossRefGoogle Scholar
  130. 130.
    Ibi D, Nagai T, Koike H, Kitahara Y, Mizoguchi H, Niwa M, Jaaro-Peled H, Nitta A, Yoneda Y, Nabeshima T, Sawa A, Yamada K (2010) Combined effect of neonatal immune activation and mutant DISC1 on phenotypic changes in adulthood. Behav Brain Res 206:32–37PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Konat GW, Lally BE, Toth AA, Salm AK (2011) Peripheral immune challenge with viral mimic during early postnatal period robustly enhances anxiety-like behavior in young adult rats. Metab Brain Dis 26:237–240PubMedCrossRefGoogle Scholar
  132. 132.
    Ellis S, Mouihate A, Pittman QJ (2006) Neonatal programming of the rat neuroimmune response: stimulus specific changes elicited by bacterial and viral mimetics. J Physiol 571:695–701PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Packard AE, Hedges JC, Bahjat FR, Stevens SL, Conlin MJ, Salazar AM, Stenzel-Poore MP (2012) Poly-IC preconditioning protects against cerebral and renal ischemia-reperfusion injury. J Cereb Blood Flow Metab 32:242–247PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Gesuete R, Packard AE, Vartanian KB, Conrad VK, Stevens SL, Bahjat FR, Yang T, Stenzel-Poore MP (2012) Poly-ICLC preconditioning protects the blood–brain barrier against ischemic injury in vitro through type I interferon signaling. J Neurochem 123(Suppl 2):75–85PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Wang PF, Fang H, Chen J, Lin S, Liu Y, Xiong XY, Wang YC, Xiong RP, Lv FL, Wang J, Yang QW (2014) Polyinosinic-polycytidylic acid has therapeutic effects against cerebral ischemia/reperfusion injury through the downregulation of TLR4 signaling via TLR3. J Immunol 192:4783–4794PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of Neurobiology and AnatomyWest Virginia University School of MedicineMorgantownUSA

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