Home LiteratureArticle Details
PMID: 17482371 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Lipopolysaccharide induces delayed FosB/DeltaFosB immunostaining within the mouse extended amygdala, hippocampus and hypothalamus, that parallel the expression of depressive-like behavior.

Psychoneuroendocrinology ·Vol. 32 ·No. 5 ·2007-06-00 ·Pages 516-31

Frenois F, Moreau M, O'Connor J, Lawson M, Micon C, Lestage J, Kelley KW, Dantzer R, Castanon N

Abstract

Proinflammatory cytokines induce both sickness behavior and depression, but their respective neurobiological correlates are still poorly understood. The aim of the present study was therefore to identify in mice the neural substrates of sickness and depressive-like behavior induced by lipopolysaccharide (LPS, 830 microg/kg, intraperitoneal). LPS-induced depressive-like behavior was dissociated from LPS-induced sickness by testing mice either at 6 h (at which time sickness was expected to be maximal) or at 24 h post-LPS (at which time sickness was expected to be minimal and not to bias the measurement of depressive-like behavior). Concurrently, the expression of acute and chronic cellular reactivity markers (c-Fos and FosB/DeltaFosB, respectively) was mapped by immunohistochemistry at these two time points. In comparison to saline, LPS decreased motor activity in a new cage at 6 h but not at 24 h. In contrast, the duration of immobility in the tail suspension test was increased at both 6 and 24 h. This dissociation between decreased motor activity and depressive-like behavior was confirmed at 24 h post-LPS in the forced swim test. LPS also decreased sucrose consumption at 24 and 48 h, despite normal food and water consumption by that time. At 24 h post-LPS, LPS-induced depressive-like behavior was associated with a delayed cellular activity (as assessed by FosB/DeltaFosB immunostaining) in specific brain structures, particularly within the extended amygdala, hippocampus and hypothalamus, whereas c-Fos labeling was markedly decreased by that time in all the brain areas at 6 h post-LPS. These results provide the first evidence in favor of a functional dissociation between the brain structures that underlie cytokine-induced sickness behavior and cytokine-induced depressive-like behavior, and provide important cues about the neuroanatomical brain circuits through which cytokines could have an impact on affect.

MeSH Terms
Amygdala/metabolism Animals Cytokines/physiology Depression/immunology,metabolism Disease Models, Animal Exploratory Behavior/physiology Hippocampus/metabolism Hypothalamus/metabolism Immunohistochemistry Lipopolysaccharides/immunology,pharmacology Male Mice Motor Activity/immunology,physiology Proto-Oncogene Proteins c-fos/metabolism Sick Role
Chemicals
Cytokines Fosb protein, mouse Lipopolysaccharides Proto-Oncogene Proteins c-fos
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Frenois François
Integrative Immunology and Behavior Program, University of Illinois at Urbana-Champaign, 212 Edward R. Madigan Laboratory, 1201 West Gregory Drive, Urbana, IL 61801, USA.
Moreau Maïté
O'Connor Jason
Lawson Marc
Micon Charlotte
Lestage Jacques
Kelley Keith W
Dantzer Robert
Castanon Nathalie
References (85)
85 references, click to expand
  1. Chronic administration of tianeptine balances lipopolysaccharide-induced expression of cytokines in the spleen and hypothalamus of rats.
    Psychoneuroendocrinology. 2004 Jul;29(6):778-90 PMID: 15110927
  2. Distribution of Fos-like immunoreactivity in the rat brain following intravenous lipopolysaccharide administration.
    J Comp Neurol. 1996 Jul 15;371(1):85-103 PMID: 8835720
  3. Cytokines and depression: the need for a new paradigm.
    Brain Behav Immun. 2003 Feb;17 Suppl 1:S119-24 PMID: 12615197
  4. Conditioned taste aversion with lipopolysaccharide and peptidoglycan does not activate cytokine gene expression in the spleen and hypothalamus of mice.
    Brain Behav Immun. 2004 Mar;18(2):186-200 PMID: 14759596
  5. Immune-neuro-endocrine interactions: facts and hypotheses.
    Endocr Rev. 1996 Feb;17(1):64-102 PMID: 8641224
  6. Endogenous neurotoxins from tryptophan.
    Toxicon. 2001 Jan;39(1):61-73 PMID: 10936623
  7. Chronic Fos-related antigens: stable variants of deltaFosB induced in brain by chronic treatments.
    J Neurosci. 1997 Jul 1;17(13):4933-41 PMID: 9185531
  8. Attenuation of sucrose consumption in mice by chronic mild stress and its restoration by imipramine.
    Psychopharmacology (Berl). 1995 Feb;117(4):453-7 PMID: 7604147
  9. Human interferon-alpha increases immobility in the forced swimming test in rats.
    Psychopharmacology (Berl). 2000 Jan;148(1):106-10 PMID: 10663424
  10. New perspectives in basal forebrain organization of special relevance for neuropsychiatric disorders: the striatopallidal, amygdaloid, and corticopetal components of substantia innominata.
    Neuroscience. 1988 Oct;27(1):1-39 PMID: 3059226
  11. A specific limbic circuit underlies opiate withdrawal memories.
    J Neurosci. 2005 Feb 9;25(6):1366-74 PMID: 15703390
  12. Neurobehavioral effects of interferon-alpha in cancer patients: phenomenology and paroxetine responsiveness of symptom dimensions.
    Neuropsychopharmacology. 2002 May;26(5):643-52 PMID: 11927189
  13. Effects of cytokines on cerebral neurotransmission. Comparison with the effects of stress.
    Adv Exp Med Biol. 1999;461:117-27 PMID: 10442171
  14. Emotion and motivation: the role of the amygdala, ventral striatum, and prefrontal cortex.
    Neurosci Biobehav Rev. 2002 May;26(3):321-52 PMID: 12034134
  15. Chronic LPS exposure produces changes in intrinsic membrane properties and a sustained IL-beta-dependent increase in GABAergic inhibition in hippocampal CA1 pyramidal neurons.
    Hippocampus. 2005;15(5):656-64 PMID: 15889405
  16. Temporal and spatial relationships between lipopolysaccharide-induced expression of Fos, interleukin-1beta and inducible nitric oxide synthase in rat brain.
    Neuroscience. 1999 Mar;89(2):535-48 PMID: 10077334
  17. Cytokines, stress and depressive illness: brain-immune interactions.
    Ann Med. 2003;35(1):2-11 PMID: 12693607
  18. The motivational component of withdrawal in opiate addiction: role of associative learning and aversive memory in opiate addiction from a behavioral, anatomical and functional perspective.
    Rev Neurosci. 2005;16(3):255-76 PMID: 16323564
  19. Effects of vagotomy on lipopolysaccharide-induced brain interleukin-1beta protein in rats.
    Auton Neurosci. 2000 Dec 20;85(1-3):119-26 PMID: 11189018
  20. Behavioral responses during the forced swim test are not affected by anti-inflammatory agents or acute illness induced by lipopolysaccharide.
    Behav Brain Res. 2005 May 7;160(1):125-34 PMID: 15836907
  21. Cytokines as mediators of depression: what can we learn from animal studies?
    Neurosci Biobehav Rev. 2005;29(4-5):891-909 PMID: 15885777
  22. Cytokines and depression: fortuitous or causative association?
    Mol Psychiatry. 1999 Jul;4(4):328-32 PMID: 10483048
  23. Depression duration but not age predicts hippocampal volume loss in medically healthy women with recurrent major depression.
    J Neurosci. 1999 Jun 15;19(12):5034-43 PMID: 10366636
  24. Immediate-early genes: ten years on.
    Trends Neurosci. 1995 Feb;18(2):66-7 PMID: 7537412
  25. Cytokines, stress, and depressive illness.
    Brain Behav Immun. 2002 Oct;16(5):513-24 PMID: 12401465
  26. The role of indoleamine 2,3-dioxygenase (IDO) in the pathophysiology of interferon-alpha-induced depression.
    J Psychiatry Neurosci. 2004 Jan;29(1):11-7 PMID: 14719046
  27. History and evolution of the monoamine hypothesis of depression.
    J Clin Psychiatry. 2000;61 Suppl 6:4-6 PMID: 10775017
  28. Cytokine-induced sickness behaviour: a neuroimmune response to activation of innate immunity.
    Eur J Pharmacol. 2004 Oct 1;500(1-3):399-411 PMID: 15464048
  29. The immunobiology of sexual behavior: gender differences in the suppression of sexual activity during illness.
    Pharmacol Biochem Behav. 1999 Dec;64(4):787-96 PMID: 10593202
  30. Antidepressant reversal of interferon-alpha-induced anhedonia.
    Physiol Behav. 2002 Apr 15;75(5):765-72 PMID: 12020742
  31. Interleukin-1 affects the behavioral despair response in rats by an indirect mechanism which requires endogenous CRF.
    Brain Res. 1990 Sep 24;528(1):162-4 PMID: 2245334
  32. Association between decreased serum tryptophan concentrations and depressive symptoms in cancer patients undergoing cytokine therapy.
    Mol Psychiatry. 2002;7(5):468-73 PMID: 12082564
  33. Effects of antidepressants on cytokine production and actions.
    Brain Behav Immun. 2002 Oct;16(5):569-74 PMID: 12401470
  34. Behavioral effects of infection with interferon-gamma adenovector.
    Behav Brain Res. 2004 May 5;151(1-2):73-82 PMID: 15084423
  35. The neuroendocrinology of depression and chronic stress.
    Br Med Bull. 1996 Jul;52(3):597-617 PMID: 8949260
  36. Corticotropin-releasing hormone receptors mediate consensus interferon-alpha YM643-induced depression-like behavior in mice.
    J Pharmacol Exp Ther. 2000 Jan;292(1):181-7 PMID: 10604946
  37. Subdiaphragmatic vagotomy does not block intraperitoneal lipopolysaccharide-induced fever.
    Auton Neurosci. 2000 Dec 20;85(1-3):83-7 PMID: 11189031
  38. The tail suspension test: a new method for screening antidepressants in mice.
    Psychopharmacology (Berl). 1985;85(3):367-70 PMID: 3923523
  39. Substantia innominata: a notion which impedes clinical-anatomical correlations in neuropsychiatric disorders.
    Neuroscience. 1997 Feb;76(4):957-1006 PMID: 9027863
  40. Depression in medical illness: the role of the immune system.
    West J Med. 2000 Nov;173(5):333-6 PMID: 11069873
  41. The vagus nerve mediates behavioural depression, but not fever, in response to peripheral immune signals; a functional anatomical analysis.
    Eur J Neurosci. 2000 Dec;12(12):4434-46 PMID: 11122354
  42. Neuroinflammation alters the hippocampal pattern of behaviorally induced Arc expression.
    J Neurosci. 2005 Jan 19;25(3):723-31 PMID: 15659610
  43. Differential effect of chronic antidepressant treatments on lipopolysaccharide-induced depressive-like behavioural symptoms in the rat.
    Life Sci. 1999;65(17):1773-86 PMID: 10576557
  44. Early depressive symptoms in cancer patients receiving interleukin 2 and/or interferon alfa-2b therapy.
    J Clin Oncol. 2000 May;18(10):2143-51 PMID: 10811680
  45. The accumbens: beyond the core-shell dichotomy.
    J Neuropsychiatry Clin Neurosci. 1997 Summer;9(3):354-81 PMID: 9276840
  46. Alteration of locus coeruleus neuronal activity by interleukin-1 and the involvement of endogenous corticotropin-releasing hormone.
    Neuroimmunomodulation. 2002-2003;10(2):101-21 PMID: 12372984
  47. Dissociating anorexia and anhedonia elicited by interleukin-1beta: antidepressant and gender effects on responding for "free chow" and "earned" sucrose intake.
    Psychopharmacology (Berl). 2003 Feb;165(4):413-8 PMID: 12459927
  48. DeltaFosB: a molecular switch for long-term adaptation in the brain.
    Brain Res Mol Brain Res. 2004 Dec 20;132(2):146-54 PMID: 15582154
  49. Endotoxin- or pro-inflammatory cytokine-induced sickness behavior as an animal model of depression: focus on anhedonia.
    Neurosci Biobehav Rev. 2005;29(4-5):761-70 PMID: 15878621
  50. Further evidence for the depressive effects of cytokines: anhedonia and neurochemical changes.
    Brain Behav Immun. 2002 Oct;16(5):544-56 PMID: 12401468
  51. Mediation of osmoregulatory influences on neuroendocrine corticotropin-releasing factor expression by the ventral lamina terminalis.
    Proc Natl Acad Sci U S A. 1993 Aug 15;90(16):7681-5 PMID: 8356069
  52. Animal models of depression: utility for transgenic research.
    Rev Neurosci. 2000;11(1):53-8 PMID: 10716655
  53. Peripheral administration of lipopolysaccharide induces the expression of cytokine transcripts in the brain and pituitary of mice.
    Brain Res Mol Brain Res. 1994 Nov;27(1):157-62 PMID: 7877446
  54. Hippocampal volume reduction in major depression.
    Am J Psychiatry. 2000 Jan;157(1):115-8 PMID: 10618023
  55. Assessing antidepressant activity in rodents: recent developments and future needs.
    Trends Pharmacol Sci. 2002 May;23(5):238-45 PMID: 12008002
  56. Theories of basal forebrain organization and the "emotional motor system".
    Prog Brain Res. 1996;107:461-84 PMID: 8782537
  57. Neurobiology of depression.
    Neuron. 2002 Mar 28;34(1):13-25 PMID: 11931738
  58. Lipopolysaccharide, central in vivo biogenic amine variations, and anhedonia.
    Neuroreport. 1998 Dec 1;9(17):3797-802 PMID: 9875707
  59. Lipopolysaccharide-mediated immobility in mice: reversal by cyclooxygenase enzyme inhibitors.
    Methods Find Exp Clin Pharmacol. 2001 Oct;23(8):441-4 PMID: 11838318
  60. Induction of deltaFosB in reward-related brain structures after chronic stress.
    J Neurosci. 2004 Nov 24;24(47):10594-602 PMID: 15564575
  61. Enhancement of laminar FosB expression in frontal cortex of rats receiving long chronic clozapine administration.
    Exp Neurol. 2001 Apr;168(2):392-401 PMID: 11259127
  62. Contribution of functional neuroimaging to understanding neuropsychiatric side effects of interferon in hepatitis C.
    Psychosomatics. 2004 Jul-Aug;45(4):281-6 PMID: 15232040
  63. Cytokine-induced sickness behaviour: mechanisms and implications.
    Trends Neurosci. 2002 Mar;25(3):154-9 PMID: 11852148
  64. Both products of the fosB gene, FosB and its short form, FosB/SF, are transcriptional activators in fibroblasts.
    Mol Cell Biol. 1991 Nov;11(11):5470-8 PMID: 1922060
  65. A comparison of two immediate-early genes, c-fos and NGFI-B, as markers for functional activation in stress-related neuroendocrine circuitry.
    J Neurosci. 1993 Dec;13(12):5126-38 PMID: 8254363
  66. The enzyme indoleamine 2,3-dioxygenase is induced in the mouse brain in response to peripheral administration of lipopolysaccharide and superantigen.
    Brain Behav Immun. 2002 Oct;16(5):596-601 PMID: 12401474
  67. c-Fos as a transcription factor: a stressful (re)view from a functional map.
    Neurochem Int. 1998 Oct;33(4):287-97 PMID: 9840219
  68. Effects of interleukin-1 and endotoxin in the forced swim and tail suspension tests in mice.
    Pharmacol Biochem Behav. 2005 Jul;81(3):688-93 PMID: 15982728
  69. Cytokines and acute neurodegeneration.
    Nat Rev Neurosci. 2001 Oct;2(10):734-44 PMID: 11584311
  70. The subdiaphragmatic vagus nerves mediate activation of locus coeruleus neurons by peripherally administered microbial substances.
    Neuroscience. 2005;131(1):235-45 PMID: 15680706
  71. Effects of a lipopolysaccharide from Pantoea agglomerans on the cocaine-induced place preference.
    Life Sci. 1994;54(6):PL75-80 PMID: 8295482
  72. Cytokine-induced sickness behavior: mechanisms and implications.
    Ann N Y Acad Sci. 2001 Mar;933:222-34 PMID: 12000023
  73. IDO and interferon-alpha-induced depressive symptoms: a shift in hypothesis from tryptophan depletion to neurotoxicity.
    Mol Psychiatry. 2005 Jun;10(6):538-44 PMID: 15494706
  74. DeltaFosB: a sustained molecular switch for addiction.
    Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11042-6 PMID: 11572966
  75. Region-specific induction of deltaFosB by repeated administration of typical versus atypical antipsychotic drugs.
    Synapse. 1999 Aug;33(2):118-28 PMID: 10400890
  76. Extended amygdala and basal forebrain.
    Ann N Y Acad Sci. 2003 Apr;985:185-205 PMID: 12724159
  77. Endotoxin produces a depressive-like episode in rats.
    Brain Res. 1996 Mar 4;711(1-2):163-74 PMID: 8680860
  78. Chronic brain inflammation leads to a decline in hippocampal NMDA-R1 receptors.
    J Neuroinflammation. 2004 Jul 7;1(1):12 PMID: 15285803
  79. Inducible and constitutive transcription factors in the mammalian nervous system: control of gene expression by Jun, Fos and Krox, and CREB/ATF proteins.
    Brain Res Brain Res Rev. 1998 Dec;28(3):370-490 PMID: 9858769
  80. Association between immune activation and early depressive symptoms in cancer patients treated with interleukin-2-based therapy.
    Psychoneuroendocrinology. 2001 Nov;26(8):797-808 PMID: 11585680
  81. The effects of endogenous interleukin-1 bioactivity on locus coeruleus neurons in response to bacterial and viral substances.
    Brain Res. 2004 May 8;1007(1-2):39-56 PMID: 15064134
  82. The tail suspension test as a model for assessing antidepressant activity: review of pharmacological and genetic studies in mice.
    Neurosci Biobehav Rev. 2005;29(4-5):571-625 PMID: 15890404
  83. DeltaFosB: a molecular mediator of long-term neural and behavioral plasticity.
    Brain Res. 1999 Jul 17;835(1):10-7 PMID: 10448191
  84. The immune system, depression and the action of antidepressants.
    Prog Neuropsychopharmacol Biol Psychiatry. 2001 May;25(4):767-80 PMID: 11383977
  85. The role of functional neuroimaging in the neuropsychology of depression.
    J Clin Exp Neuropsychol. 2001 Feb;23(1):121-36 PMID: 11320448
Article Info
Journal
Psychoneuroendocrinology
Abbr.
Psychoneuroendocrinology
ISSN
0306-4530
DOI
10.1016/j.psyneuen.2007.03.005
Published
2007-06-00
Epub
2007-00-04
Pages
516-31
Language
English
Region
England
NLM ID
7612148
PMCID
PMC1978247
Subset
IM
Grants
NIMH NIH HHS · R01 MH-71349 · United States
NIMH NIH HHS · R01 MH071349 · United States
NIMH NIH HHS · MH-079829 · United States
NIMH NIH HHS · R01 MH071349-03 · United States
NIMH NIH HHS · R01 MH079829-01 · United States
NIMH NIH HHS · R01 MH079829 · United States
NIMH NIH HHS · R01 MH071349-02 · United States
External Links
PubMed source DOI: 10.1016/j.psyneuen.2007.03.005 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2