Molecular Neurobiology

, Volume 54, Issue 9, pp 7327–7334 | Cite as

Fish Oil Prevents Lipopolysaccharide-Induced Depressive-Like Behavior by Inhibiting Neuroinflammation

  • Zhe Shi
  • Huixia Ren
  • Zhijian Huang
  • Yu Peng
  • Baixuan He
  • Xiaoli YaoEmail author
  • Ti-Fei YuanEmail author
  • Huanxing SuEmail author


Depression is associated with somatic immune changes, and neuroinflammation is now recognized as hallmark for depressive disorders. N-3 (or omega-3) polyunsaturated fatty acids (PUFAs) are well known to suppress neuroinflammation, reduce oxidative stress, and protect neuron from injury. We pretreated animals with fish oil and induced acute depression-like behaviors with systemic lipopolysaccharide (LPS) injection. The levels of cytokines and stress hormones were determined from plasma and different brain areas. The results showed that fish oil treatment prevent LPS-induce depressive behavior by suppression of neuroinflammation. LPS induced acute neuroinflammation in different brain regions, which were prevented in fish oil fed mice. However, neither LPS administration nor fish oil treatment has strong effect on stress hormone secretion in the hypothalamus and adrenal. Fish oil might provide a useful therapy against inflammation-associated depression.


Fish oil Neuroinflammation Depression LPS HPA axis 


Compliance with Ethical Standards

All animal experiments were carried out in strict accordance with the ethical guidelines of Institute of Chinese Medical Science (ICMS), University of Macau. The study has been approved by animal research committee in University of Macau, Sun Yat-sen University, and Nanjing Normal University.


  1. 1.
    Moussavi S, Chatterji S, Verdes E, Tandon A, Patel V, Ustun B (2007) Depression, chronic diseases, and decrements in health: results from the world health surveys. Lancet 370(9590):851–858. doi: 10.1016/S0140-6736(07)61415-9 CrossRefPubMedGoogle Scholar
  2. 2.
    Krishnan V, Nestler EJ (2008) The molecular neurobiology of depression. Nature 455(7215):894–902. doi: 10.1038/nature07455 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Niculescu AB, Levey D, Le-Niculescu H, Niculescu E, Kurian SM, Salomon D (2015) Psychiatric blood biomarkers: avoiding jumping to premature negative or positive conclusions. Mol Psychiatry 20(3):286–288. doi: 10.1038/mp.2014.180 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Dantzer R, O'Connor JC, Freund GG, Johnson RW, Kelley KW (2008) From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 9(1):46–56. doi: 10.1038/nrn2297 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Gold PW (2015) The organization of the stress system and its dysregulation in depressive illness. Mol Psychiatry 20(1):32–47. doi: 10.1038/mp.2014.163 CrossRefPubMedGoogle Scholar
  6. 6.
    Miller AH, Maletic V, Raison CL (2009) Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry 65(9):732–741. doi: 10.1016/j.biopsych.2008.11.029 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Raetz CR, Whitfield C (2002) Lipopolysaccharide endotoxins. Annu Rev Biochem 71:635–700. doi: 10.1146/annurev.biochem.71.110601.135414 CrossRefPubMedGoogle Scholar
  8. 8.
    Bazan NG, Molina MF, Gordon WC (2011) Docosahexaenoic acid signalolipidomics in nutrition: significance in aging, neuroinflammation, macular degeneration, Alzheimer's, and other neurodegenerative diseases. Annu Rev Nutr 31:321–351. doi: 10.1146/annurev.nutr.012809.104635 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Lukiw WJ, Cui JG, Marcheselli VL, Bodker M, Botkjaer A, Gotlinger K, Serhan CN, Bazan NG (2005) A role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and Alzheimer disease. J Clin Invest 115(10):2774–2783. doi: 10.1172/JCI25420 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Palacios-Pelaez R, Lukiw WJ, Bazan NG (2010) Omega-3 essential fatty acids modulate initiation and progression of neurodegenerative disease. Mol Neurobiol 41(2–3):367–374. doi: 10.1007/s12035-010-8139-z CrossRefPubMedGoogle Scholar
  11. 11.
    Calder PC (2012) Long-chain fatty acids and inflammation. Proc Nutr Soc 71(2):284–289. doi: 10.1017/S0029665112000067 CrossRefPubMedGoogle Scholar
  12. 12.
    Tan Y, Ren H, Shi Z, Yao X, He C, Kang JX, Wan JB, Li P (2016) Endogenous docosahexaenoic acid (DHA) prevents Abeta1-42 oligomer-induced neuronal injury. Mol Neurobiol 53(5):3146–3153. doi: 10.1007/s12035-015-9224-0 CrossRefPubMedGoogle Scholar
  13. 13.
    Shi Z, Ren H, Luo C, Yao X, Li P, He C, Kang JX, Wan JB (2015) Enriched endogenous omega-3 polyunsaturated fatty acids protect cortical neurons from experimental ischemic injury. Mol Neurobiol. doi: 10.1007/s12035-015-9554-y PubMedCentralGoogle Scholar
  14. 14.
    Tsuchimine S, Saito M, Kaneko S, Yasui-Furukori N (2015) Decreased serum levels of polyunsaturated fatty acids and folate, but not brain-derived neurotrophic factor, in childhood and adolescent females with depression. Psychiatry Res 225(1–2):187–190. doi: 10.1016/j.psychres.2014.11.018 CrossRefPubMedGoogle Scholar
  15. 15.
    Riemer S, Maes M, Christophe A, Rief W (2010) Lowered omega-3 PUFAs are related to major depression, but not to somatization syndrome. J Affect Disord 123(1–3):173–180. doi: 10.1016/j.jad.2009.08.004 CrossRefPubMedGoogle Scholar
  16. 16.
    DeMar JC Jr, Ma K, Bell JM, Igarashi M, Greenstein D, Rapoport SI (2006) One generation of n-3 polyunsaturated fatty acid deprivation increases depression and aggression test scores in rats. J Lipid Res 47(1):172–180. doi: 10.1194/jlr.M500362-JLR200 CrossRefPubMedGoogle Scholar
  17. 17.
    Song C, Li X, Kang Z, Kadotomi Y (2007) Omega-3 fatty acid ethyl-eicosapentaenoate attenuates IL-1beta-induced changes in dopamine and metabolites in the shell of the nucleus accumbens: involved with PLA2 activity and corticosterone secretion. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 32(3):736–744. doi: 10.1038/sj.npp.1301117 CrossRefGoogle Scholar
  18. 18.
    Rapaport MH, Nierenberg AA, Schettler PJ, Kinkead B, Cardoos A, Walker R, Mischoulon D (2015) Inflammation as a predictive biomarker for response to omega-3 fatty acids in major depressive disorder: a proof-of-concept study. Mol Psychiatry. doi: 10.1038/mp.2015.22 PubMedPubMedCentralGoogle Scholar
  19. 19.
    O'Connor JC, Lawson MA, Andre C, Moreau M, Lestage J, Castanon N, Kelley KW, Dantzer R (2009) Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice. Mol Psychiatry 14(5):511–522. doi: 10.1038/ CrossRefPubMedGoogle Scholar
  20. 20.
    Shih RH, Yang CM (2010) Induction of heme oxygenase-1 attenuates lipopolysaccharide-induced cyclooxygenase-2 expression in mouse brain endothelial cells. J Neuroinflammation 7:86. doi: 10.1186/1742-2094-7-86 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Dantzer R (2001) Cytokine-induced sickness behavior: where do we stand? Brain Behav Immun 15(1):7–24. doi: 10.1006/brbi.2000.0613 CrossRefPubMedGoogle Scholar
  22. 22.
    Biesmans S, Meert TF, Bouwknecht JA, Acton PD, Davoodi N, De Haes P, Kuijlaars J, Langlois X (2013) Systemic immune activation leads to neuroinflammation and sickness behavior in mice. Mediat Inflamm 2013:271359. doi: 10.1155/2013/271359 CrossRefGoogle Scholar
  23. 23.
    Yuan TF, Paes F, Arias-Carrion O, Ferreira Rocha NB, de Sa Filho AS, Machado S (2015) Neural mechanisms of exercise: anti-depression, neurogenesis, and serotonin signaling. CNS & neurological disorders drug targets 14(10):1307–1311CrossRefGoogle Scholar
  24. 24.
    Carlezon WA Jr, Mague SD, Parow AM, Stoll AL, Cohen BM, Renshaw PF (2005) Antidepressant-like effects of uridine and omega-3 fatty acids are potentiated by combined treatment in rats. Biol Psychiatry 57(4):343–350. doi: 10.1016/j.biopsych.2004.11.038 CrossRefPubMedGoogle Scholar
  25. 25.
    Song C, Leonard BE, Horrobin DF (2004) Dietary ethyl-eicosapentaenoic acid but not soybean oil reverses central interleukin-1-induced changes in behavior, corticosterone and immune response in rats. Stress 7(1):43–54. doi: 10.1080/10253890410001667188 CrossRefPubMedGoogle Scholar
  26. 26.
    Laye S, Parnet P, Goujon E, Dantzer R (1994) Peripheral administration of lipopolysaccharide induces the expression of cytokine transcripts in the brain and pituitary of mice. Brain Res Mol Brain Res 27(1):157–162CrossRefPubMedGoogle Scholar
  27. 27.
    Shih RH, Wang CY, Yang CM (2015) NF-kappaB signaling pathways in neurological inflammation: a mini review. Front Mol Neurosci 8:77. doi: 10.3389/fnmol.2015.00077 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Ben-Neriah Y, Karin M (2011) Inflammation meets cancer, with NF-kappaB as the matchmaker. Nat Immunol 12(8):715–723. doi: 10.1038/ni.2060 CrossRefPubMedGoogle Scholar
  29. 29.
    Niranjan R (2013) Molecular basis of etiological implications in Alzheimer's disease: focus on neuroinflammation. Mol Neurobiol 48(3):412–428. doi: 10.1007/s12035-013-8428-4 CrossRefPubMedGoogle Scholar
  30. 30.
    Capuron L, Ravaud A, Neveu PJ, Miller AH, Maes M, Dantzer R (2002) Association between decreased serum tryptophan concentrations and depressive symptoms in cancer patients undergoing cytokine therapy. Mol Psychiatry 7(5):468–473. doi: 10.1038/ CrossRefPubMedGoogle Scholar
  31. 31.
    Yuan TF, Li A, Sun X, Ouyang H, Campos C, Rocha NB, Arias-Carrion O, Machado S (2015) Transgenerational inheritance of paternal neurobehavioral phenotypes: stress, addiction, ageing and metabolism. Mol Neurobiol. doi: 10.1007/s12035-015-9526-2 Google Scholar
  32. 32.
    Yuan TF, Slotnick BM (2014) Roles of olfactory system dysfunction in depression. Prog Neuro-Psychopharmacol Biol Psychiatry 54:26–30. doi: 10.1016/j.pnpbp.2014.05.013 CrossRefGoogle Scholar
  33. 33.
    Yuan TF, Li J, Ding F, Arias-Carrion O (2014) Evidence of adult neurogenesis in non-human primates and human. Cell Tissue Res 358(1):17–23. doi: 10.1007/s00441-014-1980-z CrossRefPubMedGoogle Scholar
  34. 34.
    Henry CJ, Huang Y, Wynne A, Hanke M, Himler J, Bailey MT, Sheridan JF, Godbout JP (2008) Minocycline attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia. J Neuroinflammation 5:15. doi: 10.1186/1742-2094-5-15 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Arnett MG, Muglia LM, Laryea G, Muglia LJ (2015) Genetic approaches to hypothalamic-pituitary-adrenal axis regulation. Neuropsychopharmacology. doi: 10.1038/npp.2015.215 PubMedPubMedCentralGoogle Scholar
  36. 36.
    Qadri F, Rimmele F, Mallis L, Hauser W, Dendorfer A, Johren O, Dominiak P, Leeb-Lundberg LM (2016) Acute hypothalamo-pituitary-adrenal axis response to LPS-induced endotoxemia: expression pattern of kinin type B1 and B2 receptors. Biol Chem 397(2):97–109. doi: 10.1515/hsz-2015-0206 CrossRefPubMedGoogle Scholar
  37. 37.
    Delpech JC, Thomazeau A, Madore C, Bosch-Bouju C, Larrieu T, Lacabanne C, Remus-Borel J, Aubert A (2015) Dietary n-3 PUFAs deficiency increases vulnerability to inflammation-induced spatial memory impairment. Neuropsychopharmacology. doi: 10.1038/npp.2015.127 PubMedCentralGoogle Scholar
  38. 38.
    Bagosi Z, Balango B, Pinter D, Csabafi K, Jaszberenyi M, Szabo G, Telegdy G (2015) The effects of CRF and urocortins on the hippocampal glutamate release. Neurochem Int 90:67–71. doi: 10.1016/j.neuint.2015.07.015 CrossRefPubMedGoogle Scholar
  39. 39.
    Dong H, Murphy KM, Meng L, Montalvo-Ortiz J, Zeng Z, Kolber BJ, Zhang S, Muglia LJ (2012) Corticotrophin releasing factor accelerates neuropathology and cognitive decline in a mouse model of Alzheimer’s disease. J Alzheimers Dis 28(3):579–592PubMedPubMedCentralGoogle Scholar
  40. 40.
    Smith SM, Vale WW (2006) The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress. Dialogues Clin Neurosci 8(4):383–395PubMedPubMedCentralGoogle Scholar
  41. 41.
    Jiang LH, Liang QY, Shi Y (2012) Pure docosahexaenoic acid can improve depression behaviors and affect HPA axis in mice. Eur Rev Med Pharmacol Sci 16(13):1765–1773PubMedGoogle Scholar
  42. 42.
    Mocking RJ, Ruhe HG, Assies J, Lok A, Koeter MW, Visser I, Bockting CL, Schene AH (2013) Relationship between the hypothalamic-pituitary-adrenal-axis and fatty acid metabolism in recurrent depression. Psychoneuroendocrinology 38(9):1607–1617. doi: 10.1016/j.psyneuen.2013.01.013 CrossRefPubMedGoogle Scholar
  43. 43.
    Ziemann U, Reis J, Schwenkreis P, Rosanova M, Strafella A, Badawy R, Muller-Dahlhaus F (2015) TMS and drugs revisited 2014. Clinical neurophysiology: official journal of the International Federation of Clinical Neurophysiology 126(10):1847–1868. doi: 10.1016/j.clinph.2014.08.028 CrossRefGoogle Scholar
  44. 44.
    Shen Y, Cao X, Tan T, Shan C, Wang Y, Pan J, He H, Yuan TF (2016) 10-Hz repetitive transcranial magnetic stimulation of the left dorsolateral prefrontal cortex reduces heroin cue craving in long-term addicts. Biol Psychiatry 80(3):e13–e14. doi: 10.1016/j.biopsych.2016.02.006 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical SciencesUniversity of MacauMacaoChina
  2. 2.Department of Neurology, National Key Clinical Department and Key Discipline of Neurology, The First Affiliated HospitalSun Yat-Sen UniversityGuangzhouChina
  3. 3.School of PsychologyNanjing Normal UniversityNanjingChina

Personalised recommendations