Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Polyunsaturated fatty acids and their metabolites in brain function and disease

Key Points

  • The brain is especially enriched with the two polyunsaturated fatty acids arachidonic acid and docosahexaenoic acid. Although, quantitatively speaking, they are primarily esterified to brain phophospholipids, they can be released from the membrane and transformed into highly biologically active molecules.

  • The mechanisms by which the brain takes up polyunsaturated fatty acids are not clear and remain controversial. Candidate plasma pools include phospholipids as part of lipoproteins, unesterified fatty acids and lysophospholipids. Because polyunsaturated fatty acids are derived from the diet, changes in their intakes can alter brain levels and thus the activity of pathways regulated by polyunsaturated fatty acids in the brain.

  • In response to neuroreceptor activation, fatty acids are released from the membrane and participate in cell signalling.

  • So far, polyunsaturated fatty acids and their biologically active derivatives have been shown to regulate cell survival, neurogenesis, brain inflammation and synaptic function.

  • Altered fatty acid signalling has been implicated in mood disorders, cognition, Alzheimer's disease, schizophrenia and other conditions. Research using animal models has shown promise in targeting brain polyunsaturated fatty acid metabolism with diet or drugs; however, translational studies often do not yield statistically significant results. New methods to target brain polyunsaturated metabolism are emerging as novel approaches to treat brain disorders.

Abstract

The brain is highly enriched with fatty acids. These include the polyunsaturated fatty acids (PUFAs) arachidonic acid and docosahexaenoic acid, which are largely esterified to the phospholipid cell membrane. Once PUFAs are released from the membrane, they can participate in signal transduction, either directly or after enzymatic conversion to a variety of bioactive derivatives ('mediators'). PUFAs and their mediators regulate several processes within the brain, such as neurotransmission, cell survival and neuroinflammation, and thereby mood and cognition. PUFA levels and the signalling pathways that they regulate are altered in various neurological disorders, including Alzheimer's disease and major depression. Diet and drugs targeting PUFAs may lead to novel therapeutic approaches for the prevention and treatment of brain disorders.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Synthesis of PUFAs in the liver.
Figure 2: Fatty acid entry from the plasma into the brain.
Figure 3: Fatty acid release and conversion to mediators upon receptor-mediated signal transduction.
Figure 4: Dietary PUFAs influence endocannabinoid-mediated synaptic plasticity.
Figure 5: Roles of PUFAs in the brain.

References

  1. Rapoport, S. I. Translational studies on regulation of brain docosahexaenoic acid (DHA) metabolism in vivo. Prostaglandins Leukot. Essent. Fatty Acids 88, 79–85 (2013).

    CAS  PubMed  Google Scholar 

  2. Mitchell, R. W. & Hatch, G. M. Fatty acid transport into the brain: of fatty acid fables and lipid tails. Prostaglandins Leukot. Essent. Fatty Acids 85, 293–302 (2011).

    CAS  PubMed  Google Scholar 

  3. Nguyen, L. N. et al. Mfsd2a is a transporter for the essential ω-3 fatty acid docosahexaenoic acid. Nature 509, 503–506 (2014).

    CAS  PubMed  Google Scholar 

  4. Chen, C. T. & Bazinet, R. P. β-oxidation and rapid metabolism, but not uptake regulate brain eicosapentaenoic acid levels. Prostaglandins Leukot. Essent. Fatty Acids http://dx.doi.org/10.1016/j.plefa.2014.05.007 (2014).

  5. Goldberg, I. J., Eckel, R. H. & Abumrad, N. A. Regulation of fatty acid uptake into tissues: lipoprotein lipase- and CD36-mediated pathways. J. Lipid Res. 50 (Suppl.), S86–S90 (2009).

    PubMed  PubMed Central  Google Scholar 

  6. Chen, S. & Subbaiah, P. V. Regioisomers of phosphatidylcholine containing DHA and their potential to deliver DHA to the brain: role of phospholipase specificities. Lipids 48, 675–686 (2013).

    CAS  PubMed  Google Scholar 

  7. Hamilton, J. A. & Brunaldi, K. A model for fatty acid transport into the brain. J. Mol. Neurosci. 33, 12–17 (2007).

    CAS  PubMed  Google Scholar 

  8. Jia, Z., Pei, Z., Maiguel, D., Toomer, C. J. & Watkins, P. A. The fatty acid transport protein (FATP) family: very long chain acyl-CoA synthetases or solute carriers? J. Mol. Neurosci. 33, 25–31 (2007).

    CAS  PubMed  Google Scholar 

  9. Mashek, D. G. & Coleman, R. A. Cellular fatty acid uptake: the contribution of metabolism. Curr. Opin. Lipidol. 17, 274–278 (2006).

    CAS  PubMed  Google Scholar 

  10. Xu, S., Jay, A., Brunaldi, K., Huang, N. & Hamilton, J. A. CD36 enhances fatty acid uptake by increasing the rate of intracellular esterification but not transport across the plasma membrane. Biochemistry 52, 7254–7261 (2013).

    CAS  PubMed  Google Scholar 

  11. Neculai, D. et al. Structure of LIMP-2 provides functional insights with implications for SR-BI and CD36. Nature 504, 172–176 (2013).

    CAS  PubMed  Google Scholar 

  12. Kuipers, R. S. et al. Fetal intrauterine whole body linoleic, arachidonic and docosahexaenoic acid contents and accretion rates. Prostaglandins Leukot. Essent. Fatty Acids 86, 13–20 (2012).

    CAS  PubMed  Google Scholar 

  13. Hadley, K. B., Ryan, A. S., Nelson, E. B. & Salem, N. An assessment of dietary docosahexaenoic acid requirements for brain accretion and turnover during early childhood. World Rev. Nutr. Dietet. 99, 97–104 (2009).

    CAS  Google Scholar 

  14. Innis, S. M. Dietary ω 3 fatty acids and the developing brain. Brain Res. 1237, 35–43 (2008).

    CAS  PubMed  Google Scholar 

  15. Lauritzen, L. & Carlson, S. E. Maternal fatty acid status during pregnancy and lactation and relation to newborn and infant status. Maternal Child Nutr. 7 (Suppl. 2), 41–58 (2011).

    Google Scholar 

  16. Makrides, M., Anderson, A., Gibson, R. A. & Collins, C. T. Improving the neurodevelopmental outcomes of low-birthweight infants. Nestle Nutr. Institute Workshop Series 74, 211–221 (2013).

    Google Scholar 

  17. Carver, J. D., Benford, V. J., Han, B. & Cantor, A. B. The relationship between age and the fatty acid composition of cerebral cortex and erythrocytes in human subjects. Brain Res. Bull. 56, 79–85 (2001).

    CAS  PubMed  Google Scholar 

  18. Rapoport, S. I., Rao, J. S. & Igarashi, M. Brain metabolism of nutritionally essential polyunsaturated fatty acids depends on both the diet and the liver. Prostaglandins Leukot. Essent. Fatty Acids 77, 251–261 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Watkins, P. A. Fatty acid activation. Progress Lipid Res. 36, 55–83 (1997).

    CAS  Google Scholar 

  20. Mashek, D. G., Li, L. O. & Coleman, R. A. Long-chain acyl-CoA synthetases and fatty acid channeling. Future Lipidol. 2, 465–476 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. DiRusso, C. C. et al. Comparative biochemical studies of the murine fatty acid transport proteins (FATP) expressed in yeast. J. Biol. Chem. 280, 16829–16837 (2005).

    CAS  PubMed  Google Scholar 

  22. Liu, R. Z., Mita, R., Beaulieu, M., Gao, Z. & Godbout, R. Fatty acid binding proteins in brain development and disease. Int. J. Dev. Biol. 54, 1229–1239 (2010).

    CAS  PubMed  Google Scholar 

  23. Eto, M., Shindou, H. & Shimizu, T. A novel lysophosphatidic acid acyltransferase enzyme (LPAAT4) with a possible role for incorporating docosahexaenoic acid into brain glycerophospholipids. Biochem. Biophys. Res. Commun. 443, 718–724 (2014).

    CAS  PubMed  Google Scholar 

  24. Vannucci, S. & Hawkins, R. Substrates of energy metabolism of the pituitary and pineal glands. J. Neurochem. 41, 1718–1725 (1983).

    CAS  PubMed  Google Scholar 

  25. Schonfeld, P. & Reiser, G. Why does brain metabolism not favor burning of fatty acids to provide energy? - Reflections on disadvantages of the use of free fatty acids as fuel for brain. J. Cerebral Blood Flow Metabolism 33, 1493–1499 (2013).

    Google Scholar 

  26. Speijer, D. Oxygen radicals shaping evolution: why fatty acid catabolism leads to peroxisomes while neurons do without it: FADH(2)/NADH flux ratios determining mitochondrial radical formation were crucial for the eukaryotic invention of peroxisomes and catabolic tissue differentiation. BioEssays 33, 88–94 (2011).

    CAS  PubMed  Google Scholar 

  27. Chen, C. T. et al. Inhibiting mitochondrial β-oxidation selectively reduces levels of nonenzymatic oxidative polyunsaturated fatty acid metabolites in the brain. J. Cerebral Blood Flow Metabolism 34, 376–379 (2014).

    CAS  Google Scholar 

  28. Burke, J. E. & Dennis, E. A. Phospholipase A2 structure/function, mechanism, and signaling. J. Lipid Res. 50 (Suppl.), S237–242 (2009).

    PubMed  PubMed Central  Google Scholar 

  29. Contreras, M. A. & Rapoport, S. I. Recent studies on interactions between n-3 and n-6 polyunsaturated fatty acids in brain and other tissues. Curr. Opin. Lipidol. 13, 267–272 (2002).

    CAS  PubMed  Google Scholar 

  30. Strokin, M., Sergeeva, M. & Reiser, G. Role of Ca2+-independent phospholipase A2 and n-3 polyunsaturated fatty acid docosahexaenoic acid in prostanoid production in brain: perspectives for protection in neuroinflammation. Int. J. Dev. Neurosci. 22, 551–557 (2004).

    CAS  PubMed  Google Scholar 

  31. Green, J. T., Orr, S. K. & Bazinet, R. P. The emerging role of group VI calcium-independent phospholipase A2 in releasing docosahexaenoic acid from brain phospholipids. J. Lipid Res. 49, 939–944 (2008).

    CAS  PubMed  Google Scholar 

  32. Purdon, A. D., Rosenberger, T. A., Shetty, H. U. & Rapoport, S. I. Energy consumption by phospholipid metabolism in mammalian brain. Neurochem. Res. 27, 1641–1647 (2002).

    CAS  PubMed  Google Scholar 

  33. Vial, D. & Piomelli, D. Dopamine D2 receptors potentiate arachidonate release via activation of cytosolic, arachidonate-specific phospholipase A2. J. Neurochem. 64, 2765–2772 (1995).

    CAS  PubMed  Google Scholar 

  34. Felder, C. C., Williams, H. L. & Axelrod, J. A transduction pathway associated with receptors coupled to the inhibitory guanine nucleotide binding protein Gi that amplifies ATP-mediated arachidonic acid release. Proc. Natl Acad. Sci. USA 88, 6477–6480 (1991).

    CAS  PubMed  Google Scholar 

  35. Felder, C. C., Kanterman, R. Y., Ma, A. L. & Axelrod, J. Serotonin stimulates phospholipase A2 and the release of arachidonic acid in hippocampal neurons by a type 2 serotonin receptor that is independent of inositolphospholipid hydrolysis. Proc. Natl Acad. Sci. USA 87, 2187–2191 (1990).

    CAS  PubMed  Google Scholar 

  36. Dumuis, A., Sebben, M., Haynes, L., Pin, J. P. & Bockaert, J. NMDA receptors activate the arachidonic acid cascade system in striatal neurons. Nature 336, 68–70 (1988).

    CAS  PubMed  Google Scholar 

  37. Axelrod, J. Receptor-mediated activation of phospholipase A2 and arachidonic acid release in signal transduction. Biochem. Soc. Trans. 18, 503–507 (1990).

    CAS  PubMed  Google Scholar 

  38. Rapoport, S. I. Lithium and the other mood stabilizers effective in bipolar disorder target the rat brain arachidonic acid cascade. ACS Chem. Neurosci. 5, 459–467 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Bazan, N. G., Molina, M. F. & Gordon, W. C. Docosahexaenoic acid signalolipidomics in nutrition: significance in aging, neuroinflammation, macular degeneration, Alzheimer's, and other neurodegenerative diseases. Annu. Rev. Nutr. 31, 321–351 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Basselin, M., Ramadan, E. & Rapoport, S. I. Imaging brain signal transduction and metabolism via arachidonic and docosahexaenoic acid in animals and humans. Brain Res. Bull. 87, 154–171 (2012).

    CAS  PubMed  Google Scholar 

  41. Murphy, E. J. Brain fixation for analysis of brain lipid-mediators of signal transduction and brain eicosanoids requires head-focused microwave irradiation: an historical perspective. Prostaglandins Other Lipid Mediators 91, 63–67 (2010). A detailed review of the important, but underappreciated, use of microwave fixation to measure biologically active lipids in the brain.

    CAS  PubMed  Google Scholar 

  42. Serhan, C. N. Pro-resolving lipid mediators are leads for resolution physiology. Nature 510, 92–101 (2014). A recent overview of lipid mediator biology, including its history and role in resolution and future directions.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Bosetti, F. Arachidonic acid metabolism in brain physiology and pathology: lessons from genetically altered mouse models. J. Neurochem. 102, 577–586 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Farooqui, A. A., Horrocks, L. A. & Farooqui, T. Modulation of inflammation in brain: a matter of fat. J. Neurochem. 101, 577–599 (2007).

    CAS  PubMed  Google Scholar 

  45. Orr, S. K. et al. Unesterified docosahexaenoic acid is protective in neuroinflammation. J. Neurochem. 127, 378–393 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Hong, S., Gronert, K., Devchand, P. R., Moussignac, R. L. & Serhan, C. N. Novel docosatrienes and 17S-resolvins generated from docosahexaenoic acid in murine brain, human blood, and glial cells. Autacoids in anti-inflammation. J. Biol. Chem. 278, 14677–14687 (2003).

    CAS  PubMed  Google Scholar 

  47. Marcheselli, V. L. et al. Novel docosanoids inhibit brain ischemia-reperfusion-mediated leukocyte infiltration and pro-inflammatory gene expression. J. Biol. Chem. 278, 43807–43817 (2003). The first paper to show that NPD1 is biologically active in the brain.

    CAS  PubMed  Google Scholar 

  48. Thambisetty, M. et al. The utility of (11)C-arachidonate PET to study in vivo dopaminergic neurotransmission in humans. J. Cereb. Blood Flow Metab. 32, 676–684 (2012).

    CAS  PubMed  Google Scholar 

  49. Lam, T. K., Schwartz, G. J. & Rossetti, L. Hypothalamic sensing of fatty acids. Nature Neurosci. 8, 579–584 (2005).

    CAS  PubMed  Google Scholar 

  50. Di Marzo, V. et al. Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 410, 822–825 (2001).

    CAS  PubMed  Google Scholar 

  51. Hohmann, A. G. et al. An endocannabinoid mechanism for stress-induced analgesia. Nature 435, 1108–1112 (2005).

    CAS  PubMed  Google Scholar 

  52. Salem, N. Jr, Litman, B., Kim, H. Y. & Gawrisch, K. Mechanisms of action of docosahexaenoic acid in the nervous system. Lipids 36, 945–959 (2001). An older, but important, review of brain lipid chemistry and the candidate mechanisms of action of DHA.

    CAS  PubMed  Google Scholar 

  53. Gawrisch, K., Eldho, N. V. & Holte, L. L. The structure of DHA in phospholipid membranes. Lipids 38, 445–452 (2003).

    CAS  PubMed  Google Scholar 

  54. Shaikh, S. R. & Teague, H. N-3 fatty acids and membrane microdomains: from model membranes to lymphocyte function. Prostaglandins Leukot. Essent. Fatty Acids 87, 205–208 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Rao, J. S., Lee, H. J., Rapoport, S. I. & Bazinet, R. P. Mode of action of mood stabilizers: is the arachidonic acid cascade a common target? Mol. Psychiatry 13, 585–596 (2008).

    CAS  PubMed  Google Scholar 

  56. Piomelli, D. & Sasso, O. Peripheral gating of pain signals by endogenous lipid mediators. Nature Neurosci. 17, 164–174 (2014).

    CAS  PubMed  Google Scholar 

  57. Stella, N. Endocannabinoid signaling in microglial cells. Neuropharmacology 56 (Suppl. 1), 244–253 (2009).

    CAS  PubMed  Google Scholar 

  58. Castillo, P. E., Younts, T. J., Chavez, A. E. & Hashimotodani, Y. Endocannabinoid signaling and synaptic function. Neuron 76, 70–81 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Grueter, B. A., Brasnjo, G. & Malenka, R. C. Postsynaptic TRPV1 triggers cell type-specific long-term depression in the nucleus accumbens. Nature Neurosci. 13, 1519–1525 (2010).

    CAS  PubMed  Google Scholar 

  60. Berger, A. et al. Anandamide and diet: inclusion of dietary arachidonate and docosahexaenoate leads to increased brain levels of the corresponding N-acylethanolamines in piglets. Proc. Natl Acad. Sci. USA 98, 6402–6406 (2001). The first study to show that diet can influence brain fatty acid ethanolamides.

    CAS  PubMed  Google Scholar 

  61. Piscitelli, F. et al. Effect of dietary krill oil supplementation on the endocannabinoidome of metabolically relevant tissues from high-fat-fed mice. Nutr. Metab. 8, 51 (2011).

    CAS  Google Scholar 

  62. Watanabe, S., Doshi, M. & Hamazaki, T. n-3 polyunsaturated fatty acid (PUFA) deficiency elevates and n-3 PUFA enrichment reduces brain 2-arachidonoylglycerol level in mice. Prostaglandins Leukot Essent. Fatty Acids 69, 51–59 (2003).

    CAS  PubMed  Google Scholar 

  63. Hutchins, H. L., Li, Y., Hannon, K. & Watkins, B. A. Eicosapentaenoic acid decreases expression of anandamide synthesis enzyme and cannabinoid receptor 2 in osteoblast-like cells. J. Nutr. Biochem. 22, 195–200 (2011).

    CAS  PubMed  Google Scholar 

  64. Larrieu, T., Madore, C., Joffre, C. & Laye, S. Nutritional n-3 polyunsaturated fatty acids deficiency alters cannabinoid receptor signaling pathway in the brain and associated anxiety-like behavior in mice. J. Physiol. Biochem. 68, 671–681 (2012).

    CAS  PubMed  Google Scholar 

  65. Lafourcade, M. et al. Nutritional ω-3 deficiency abolishes endocannabinoid-mediated neuronal functions. Nature Neurosci. 14, 345–350 (2011). In this paper, brain DHA is shown to regulate endocannabinoid-dependant synaptic plasticity through the impairment of the CB1 receptor signalling pathway.

    CAS  PubMed  Google Scholar 

  66. Calon, F. et al. Docosahexaenoic acid protects from dendritic pathology in an Alzheimer's disease mouse model. Neuron 43, 633–645 (2004). A landmark paper demonstrating that DHA decreases β-amyloid in a mouse model of Alzheimer's disease.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Calon, F. et al. Dietary n-3 polyunsaturated fatty acid depletion activates caspases and decreases NMDA receptors in the brain of a transgenic mouse model of Alzheimer's disease. Eur. J. Neurosci. 22, 617–626 (2005).

    PubMed  Google Scholar 

  68. Davletov, B., Connell, E. & Darios, F. Regulation of SNARE fusion machinery by fatty acids. Cell. Mol. Life Sci. 64, 1597–1608 (2007).

    CAS  PubMed  Google Scholar 

  69. Pongrac, J. L., Slack, P. J. & Innis, S. M. Dietary polyunsaturated fat that is low in (n-3) and high in (n-6) fatty acids alters the SNARE protein complex and nitrosylation in rat hippocampus. J. Nutr. 137, 1852–1856 (2007).

    CAS  PubMed  Google Scholar 

  70. Darios, F. & Davletov, B. ω-3 and ω-6 fatty acids stimulate cell membrane expansion by acting on syntaxin 3. Nature 440, 813–817 (2006).

    CAS  PubMed  Google Scholar 

  71. Mazelova, J., Ransom, N., Astuto-Gribble, L., Wilson, M. C. & Deretic, D. Syntaxin 3 and SNAP-25 pairing, regulated by ω-3 docosahexaenoic acid, controls the delivery of rhodopsin for the biogenesis of cilia-derived sensory organelles, the rod outer segments. J. Cell Sci. 122, 2003–2013 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Mathieu, G. et al. DHA enhances the noradrenaline release by SH-SY5Y cells. Neurochem. Int. 56, 94–100 (2010).

    PubMed  Google Scholar 

  73. Fedorova, I. & Salem, N. Jr. ω-3 fatty acids and rodent behavior. Prostaglandins Leukot. Essent. Fatty Acids 75, 271–289 (2006).

    CAS  PubMed  Google Scholar 

  74. Kim, H. Y., Akbar, M., Lau, A. & Edsall, L. Inhibition of neuronal apoptosis by docosahexaenoic acid (22:6n-3). Role of phosphatidylserine in antiapoptotic effect. J. Biol. Chem. 275, 35215–35223 (2000).

    CAS  PubMed  Google Scholar 

  75. Calderon, F. & Kim, H. Y. Docosahexaenoic acid promotes neurite growth in hippocampal neurons. J. Neurochem. 90, 979–988 (2004).

    CAS  PubMed  Google Scholar 

  76. Garcia, M. C., Ward, G., Ma, Y. C., Salem, N. Jr & Kim, H. Y. Effect of docosahexaenoic acid on the synthesis of phosphatidylserine in rat brain in microsomes and C6 glioma cells. J. Neurochem. 70, 24–30 (1998).

    CAS  PubMed  Google Scholar 

  77. Kim, H. Y. & Spector, A. A. Synaptamide, endocannabinoid-like derivative of docosahexaenoic acid with cannabinoid-independent function. Prostaglandins Leukot. Essent. Fatty Acids 88, 121–125 (2013).

    CAS  PubMed  Google Scholar 

  78. Kim, H. Y., Spector, A. A. & Xiong, Z. M. A synaptogenic amide N-docosahexaenoylethanolamide promotes hippocampal development. Prostaglandins Other Lipid Mediators 96, 114–120 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Rashid, M. A., Katakura, M., Kharebava, G., Kevala, K. & Kim, H. Y. N-Docosahexaenoylethanolamine is a potent neurogenic factor for neural stem cell differentiation. J. Neurochem. 125, 869–884 (2013). The first paper to demonstrate that the fatty acid ethanolamide, a derivative of DHA, is a potent neurogenic factor.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Lukiw, W. J. & Bazan, N. G. Docosahexaenoic acid and the aging brain. J. Nutr. 138, 2510–2514 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Lukiw, W. J. et al. A role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and Alzheimer disease. J. Clin. Invest. 115, 2774–2783 (2005). A seminal paper showing decreased unesterifed DHA and NPD1 in post-mortem samples from patients with Alzheimer's disease, suggesting that altered neuroprotective pathways may be an early event in disease pathogenesis.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Wu, A., Ying, Z. & Gomez-Pinilla, F. Dietary ω-3 fatty acids normalize BDNF levels, reduce oxidative damage, and counteract learning disability after traumatic brain injury in rats. J. Neurotrauma 21, 1457–1467 (2004).

    PubMed  Google Scholar 

  83. Rao, J. S. et al. n-3 polyunsaturated fatty acid deprivation in rats decreases frontal cortex BDNF via a p38 MAPK-dependent mechanism. Mol. Psychiatry 12, 36–46 (2007).

    CAS  PubMed  Google Scholar 

  84. Bousquet, M., Calon, F. & Cicchetti, F. Impact of ω-3 fatty acids in Parkinson's disease. Ageing Res. Rev. 10, 453–463 (2011).

    CAS  PubMed  Google Scholar 

  85. Orr, S. K., Trepanier, M. O. & Bazinet, R. P. n-3 Polyunsaturated fatty acids in animal models with neuroinflammation. Prostaglandins Leukot. Essent. Fatty Acids 88, 97–103 (2013).

    CAS  PubMed  Google Scholar 

  86. Bazan, N. G. et al. Novel aspirin-triggered neuroprotectin D1 attenuates cerebral ischemic injury after experimental stroke. Exp. Neurol. 236, 122–130 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Laye, S. Polyunsaturated fatty acids, neuroinflammation and well being. Prostaglandins Leukot Essent. Fatty Acids 82, 295–303 (2010).

    CAS  PubMed  Google Scholar 

  88. Orr, S. K. & Bazinet, R. P. The emerging role of docosahexaenoic acid in neuroinflammation. Curr. Opin. Investigat. Drugs 9, 735–743 (2008).

    CAS  Google Scholar 

  89. Mingam, R. et al. Uncoupling of interleukin-6 from its signalling pathway by dietary n-3-polyunsaturated fatty acid deprivation alters sickness behaviour in mice. Eur. J. Neurosci. 28, 1877–1886 (2008).

    PubMed  PubMed Central  Google Scholar 

  90. Delpech, J. C. et al. Transgenic increase in n-3/n-6 fatty acid ratio protects against cognitive deficits induced by an immune challenge through decrease of neuroinflammation. Neuropsychopharmacology http://dx.doi.org/10.1038/npp.2014.196 (2014).

  91. Lalancette-Hebert, M. et al. Accumulation of dietary docosahexaenoic acid in the brain attenuates acute immune response and development of postischemic neuronal damage. Stroke; J. Cerebral Circul. 42, 2903–2909 (2011).

    CAS  Google Scholar 

  92. Huang, W. L. et al. A combination of intravenous and dietary docosahexaenoic acid significantly improves outcome after spinal cord injury. Brain: J. Neurol. 130, 3004–3019 (2007).

    CAS  Google Scholar 

  93. Minogue, A. M., Lynch, A. M., Loane, D. J., Herron, C. E. & Lynch, M. A. Modulation of amyloid-β-induced and age-associated changes in rat hippocampus by eicosapentaenoic acid. J. Neurochem. 103, 914–926 (2007).

    CAS  PubMed  Google Scholar 

  94. Song, C., Phillips, A. G., Leonard, B. E. & Horrobin, D. F. Ethyl-eicosapentaenoic acid ingestion prevents corticosterone-mediated memory impairment induced by central administration of interleukin-1β in rats. Mol. Psychiatry 9, 630–638 (2004).

    CAS  PubMed  Google Scholar 

  95. Lynch, A. M. et al. Eicosapentaenoic acid confers neuroprotection in the amyloid-β challenged aged hippocampus. Neurobiol. Aging 28, 845–855 (2007).

    CAS  PubMed  Google Scholar 

  96. Martin, D. S. et al. Apoptotic changes in the aged brain are triggered by interleukin-1β-induced activation of p38 and reversed by treatment with eicosapentaenoic acid. J. Biol. Chem. 277, 34239–34246 (2002).

    CAS  PubMed  Google Scholar 

  97. Labrousse, V. F. et al. Short-term long chain ω3 diet protects from neuroinflammatory processes and memory impairment in aged mice. PLoS ONE 7, e36861 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. De Smedt-Peyrusse, V. et al. Docosahexaenoic acid prevents lipopolysaccharide-induced cytokine production in microglial cells by inhibiting lipopolysaccharide receptor presentation but not its membrane subdomain localization. J. Neurochem. 105, 296–307 (2008).

    CAS  PubMed  Google Scholar 

  99. Figueroa, J. D. et al. Docosahexaenoic acid pretreatment confers protection and functional improvements after acute spinal cord injury in adult rats. J. Neurotrauma 29, 551–566 (2012).

    PubMed  PubMed Central  Google Scholar 

  100. Hjorth, E. et al. ω-3 fatty acids enhance phagocytosis of Alzheimer's disease-related amyloid-β42 by human microglia and decrease inflammatory markers. J. Alzheimers Dis. 35, 697–713 (2013).

    PubMed  Google Scholar 

  101. Madore, C. et al. Nutritional n-3 PUFAs deficiency during perinatal periods alters brain innate immune system and neuronal plasticity-associated genes. Brain Behav. Immun. 41, 22–31 (2014).

    CAS  PubMed  Google Scholar 

  102. Hein, A. M. & O'Banion, M. K. Neuroinflammation and memory: the role of prostaglandins. Mol. Neurobiol. 40, 15–32 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Choi, S. H., Aid, S., Choi, U. & Bosetti, F. Cyclooxygenases-1 and -2 differentially modulate leukocyte recruitment into the inflamed brain. Pharmacogenom. J. 10, 448–457 (2010).

    CAS  Google Scholar 

  104. Choi, S. H., Langenbach, R. & Bosetti, F. Cyclooxygenase-1 and -2 enzymes differentially regulate the brain upstream NF-κ B pathway and downstream enzymes involved in prostaglandin biosynthesis. J. Neurochem. 98, 801–811 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Aid, S., Langenbach, R. & Bosetti, F. Neuroinflammatory response to lipopolysaccharide is exacerbated in mice genetically deficient in cyclooxygenase-2. J. Neuroinflamm. 5, 17 (2008).

    Google Scholar 

  106. Samuelsson, B., Dahlen, S. E., Lindgren, J. A., Rouzer, C. A. & Serhan, C. N. Leukotrienes and lipoxins: structures, biosynthesis, and biological effects. Science 237, 1171–1176 (1987).

    CAS  PubMed  Google Scholar 

  107. Funk, C. D. Prostaglandins and leukotrienes: advances in eicosanoid biology. Science 294, 1871–1875 (2001).

    CAS  PubMed  Google Scholar 

  108. Hjorth, E. & Freund-Levi, Y. Immunomodulation of microglia by docosahexaenoic acid and eicosapentaenoic acid. Curr. Opin. Clin. Nutr. Metabol. Care 15, 134–143 (2012).

    CAS  Google Scholar 

  109. Lukiw, W. J. & Bazan, N. G. Inflammatory, apoptotic, and survival gene signaling in Alzheimer's disease. A review on the bioactivity of neuroprotectin D1 and apoptosis. Mol. Neurobiol. 42, 10–16 (2010).

    CAS  PubMed  Google Scholar 

  110. Pifferi, F. et al. (n-3) polyunsaturated fatty acid deficiency reduces the expression of both isoforms of the brain glucose transporter GLUT1 in rats. J. Nutr. 135, 2241–2246 (2005).

    CAS  PubMed  Google Scholar 

  111. Pifferi, F. et al. n-3 Fatty acids modulate brain glucose transport in endothelial cells of the blood-brain barrier. Prostaglandins Leukotrienes, Essent. Fatty Acids 77, 279–286 (2007).

    CAS  Google Scholar 

  112. Green, J. T., Liu, Z. & Bazinet, R. P. Brain phospholipid arachidonic acid half-lives are not altered following 15 weeks of N-3 polyunsaturated fatty acid adequate or deprived diet. J. Lipid Res. 51, 535–543 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Igarashi, M., Kim, H. W., Chang, L., Ma, K. & Rapoport, S. I. Dietary n-6 polyunsaturated fatty acid deprivation increases docosahexaenoic acid metabolism in rat brain. J. Neurochem. 120, 985–997 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Rao, J. S. et al. Dietary n-3 PUFA deprivation alters expression of enzymes of the arachidonic and docosahexaenoic acid cascades in rat frontal cortex. Mol. Psychiatry 12, 151–157 (2007).

    CAS  PubMed  Google Scholar 

  115. DeMar, J. C. Jr, Ma, K., Bell, J. M. & Rapoport, S. I. Half-lives of docosahexaenoic acid in rat brain phospholipids are prolonged by 15 weeks of nutritional deprivation of n-3 polyunsaturated fatty acids. J. Neurochem. 91, 1125–1137 (2004).

    CAS  PubMed  Google Scholar 

  116. Stark, K. D., Lim, S. Y. & Salem, N. Jr. Artificial rearing with docosahexaenoic acid and n-6 docosapentaenoic acid alters rat tissue fatty acid composition. J. Lipid Res. 48, 2471–2477 (2007).

    CAS  PubMed  Google Scholar 

  117. Lim, S. Y., Hoshiba, J. & Salem, N. Jr. An extraordinary degree of structural specificity is required in neural phospholipids for optimal brain function: n-6 docosapentaenoic acid substitution for docosahexaenoic acid leads to a loss in spatial task performance. J. Neurochem. 95, 848–857 (2005).

    CAS  PubMed  Google Scholar 

  118. Cunnane, S. C. et al. Fish, docosahexaenoic acid and Alzheimer's disease. Progress Lipid Res. 48, 239–256 (2009).

    CAS  Google Scholar 

  119. McNamara, R. K. et al. Selective deficits in the ω-3 fatty acid docosahexaenoic acid in the postmortem orbitofrontal cortex of patients with major depressive disorder. Biol. Psychiatry 62, 17–24 (2007).

    CAS  PubMed  Google Scholar 

  120. McNamara, R. K. et al. Deficits in docosahexaenoic acid and associated elevations in the metabolism of arachidonic acid and saturated fatty acids in the postmortem orbitofrontal cortex of patients with bipolar disorder. Psychiatry Res. 160, 285–299 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Di Paolo, G. & Kim, T. W. Linking lipids to Alzheimer's disease: cholesterol and beyond. Nature Rev. Neurosci. 12, 284–296 (2011).

    CAS  Google Scholar 

  122. Lin, P. Y., Huang, S. Y. & Su, K. P. A meta-analytic review of polyunsaturated fatty acid compositions in patients with depression. Biol. Psychiatry 68, 140–147 (2010).

    CAS  PubMed  Google Scholar 

  123. McNamara, R. K. et al. Lower docosahexaenoic acid concentrations in the postmortem prefrontal cortex of adult depressed suicide victims compared with controls without cardiovascular disease. J. Psychiatr. Res. 47, 1187–1191 (2013).

    PubMed  PubMed Central  Google Scholar 

  124. Igarashi, M. et al. Brain lipid concentrations in bipolar disorder. J. Psychiatr. Res. 44, 177–182 (2010).

    PubMed  Google Scholar 

  125. McNamara, R. K. Long-chain ω-3 fatty acid deficiency in mood disorders: rationale for treatment and prevention. Curr. Drug Discov. Technol. 10, 233–244 (2013).

    CAS  PubMed  Google Scholar 

  126. Su, K. P. et al. Phospholipase A2 and cyclooxygenase 2 genes influence the risk of interferon-α-induced depression by regulating polyunsaturated fatty acids levels. Biol. Psychiatry 67, 550–557 (2010).

    CAS  PubMed  Google Scholar 

  127. Appleton, K. M., Rogers, P. J. & Ness, A. R. Updated systematic review and meta-analysis of the effects of n-3 long-chain polyunsaturated fatty acids on depressed mood. Am. J. Clin. Nutr. 91, 757–770 (2010).

    CAS  PubMed  Google Scholar 

  128. Sublette, M. E., Ellis, S. P., Geant, A. L. & Mann, J. J. Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression. J. Clin. Psychiatry 72, 1577–1584 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Lin, P. Y. & Su, K. P. A meta-analytic review of double-blind, placebo-controlled trials of antidepressant efficacy of ω-3 fatty acids. J. Clin. Psychiatry 68, 1056–1061 (2007).

    CAS  PubMed  Google Scholar 

  130. Martins, J. G. EPA but not DHA appears to be responsible for the efficacy of ω-3 long chain polyunsaturated fatty acid supplementation in depression: evidence from a meta-analysis of randomized controlled trials. J. Am. College Nutr. 28, 525–542 (2009).

    CAS  Google Scholar 

  131. Bloch, M. H. & Hannestad, J. ω-3 fatty acids for the treatment of depression: systematic review and meta-analysis. Mol. Psychiatry 17, 1272–1282 (2012).

    CAS  PubMed  Google Scholar 

  132. DeMar, J. C. Jr et al. One generation of n-3 polyunsaturated fatty acid deprivation increases depression and aggression test scores in rats. J. Lipid Res. 47, 172–180 (2006).

    CAS  PubMed  Google Scholar 

  133. Chalon, S. ω-3 fatty acids and monoamine neurotransmission. Prostaglandins Leukot Essent. Fatty Acids 75, 259–269 (2006).

    CAS  PubMed  Google Scholar 

  134. de la Presa Owens, S. & Innis, S. M. Docosahexaenoic and arachidonic acid prevent a decrease in dopaminergic and serotoninergic neurotransmitters in frontal cortex caused by a linoleic and α-linolenic acid deficient diet in formula-fed piglets. J. Nutr. 129, 2088–2093 (1999).

    CAS  PubMed  Google Scholar 

  135. Kodas, E. et al. Serotoninergic neurotransmission is affected by n-3 polyunsaturated fatty acids in the rat. J. Neurochem. 89, 695–702 (2004).

    CAS  PubMed  Google Scholar 

  136. Bondi, C. O. et al. Adolescent behavior and dopamine availability are uniquely sensitive to dietary ω-3 fatty acid deficiency. Biol. Psychiatry 75, 38–46 (2013).

    PubMed  Google Scholar 

  137. Mocking, R. J. et al. Relationship between the hypothalamic-pituitary-adrenal-axis and fatty acid metabolism in recurrent depression. Psychoneuroendocrinology 38, 1607–1617 (2013).

    CAS  PubMed  Google Scholar 

  138. Kiecolt-Glaser, J. K., Belury, M. A., Andridge, R., Malarkey, W. B. & Glaser, R. ω-3 supplementation lowers inflammation and anxiety in medical students: a randomized controlled trial. Brain Behav. Immun. 25, 1725–1734 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Delarue, J. et al. Fish oil prevents the adrenal activation elicited by mental stress in healthy men. Diabetes Metab. 29, 289–295 (2003).

    CAS  PubMed  Google Scholar 

  140. Michaeli, B., Berger, M. M., Revelly, J. P., Tappy, L. & Chiolero, R. Effects of fish oil on the neuro-endocrine responses to an endotoxin challenge in healthy volunteers. Clin. Nutr. 26, 70–77 (2007).

    CAS  PubMed  Google Scholar 

  141. Levant, B. et al. Decreased brain docosahexaenoic acid content produces neurobiological effects associated with depression: Interactions with reproductive status in female rats. Psychoneuroendocrinology 33, 1279–1292 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Ferraz, A. C. et al. Chronic ω-3 fatty acids supplementation promotes beneficial effects on anxiety, cognitive and depressive-like behaviors in rats subjected to a restraint stress protocol. Behav. Brain Res. 219, 116–122 (2011).

    CAS  PubMed  Google Scholar 

  143. Larrieu, T. et al. Hypothalamo-pituitary-adrenal axis mediates n-3 polyunsaturated fatty acids deficient-diet induced depressive- and anxiety-like symptoms along with neuronal atrophy. Transl. Psychiatry 4, e437 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Song, C., Zhang, X. Y. & Manku, M. Increased phospholipase A2 activity and inflammatory response but decreased nerve growth factor expression in the olfactory bulbectomized rat model of depression: effects of chronic ethyl-eicosapentaenoate treatment. J. Neurosci. 29, 14–22 (2009).

    PubMed  PubMed Central  Google Scholar 

  145. Joffre, C., Nadjar, A., Lebbadi, M., Calon, F. & Laye, S. n-3 LCPUFA improves cognition: The young, the old and the sick. Prostaglandins Leukot Essent. Fatty Acids 91, 1–20 (2014).

    CAS  PubMed  Google Scholar 

  146. Ramakrishnan, U., Imhoff-Kunsch, B. & DiGirolamo, A. M. Role of docosahexaenoic acid in maternal and child mental health. Am. J. Clin. Nutr. 89, 958S–962S (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Young, G. S., Maharaj, N. J. & Conquer, J. A. Blood phospholipid fatty acid analysis of adults with and without attention deficit/hyperactivity disorder. Lipids 39, 117–123 (2004).

    CAS  PubMed  Google Scholar 

  148. Frensham, L. J., Bryan, J. & Parletta, N. Influences of micronutrient and ω-3 fatty acid supplementation on cognition, learning, and behavior: methodological considerations and implications for children and adolescents in developed societies. Nutr. Rev. 70, 594–610 (2012).

    PubMed  Google Scholar 

  149. Montgomery, P., Burton, J. R., Sewell, R. P., Spreckelsen, T. F. & Richardson, A. J. Low blood long chain ω-3 fatty acids in UK children are associated with poor cognitive performance and behavior: a cross-sectional analysis from the DOLAB study. PloS one 8, e66697 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Kuratko, C. N., Barrett, E. C., Nelson, E. B. & Salem, N. Jr. The relationship of docosahexaenoic acid (DHA) with learning and behavior in healthy children: a review. Nutrients 5, 2777–2810 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Moranis, A. et al. Long term adequate n-3 polyunsaturated fatty acid diet protects from depressive-like behavior but not from working memory disruption and brain cytokine expression in aged mice. Brain Behav. Immun. 26, 721–731 (2012).

    CAS  PubMed  Google Scholar 

  152. Fedorova, I. et al. An n-3 fatty acid deficient diet affects mouse spatial learning in the Barnes circular maze. Prostaglandins Leukot Essent. Fatty Acids 77, 269–277 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Connor, S., Tenorio, G., Clandinin, M. T. & Sauve, Y. DHA supplementation enhances high-frequency, stimulation-induced synaptic transmission in mouse hippocampus. Appl. Physiol. Nutr. Metab. 37, 880–887 (2012).

    CAS  PubMed  Google Scholar 

  154. Kavraal, S. et al. Maternal intake of ω-3 essential fatty acids improves long term potentiation in the dentate gyrus and Morris water maze performance in rats. Brain Res. 1482, 32–39 (2012).

    CAS  PubMed  Google Scholar 

  155. Cunnane, S. C., Chouinard-Watkins, R., Castellano, C. A. & Barberger-Gateau, P. Docosahexaenoic acid homeostasis, brain aging and Alzheimer's disease: Can we reconcile the evidence? Prostaglandins Leukot Essent. Fatty Acids 88, 61–70 (2013).

    CAS  PubMed  Google Scholar 

  156. Igarashi, M. et al. Disturbed choline plasmalogen and phospholipid fatty acid concentrations in Alzheimer's disease prefrontal cortex. J. Alz. Dis. 24, 507–517 (2011).

    CAS  Google Scholar 

  157. Samieri, C. et al. ω-3 fatty acids and cognitive decline: modulation by ApoEepsilon4 allele and depression. Neurobiol. Aging 32, 2317.e13-22 (2011).

    PubMed  Google Scholar 

  158. Tan, Z. S. et al. Red blood cell ω-3 fatty acid levels and markers of accelerated brain aging. Neurology 78, 658–664 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Samieri, C. et al. Plasma long-chain ω-3 fatty acids and atrophy of the medial temporal lobe. Neurology 79, 642–650 (2012).

    CAS  PubMed  Google Scholar 

  160. Ronnemaa, E. et al. Serum fatty-acid composition and the risk of Alzheimer's disease: a longitudinal population-based study. Eur. J. Clin. Nutr. 66, 885–890 (2012).

    CAS  PubMed  Google Scholar 

  161. Quinn, J. F. et al. Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: a randomized trial. JAMA 304, 1903–1911 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Feart, C. et al. Plasma eicosapentaenoic acid is inversely associated with severity of depressive symptomatology in the elderly: data from the Bordeaux sample of the Three-City Study. Am. J. Clin. Nutr. 87, 1156–1162 (2008).

    CAS  PubMed  Google Scholar 

  163. Mazereeuw, G., Lanctot, K. L., Chau, S. A., Swardfager, W. & Herrmann, N. Effects of ω-3 fatty acids on cognitive performance: a meta-analysis. Neurobiol. Aging 33, e17–29 (2012).

    Google Scholar 

  164. Freund-Levi, Y. et al. ω-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: ωD study: a randomized double-blind trial. Arch. Neurol. 63, 1402–1408 (2006).

    PubMed  Google Scholar 

  165. Huang, T. L. et al. Benefits of fatty fish on dementia risk are stronger for those without APOE ε4. Neurology 65, 1409–1414 (2005).

    CAS  PubMed  Google Scholar 

  166. Plourde, M. et al. Plasma n-3 fatty acid response to an n-3 fatty acid supplement is modulated by apoE epsilon4 but not by the common PPAR-α L162V polymorphism in men. Br. J. Nutr. 102, 1121–1124 (2009).

    CAS  PubMed  Google Scholar 

  167. Vandal, M. et al. Reduction in DHA transport to the brain of mice expressing human APOE4 compared to APOE2. J. Neurochem. 129, 516–526 (2014). This paper connects the Alzheimer's risk factor APOE4 to decreased uptake of DHA in the brain.

    CAS  PubMed  Google Scholar 

  168. Lim, G. P. et al. A diet enriched with the ω-3 fatty acid docosahexaenoic acid reduces amyloid burden in an aged Alzheimer mouse model. J. Neurosci. 25, 3032–3040 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Green, K. N. et al. Dietary docosahexaenoic acid and docosapentaenoic acid ameliorate amyloid-β and tau pathology via a mechanism involving presenilin 1 levels. J. Neurosci. 27, 4385–4395 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Zhao, Y. et al. Docosahexaenoic acid-derived neuroprotectin D1 induces neuronal survival via secretase- and PPARgamma-mediated mechanisms in Alzheimer's disease models. PloS one 6, e15816 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Calon, F. & Cole, G. Neuroprotective action of ω-3 polyunsaturated fatty acids against neurodegenerative diseases: evidence from animal studies. Prostaglandins Leukot. Essent. Fatty Acids 77, 287–293 (2007).

    CAS  PubMed  Google Scholar 

  172. Frautschy, S. A. & Cole, G. M. What was lost in translation in the DHA trial is whom you should intend to treat. Alzheimer Res. Ther. 3, 2 (2011).

    Google Scholar 

  173. Evans, D. R. et al. Red blood cell membrane essential fatty acid metabolism in early psychotic patients following antipsychotic drug treatment. Prostaglandins Leukot Essent. Fatty Acids 69, 393–399 (2003).

    CAS  PubMed  Google Scholar 

  174. Sethom, M. M. et al. Polyunsaturated fatty acids deficits are associated with psychotic state and negative symptoms in patients with schizophrenia. Prostaglandins Leukot Essent. Fatty Acids 83, 131–136 (2010).

    CAS  PubMed  Google Scholar 

  175. Hamazaki, K., Hamazaki, T. & Inadera, H. Abnormalities in the fatty acid composition of the postmortem entorhinal cortex of patients with schizophrenia, bipolar disorder, and major depressive disorder. Psychiatry Res. 210, 346–350 (2013).

    CAS  PubMed  Google Scholar 

  176. Taha, A. Y., Cheon, Y., Ma, K., Rapoport, S. I. & Rao, J. S. Altered fatty acid concentrations in prefrontal cortex of schizophrenic patients. J. Psychiatr. Res. 47, 636–643 (2013).

    PubMed  PubMed Central  Google Scholar 

  177. McNamara, R. K. et al. Abnormalities in the fatty acid composition of the postmortem orbitofrontal cortex of schizophrenic patients: gender differences and partial normalization with antipsychotic medications. Schizophr. Res. 91, 37–50 (2007).

    PubMed  PubMed Central  Google Scholar 

  178. Liu, Y., Jandacek, R., Rider, T., Tso, P. & McNamara, R. K. Elevated delta-6 desaturase (FADS2) expression in the postmortem prefrontal cortex of schizophrenic patients: relationship with fatty acid composition. Schizophr. Res. 109, 113–120 (2009).

    PubMed  Google Scholar 

  179. Watanabe, A. et al. Fabp7 maps to a quantitative trait locus for a schizophrenia endophenotype. PLoS Biol. 5, e297 (2007).

    PubMed  PubMed Central  Google Scholar 

  180. Amminger, G. P. et al. Long-chain ω-3 fatty acids for indicated prevention of psychotic disorders: a randomized, placebo-controlled trial. Arch. Gen. Psychiatry 67, 146–154 (2010).

    CAS  PubMed  Google Scholar 

  181. Wymann, M. P. & Schneiter, R. Lipid signalling in disease. Nature Rev. Mol. Cell Biol. 9, 162–176 (2008).

    CAS  Google Scholar 

  182. Nery, F. G. et al. Celecoxib as an adjunct in the treatment of depressive or mixed episodes of bipolar disorder: a double-blind, randomized, placebo-controlled study. Hum. Psychopharmacol. 23, 87–94 (2008).

    CAS  PubMed  Google Scholar 

  183. Kim, H. W., Rapoport, S. I. & Rao, J. S. Altered arachidonic acid cascade enzymes in postmortem brain from bipolar disorder patients. Mol. Psychiatry 16, 419–428 (2011).

    CAS  PubMed  Google Scholar 

  184. Kushner, S. F., Khan, A., Lane, R. & Olson, W. H. Topiramate monotherapy in the management of acute mania: results of four double-blind placebo-controlled trials. Bipolar Disord. 8, 15–27 (2006).

    CAS  PubMed  Google Scholar 

  185. Musto, A. E., Gjorstrup, P. & Bazan, N. G. The ω-3 fatty acid-derived neuroprotectin D1 limits hippocampal hyperexcitability and seizure susceptibility in kindling epileptogenesis. Epilepsia 52, 1601–1608 (2011).

    CAS  PubMed  Google Scholar 

  186. Taha, A. Y. et al. A minimum of 3 months of dietary fish oil supplementation is required to raise amygdaloid afterdischarge seizure thresholds in rats—implications for treating complex partial seizures. Epilepsy Behav. 27, 49–58 (2013).

    PubMed  Google Scholar 

  187. Trepanier, M. O. et al. Increases in seizure latencies induced by subcutaneous docosahexaenoic acid are lost at higher doses. Epilepsy Res. 99, 225–232 (2012).

    CAS  PubMed  Google Scholar 

  188. Chauveau, F. et al. Brain-targeting form of docosahexaenoic acid for experimental stroke treatment: MRI evaluation and anti-oxidant impact. Curr. Neurovascular Res. 8, 95–102 (2011). A novel example of how to target the brain with DHA in brain injury.

    CAS  Google Scholar 

  189. King, V. R. et al. ω-3 fatty acids improve recovery, whereas ω-6 fatty acids worsen outcome, after spinal cord injury in the adult rat. J. Neurosci. 26, 4672–4680 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Picq, M. et al. DHA metabolism: targeting the brain and lipoxygenation. Mol. Neurobiol. 42, 48–51 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Fischer, R. et al. Dietary ω-3 fatty acids modulate the eicosanoid profile in man primarily via the CYP-epoxygenase pathway. J. Lipid Res. 55, 1150–1164 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. Topol, E. J. et al. Rimonabant for prevention of cardiovascular events (CRESCENDO): a randomised, multicentre, placebo-controlled trial. Lancet 376, 517–523 (2010).

    CAS  PubMed  Google Scholar 

  193. Cunnane, S. C., Francescutti, V., Brenna, J. T. & Crawford, M. A. Breast-fed infants achieve a higher rate of brain and whole body docosahexaenoate accumulation than formula-fed infants not consuming dietary docosahexaenoate. Lipids 35, 105–111 (2000).

    CAS  PubMed  Google Scholar 

  194. Holman, R. T., Johnson, S. B. & Hatch, T. F. A case of human linolenic acid deficiency involving neurological abnormalities. Am. J. Clin. Nutr. 35, 617–623 (1982).

    CAS  PubMed  Google Scholar 

  195. Scott, B. L. & Bazan, N. G. Membrane docosahexaenoate is supplied to the developing brain and retina by the liver. Proc. Natl Acad. Sci. USA 86, 2903–2907 (1989).

    CAS  PubMed  Google Scholar 

  196. Domenichiello, A. F., Chen, C. T., Trepanier, M. O., Stavro, P. M. & Bazinet, R. P. Whole body synthesis rates of DHA from α-linolenic acid are greater than brain DHA accretion and uptake rates in adult rats. J. Lipid Res. 55, 62–74 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. McCloy, U., Ryan, M. A., Pencharz, P. B., Ross, R. J. & Cunnane, S. C. A comparison of the metabolism of eighteen-carbon 13C-unsaturated fatty acids in healthy women. J. Lipid Res. 45, 474–485 (2004).

    CAS  PubMed  Google Scholar 

  198. Lefkowitz, W., Lim, S. Y., Lin, Y. & Salem, N. Jr. Where does the developing brain obtain its docosahexaenoic acid? Relative contributions of dietary α-linolenic acid, docosahexaenoic acid, and body stores in the developing rat. Pediatr. Res. 57, 157–165 (2005).

    CAS  PubMed  Google Scholar 

  199. Greiner, R. C., Winter, J., Nathanielsz, P. W. & Brenna, J. T. Brain docosahexaenoate accretion in fetal baboons: bioequivalence of dietary α-linolenic and docosahexaenoic acids. Pediatr. Res. 42, 826–834 (1997).

    CAS  PubMed  Google Scholar 

  200. Barden, A., Mas, E., Croft, K. D., Phillips, M. & Mori, T. A. Short-term n-3 fatty acid supplementation but not aspirin increases plasma proresolving mediators of inflammation. J. Lipid. Res. 55, 2401–2407 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors apologize to those whose valuable work was not cited owing to space limitations. R.P.B. acknowledges funding from the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council of Canada and holds a Canada Research Chair in Brain Lipid Metabolism. S.L. is supported by Institut National de la Recherche Agronomique (INRA), Bordeaux University, Région Aquitaine and Agence Nationale de la Recherche (ANR).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Richard P. Bazinet.

Ethics declarations

Competing interests

R.P.B. has received grants from Bunge Ltd and the International Life Sciences Institute for studies related to fatty acids and the brain.

PowerPoint slides

Glossary

Accretion

Gradual accumulation.

Paresthesias

Sensations of tingling, tickling, prickling or burning of a person's skin.

Lands cycle

The process of deacylation and reacylation of fatty acids, sometimes referred to as recycling within membrane phospholipids. The pathway was discovered by William Lands.

Mediators

Derivatives of a fatty acid that are bioactive. The term lipid mediator is distinct from derivative as it implies that the molecule is bioactive.

Specialized pro-resolving mediators

Mediators that promote pro-resolution, which is an active process involving several lipids that turns off pro-inflammatory signalling and promotes the clearance of leukocytes and cellular debris, thereby returning the tissue to homeostasis.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Bazinet, R., Layé, S. Polyunsaturated fatty acids and their metabolites in brain function and disease. Nat Rev Neurosci 15, 771–785 (2014). https://doi.org/10.1038/nrn3820

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn3820

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing