Essential fatty acids are structural components of all tissues and are indispensable for cell membrane synthesis; the brain, retina and other neural tissues are particularly rich in long-chain polyunsaturated fatty acids (LC-PUFA). These fatty acids serve as specific precursors for eicosanoids, which regulate numerous cell and organ functions. Recent human studies support the essential nature of n-3 fatty acids in addition to the well-established role of n−6 essential fatty acids in humans, particularly in early life. The main findings are that light sensitivity of retinal rod photoreceptors is significantly reduced in newborns with n−3 fatty acid deficiency, and that docosahexaenoic acid (DHA) significantly enhances visual acuity maturation and cognitive functions. DHA is a conditionally essential nutrient for adequate neurodevelopment in humans. Comprehensive clinical studies have shown that dietary supplementation with marine oil or single-cell oil sources of LC-PUFA results in increased blood levels of DHA and arachidonic acid, as well as an associated improvement in visual function in formula-fed infants matching that of human breast-fed infants. The effect is mediated not only by the known effects on membrane biophysical properties, neurotransmitter content, and the corresponding electrophysiological correlates but also by a modulating gene expression of the developing retina and brain. Intracellular fatty acids or their metabolites regulate transcriptional activation of gene expression during adipocyte differentiation and retinal and nervous system development. Regulation of gene expression by LC-PUFA occurs at the transcriptional level and may be mediated by nuclear transcription factors activated by fatty acids. These nuclear receptors are part of the family of steroid hormone receptors. DHA also has significant effects on photoreceptor membranes and neurotransmitters involved in the signal transduction process; rhodopsin activation, rod and cone development, neuronal dendritic connectivity, and functional maturation of the central nervous system.
This is a preview of subscription content, access via your institution.
arachidonic acid (20∶4n−6)
auditory brainstemevoked response
α-linolenic acid (18∶3n−3)
central nervous system
docosahexaenoic acid (22∶6n−3)
essential fatty acid
forced-choice preferential looking
γ-linolenic acid (18∶3n−6)
linoleic acid (18∶2n−6)
long-chain polyunsaturated fatty acids
- M II:
Mental Development Index
peroxisome proliferator-activated receptor
polyunsaturated fatty acid
red blood cell
retinoic acid receptor
Dobbing, J., Hopewell, J.W., and Lynch, A. (1971) Vulnerability of Developing Brain. VII. Permanent Deficit of Neurons in Cerebral and Cerebellar Cortex Following Early Mild Undernutrition, Exp. Neurol. 32, 439–447.
Pollitt, E. (1988) A Critical View of Three Decades of Research on the Effects of Chronic Energy Undernutrition on Behavioral Development, in Chronic Energy Deficiency, (Schurch, B., and Scrimshaw, N., eds.), IDECG, Lausanne Switzerland.
Fagioli, I., Peirano, P., Bes, F., and Salzarulo, P. (1989) Sleep in Early Human Malnutrition, in Sleep '88, (Horne, J.A., ed.), pp. 58–62, Gustav Fischer Verlag, Stuttgart.
Spassov, L., Curzi-Dascalova, L., Clairambault, J., Kauffmann, F., Eiselt, M., Médigue, C., and Peirano, P. (1994) Heart Rate and Heart Rate Variability During Sleep in Small-for-Gestational Age Newborns, Pediatr. Res. 35, 500–505.
Grantham-McGregor, S. (1995) A Review of Studies of the Effect of Severe Malnutrition on Mental Development, J. Nutr. 125, 2233S-2238S.
Uauy, R., Birch, D.G., Birch, E.E., Tyson, J.E., and Hoffman, D.R. (1990) Effect of Dietary Omega-3 Fatty Acids on Retinal Function of Very Low Birth Weight Neonates, Pediatr. Res. 28, 485–492.
Birch, E.E., Birch, D.G., and Hoffman, D.R. (1992) Retinal Development in Very Low Birth Weight Infants Fed Diets Differing in Omega-3 Fatty Acids, Invest. Ophthalmol. Vis. Sci. 33, 2365–2376.
Birch, E.E., Birch, D.G., Hoffman, D.R., and Uauy, R.D. (1992) Dietary Essential Fatty Acid Supply and Visual Acuity Development, Invest. Ophthalmol. Vis. Sci. 33, 3242–3253.
Carlson, S.E., Werkman, S.H., Rhodes, P.G., and Tolley, E.A. (1993) Visual-Acuity Development in Healthy Preterm Infants: Effect of Marine-Oil Supplementation, Am. J. Clin. Nutr. 58, 35–42.
Carlson, S.E., Werkman, S.H., Peeples, J.M., and Wilson, W.M., III (1994) Growth and Development of Premature Infants in Relation to ω-3 and ω-6 Fatty Acid Status, World Rev. Nutr. Diet. 75, 63–69.
Carlson, S.E., and Werkman, S.H. (1996) A Randomized Trial of Visual Attention of Preterm Infants Fed Docosahexaenoic Acid Until Two Months, Lipids 31, 85–91.
Werkman, S.H., and Carlson, S.E. (1996) A Randomized Trial of Visual Attention of Preterm Infants Fed Docosahexaenoic Acid Until Nine Months, Lipids 31, 91–97.
Carlson, S.E., Werkman, S.H., and Tolley, E.A. (1996) Effect of Long Chain n−3 Fatty Acid Supplementation on Visual Acuity and Growth of Preterm Infants With and Without Bronchopulmonary Dysplasia, Am. J. Clin. Nutr. 63, 687–697.
Faldella, G., Govoni, M., Alessandroni, R., Marchiani, E., Salvioli, G.P., Biagi, P.L., and Spano, C. (1996) Visual Evoked Potentials and Dietary Long Chain Polyunsaturated Fatty Acids in Preterm Infants, Arch. Dis. Child. 75, F108-F112.
O'Connor, D.L., Hall, R., Adamkin, D., Auestad, N., Castillo, M., Connor, W.E., Connor, S.L., Fitzgerald, K., Groh-Wargo, S., Hartmann, E.E., et al. (2001) Growth and Development in Preterm Infants Fed Long-Chain Polyunsaturated Fatty Acids: A Prospective, Randomized Control Trial, Pediatrics 108, 359–371.
Birch, E., Birch, D., Hoffman, D., Hale, L., Everett, M., and Uauy, R. (1993) Breast-Feeding and Optimal Visual Development, J. Pediatr. Ophthalmol. Strabismus 30, 33–38.
Bjerve, K.S., Brubakk, A.M., Fougner, K.J., Johnsen, H., Midthjell, K., and Vik, T. (1993) Omega-3 Fatty Acids: Essential Fatty Acids with Important Biological Effects, and Serum Phospholipid Fatty Acids as Markers of Dietary Omega-3 Fatty Acid Intake, Am. J. Clin. Nutr. 57, 801S-806S.
Makrides, M., Simmer, K., Goggin, M., and Gibson, R.A. (1993) Erythrocyte Docosahexaenoic Acid Correlates with the Visual Response of Healthy, Term Infants, Pediatr. Res. 34, 425–427.
Courage, M.L., McCloy, U.R., Herzberg, G.R., Andrews, W.L., Simmons, B.S., McDonald, A.C., Mercer, C.N., and Friel, J.K. (1998) Visual Acuity Development and Fatty Acid Composition of Erythrocytes in Full-Term Infants Fed Breast Milk, Commercial Formula, or Evaporated Milk, J. Dev. Behav. Pediatr. 19, 9–17.
Jorgensen, M.H., Hernell, O., Lund, P., Holmer, G., and Michaelsen, K.F. (1996) Visual Acuity and Erythrocyte Docosahexaenoic Acid Status in Breast-Fed and Formula-Fed Term Infants During the First Four Months of Life, Lipids 31, 99–105.
Innis, S., Nelson, C., Lwanga, D., Rioux, F.M., and Waslen, P. (1996) Feeding Formula Without Arachidonic Acid and Docosahexaenoic Acid Has No Effect on Preferential Looking Acuity or Recognition Memory in Healthy Full-Term Infants at 9 Months of Age, Am. J. Clin. Nutr. 64, 40–46.
Innis, S.M., Nelson, C.M., Rioux, M.F., and King, D.J. (1994) Development of Visual Acuity in Relation to Plasma and Erythrocyte ω-6 and ω-3 Fatty Acids in Healthy Term Gestation Infants, Am. J. Clin. Nutr. 60, 347–352.
Innis, S.M., Akrabawi, S., Diersen-Schade, D., Dobson, M.V., and Guy, D.G. (1997) Visual Acuity and Blood Lipids in Term Infants Fed Human Milk or Formulae, Lipids 32, 63–72.
Jensen, C., Prager, T., Fraley, J., Chen, H., Anderson, R., and Heird, W. (1997) Functional Effects of Dietary Linoleic/Linolenic Acid Ratio in Term Infants, J. Pediatr. 130, 200–204.
Makrides, M., Neumann, M., Simmer, K., Pater, J., and Gibson, R. (1995) Are Long-Chain Polyunsaturated Fatty Acids Essential Nutrients in Infancy? Lancet 345, 1463–1468.
Carlson, S.E., Ford, A.J., Werkman, S.H., Peeples, J.M., and Koo, W.W. (1996) Visual Acuity and Fatty Acid Status of Term Infants Fed Human Milk and Formulas With and Without Docosahexaenoate and Arachidonate from Egg Yolk Lecithin, Pediatr. Res. 39, 882–888.
Jorgensen, H.M., Holmer, G., Lund, P., Hernell, O., and Michaelsen, K.F. (1998) Effect of Formula Supplemented with Docosahexaenoic Acid and Gamma-Linolenic Acid on Fatty Acid Status and Visual Acuity in Term Infants, J. Pediatr. Gastroenterol. Nutr. 26, 412–421.
Auestad, N., Montalto, M., Hill, R., Fitzgerald, K.M., Wheeler, R.E., Connor, W.E., Neuringer, M., Connor, S.L., Taylor, J.A., and Hartmann, E.E. (1997) Visual Acuity, Erythrocyte Fatty Acid Composition, and Growth in Term Infants Fed Formulas with Long Chain Polyunsaturated Fatty Acid for One Year, Pediatr. Res. 41, 1–10.
Scott, D.T., Janowsky, J.S., Hall, R.T., Carroll, R.E., Taylor, J.A., Auestad, N., and Montalto, M.B. (1998) Formula Supplementation with Long-Chain Polyunsaturated Fatty Acids: Are There Developmental Benefits? Pediatrics 102, E59.
Agostoni, C., Trojan, S., Bellu, R., Riva, E., and Giovannini, M. (1995) Neurodevelopmental Quotient of Healthy Term Infants at 4 Months and Feeding Practice: The Role of Long Chain Polyunsaturated Fatty Acids, Pediatr. Res. 38, 262–266.
Agostoni, C., Trojan, S., Bellu, R., Riva, E., Bruzzese, M.G., and Giovannini, M. (1997) Developmental Quotient at 24 Months and Fatty Acid Composition of Diet in Early Infancy: A Follow-Up Study, Arch. Dis. Child. 76, 421–424.
Gibson, R., Neumann, M., and Makrides, M. (1997) Effect of Increasing Breast Milk Docosahexaenoic Acid on Plasma and Erythrocyte Phospholipid Fatty Acids and Neural Indices of Exclusively Breast-Fed Infants, Eur. J. Clin. Nutr. 51, 578–584.
Birch, E.E., Hoffman, D.R., Uauy, R., Birch, D.G., and Prestidge, C. (1998) Visual Acuity and the Essentiality of Docosahexaenoic Acid and Arachidonic Acid in the Diet of Term Infants, Pediatr. Res. 44, 201–209.
Birch, E.E., Garfield, S., Hoffman, D.R., Uauy, R., and Birch, D.G. (2000) A Randomized Controlled Trial of Early Dietary Supply of Long-Chain Polyunsaturated Fatty Acids and Mental Development in Term Infants, Dev. Med. Child Neurol. 42, 174–181.
Forsyth, J.S., and Willatts, P. (1996) Do LC-PUFA Influence Infant Cognitive Behavior? in Recent Developments in Infant Nutrition (Bindles, J.G., Goedhart, A.C., and Visser, H.K., eds.), pp. 225–234, Kluwer Academic Publishers, London.
Willatts, P., Forsyth, J.S., DiModugno, M.K., Varma, S., and Colvin, M. (1998) Effect of Long Chain Polyunsaturated Fatty Acids in Infant Formula on Problem Solving at 10 Months of Age [comment], Lancet 352, 688–691.
Slater, A. (1995) Individual Differences in Infancy and Later IQ, J. Child Psychol. Psychiatry 36, 69–112.
Lucas, A., Stafford, M., Morley, R., Abbott, R., Stephenson, T., MacFayden, U., Elias-Jones, A., and Clements, H. (1999) Efficacy and Safety of Long-Chain Polyunsaturated Fatty Acid Supplementation of Infant-Formula Milk: A Randomised Trial, Lancet 354, 1948–1954.
Gibson, R. (1999) Long-Chain Polyunsaturated Fatty Acids and Infant Development, Lancet 354, 1919–1920.
Makrides, M., Neumann, A., Simmer, K., and Gibson, R.A. (2000) A Critical Appraisal of the Role of Dietary Long-Chain Polyunsaturated Fatty Acids on Neural Indices of Term Infants: A Randomized. Controlled Trial, Pediatrics 105, 32–38.
San Giovanni, J.P., Parra-Cabrera, S., Colditz, G.A., Berkey, C.S., and Dwyer, J.T. (2000) Meta-Analysis of Dietary Essential Fatty Acids and Long Chain Polyunsaturated Fatty Acids as They Relate to Visual Resolution Acuity in Healthy Preterm Infants, Pediatrics 105, 1292–1298.
San Giovanni, J.P., Berkey, C.S., Dwyer, J.T., and Colditz, G.A. (2000) Dietary Essential Fatty Acids, Long Chain Polyunsaturated Fatty Acids, and Visual Resolution Acuity in Healthy Fullterm Infants: A Systematic Review, Early Hum. Dev. 57, 165–188.
Cousins, R. (1994) Metal Elements and Gene Expression, Annu. Rev. Nutr. 14, 449–469.
Clarke, S.D., and Jump, D.D. (1994) Dietary Polyunsaturated Fatty Acid Regulation of Gene Transcription, Annu. Rev. Nutr. 14, 83–98.
Gottlicher, M., Demoz, A., Svenson, D., Tollet, P., Berge, R.K., and Gustaffson, J.A. (1993) Structural and Metabolic Requirements for Activators of the Peroxisome Proliferator-Activated Receptor, Biochem. Pharmacol. 46, 2177–2184.
Rotstein, N.P., Politi, L.E., and Aveldaño, M.I. (1998) Docosahexaenoic Acid Promotes Differentiation of Developing Photoreceptors in Culture, Invest. Ophthalmol. Vis. Sci. 39, 2750–2758.
Rodriguez de Turco, E.B., Deretic, D., Bazan, N.G., and Papermaster, D.S. (1997) Post Golgi Vesicles Cotransport Docosahexaenoyl Phospholipids and Rhodopsin During Frog Photoreceptor Membranes Biogenesis, J. Biol. Chem. 272, 10494–10497.
Dreyer, C., Keller, H., Mahfaudi, A., Laudet, V., Krey, G., and Wahli, W. (1993) Positive Regulation of the Peroxisomal Beta-Oxidation Pathway by Fatty Acids Through Activation of Peroxisome Proliferator-Activated Receptor (PPAR), Biol. Cell 77, 67–76.
Yu, K., Bayona, W., Kallen, C.B., Harding, H.P., Ravera, C.P., MacMahon, G., Brown, M., and Lazar, M.A. (1995) Differential Activation of Peroxisome Proliferator Activated Receptor by Eicosanoids, J. Biol. Chem. 270, 23975–23983.
Kersten, S., Desvergne, B., and Wahli, W. (2000) Roles of PPARs in Health and Disease, Nature 405, 421–424.
Wheeler, T., Benolken, R., and Anderson, R. (1997) Visual Membranes: Specificity of Fatty Acid Precursors for the Electrical Response to Illumination, Science 188, 1312–1314.
Stubbs, C., and Smith, A. (1984) The Modification of Mammalian Membrane Polyunsaturated Fatty Acid Composition in Relation to Membrane Fluidity and Function, Biochim. Biophys. Acta 779, 89–137.
Lee, A., East, J., and Froud, R. (1986) Are Essential Fatty Acids Essential for Membrane Function?, Prog. Lipid Res. 25, 41–46.
Treen, M., Uauy, R., Jameson, D., Thomas, V., and Hoffman, D. (1992) Effect of Docosahexaenoic Acid on Membrane Fluidity and Function in Intact Cultured Y-79 Retinoblastoma Cells, Arch. Biophys. 294, 564–570.
Lin, D., Connor, W., Anderson, G., and Neuringer, M. (1990) Effects of Dietary n−3 Fatty Acids on the Phospholipid Molecular Species of Monkey Brain, J. Neurochem. 55, 1200–1207.
Litman, B., and Mitchell, D. (1996) A Role for Phospholipid Polyunsaturation in Modulating Membrane Protein Function, Lipids 31, S193-S197.
Weidmann, T., Pates, R., Beach, J., Salmon, A., and Brown, M. (1988) Lipid-Protein Interactions Mediate the Photochemical Function of Rhodopsin, Biochemistry 27, 6469–6474.
Mitchell, D., Straume, M., and Litman, B. (1992) Role of sn-1-Saturated, sn-2-Polyunsaturated Phospholipids in Control of Membrane Receptor Conformational Equilibrium: Effects of Cholesterol and Acyl Chain Unsaturation on the Metarhodopsin I in Equilibrium with Metarhodopsin II, Biochemistry 31, 662–670.
Love, J., Saurn, W., and McGee, R. (1985) The Effects of Exposure to Exogenous Fatty Acids and Membrane Fatty Acid Modification on the Electrical Properties of NG108-15 Cells, Cell. Mol. Neurobiol. 5, 333–352.
Vreugdenhil, M., Bruehl, C., Voskuyl, R., Kang, J., Leaf, A., and Wadman, W. (1996) Polyunsaturated Fatty Acids Modulate Sodium and Calcium Currents in CA1 Neurons, Proc. Natl. Acad. Sci. USA 93, 12559–12563.
Weylandt, K., Kang, J., and Leaf, A. (1996) Polyunsaturated Fatty Acids Exert Anti-Arrhythmic Actions as Free Acids Rather than in Phospholipids, Lipids 31, 977–982.
Voskuyl, R., Vreugdenhil, M., Kang, J., and Leaf, A. (1998) Anticonvulsant Effect of Polyunsaturated Fatty Acids in Rats. Using the Cortical Stimulation Model, Eur. J. Pharmacol. 341, 145–152.
Farquharson, J., Cockburn, F., Patrick, W.A., Jamieson, E.C., and Logan, R.W. (1992) Infant Cerebral Cortex Phospholipid Fatty-Acid Composition and Diet, Lancet 340, 810–813.
Neuringer, M., Connor, W.E., Van Petten, C., and Barstad, L. (1984) Dietary Omega-3 Fatty Acid Deficiency and Visual Loss in Infant Rhesus Monkeys, J. Clin. Investig. 73, 272–276.
Hubel, D., and Wiesel, T. (1970) The Period of Susceptibility to the Physiological Effects of Unilateral Eye Closure in Kittens, J. Physiol. 206, 419–436.
Hubel, D.H., and Wiesel, T.N. (1977) Plasticity of Ocular Dominance Columns in Monkey Striate Cortex, Phil. Trans. R. Soc. Lond. B Biol. Sci. 278, 377–409.
Jameson, L., and Caplow, M. (1981) Modification of Microtubule Steady-State Dynamics by Phosphorylation of the Microtubule-Associated Proteins, Proc. Natl. Acad. Sci. USA 78, 3413–3417.
Aoki, C., and Siekevitz, P. (1985) Ontogenetic Changes in the Cyclic Adenosine 3′,5′-Monophosphate-Stimulatable Phosphorylation of Cat Visual Cortex Proteins, Particularly of Microtubule-Associated Protein 2 (MAP 2): Effects of Normal and Dark Rearing and of the Exposure to Light, J. Neurosci. 5, 2465–2483.
Bornstein, M.H. (1989) Sensitive Periods in Development: Structural Characteristics and Causal Interpretations, Psychol. Bull. 105, 179–197.
Blakemore, C. (1991) Sensitive and Vulnerable Periods in the Development of the Visual System, in The Childhood Environment and Adult Disease, (Bock, G.R., and Whelan, J., eds.) pp. 129–154, Ciba Foundation Symposium, John Wiley & Sons, Chichester.
Williams, C., Birch, E.E., Emmet, P., North, K., and ALSPAC Team (2001) Stereoacuity at 3.5 Years of Age in Children Born Full-Term Is Associated with Prenatal and Postnatal Dietary Factors, a Report from a Population Based Cohort Study, Am. J. Clin. Nutr. 73, 316–322.
About this article
Cite this article
Uauy, R., Hoffman, D.R., Peirano, P. et al. Essential fatty acids in visual and brain development. Lipids 36, 885–895 (2001). https://doi.org/10.1007/s11745-001-0798-1
- Visual Acuity
- Essential Fatty Acid
- Term Infant
- Chain Polyunsaturated Fatty Acid
- Mental Development Index