Abstract
The concentration of the major polyunsaturated fatty acid (PUFA) in brain, docosahexaenoate, may be markedly reduced by two or more generations of dietary restriction of sources of n-3 fatty acids in the diet. Such a deficiency was induced through the feeding of safflower oil as the principal source of essential fatty acids. The reference point for this diet was an n-3 adequate diet to which alpha-linoleate and docosahexaenoate were added through the addition of a small quantity of flax seed or algael oils, respectively. The loss of brain DHA was associated with poorer performance in spatial tasks and an olfactory-cued reversal learning task. No difference could be observed in the hippocampal gross morphology. This study demonstrates the importance of providing a source of n-3 fatty acids during mammalian growth and development.
Similar content being viewed by others
References
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.
Ahmad A., Greiner R. S., Moriguchi T., and Salem N. Jr. (2000) Effects of dietary omega-3 fatty acid on the morphology of the hippocampus. J. Neurochem. 74, S88A.
Auestad N., Montalto M. B., Hall R. T., Fitzgerald K. M., Wheeler R. E., Connor W. E., et al. (1997) Visual acuity, erythrocyte fatty acid composition, and growth in term infants fed formulas with long-chain polyunsaturated fatty acids for one year. Pediatr. Res. 41, 1–10.
Birch E. E., Birch D. G., Hoffman D. R., and Uauy R. (1992) Dietary essential fatty acid supply and visual acuity development. Invest. Ophthalmol. Vis. Sci. 33, 3242–3253.
Birch E. E., Hoffman D. R., Uauy R. D., 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. D., 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.
Bourre J. M., Pascal G., Durand G., Masson M., Dumont O., and Picotti M. (1984) Alterations in the fatty acid composition of rat brain cells (neurons, astrocytes, and oligodendrocytes) and of subcellular fractions (myelin and synaptosomes) induced by a diet devoid of n-3 fatty acids. J. Neurochem. 43, 342–348.
Bourre J-M., François M., Youyou A., Dumont O., Piciotti M., Pascal G., and Durand G. (1989) The effect of dietary α linolenic acid on the composition of nerve membranes, enzymatic activity, amplitude of electrophysiological parameters, resistance to poisons and performance of learning tasks in rats. J. Nutr. 119, 1880–1892.
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 ω3 and ω6 fatty acid status. World Rev. Nutr. Diet. 75, 63–69.
Carlson S. E., Ford A. J., Werkman S. H., Peeples J. M., and Koo W. W. K. (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.
Coscina D. V., Yehuda S., Dixon L. M., Kish S. K., and Leprohon-Greenwood C. E. (1985) Learning is improved by a soybean oil diet in rats. Life Sci. 38, 1789–1794.
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.
Folch J., Rees M., and Sloane-Stanley G. H. (1957) Simple method for the isolation and purification of total lipids from animal tissues. J. Biol. Chem. 226, 497–509.
Frances H., Coudereau J. P., Sandouk P., Clement M., Monier C., and Bourre J. M. (1996) Influence of a dietary alpha-linolenic acid deficiency on learning in the Morris water maze and on the effects of morphine. Eur. J. Pharmacol. 298, 217–225.
Galli C., Treciak H., and Paoletti R. (1971) Effects of dietary fatty acids on the fatty acid composition of brain ethanolamine-phosphoglyceride: reciprocal replacement of n-6 and n-3 polyunsaturated fatty acids. Biochim. Biophys. Acta 248, 449–454.
Gibson R. A. and Makrides M. (1998) The role of long chain polyunsaturated fatty acids (LCPUFA) in neonatal nutrition. Acta Paediatr. 87, 1017–1022.
Greiner R. S., Moriguchi T., Hutton A., Slotnick B. M., and Salem N. Jr. (1999) Rats with low levels of brain docosa-hexaenoic acid show impaired performance in olfactory-based and spatial learning tasks. Lipids 34, S239-S243.
Greiner R. S., Moriguchi T., Hutton A., Slotnick B. M., and Salem N. Jr. (2001) Olfactory discrimination deficits in n-3 fatty acid deficient rats. Physiol. Behav. 72, 1–7.
Hamosh M. and Salem N. Jr. (1998) Long-chain polyun-saturated fatty acids. Biol. Neonate. 74, 106–120.
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., Nelson C. M., 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.
Jamieson E. C., Farquharson J., Logan R. W., Howatson A. G., Patrick W. J. A., Weaver L. T., and Cockburn F. (1999) Infant cerebellar gray and white matter fatty acids in relation to age and diet. Lipids 34, 1065–1071.
Jensen M. M., Skarsfeldt T., and Hoy C. E. (1996) Correlation between level of (n-3) polyunsaturated fatty acids in brain phospholipids and learning ability in rats. A multiple generation study. Biochim. Biophys. Acta 1300, 203–209.
Jensen R. G. (1999) Lipids in human milk. Lipids 34, 1243–1271.
Jensen C. L., Prager T. C., Fraley J. K., Chen H., Anderson R. E., and Heird W. C. (1997) Effect of dietary linoleic/alpha linolenic acid ratio on growth and visual function in term infants. J. Pediatr. 131, 200–209.
Jorgensen M. H., Hernell O., Lund P., Holmer G., and Michaelsen K. F. (1996) Visual acuity and erythrocyte docosahexaenoic acid status I: breast-fed and formulafed term infants during the first four months of life. Lipids 31, 99–105.
Lamptey M. S. and Walker B. L. (1976) A possible role for dietary linolenic acid in the development of the rat. J. Nutr. 106, 86–93.
Lands W. E. M. (1991) Polyunsaturated fatty acid effects on cellular interactions, in Micronutrients in Health and Disease (Bendich, A. and Butterworth C. E. Jr., eds.), Marcel Dekker, NY, pp. 9–34.
Lu X-C.M., Slotnick B. M., and Silberberg A. M. (1993) Odor matching and odor memory in the rat. Physiol. Behav. 53, 795–804.
Makrides M., Neumann M. A., Byard R. W., Simmer K., and Gibson R.A. (1994) Fatty acid composition of brain, retina, and erythrocytes in breast- and formula-fed infants. Am. J. Clin. Nutr. 60, 189–194.
Makrides M., Neumann M. 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.
McBride S. A. and Slotnick B. M. (1997) The olfactory thalamocortical system and odor reversal learning examined using an asymmetrical lesion paradigm in rats. Behav. Neurosci. 111(6), 1273–1284.
Mohrhauer H. and Holman R. T. (1963) Alteration of the fatty acid composition of brain lipids by varying levels of dietary essential fatty acids. J. Neurochem. 10, 523–530.
Moriguchi T., Greiner R. S., and Salem N. Jr. (2000) Behavioral deficits associated with dietary induction of decreased brain docosahexaenoic acid concentration. J. Neurochem. 75, 2563–2573.
Morris R. G. M., Garrud P., Rawlins J. N. P., and O’Keefe J. (1982) Place navigation impaired in rats with hippocampal lesions. Nature 297, 681–683.
Morris R. G. M. (1984) Developments of a water-maze procedure for studying spatial learning in the rat. J. Neurosci. Methods 11, 47–60.
Morrison W. R. and Smith L. M. (1964) Preparation of fatty acid methyl esters and dimethylacetals from lipids with boron fluoride-methanol. J. Lipid Res. 5, 600–608.
Nakashima Y., Yuasa S., Hukamizu Y., Okuyama H., Ohhara T., Kameyama T., and Nabeshima T. (1993) Effect of a high linoleate and a high alpha-linolenate diet on general behavior and drug sensitivity in mice. J. Lipid Res. 34, 239–247.
Nigrosh B. J., Slotnick B. M., and Nevin J. A. (1975) Olfactory discrimination, reversal learning, and stimulus control in rats. J. Comp. Physiol. Psychol. 89(4), 285–294.
Okuyama H., Kobayashi T., and Watanabe S. (1997) Dietary fatty acids. The n-6/n-3 balances and chronic elderly diseases. Excess linoleic acid and relative n-3 deficiency syndrome seen in Japan. Prog. Lipid Res. 35, 409–457.
Reeves P. G., Neilsen F. H., and Fahey G. C. (1993) Committee report on the AIN-93 purified rodent diet. J. Nutr. 123, 1939–1951.
SanGiovanni J. P., Parra-Cabrera S., Colditz G. A., Berkey C. S., and Dwyer J. T. (2000a) 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.
SanGiovanni J. P., Berkey C. S., Dwyer J. T., and Colditz G. A. (2000b) Dietary essential fatty acids, long-chain polyunsaturated fatty acids, and visual resolution acuity in healthy fullterm infants: a systematic review. Early Human Dev. 57, 165–188.
Salem N. Jr, Kim H-Y., and Yergey J. A. (1986) Docosa-hexaenoic acid: membrane function and metabolism, in Health Effects of Polyunsaturated Fatty Acids in Seafoods, Academic Press, New York, pp. 263–317.
Salem N. Jr. (1989) Omega-3 fatty acids: Molecular and biochemical aspects, in New Protective Roles of Selected Nutrients in Human Nutrition (Spiller G. and Scala J., eds.), Liss, New York, pp. 109–228.
Salem N. Jr. and Niebylski C. D. (1995) The nervous system has an absolute molecular species requirement for proper function. Mol. Mem. Biol. 12, 131–134.
Salem N. Jr., Reyzer M., and Karanian J. (1996) Losses of arachidonic acid in rat liver after alcohol inhalation. Lipids 31, S153-S156.
Scott D. T., Janowsky J. S., 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 E59 (Electronic Publication).
Slotnick B. M. (1990) Olfactory perception in animals, in Comparative Perception, vol. 1. Basic Mechanisms (Stebbins W. and Berkley M., eds.) J. Wiley, New York, pp. 155–214.
Slotnick, B. M. (1994) The enigma of olfactory learning revisited. Neuroscience 58, 1–12.
Tinoco J., Babcock R., Hincenbergs I., Medwadowski B., Miljanich P., and Williams M. A. (1979) Linolenic acid deficiency. Lipids 14, 166–173.
Uauy R. D., 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.
Wainwright P. E., Huang Y. S., Coscina D. V., Levesque S., and McCutcheon D. (1994) Brain and behavioral effects of dietary n-3 deficiency in mice: a three generational study. Dev. Psychobiol. 27, 467–487.
Wainwright P. E., Xing H. C., Girard T., Parker L., and Ward G. R. (1998) Effects of dietary n-3 fatty acid deficiency on Morris water-maze performance and amphetamine-induced conditioned place preference in rats. Nutr. Neurosci. 1, 281–293.
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.
West M. J. and Gundersen H. J. G. (1990) Unbiased stereological estimation of the number of neurons in the human hippocampus. J. Comp. Neurol. 296, 1–22.
West M. J. (1999). New stereological methods for counting neurons. Neurobiol. Aging 14, 275–285.
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. Lancet 352, 688–691.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Salem, N., Moriguchi, T., Greiner, R.S. et al. Alterations in brain function after loss of docosahexaenoate due to dietary restriction of n-3 fatty acids. J Mol Neurosci 16, 299–307 (2001). https://doi.org/10.1385/JMN:16:2-3:299
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1385/JMN:16:2-3:299