Improved spatial learning performance of fat-1 mice is associated with enhanced neurogenesis and neuritogenesis by docosahexaenoic acid
Open accessAbstract
Docosahexaenoic acid (DHA), an n-3 long chain polyunsaturated fatty acid (LC-PUFA), highly enriched in the central nervous system, is critical for brain development and function. It has been shown that DHA deficiency impairs cognitive performance whereas DHA supplementation improves the condition. However, the mechanisms underlying the role of DHA in brain development and function remain to be elucidated. By using transgenic fat-1 mice rich in endogenous n-3 PUFA, we show that increased brain DHA significantly enhances hippocampal neurogenesis shown by an increased number of proliferating neurons and neuritogenesis, evidenced by increased density of dendritic spines of CA1 pyramidal neurons in the hippocampus. Concurrently, fat-1 mice exhibit a better spatial learning performance in the Morris water maze compared with control WT littermates. In vitro experiments further demonstrate that DHA promotes differentiation and neurite outgrowth of neuronal cells derived from mouse ES cells and increases the proliferation of cells undergoing differentiation into neuronal lineages from the ES cells. These results together provide direct evidence for a promoting effect of DHA on neurogenesis and neuritogenesis and suggest that this effect may be a mechanism underlying its beneficial effect on behavioral performance.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Different esterified forms of polyunsaturated fatty acids exhibit different levels of bioavailability and effectiveness of their bioactivities.
“Several studies have shown that different esterified forms of polyunsaturated fatty acids exhibited different levels of bioavailability and effectiveness of their bioactivities.”
From Solid Matrix-Supported Supercritical CO2 Enhances Extraction of γ-Linolenic Acid from the Cyanobacterium Arthrospira (Spirulina) platensis and Bioactivity Evaluation of the Molecule in Zebrafish (2019) · cites this paper as [56]
The Discussion (page unavailable) describes different biological actions of DHA esterified in membrane phospholipids and unesterified free DHA. It does not compare different esterified forms of polyunsaturated fatty acids or report differences in their bioavailability or effectiveness. (LLM, conf=0.82)
Experimental — accuracy not yet measuredDHA-PC produced a more significant improvement in brain development, cognitive performance and emotional well-being than DHA-TG.
“For example, docosahexaenoic acid-phosphatidylcholine (DHA-PC) produced a more significant improvement in brain development, cognitive performance and emotional well-being than docosahexaenoic acid-triglyceride (DHA-TG) [56,57,58].”
From Solid Matrix-Supported Supercritical CO2 Enhances Extraction of γ-Linolenic Acid from the Cyanobacterium Arthrospira (Spirulina) platensis and Bioactivity Evaluation of the Molecule in Zebrafish (2019) · cites this paper as [56]
The Abstract and Discussion report that higher brain DHA in fat-1 mice was associated with enhanced hippocampal neurogenesis and better spatial learning. The paper does not compare DHA-PC with DHA-TG or report a comparative effect on emotional well-being; its comparison is between fat-1 mice and wild-type littermates. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Developments of a water-maze procedure for studying spatial learning in the rat
Morris, R. (1984) · Journal of Neuroscience Methods · doi:10.1016/0165-0270(84)90007-4 · Cited by 7,180 · see citing works
Neurogenesis in the adult is involved in the formation of trace memories
Shors, T. J., Miesegaes, G. R., Beylin, A. V., Zhao, M., Rydel, T. A., & Gould, E. (2001) · Nature · doi:10.1038/35066584 · Cited by 2,014 · see citing works
Adult neurogenesis produces a large pool of new granule cells in the dentate gyrus
Cameron, H. A., & Mckay, R. D. G. (2001) · Journal of Comparative Neurology · doi:10.1002/cne.1040 · Cited by 1,585 · see citing works
Embryonic Stem Cells Express Neuronal Properties in Vitro
Bain, G., Kitchens, D. L., Yao, M., Huettner, J. E., & Gottlieb, D. I. (1995) · Developmental Biology · doi:10.1006/dbio.1995.1085 · Cited by 1,168 · see citing works
Kee, N., Teixeira, C. M., Wang, A. H., & Frankland, P. W. (2007) · Nature Neuroscience · doi:10.1038/nn1847 · Cited by 875 · see citing works
Marcheselli, V. L., Hong, S., Lukiw, W. J., Tian, X. H., Gronert, K., Musto, A., Hardy, M., Gimenez, J. M., Chiang, N., Serhan, C. N., et al. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m305841200 · Cited by 802 · see citing works
Okabe, S., Forsberg‐Nilsson, K., Spiro, A. C., Segal, M., & McKay, R. D. G. (1996) · Mechanisms of Development · doi:10.1016/0925-4773(96)00572-2 · Cited by 770 · see citing works
Mukherjee, P. K., Marcheselli, V. L., Serhan, C. N., & Bazan, N. G. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0402531101 · Cited by 753 · see citing works
Docosahexaenoic Acid, a Ligand for the Retinoid X Receptor in Mouse Brain
de Urquiza, A. M., Liu, S., Sjöberg, M., Zetterström, R. H., Griffiths, W. J., Sjövall, J., & Perlmann, T. (2000) · Science · doi:10.1126/science.290.5499.2140 · Cited by 745 · see citing works
Birch, E. E., Garfield, S., Hoffman, D. R., Uauy, R. D., & Birch, D. G. (2000) · Developmental Medicine & Child Neurology · doi:10.1017/s0012162200000311 · Cited by 619 · see citing works
Fat-1 mice convert n-6 to n-3 fatty acids
Kang, J. X., Wang, J., Wu, L., & Kang, Z. B. (2004) · Nature · doi:10.1038/427504a · Cited by 545 · see citing works
Self-citationDocosahexaenoic acid promotes neurite growth in hippocampal neurons
Calderón, F. H., & Kim, H. (2004) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2004.02520.x · Cited by 416 · see citing works
Docosahexaenoic acid promotes neurogenesis in vitro and in vivo
Kawakita, E., Hashimoto, M., & Shido, O. (2006) · Neuroscience · doi:10.1016/j.neuroscience.2006.01.021 · Cited by 410 · see citing works
Ganglioside Stimulation of Axonal Sprouting in Vitro
Roisen, F. J., Bartfeld, H., Nagele, R. G., et al. (1981) · Science · doi:10.1126/science.7291999 · Cited by 387 · see citing works
Glaser, E. M., & der Loos, H. V. (1981) · Journal of Neuroscience Methods · doi:10.1016/0165-0270(81)90045-5 · Cited by 374 · see citing works
Horrocks, L. A., & Farooqui, A. A. (2004) · Prostaglandins, Leukotrienes and Essential Fatty Acids · doi:10.1016/j.plefa.2003.12.011 · Cited by 356 · see citing works
Cell survival matters: docosahexaenoic acid signaling, neuroprotection and photoreceptors
Bazan, N. G. (2006) · Trends in Neurosciences · doi:10.1016/j.tins.2006.03.005 · Cited by 353 · see citing works
Omega-3 and omega-6 fatty acids stimulate cell membrane expansion by acting on syntaxin 3
Darios, F. D., & Davletov, B. A. (2006) · Nature · doi:10.1038/nature04598 · Cited by 352 · see citing works
Lengqvist, J., Mata de Urquiza, A., Bergman, A.-C., Willson, T. M., Sjövall, J., Perlmann, T., & Griffiths, W. J. (2004) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m400003-mcp200 · Cited by 323 · see citing works
Effects of dietary omega-3 polyunsaturated fatty acids on brain gene expression
Kitajka, K., Sinclair, A. J., Weisinger, R. S., Weisinger, H. S., Mathai, M. L., Jayasooriya, A. P., Halver, J. E., & Puskás, L. G. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0402342101 · Cited by 314 · see citing works
A simplified method for analysis of polyunsaturated fatty acids
Kang, J. X., & Wang, J. (2005) · BMC Biochemistry · doi:10.1186/1471-2091-6-5 · Cited by 210 · see citing works
Self-citationOmega-3 fatty acids upregulate adult neurogenesis
Beltz, B. S., Tlusty, M. F., Benton, J. L., & Sandeman, D. C. (2007) · Neuroscience Letters · doi:10.1016/j.neulet.2007.01.010 · Cited by 201 · see citing works
Sakamoto, T., Cansev, M., & Wurtman, R. J. (2007) · Brain Research · doi:10.1016/j.brainres.2007.08.089 · Cited by 188 · see citing works
Birch, E. E., Castañeda, Y. S., Wheaton, D. H., Birch, D. G., Uauy, R. D., & Hoffman, D. R. (2005) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/81.4.871 · Cited by 186 · see citing works
Wada, K., Nakajima, A., Katayama, K., Kudo, C., Shibuya, A., Kubota, N., Terauchi, Y., Tachibana, M., Miyoshi, H., Kamisaki, Y., et al. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m513786200 · Cited by 165 · see citing works
Novak, E. M., Dyer, R., & Innis, S. M. (2008) · Brain Research · doi:10.1016/j.brainres.2008.07.107 · Cited by 125 · see citing works
Göttlicher, M., Demoz, A., Svensson, D., Tollet, P., Berge, R. K., & Gustafsson, J.-Α. (1993) · Biochemical Pharmacology · doi:10.1016/0006-2952(93)90607-x · Cited by 120 · see citing works
Changing Fatty Acid Content of Growth Cone Lipids Prior to Synaptogenesis
Martin, R. E., & Bazan, N. G. (1992) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1992.tb08906.x · Cited by 117 · see citing works
Lim, S., Hoshiba, J., & Salem, N. (2005) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2005.03427.x · Cited by 106 · see citing works
Activity-dependent maintenance and growth of dendrites in adult cortex
Tailby, C., Wright, L. L., Metha, A. B., & Calford, M. B. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0402747102 · Cited by 98 · see citing works
Esquenazi, S., Bazán, H. E. P., Bui, V., He, J., Kim, D. B., & Bazan, N. G. (2005) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.05-0241 · Cited by 91 · see citing works
An n-3 fatty acid deficiency impairs rat spatial learning in the Barnes maze.
Fedorova, I., Hussein, N., Baumann, M. H., Martino, C., & Salem, N. (2009) · Behavioral Neuroscience · doi:10.1037/a0013801 · Cited by 90 · see citing works
An n-3 fatty acid deficient diet affects mouse spatial learning in the Barnes circular maze
Fedorova, I., Hussein, N., Martino, C., Moriguchi, T., Hoshiba, J., Majchrzak, S. F., & Salem, N. (2007) · Prostaglandins Leukotrienes and Essential Fatty Acids · doi:10.1016/j.plefa.2007.10.013 · Cited by 84 · see citing works
Gene Expression Analysis in Human Fetal Retinal Explants Treated with Docosahexaenoic Acid
Rojas, C., ́nez, J. I. M., Flores, I., Hoffman, D. R., & Uauy, R. D. (2003) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.02-1138 · Cited by 64 · see citing works
Kan, I., Melamed, E., Offen, D., & Green, P. (2006) · Journal of Lipid Research · doi:10.1194/jlr.c600022-jlr200 · Cited by 64 · see citing works
Induction of neuronal differentiation of adult human olfactory neuroepithelial-derived progenitors
Zhang, X.-D., Klueber, K. M., Guo, Z., Cai, J., Lu, C., Winstead, W. I., Qiu, M. S., & Roisen, F. J. (2006) · Brain Research · doi:10.1016/j.brainres.2005.12.059 · Cited by 57 · see citing works
Holguin, S., Huang, Y., Liu, J., & Wurtman, R. (2008) · Behavioural Brain Research · doi:10.1016/j.bbr.2008.02.042 · Cited by 57 · see citing works
Docosahexaenoic Acid in Neural Signaling Systems
Crawford, M. A. (2006) · Nutrition and Health · doi:10.1177/026010600601800309 · Cited by 47 · see citing works
Guesnet, P., Pascal, G., & Durand, G. (1988) · annales de biologie animale biochimie biophysique · doi:10.1051/rnd:19880208 · Cited by 42 · see citing works
Dividing Olig2‐expressing progenitor cells derived from ES cells
Xian, H.-Q., & Gottlieb, D. I. (2004) · Glia · doi:10.1002/glia.20010 · Cited by 23 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Layé, S., Nadjar, A., Joffre, C., & Bazinet, R. P. (2018) · Pharmacological Reviews · doi:10.1124/pr.117.014092 · Cited by 420 · see citing works
Robertson, R. C., Seira Oriach, C., Murphy, K., Moloney, G. M., Cryan, J. F., Dinan, T. G., Paul Ross, R., & Stanton, C. (2017) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2016.07.145 · Cited by 268 · see citing works
Effects of omega-3 fatty acids on cognitive performance: a meta-analysis
Mazereeuw, G., Lanctôt, K. L., Chau, S. A., Swardfager, W., & Herrmann, N. (2012) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2011.12.014 · Cited by 253 · see citing works
Guemez-Gamboa, A., Nguyen, L. N., Yang, H., Zaki, M. S., Kara, M., Ben-Omran, T., Akizu, N., Rosti, R. O., Rosti, B., Scott, E., et al. (2015) · Nature Genetics · doi:10.1038/ng.3311 · Cited by 225 · see citing works
Denis, I., Potier, B., Vancassel, S., Heberden, C., & Lavialle, M. (2013) · Ageing Research Reviews · doi:10.1016/j.arr.2013.01.007 · Cited by 150 · see citing works
Functional and Structural Benefits Induced by Omega-3 Polyunsaturated Fatty Acids During Aging
Cutuli, D. (2017) · Current Neuropharmacology · doi:10.2174/1570159x14666160614091311 · Cited by 139 · see citing works
van Wijk, N., Broersen, L. M., de Wilde, M. C., Hageman, R. J. J., Groenendijk, M., Sijben, J. W. C., & Kamphuis, P. J. G. H. (2013) · Journal of Alzheimer s Disease · doi:10.3233/jad-130998 · Cited by 128 · see citing works
Omega-3 fatty acids and the treatment of depression: a review of scientific evidence
Wani, A. L., Bhat, S. A., & Ara, A. (2015) · Integrative Medicine Research · doi:10.1016/j.imr.2015.07.003 · Cited by 97 · see citing works
Díaz, M., Mesa-Herrera, F., & Marín, R. (2021) · Antioxidants · doi:10.3390/antiox10060907 · Cited by 84 · see citing works
Yang, X., Li, Y., Li, Y., Ye, D., Yuan, L., Sun, Y., Han, D., & Hu, Q. (2019) · Marine Drugs · doi:10.3390/md17040203 · Cited by 45 · see citing works
Wu, F., Wang, D.-D., Wen, M., Che, H.-X., Xue, C.-H., Yanagita, T., Zhang, T.-T., & Wang, Y.-M. (2017) · Lipids in Health and Disease · doi:10.1186/s12944-017-0623-2 · Cited by 20 · see citing works
- Authors
- He, C., Qu, X., Cui, L., Wang, J., & Kang, J. X.
- Affiliations
- Harvard University (US)
- Department of Medicine and
- Corresponding author
- Kang, Jing X.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-07-07
- Volume
- 106
- Issue
- 27
- Pages
- 11370-11375
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2708766
- OpenAlex
- W2022932258
- Cited by
- 233
- References
- 40
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 5 · 2023: 8 · 2022: 10 · 2021: 14 · 2020: 13 · 2019: 17 · 2018: 15 · 2017: 9 · 2016: 27 · 2015: 14 · 2014: 19 · 2013: 20 · 2012: 12
- FWCI
- 14.84
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (CA-113605, R01CA113605)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK040561)
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- docosahexaenoic acid, fat-1 mice, omega-3 fatty acids, hippocampal neurogenesis, neurite outgrowth, spatial learning, dendritic spines, CA1 pyramidal neurons, neuronal differentiation, embryonic stem cells, cognitive function
- MeSH terms
- Animals, Cell Differentiation, Docosahexaenoic Acids, Fatty Acids, Hippocampus, Learning, Mice, Mutant Strains, Mice, Transgenic, Spatial Behavior, Neurites, Maze Learning, Dietary Supplements, Cell Proliferation, Dendritic Spines, Mice, Embryonic Stem Cells, Neurogenesis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
