Docosahexaenoic acid promotes neurogenesis in vitro and in vivo

doi:10.1016/j.neuroscience.2006.01.021

Neuroscience

Volume 139, Issue 3, 2006, Pages 991-997

https://doi.org/10.1016/j.neuroscience.2006.01.021 Get rights and content

Abstract

Docosahexaenoic acid (22:6n-3), one of the main structural lipids in the mammalian brain, plays crucial roles in the development and function of brain neurons. We examined the effect of docosahexaenoic acid on neuronal differentiation of neural stem cells in vitro and in vivo. Neural stem cells obtained from 15.5-day-old rat embryos were propagated as neurospheres and cultured under differential conditions with or without docosahexaenoic acid for 4 and 7 days. Docosahexaenoic acid significantly increased the number of Tuj1-positive neurons compared with the control on both culture days, and the newborn neurons in the docosahexaenoic acid group were morphologically more mature than in the control. Docosahexaenoic acid significantly decreased the incorporation ratio of 5-bromo-2′-deoxyuridine, the mitotic division marker, during the first 24 h period; it also significantly decreased the number of pyknotic cells on day 7. Thus, docosahexaenoic acid promotes the differentiation of neural stem cells into neurons by promoting cell cycle exit and suppressing cell death. Furthermore, dietary administration of docosahexaenoic acid significantly increased the number of 5-bromo-2′-deoxyuridine(+)/NeuN(+) newborn neurons in the granule cell layer of the dentate gyrus in adult rats. These results demonstrate that docosahexaenoic acid effectively promotes neurogenesis both in vitro and in vivo, suggesting that it has the new property of modulating hippocampal function regulated by neurogenesis.

Section snippets

Cell culture and differentiation into neural lineage

NSCs were cultured by the neurosphere method as described (Reynolds and Weiss, 1992). Rat embryos on embryonic day 15.5 (E15.5, with the morning of plug detection designated as E0.5) were dissected out into PBSG (0.6% glucose in PBS (−) containing 1 U/mL penicillin/streptomycin), and the telencephalons were isolated. Tissues were mechanically disrupted into single cells by repeated trituration in a serum-free conditioned medium (N2 medium) comprising DMEM/F12 1:1, 0.6% glucose, sodium

Effects of DHA on neuronal differentiation of NSCs in vitro

Cells isolated from E15.5 embryos generated neurospheres in the presence of bFGF, and numerous cells were immunoreactive to nestin (data not shown). Under differential conditions, some of the cells were immunoreactive to neural markers Tuj1, MAP2ab or to mature astrocyte marker GFAP (data not shown) and consequently identified as NSCs.

To evaluate the effect of DHA on NSCs, the cells were cultured for 4 and 7 days with or without 10 μM DHA (Fig. 1). DHA is effective in a narrow range (i.e. 2–10

Discussion

NSCs are identified in many regions of the embryonic CNS (cerebral cortex, hippocampus, spinal cord, and cerebellum; Temple 2001), where they generate the neural and glial cell lineage during the developmental period. The levels of DHA in the rat brain increase in the period between E14 and E17, which coincides with the peak of neurogenesis (Green et al., 1999). Therefore, NSCs isolated from E15.5 rats, used in this study, are fitting for examining the effects of DHA on developmental

Acknowledgment

We thank Harima Chemicals Inc. (Tokyo, Japan) for its generous gift of DHA-95E as an ethyl ester derivative of all cis-4,7,10,13,16,19-docosahexaenoic acid.

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Developmental neuroscienceDocosahexaenoic acid promotes neurogenesis in vitro and in vivo

Abstract

Section snippets

Cell culture and differentiation into neural lineage

Effects of DHA on neuronal differentiation of NSCs in vitro

Discussion

Acknowledgment

J Nutr

Brain Res Dev Brain Res

Neuron

Prostaglandins Leukot Essent Fatty Acids

Neuroscience

The preferential prenatal accumulation of docosahexaenoic acid. J Lipid Res

J Nutr

Arch Biochem Biophys

Neuroscience

Neuroscience

Docosahexaenoic acida positive modulator of Akt signaling in neuronal survival

Proc Natl Acad Sci U S A

Docosahexaenoic acid promotes neurite growth in hippocampal neurons

J Neurochem

The lipid peroxidation product 4-hydroxy-2,3-nonenal increases AP-1-binding activity through caspase activation in neurons

J Neurochem

Restoring production of hippocampal neurons in old age

Nat Neurosci

Spatial memory performances of aged rats in the water maze predict levels of hippocampal neurogenesis

Proc Natl Acad Sci U S A

Neurogenesis in the adult human hippocampus

Nat Med

Docosahexaenoic acid improves long-term potentiation attenuated by phospholipase A2 inhibitor in rat hippocampal slices

Br J Pharmacol

Chronic administration of docosahexaenoic acid improves the performance of radial arm maze task in aged rats

Clin Exp Pharmacol Physiol

Developmental neuroscience
Docosahexaenoic acid promotes neurogenesis in vitro and in vivo

Docosahexaenoic acid improves long-term potentiation attenuated by phospholipase A₂ inhibitor in rat hippocampal slices