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INRA, Laboratoire de Nutrition et Sécurité Alimentaire, Jouy-en-Josas, France
2To whom correspondence should be addressed. E-mail: vancasse{at}jouy.inra.fr.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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-linolenic acid (LNA). Chronically (n-3) PUFA–deficient females were fed, starting 2 wk before mating, the deficient diet, a control diet, or a purified diet supplying 1, 2, or 3 g DHA/kg diet as E-PL or TO. Experiments were performed on the adult male progeny fed the same diet as their dams throughout life. The form of dietary DHA (TO or E-PL) did not influence its incorporation into the hippocampus. The 1 g DHA/kg diets allowed maximal incorporation into phosphatidylethanolamine (PE), but 2 g DHA/kg diet was needed for phosphatidylcholine (PC). A minimum of 2 g DHA/kg was needed to decrease the basal Ach release and to enhance the stimulated release to that of the control; the Ach release of the 1 g/kg DHA-groups did not differ from that of the deficient group. This suggests that >1 g DHA/kg diet is needed to ensure PUFA incorporation into PE and PC, and basal and stimulated Ach release in the rat hippocampus equivalent to the control group fed only LNA. PUFA incorporation into the hippocampus depends mainly on the PUFA concentration of the diet, not on the form of dietary DHA.
KEY WORDS: • acetylcholine • hippocampus • microdialysis • docosahexaenoic acid • rats
High proportions of PUFA in the brain, especially arachidonic acid (AA)3 and docosahexaenoic acid (DHA) are crucial for maintaining the structure and physiologic function of the central nervous system (1). The brain is particularly sensitive to the availability of (n-3) PUFA in the diet, especially during gestation and early postnatal life because these are critical periods for the accumulation of PUFA [reviewed in (2)]. Thus, dietary (n-3) PUFA, including the essential precursor -linolenic acid (LNA) and its long-chain derivatives such as DHA, may be limiting factors for normal cerebral development. Although there is now good evidence that (n-3) PUFA are beneficial for health, studies have shown that people living in Western developed countries consume less than the recommended amounts of (n-3) PUFA (3,4). Animal studies using experimental diets lacking (n-3) PUFA demonstrated that a reduction in DHA in cerebral membranes is associated with disturbances of neural functions such as visual acuity, attention, learning, and memory (1,5,6). The monoaminergic and cholinergic neurotransmission systems of chronically (n-3) PUFA–deficient rodents are all affected because of the abnormal storage and release of neurotransmitters (7–9). Notably, a decrease in dopamine release in the frontal cortex and an increase in dopamine synthesis and release in the nucleus accumbens of rats were described (7). Chronic (n-3) PUFA dietary deficiency also altered the hippocampus synaptic levels of serotonin, and this modification was reversed by providing adequate (n-3) PUFA beginning in the early postnatal period (9). Recently, we found changes in the synaptic release of acetylcholine (Ach) and reduced binding of scopolamine to muscarinic receptors in the hippocampus of (n-3) PUFA–deficient rats (8). These neurochemical disturbances could lead to cognitive impairment in deficient rats.
The present study was designed to determine the effect of the dose and the source of dietary DHA (triglycerides or phospholipids) on Ach release in the rat hippocampus and to determine whether they are associated with any changes in the composition of cerebral lipids.
We compared 2 sources of DHA, tuna oil (TO) and an egg-phospholipid formula (E-PL). They differ primarily in that TO contains only triglycerides, whereas E-PL contains mainly phospholipids. The TO supplied small amounts of eicosapentaenoic acid (EPA), a metabolic competitor of AA; E-PL contained small amounts of AA. E-PL also provides substantial amounts of phosphatidylcholine (PC) and therefore choline, a precursor of Ach, making this dietary source of PUFA useful in examining Ach neurotransmission and in testing the potential synergy of the choline and DHA in PC. We examined the availability of DHA provided by E-PL and TO to the brain. We also measured by microdialysis the effects of various doses of DHA on the basal- and potassium chloride evoked–release of Ach from the hippocampus of adult rats and its hydrolysis by acetylcholinesterase (AchE). Changes in the lipid parameters in the hippocampus were verified by assaying the concentrations of phospholipids and cholesterol; the fatty acid compositions of the main membrane phospholipids, phosphatidylcholine (PC) and phosphatidylethanolamine (PE), were measured. We also examined the influence of the maternal diet on the PUFA composition of milk lipids as an indicator of DHA bioavailability.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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12 g linoleic acid [18:2(n-6)]/kg diet by incorporating peanut oil. The weaned males from each litter were housed 2/cage with free access to the same diet as their dams. All diets were stored at 4°C to avoid oxidative damage of PUFA and the fatty acid compositions of all preparations were monitored. Experiments were performed on 2- to 3-mo-old rats.
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Cholesterol and phospholipid content of cerebral membranes. After 5 to 7 rats of each dietary group were killed by decapitation, the brains were quickly removed and the hippocampus was dissected out on ice, weighed, and frozen in liquid nitrogen.
Total lipids were extracted from all samples by a modification of the Folch method (11). An aliquot of total lipids was used to separate and determine the concentrations of cholesterol, PC, PE, and sphingomyelin (SM) by TLC with flame-ionization detection (IATROSCAN MK5, Iatron Laboratories,) using a protocol adapted from De Schrijver and Vermeulen (12). Cholesterol was assayed for quantification; 1 µL of lipids diluted in chloroform was spotted on silica-coated quartz rods (Chromarods-SII, Iatrons Laboratories). The neutral lipids were separated using a developing solvent mixture for 30 min in hexane:ethyl ether:formic acid (97:3:1, by vol). The rods were dried under vacuum and passed through the IATROSCAN-MK5 with an air flow rate of 1.8 L/min and a H2 flow rate of 160 mL/min. The PC, PE, and SM contents were assayed after an initial separation of neutral lipids (see above), leaving the total phospholipids intact. The rods were then developed first during 30 min in chloroform:methanol:acetic acid:formic acid:water (80:35:2:1:3, by vol), dried under vacuum, followed by a second development (40 min) in chloroform:methanol:28% ammonia:water (45:28:0.5:1, by vol). Each sample was assayed in triplicate. A linear calibration curve was obtained for each class of lipid (r = 0.90 for cholesterol; r = 0.99 for PE; r = 0.99 for PC; r = 0.99 for SM; P < 0.001). Individual lipids were identified by comparison with authentic standards assayed simultaneously and quantified using regression equations determined for each lipid (SES-Chromstar software). Data are expressed as nmol/µg protein.
Fatty acid analysis of phospholipid classes. Another aliquot of total lipids was used to separate the 2 main phospholipid classes (PC, PE) by solid-phase extraction on an aminopropyl-bonded silica gel cartridge (BAKERBOND speTM Amino, Baker) as described by Alessandri and Goustard-Langelier (13). The fatty acid composition of PE and PC was determined by GC (Carlo Erba) (8) and quantified by peak area integration using the Nelson Analytical Program System (SRA). Results are expressed as g fatty acids/100 g of total fatty acids (TFA; wt %).
Microdialysis procedure. Rats were anesthetized with urethane (1.5 mg/kg body weight i.p.) and placed in a stereotaxic apparatus under body-temperature control. The probes (4-mm long membrane, MAB) were stereotaxically implanted into the left lateral hippocampus [–5.6 mm anterior to bregma, 4.4 mm lateral, –7.5 mm from the dura (14)]. The probe was perfused at 2 µL/min as previously described (8). The perfusate was collected at 20-min intervals after a 90-min washout period. The mean concentration of Ach in the first 3 dialysate samples was taken as "Ach baseline." Potassium chloride (KCl, 100 mmol/L) was then added to the perfusion buffer for 40 min, and the maximal concentration of Ach obtained 40 min after the initiation was taken as "Ach max." Dialysate samples were stored at –80°C until analysis by HPLC. The in vitro recovery of Ach was 20.3 ± 4.9% (mean ± SD; n = 40). At the end of each experiment, coronal cryostat sections of each brain were cut to check the probe; any results obtained with an incorrectly located probe were discarded. In the end, 5–9 rats for each dietary group were used for statistical analysis.
The Ach in the perfusate samples (20 µL) was assayed by HPLC with electrochemical detection according to (8). "Ach baseline" is expressed as nmol/L dialysate; "Ach max" is expressed as a percentage of the baseline value for each rat.
Determination of acetylcholinesterase activity. Rats were decapitated (n = 8 for each dietary group); their brains were quickly removed and dissected on ice. The 2 hippocampi were pooled and weighed, frozen in liquid nitrogen, and then stored at –80°C. AchE activity was determined colorimetrically (15) in homogenates of hippocampus. The changes in absorbance were recorded for at least 6 min at 412 nm using a UVIKON spectrophotometer (Kontron Instrument, UVK LAB Service). The protein contents were determined by the Bradford procedure (16). AchE activity is expressed as µmol/(min · g protein).
Statistical analyses. The data were analyzed using SigmaStat® statistical software (version 2.0, SPSS) by 1-way ANOVA (diet factor) followed by the multiple comparison Bonferroni t test. If the equal variance or normality test failed, the data were analyzed using the nonparametric Kruskal-Wallis test. Differences were considered significant at P < 0.05. Data are expressed as means ± SD.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Milk fatty acids at d 14 of lactation. Increased DHA intake did not modify the milk contents of SFA, monounsaturated fatty acids (MUFA), or (n-6) PUFA (Table 2). However, the increased dietary DHA led to corresponding higher contents of DHA in milk lipids, regardless of the dietary source of DHA (TO or E-PL). Thus, the DHA in milk lipids increased from 0.1% of TFA in the deficient group to 2.0% of TFA in the rats fed 3 g DHA/kg diet (P < 0.05), whereas the milk contained very little 18:3(n-3). The DHA in control group milk represented 0.3% of TFA and the 18:3(n-3) accounted for 0.6% TFA.
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Fatty acid compositions of the PC and PE. The incorporation of fatty acids into both phospholipid classes was not affected by the dietary source of DHA (Table 3). PUFAs were the main fatty acids in PE and PC affected by the experimental diets. The maximal incorporation of DHA (23% TFA) into PE was reached in rats supplemented with 1 g/kg DHA, whereas 2 g/kg DHA was needed to reach the maximum of incorporation of DHA into PC (4% of TFA). Therefore, a diet supplemented with 1 g DHA/kg led to a PUFA composition in the hippocampus that did not differ from that of the control group, except for the DHA in the PC, which accounted for only 86% of the control value.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The main change in lipid contents was in the amount of PUFA, with no difference between the E-PL and TO groups. Few studies have analyzed the accumulation of PUFA in the brain as a function of the dietary sources of PUFA, and the results were contradictory. Wijendran et al. (17) reported that baboons fed AA in the form of phospholipids had more AA in their brains than did baboons fed AA as triglycerides. We found that the incorporation of PUFA into the 2 major phospholipid classes in the rat hippocampus was not affected by the nature of the lipid structure in the diet. In agreement with our results, Goustard-Langelier et al. (18) reported that the brains of suckling piglets fed PUFA as low-EPA fish oil or E-PL showed the same degree of incorporation. A recent study also showed that supplementation of formulas for full-term infants with PUFA provided either by E-PL or triglycerides did not affect their bioavailability (19).
Our results indicated that E-PL and TO are equivalent sources of PUFA for the brain. A previous dose-effect study concluded that 600 mg DHA/ kg diet supplied by brain phospholipids led to maximal incorporation of DHA into the brain of weaned rats (20). Our lowest DHA-supplemented diet provided 1 g DHA/kg, which produced maximal DHA incorporation in PE, whereas a 100% higher dose (i.e., 2 g DHA/kg) was needed for maximal incorporation into PC. These differences may be due to differences in the dietary sources of DHA and to the fact that the authors measured PUFA in total lipids from the whole brain, whereas we analyzed the PUFA composition of PE and PC in the hippocampus. Thus, the dose-response relation for PUFA incorporation into the brain varies from one region of the brain to another, as was emphasized in a recent study by Alessandri et al. (21).
The basal and KCl-stimulated releases of Ach by the brains of rats fed 1 g DHA/kg diet as either E-PL or TO were similar to those of deficient rats. However, the "Ach baseline" value in rats fed diets supplying 
2 g DHA/kg diet was lower than that of deficient rats, whereas the "Ach max" was greater. The maximal stimulated releases were similar to those of the control group, with no difference between the E-PL and TO supplemented groups. We conclude that there is no specific "choline" effect of E-PL on Ach release. The published data on the potential of choline or PC to modulate cerebral Ach are not in complete agreement. The intracerebroventricular injection of choline into the rat striatum increased the release of Ach measured by microdialysis (22). Chung et al. (23) showed that force-feeding egg-PC for 45 d increased the brain Ach concentrations of demented mice, but had no effect on normal mice. However, the egg-PC used also provided large amounts of DHA. Our results showed that DHA from TO and E-PL has similar effects on Ach release in the hippocampus, but is dose dependent, suggesting a specific effect of (n-3) PUFA per se. We therefore suggest that the effects on Ach release are specifically due to DHA.
These results must be viewed in the light of the changes in Ach release we reported in the hippocampus of (n-3) PUFA–deficient rats (8). We described a rise in basal release of Ach and a reduction in its KCl-stimulated release. Our working hypothesis is that the diet-induced changes in neuronal lipid composition result in the leakage of Ach into the synaptic cleft, which leads to depletion of the vesicular stores that are recruited in response to stimulation. In this study, the reintroduction of DHA into brain membranes by feeding a diet containing 2 g/kg of diet normalized Ach release. This supports the idea that Ach release in the hippocampus is modulated by dietary (n-3) PUFA. This agrees with another study in which the authors showed that the impaired learning performances measured in hypertensive rats were restored to those of normotensive rats by the dietary DHA ethyl ester supplemented for several weeks, and the tissue content of Ach was increased (24). Favreliere et al. (25) used microdialysis to show that aged rats fed DHA-enriched diets for 3 mo had an enhanced stimulated release of Ach in the hippocampus. We showed that 2 g DHA/kg diet leads to the release of control levels of Ach, whereas 1 g DHA/kg diet does not. This could be because this lower dose provides only 85% of the control DHA incorporation into the PC, which may be too low to ensure the normal function of the cholinergic synapses.
The changes in Ach release were not accompanied by any change in the AchE activity in the hippocampus. This is in agreement with a recent study indicating that chronic administration of DHA does not alter the activity of the synaptic membrane–bound AchE in the rat cerebral cortex (26). Although the exact way in which (n-3) PUFAs influence brain function is not totally understood, they seem to interact with the vesicular and plasma membranes to alter their structure and/or function. However, the complexity of the neurotransmission regulation systems means that we must take into account other actions of (n-3) PUFAs, such as the production of active mediators (27) and the regulation of genes involved in synaptic function (28,29).
Thus, we find that synaptic Ach release in the hippocampus is influenced by the (n-3) PUFAs incorporated into membranes, which seems to depend mainly on the PUFA composition of the diet rather than the form of the dietary DHA supply.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: AA, arachidonic acid; Ach, acetylcholine; AchE, acetylcholinesterase; DHA, docosahexaenoic acid; DHA 0, deficient diet; EPA, eicosapentaenoic acid; E-PL, egg phospholipids; E-PL1, 1 g DHA/kg diet as egg phospholipids; E-PL2, 2 g DHA/kg diet as egg phospholipids; E-PL3, 3 g DHA/kg diet as egg phospholipids; LNA, -linolenic acid; MUFA, monounsaturated fatty acids; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PI, phosphatidylinositol; SM, sphingomyelin; TFA, total fatty acids; TO, tuna oil; TO1, 1 g DHA/kg diet as tuna oil; TO2, 2 g DHA/kg diet as tuna oil; TO3, 3 g DHA/kg diet as tuna oil.
Manuscript received 12 October 2004. Initial review completed 12 November 2004. Revision accepted 28 January 2005.
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