Enriched dairy fat matrix diet prevents early life lipopolysaccharide-induced spatial memory impairment at adulthood
Introduction
Long chain polyunsaturated fatty acids (PUFAs), in particular docosahexaenoic acid (DHA, 22:6 n-3), from the n-3 family and arachidonic acid (AA, 20:4 n-6) from the n-6 family, are crucial for the optimal development of the brain (recently reviewed in [1], [2], [3]). In humans, DHA accumulates in the intrauterine and neonatal period up to 2 years of age [4], [5], [6]. The high need and the limited synthesis of these fatty acids in the developing brain require PUFAs supply by the mother through gestation and lactation [7]. This is one of the reasons why breastfeeding is highly recommended by the World Health Organization (WHO). However, when breastfeeding is not possible, formulas have to be used. In milk formula, n-6 and n-3 PUFAs are provided by vegetable oil containing alpha-linolenic acid (ALA) and linoleic acid (LA), which are the precursors of DHA and ARA respectively. In addition of being far from breast milk lipid composition with little content in cholesterol and short-chain fatty acids, these formula do not optimize DHA accretion in the infant brain [8], [9]. Several studies have established that the enrichment of maternal diet with long chain n-3 PUFAs such as DHA and/or eicosapentaenoic acid (EPA, 20:5 n-3) leads to higher DHA accretion in the brain of the offspring not only at embryonic and weaning stage but also later in life when switched to a low DHA diet [10], [11], [12]. Recently, we demonstrated that adding up dairy blend to the diet leads to increased DHA level in the brain of pups [8], [9], [13]. Importantly, the partial replacement of vegetable oil containing ALA by dairy fat in infant formula increases DHA level in the brain both at early post-natal stage and adulthood [9], [13]. Dairy lipids consumption therefore represents an interesting perinatal nutritional strategy to improve brain DHA accretion over development.
Accumulation of DHA in the brain is a necessary step for both brain shaping and cognitive functions, not only in infants but also later in life, including for aging [14], [15]. In humans, some studies investigated the link between breast milk, DHA concentration and cognition [16], [17], [18], [19]. In most of the studies performed, DHA status was positively associated with academic performances. A high concentration in n-3 PUFAs, especially DHA, in, breast milk, was associated with better academic results in 12-years old girls [20]. Some studies report a short-term benefit of maternal DHA supplementation on cognitive processes, executive functions and memory in preterm [21], [22]. Of note, short term DHA enteral supply to preterm born infants poorly improved memory outcome later in life [Makrides, 2010 #1608], further suggesting the importance of promoting DHA accretion in the brain throughout gestation and lactation for optimal cognitive functions [14].
DHA accretion in the brain is not only crucial for optimal brain development [1], [3], [9], [23], but could be protective toward adverse events. The postnatal period is a critical time-window during which an inflammatory episode can have significant and enduring effects on the development of the central nervous system (CNS) with long-term consequences, in particular on cognitive functions [24], [25], [26], [27], [28], [29], [30]. In rodents, the early-life exposure to lipopolysaccharide (LPS), a Gram-negative bacteria endotoxin, increases the risk of developing spatial memory alterations later in life [27], [31]. Indeed, LPS administration at postnatal day (PND) 14 induces the expression of proinflammatory cytokines interleukin (IL)-1β, IL-6 and tumor necrosis factor alpha (TNFα), both at the periphery and in several brain structures (prefrontal cortex and hippocampus) and sustained spatial memory impairment [27], [31]. DHA protects from neuroinflammatory processes at adulthood and aging and from their deleterious effect on memory processes [15], [32], [33], [34], [35]. Recently, the protective effect of DHA-enriched diets on prenatal LPS administration outcomes in the offspring has been revealed [36]. Several in vitro and in vivo data suggest that the protective effects of DHA toward neuroinflammation is linked to the action of DHA and/or its derivatives (resolvins, neuroprotectins, maresins) on microglia, the brain innate immune cells and producers of proinflammatory cytokines [1], [34], [37], [38].
All together, these data suggest that brain DHA is key in the regulation of early life neuroinflammatory events and their detrimental effects on memory later in life. However, the protective effects of diets promoting brain accretion of DHA on long-term effect of post-natal inflammation have been poorly examined. The aim of this study was to evaluate the protective action of partial replacement of vegetable oil by dairy fat in infant formula, supplemented or not with DHA and ARA, on early-life LPS-induced memory impairment.
Section snippets
Animals, diets and experimental design
All experiments were conducted according to the INRA Quality Reference System, and to relevant French (Directive 87/148, Ministère de l’Agriculture et de la Pêche) and European (Directive 86/609, November 24th, 1986, European Community) legislations. They followed ethic protocols approved by the Région Aquitaine Veterinary Services (Direction Départementale de la Protection des Animaux, approval ID: A33-063-920) and by ethics committee (N° 50120112-A). Every effort was made to minimize
Dietary lipids and early life LPS effects on spatial memory at adulthood
Spatial memory was measured using a Y maze test in adult mice fed with the different diets under study (Def VL, Bal VL, Bal DL, Supp VL, Supp DL) and administered at PND14 with LPS or Sal (Fig. 1). Whatever diets consumed, adult mice receiving a saline treatment at PND14 significantly spent more time exploring the novel arm as compared to the familiar arm (Def DL : t=3.560, p<0.01; Bal VL: t=6.1, p<0.001; Bal DL: t=2.557, p<0.05; Def VL+Bal DL: t=3.375, p<0.01; Supp VL: t=2.787, p<0.05; Supp
Discussion
Our results indicate that the effect of early-life exposure to a single inflammatory event on memory capacities is modulated by the lipid composition of diets. In particular, our results bring new insights on the protective role of dietary dairy lipids against early LPS-induced memory deficits. This could be linked to brain n-3/n-6 PUFAs contents, which have previously been shown to be crucial for the regulation of brain inflammation, neurogenesis and memory [9], [15], [32], [52]. First, we
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