Page personnelle

Agnes NADJAR





Tél : 33(0)5 57 57 37 78
Envoyer un email








40 publication(s) depuis Novembre 2003:


Trier par

* equal contribution
Les IF indiqués ont été collectés par le Web of Sciences en


11/08/2020 | Neuropsychopharmacology   IF 6.8
Maternal dietary omega-3 deficiency worsens the deleterious effects of prenatal inflammation on the gut-brain axis in the offspring across lifetime.
Leyrolle Q, Decoeur F, Briere G, Amadieu C, Quadros ARAA, Voytyuk I, Lacabanne C, Benmamar-Badel A, Bourel J, Aubert A, Sere A, Chain F, Schwendimann L, Matrot B, Bourgeois T, Gregoire S, Leblanc JG, De Moreno De Leblanc A, Langella P, Fernandes GR, Bretillon L, Joffre C, Uricaru R, Thebault P, Gressens P, Chatel JM, Laye S, Nadjar A

Abstract:
Maternal immune activation (MIA) and poor maternal nutritional habits are risk factors for the occurrence of neurodevelopmental disorders (NDD). Human studies show the deleterious impact of prenatal inflammation and low n-3 polyunsaturated fatty acid (PUFA) intake on neurodevelopment with long-lasting consequences on behavior. However, the mechanisms linking maternal nutritional status to MIA are still unclear, despite their relevance to the etiology of NDD. We demonstrate here that low maternal n-3 PUFA intake worsens MIA-induced early gut dysfunction, including modification of gut microbiota composition and higher local inflammatory reactivity. These deficits correlate with alterations of microglia-neuron crosstalk pathways and have long-lasting effects, both at transcriptional and behavioral levels. This work highlights the perinatal period as a critical time window, especially regarding the role of the gut-brain axis in neurodevelopment, elucidating the link between MIA, poor nutritional habits, and NDD. Fig. 1 EFFECT OF N-3 PUFA DEFICIENCY ON MIA-INDUCED BEHAVIORAL DEFICITS IN NEONATES AND IN ADULT OFFSPRING.: All graphs show Means +/- SEM. a Experimental setup. b Average time spent by pups to achieve the Fox battery tests (negative geotaxis and righting reflex; 3 trials per day from PND4 to PND6). N = 14-19. Two-way ANOVA: MIA effect, F(1,62) = 11.67, p = 0.0011. c Average vocalization time (15-min sessions at PND7-8). N = 14-19. Kruskal-Wallis test followed by Mann-Whitney comparison; n-3 sufficient-Saline vs n-3 sufficient-LPS, **p < 0.01. d Neonate average locomotion measured as the distance traveled (in cm/min) during 1 min-session from PND5 to PND8. N = 14-19. Kruskal-Wallis test followed by Mann-Whitney comparison; n-3 sufficient-Saline vs n-3 deficient-saline, **p = 0.009, n-3 deficient-Saline vs n-3 deficient-LPS, ***p < 0.001. e Time course of locomotor activity of newborns from PND5 to PND8. N = 14-19. Two-way ANOVA on repeated measures followed by Bonferroni's multiple comparisons test: n-3 deficient-Saline vs n-3 deficient-LPS, *p = 0.02. f Time course of the distance traveled in the Morris Water Maze during the learning phase (in cm). N = 10. Two-way ANOVA on repeated measures: diet effect, F(1,36) = 9.22, p = 0.004. g Percentage of time spent in the target quadrant. N = 10. One-sample t test; n-3 sufficient-Saline, ***p < 0.001; n-3 sufficient-LPS, **p = 0.004; n-3 deficient-saline, ***p < 0.001; n-3 deficient-LPS, p = 0.11. h. Time course of the distance traveled in the Morris Water Maze during the reversal learning phase (in cm). N = 10. Two-way ANOVA on repeated measures: MIA effect, F(1,36) = 3.27, p = 0.008; time effect, F(1,36) = 19, p < 0.001. i Basal locomotor activity (in cm). N = 12. Kruskal-Wallis test followed by Mann-Whitney comparison; n-3 deficient-Saline vs n-3 deficient-LPS, **p = 0.008. j Time spent in the light box (anxiogenic area) of the light-dark test. N = 11. Kruskal-Wallis test followed by Mann-Whitney comparison. k Percentage of time spent in the center of the open-field arena (anxiogenic area). N = 8-11. Kruskal-Wallis test followed by Mann-Whitney comparison. Fig. 2 DIETARY N-3 PUFA DEFICIENCY EXACERBATES MIA-INDUCED ALTERATIONS OF THE HIPPOCAMPAL LIPID AND TRANSCRIPTIONAL PROFILES IN ADULTHOOD.: Quantification of the levels of total PUFAs (a), n-6 PUFAs (b), DTA n-6 (c) or DPAn-6 (d) in the hippocampus of adult mice, expressed as the percentage of total fatty acids. All graphs show Means +/- SEM. N = 6. Two-way ANOVA followed by Bonferroni's multiple comparisons test: Total PUFAs: n-3 sufficient-Saline vs n-3 deficient-Saline, ***p = 0.0001; n-3 deficient-Saline vs n-3 deficient-LPS, *p = 0.0156; n-3 deficient-Saline vs n-3 sufficient-LPS, ***p = 0.0003. Total n-6 PUFAs: n-3 sufficient-Saline vs n-3 deficient-Saline, ***p < 0.0001; n-3 deficient-Saline vs n-3 deficient-LPS, **p = 0.0055; n-3 deficient-Saline vs n-3 sufficient-LPS, ***p < 0.0001; n-3 sufficient-Saline vs n-3 deficient LPS, ***p < 0.0001; n-3 deficient-LPS vs n-3 sufficient-LPS, ***p < 0.0001. DTA n-6: n-3 sufficient-Saline vs n-3 deficient-Saline, ***p < 0.0001; n-3 deficient-Saline vs n-3 deficient-LPS, **p = 0.0013; n-3 deficient-Saline vs n-3 sufficient-LPS, ***p < 0.0001; n-3 sufficient-Saline vs n-3 deficient LPS, ***p = 0.0004; n-3 deficient-LPS vs n-3 sufficient-LPS, *p = 0.0158. DPA n-6: n-3 sufficient-Saline vs n-3 deficient-Saline, ***p < 0.0001; n-3 deficient-Saline vs n-3 deficient-LPS, **p = 0.0045; n-3 deficient-Saline vs n-3 sufficient-LPS, ***p < 0.0001; n-3 sufficient-Saline vs n-3 deficient LPS, ***p < 0.0001; n-3 deficient-LPS vs n-3 sufficient-LPS, ***p < 0.0001. e Venn diagram highlighting the number of genes that were modulated by MIA in the hippocampi of adult n-3 sufficient (blue) or n-3 deficient (red) mice. Lower panel: Number of genes that were up- or down-regulated in n-3 sufficient and n-3 deficient mice. Representation of the 20 most significantly dysregulated genes in n-3 sufficient (f) and n-3 deficient (g) mice. Genes that appear in both n-3 sufficient and n-3 deficient mice are bold. h PCA analysis of MIA-induced differentially expressed genes (DEG) in both dietary groups. Confidence ellipses appear around each group. i, j Gene Ontology analysis of DEGs (light red and blue: up-regulated genes; dark red and blue: down-regulated genes). Fig. 3 EFFECT OF N-3 PUFA DEFICIENCY AND MIA ON MICROGLIA-NEURON CROSSTALK PATHWAYS, SPINE DENSITY, OLIGODENDROCYTE AND MYELIN PROTEIN EXPRESSION.: All graphs show Means +/- SEM. a Colocalization of Iba-1 and PSD95 proteins immunoreactivity in the CA1 region of the hippocampus of PND14 pups. Representative confocal image of Iba-1 (green) PSD95 (red) costaining (Top panel: scale bar = 10 microm) and Imaris 3D reconstruction (Bottom panel, scale bar = 1 microm). N = 72-122. Kruskal-Wallis test followed by Mann-Whitney comparisons; n-3 deficient-Saline vs n-3 sufficient-Saline, ***p < 0.0001; n-3 deficient-LPS vs n-3 sufficient-LPS, ***p < 0.0001. b qRT-PCR quantification of microglia-neuron interaction mRNA markers in the hippocampus of PND14 mice (data normalized to the saline group, dotted line). N = 4-6. Kruskal-Wallis test followed by Mann-Whitney comparisons; *p < 0.05, **p < 0.01 (all comparisons in Table S2). c Quantification and representative images of Golgi staining spine density in the CA1 region of the hippocampus at PND28. N = 8-21. Kruskal-Wallis test followed by Mann-Whitney comparisons; n-3 deficient-Saline vs n-3 deficient-LPS, ***p < 0.0001; n-3 deficient-Saline vs n-3 sufficient-Saline, **p = 0.001; n-3 deficient-LPS vs n-3 sufficient-LPS, *p = 0.025. d Western blot-based quantification and representative images of PSD95 protein expression in the hippocampus of PND28 mice. N = 4-8. Kruskal-Wallis test followed by Mann-Whitney comparisons; n-3 deficient-Saline vs n-3 deficient-LPS, **p = 0.004; n-3 deficient-LPS vs n-3 sufficient-LPS, *p = 0.03. Quantification of Olig2 (e), PLP (f), APC (g), MAG (h) and MBP (i) immunoreactivity in the hippocampus of PND14 mice. N = 4-7. Two-way ANOVA. Olig2: diet effect, F(1,20) = 3.48, p = 0.08; MIA effect, F(1,20) = 4.78, p = 0.041. PLP: MIA effect, F(1,22) = 5.01, p = 0.036. APC: diet effect, F(1,17) = 4.96, p = 0.0397. Fig. 4 EFFECT OF N-3 PUFA DEFICIENCY AND MIA ON GUT MICROBIOTA COMPOSITION AT PND14 AND PND21.: All graphs show Means +/- SEM. a 16S rRNA-sequencing-based alpha diversity analysis of the microbiota, measured by Shannon index in PND14 mice. N = 8-12. Two-way ANOVA: diet effect, F(1,39) = 12.76, p < 0.001; MIA effect, F(1,39) = 5.39, p = 0.026. Bacteria phyla (b) and family (c) observed in all experimental groups at PND14. d PCA of all subjects at PND14. Confidence ellipses appear around each group. e 16S rRNA-sequencing-based alpha diversity analysis, measured by Shannon index in PND21 mice. N=8-13. Two-way ANOVA: n-3 sufficient-Saline vs n-3 sufficient-LPS, ***p = 0.0005; n-3 sufficient-LPS vs n-3 deficient-LPS, *p = 0.019; n-3 sufficient-Saline vs n-3 deficient-Saline, **p = 0.0078. Bacteria phyla (f) and family (g) observed in all experimental groups at PND21. h PCA of all subjects at PND14. Confidence ellipses appear around each group. Quantification of MLN lymphocytes cytokine release measured by ELISA at PND14 (i) and PND21 (j). N = 6-15; Kruskal-Wallis test followed by Mann-Whitney comparisons; *p < 0.05, **p < 0.01, ***p < 0.001 (all comparisons in Table S2). Z-score of T cells inflammatory reactivity in PND14 (k) and PND21 (l) mice. N = 7-15. Kruskal-Wallis test followed by Mann-Whitney comparisons; PND14: n-3 deficient-Saline vs n-3 deficient-LPS, ***p < 0.001. PND21: n-3 sufficient-Saline vs n-3 sufficient-LPS, **p = 0.0011, n-3 sufficient-LPS vs n-3 deficient-LPS, ***p = <0.0004. Fig. 5 CORRELATIONS BETWEEN MICROBIAL MODIFICATIONS, GUT INFLAMMATION, AND NEUROBIOLOGICAL PARAMETERS.: a Spearman's correlation matrix between gut immune cells reactivity (e.g cytokine release after T-cells stimulation) and bacterial genera in PND14 mice (*p = 0.05). b Spearman's correlation matrix between neurobiological measurements (PLP, Olig2, Iba-1 and MAP2) and bacterial genera in PND14 mice (*p = 0.05). c Spearman's correlation matrix between gut immune cells reactivity (e.g cytokine release after T-cells stimulation) and bacterial genera in PND21 mice (*p = 0.05). d Spearman's correlation matrix between neurobiological measurements (PLP, Olig2, Iba-1, and MAP2) and bacterial genera in PND21 mice (*p = 0.05). e Spearman's correlation between gut immune cells reactivity (e.g released cytokines after stimulation) and neurobiological parameters in PND21 mice (*p = 0.05). N = 20-22. Escherichia-Shig: Escherichia-Shigella; Eubacterium copro: Eubacterium coprostanoligenes group; Lachno NK4A136: Lachnospiraceae NK4A136 group; Lachno UCG-008: Lachnospiraceae UCG-008; Prevo UCG-001: Prevotellaceae UCG-001; Rikenellaceae RC9: Rikenellaceae RC9 gut group; Ruminococcus gg: Ruminococcus gnavus group. f Schematic summarizing the main findings. Exposure of n-3 PUFA deficient dams to MIA alters the gut microbiota composition and increases the inflammatory reactivity of the gut T-lymphocytes in the offspring during the post-natal period. This is correlated with an impairment in microglia-neuron crosstalk during this phase, with consequences on hippocampus function and memory abilities later in life.




12/03/2020 | compr physiol
Role of Glia in the Regulation of Sleep in Health and Disease.
Garofalo S, Picard K, Limatola C, Nadjar A, Pascual O, Tremblay ME

Abstract:
Sleep is a naturally occurring physiological state that is required to sustain physical and mental health. Traditionally viewed as strictly regulated by top-down control mechanisms, sleep is now known to also originate locally. Glial cells are emerging as important contributors to the regulation of sleep-wake cycles, locally and among dedicated neural circuits. A few pioneering studies revealed that astrocytes and microglia may influence sleep pressure, duration as well as intensity, but the precise involvement of these two glial cells in the regulation of sleep remains to be fully addressed, across contexts of health and disease. In this overview article, we will first summarize the literature pertaining to the role of astrocytes and microglia in the regulation of sleep under normal physiological conditions. Afterward, we will discuss the beneficial and deleterious consequences of glia-mediated neuroinflammation, whether it is acute, or chronic and associated with brain diseases, on the regulation of sleep. Sleep disturbances are a main comorbidity in neurodegenerative diseases, and in several brain diseases that include pain, epilepsy, and cancer. Identifying the relationships between glia-mediated neuroinflammation, sleep-wake rhythm disruption and brain diseases may have important implications for the treatment of several disorders. (c) 2020 American Physiological Society. Compr Physiol 10:687-712, 2020.




03/2020 | Brain Behav Immun   IF 6.6
Brain eicosapentaenoic acid metabolism as a lead for novel therapeutics in major depression.
Bazinet RP, Metherel AH, Chen CT, Shaikh SR, Nadjar A, Joffre C, Laye S

Abstract:
The results of several meta-analyses suggest that eicosapentaenoic acid (EPA) supplementation is therapeutic in managing the symptoms of major depression. It was previously assumed that because EPA is extremely low in the brain it did not cross the blood-brain barrier and any therapeutic effects it exerted would be via the periphery. However, more recent studies have established that EPA does enter the brain, but is rapidly metabolised following entry. While EPA does not accumulate within the brain, it is present in microglia and homeostatic mechanisms may regulate its esterification to phospholipids that serve important roles in cell signaling. Furthermore, a variety of signaling molecules from EPA have been described in the periphery and they have the potential to exert effects within the brain. If EPA is confirmed to be therapeutic in major depression as a result of adequately powered randomized clinical trials, future research on brain EPA metabolism could lead to the discovery of novel targets for treating or preventing major depression.




03/2020 | Brain Behav Immun   IF 6.6
Dietary N-3 PUFA deficiency affects sleep-wake activity in basal condition and in response to an inflammatory challenge in mice.
Decoeur F, Benmamar-Badel A, Leyrolle Q, Persillet M, Laye S, Nadjar A

Abstract:
Essential polyunsaturated fatty acids (PUFA) from the n-3 and n-6 series constitute the building blocks of brain cell membranes where they regulate most aspects of cell physiology. They are either biosynthesized from their dietary precursors or can be directly sourced from the diet. An overall increase in the dietary n-6/n-3 PUFA ratio, as observed in the Western diet, leads to reduced n-3 PUFAs in tissues that include the brain. Some clinical studies have shown a positive correlation between dietary n-3 PUFA intake and sleep quantity, yet evidence is still sparse. We here used a preclinical model of dietary n-3 PUFA deficiency to assess the precise relationship between dietary PUFA intake and sleep/wake activity. Using electroencephalography (EEG)/electromyography (EMG) recordings on n-3 PUFA deficient or sufficient mice, we showed that dietary PUFA deficiency affects the architecture of sleep-wake activity and the oscillatory activity of cortical neurons during sleep. In a second part of the study, and since PUFAs are a potent modulator of inflammation, we assessed the effect of dietary n-3 PUFA deficiency on the sleep response to an inflammatory stimulus known to modulate sleep/wake activity. We injected mice with the endotoxin lipopolysaccharide (LPS) and quantified the sleep response across the following 12h. Our results revealed that n-3 PUFA deficiency affects the sleep response in basal condition and after a peripheral immune challenge. More studies are now required aimed at deciphering the molecular mechanisms underlying the intimate relationship between n-3 PUFAs and sleep/wake activity.




24/08/2019 | Neurosci Lett   IF 2.3
Direct and indirect effects of lipids on microglia function.
Leyrolle Q, Laye S, Nadjar A

Abstract:
Microglia are key players in brain function by maintaining brain homeostasis across lifetime. They participate to brain development and maturation through their ability to release neurotrophic factors, to remove immature synapses or unnecessary neural progenitors. They modulate neuronal activity in healthy adult brains and they also orchestrate the neuroinflammatory response in various pathophysiological contexts such as aging and neurodegenerative diseases. One of the main features of microglia is their high sensitivity to environmental factors, partly via the expression of a wide range of receptors. Recent data pinpoint that dietary fatty acids modulate microglia function. Both the quantity and the type of fatty acid are potent modulators of microglia physiology. The present review aims at dissecting the current knowledge on the direct and indirect mechanisms (focus on gut microbiota and hormones) through which fatty acids influence microglial physiology. We summarize main discoveries from in vitro and in vivo models on fatty acid-mediated microglial modulation. All these studies represent a promising field of research that could promote using nutrition as a novel therapeutic or preventive tool in diseases involving microglia dysfunctions.




02/2019 | Brain Behav Immun   IF 6.6
Dietary n-3 long chain PUFA supplementation promotes a pro-resolving oxylipin profile in the brain.
Rey C, Delpech JC, Madore C, Nadjar A, Greenhalgh AD, Amadieu C, Aubert A, Pallet V, Vaysse C, Laye S, Joffre C

Abstract:
The brain is highly enriched in long chain polyunsaturated fatty acids (LC-PUFAs) that display immunomodulatory properties in the brain. At the periphery, the modulation of inflammation by LC-PUFAs occurs through lipid mediators called oxylipins which have anti-inflammatory and pro-resolving activities when derived from n-3 LC-PUFAs and pro-inflammatory activities when derived from n-6 LC-PUFAs. However, whether a diet rich in LC-PUFAs modulates oxylipins and neuroinflammation in the brain has been poorly investigated. In this study, the effect of a dietary n-3 LC-PUFA supplementation on oxylipin profile and neuroinflammation in the brain was analyzed. Mice were given diets deficient or supplemented in n-3 LC-PUFAs for a 2-month period starting at post-natal day 21, followed by a peripheral administration of lipopolysaccharide (LPS) at adulthood. We first showed that dietary n-3 LC-PUFA supplementation induced n-3 LC-PUFA enrichment in the hippocampus and subsequently an increase in n-3 PUFA-derived oxylipins and a decrease in n-6 PUFA-derived oxylipins. In response to LPS, n-3 LC-PUFA deficient mice presented a pro-inflammatory oxylipin profile whereas n-3 LC-PUFA supplemented mice displayed an anti-inflammatory oxylipin profile in the hippocampus. Accordingly, the expression of cyclooxygenase-2 and 5-lipoxygenase, the enzymes implicated in pro- and anti-inflammatory oxylipin synthesis, was induced by LPS in both diets. In addition, LPS-induced pro-inflammatory cytokine increase was reduced by dietary n-3 LC-PUFA supplementation. These results indicate that brain n-3 LC-PUFAs increase by dietary means and promote the synthesis of anti-inflammatory derived bioactive oxylipins. As neuroinflammation plays a key role in all brain injuries and many neurodegenerative disorders, the present data suggest that dietary habits may be an important regulator of brain cytokine production in these contexts.




10/2018 | Brain Behav Immun   IF 6.6
Dietary omega-3 deficiency exacerbates inflammation and reveals spatial memory deficits in mice exposed to lipopolysaccharide during gestation.
Labrousse VF, Leyrolle Q, Amadieu C, Aubert A, Sere A, Coutureau E, Gregoire S, Bretillon L, Pallet V, Gressens P, Joffre C, Nadjar A, Laye S

Abstract:
Maternal immune activation (MIA) is a common environmental insult on the developing brain and represents a risk factor for neurodevelopmental disorders. Animal models of in utero inflammation further revealed a causal link between maternal inflammatory activation during pregnancy and behavioural impairment relevant to neurodevelopmental disorders in the offspring. Accumulating evidence point out that proinflammatory cytokines produced both in the maternal and fetal compartments are responsible for social, cognitive and emotional behavioral deficits in the offspring. Polyunsaturated fatty acids (PUFAs) are essential fatty acids with potent immunomodulatory activities. PUFAs and their bioactive derivatives can promote or inhibit many aspects of the immune and inflammatory response. PUFAs of the n-3 series ('n-3 PUFAs', also known as omega-3) exhibit anti-inflammatory/pro-resolution properties and promote immune functions, while PUFAs of the n-6 series ('n-6 PUFAs' or omega-6) favor pro-inflammatory responses. The present study aimed at providing insight into the effects of n-3 PUFAs on the consequences of MIA on brain development. We hypothesized that a reduction in n-3 PUFAs exacerbates both maternal and fetal inflammatory responses to MIA and later-life defects in memory in the offspring. Based on a lipopolysaccharide (LPS) model of MIA (LPS injection at embryonic day 17), we showed that n-3 PUFA deficiency 1) alters fatty acid composition of the fetal and adult offspring brain; 2) exacerbates maternal and fetal inflammatory processes with no significant alteration of microglia phenotype, and 3) induces spatial memory deficits in the adult offspring. We also showed a strong negative correlation between brain content in n-3 PUFA and cytokine production in MIA-exposed fetuses. Overall, our study is the first to address the deleterious effects of n-3 PUFA deficiency on brain lipid composition, inflammation and memory performances in MIA-exposed animals and indicates that it should be considered as a potent environmental risk factor for the apparition of neurodevelopmental disorders.




08/2018 | Prostaglandins Leukot Essent Fatty Acids   IF 2.9
Role of metabolic programming in the modulation of microglia phagocytosis by lipids.
Nadjar A

Abstract:
Microglia phagocytosis is an essential process to maintain lifelong brain homeostasis and clear potential toxic factors from the neuropil. Microglia can engulf cells or part of cells through the expression of specific receptors at their surface and activation of downstream signaling pathways to engulf material. Microglia phagocytosis is finely regulated and is under the dependence of many factors, including environmental cues such as dietary lipids. Yet, the molecular mechanisms implicated are still largely unknown. The present publication is a 'hypothesis review', assessing the possibility that lipid-mediated modulation of phagocytosis occurs by affecting bioenergetic pathways within microglia. I assess our present knowledge and the elements that allow drawing such hypothesis. I also list some of the important gaps in the literature that need to be filled in. I also consider opportunities for future therapeutic target including nutritional interventions.




06/2018 | Prostaglandins Leukot Essent Fatty Acids   IF 2.9
Maternal n-3 polyunsaturated fatty acid dietary supply modulates microglia lipid content in the offspring.
Rey C, Nadjar A, Joffre F, Amadieu C, Aubert A, Vaysse C, Pallet V, Laye S, Joffre C

Abstract:
The brain is highly enriched in long chain polyunsaturated fatty acids (LC-PUFAs) that are esterified into phospholipids, the major components of cell membranes. They accumulate during the perinatal period when the brain is rapidly developing. Hence, the levels of LC-PUFAs in the brains of the offspring greatly depend on maternal dietary intake. Perinatal n-3 PUFA consumption has been suggested to modulate the activity of microglial cells, the brain's innate immune cells which contribute to the shaping of neuronal network during development. However, the impact of maternal n-3 PUFA intake on microglial lipid composition in the offspring has never been studied. To investigate the impact of maternal dietary n-3 PUFA supply on microglia lipid composition, pregnant mice were fed with n-3 PUFA deficient, n-3 PUFA balanced or n-3 PUFA supplemented diets during gestation and lactation. At weaning, microglia were isolated from the pup's brains to analyze their fatty acid composition and phospholipid class levels. We here report that post-natal microglial cells displayed a distinctive lipid profile as they contained high levels of eicosapentaenoic acid (EPA), more EPA than docosahexaenoic acid (DHA) and large amount of phosphatidylinositol (PI) / phosphatidylserine (PS). Maternal n-3 PUFA supply increased DHA levels and decreased n-6 docosapentaenoic acid (DPA) levels whereas the PI/PS membrane content was inversely correlated to the quantity of PUFAs in the diet. These results raise the possibility of modulating microglial lipid profile and their subsequent activity in the developing brain.




Abstract:
Classically, polyunsaturated fatty acids (PUFA) were largely thought to be relatively inert structural components of brain, largely important for the formation of cellular membranes. Over the past 10 years, a host of bioactive lipid mediators that are enzymatically derived from arachidonic acid, the main n-6 PUFA, and docosahexaenoic acid, the main n-3 PUFA in the brain, known to regulate peripheral immune function, have been detected in the brain and shown to regulate microglia activation. Recent advances have focused on how PUFA regulate the molecular signaling of microglia, especially in the context of neuroinflammation and behavior. Several active drugs regulate brain lipid signaling and provide proof of concept for targeting the brain. Because brain lipid metabolism relies on a complex integration of diet, peripheral metabolism, including the liver and blood, which supply the brain with PUFAs that can be altered by genetics, sex, and aging, there are many pathways that can be disrupted, leading to altered brain lipid homeostasis. Brain lipid signaling pathways are altered in neurologic disorders and may be viable targets for the development of novel therapeutics. In this study, we discuss in particular how n-3 PUFAs and their metabolites regulate microglia phenotype and function to exert their anti-inflammatory and proresolving activities in the brain.