Anne-Laure Dinel

Cognitive and Emotional Alterations Are Related to Hippocampal Inflammation in a Mouse Model of Metabolic Syndrome

Converging clinical data suggest that peripheral inflammation is likely involved in the pathogenesis of the neuropsychiatric symptoms associated with metabolic syndrome (MetS). However, the question arises as to whether the increased prevalence of behavioral alterations in MetS is also associated with central inflammation, i.e. cytokine activation, in brain areas particularly involved in controlling behavior. To answer this question, we measured in a mouse model of MetS, namely the diabetic and obese db/db mice, and in their healthy db/+ littermates emotional behaviors and memory performances, as well as plasma levels and brain expression (hippocampus; hypothalamus) of inflammatory cytokines. Our results shows that db/db mice displayed increased anxiety-like behaviors in the open-field and the elevated plus-maze (i.e. reduced percent of time spent in anxiogenic areas of each device), but not depressive-like behaviors as assessed by immobility time in the forced swim and tail suspension tests. Moreover, db/db mice displayed impaired spatial recognition memory (hippocampus-dependent task), but unaltered object recognition memory (hippocampus-independent task). In agreement with the well-established role of the hippocampus in anxiety-like behavior and spatial memory, behavioral alterations of db/db mice were associated with increased inflammatory cytokines (interleukin-1β, tumor necrosis factor-α and interleukin-6) and reduced expression of brain-derived neurotrophic factor (BDNF) in the hippocampus but not the hypothalamus. These results strongly point to interactions between cytokines and central processes involving the hippocampus as important contributing factor to the behavioral alterations of db/db mice. These findings may prove valuable for introducing novel approaches to treat neuropsychiatric complications associated with MetS.

Diet-induced obesity progressively alters cognition, anxiety-like behavior and lipopolysaccharide-induced depressive-like behavior: Focus on brain indoleamine 2,3-dioxygenase activation

Obesity is associated with a high prevalence of mood symptoms and cognitive dysfunctions that emerges as significant risk factors for important health complications such as cardiovascular diseases and type 2 diabetes. It is therefore important to identify the dynamic of development and the pathophysiological mechanisms underlying these neuropsychiatric symptoms. Obesity is also associated with peripheral low-grade inflammation and increased susceptibility to immune-mediated diseases. Excessive production of proinflammatory cytokines and the resulting activation of the brain tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) have been shown to promote neurobehavioral complications, particularly depression. In that context, questions arise about the impact of diet-induced obesity on the onset of neuropsychiatric alterations and the increased susceptibility to immune-mediated diseases displayed by obese patients, particularly through brain IDO activation. To answer these questions, we used C57Bl/6 mice exposed to standard diet or western diet (WD; consisting of palatable energy-dense food) since weaning and for 20 weeks. We then measured inflammatory and behavioral responses to a systemic immune challenge with lipopolysaccharide (LPS) in experimental conditions known to alter cognitive and emotional behaviors independently of any motor impairment. We first showed that in absence of LPS, 9 weeks of WD is sufficient to impair spatial recognition memory (in the Y-maze). On the other hand, 18 weeks of WD increased anxiety-like behavior (in the elevated plus-maze), but did not affect depressive-like behavior (in the tail-suspension and forced-swim tests). However, 20 weeks of WD altered LPS-induced depressive-like behavior compared to LPS-treated lean mice and exacerbated hippocampal and hypothalamic proinflammatory cytokine expression and brain IDO activation. Taken together, these results show that WD exposure alters cognition and anxiety in unstimulated conditions and enhances activation of neurobiological mechanisms underlying depression after immune stimulation. They suggest therefore that obesity, and possibly obesity-associated inflammatory priming, may represent a vulnerability state to immune-mediated depressive symptoms.

Inflammation early in life is a vulnerability factor for emotional behavior at adolescence and for lipopolysaccharide-induced spatial memory and neurogenesis alteration at adulthood

BackgroundThe postnatal period is a critical time window during which inflammatory events have significant and enduring effects on the brain, and as a consequence, induce alterations of emotional behavior and/or cognition later in life. However, the long-term effect of neonatal inflammation on behavior during adolescence, a sensitive period for the development of neurodevelopmental psychiatric disorders, has been little studied. In this study, we examined whether an early-life inflammatory challenge could alter emotional behaviors and spatial memory at adolescence and adulthood and whether stress axis activity, inflammatory response and neurogenesis were affected.MethodsLipopolysaccharide (LPS, 100 μg/kg) was administered to mice on postnatal day (PND) 14 and cytokine expression was measured in the plasma and in brain structures 3 hours later. Anxiety-like and depressive-like behavior (measured in the novelty-suppressed feeding test and the forced swim test, respectively) and spatial memory (Y-maze test) were measured at adolescence (PND30) and adulthood (PND90). Hypothalamic-pituitary-adrenal (HPA) axis activity (plasma corticosterone and glucocorticoid receptors in the hippocampus and prefrontal cortex) was measured at adulthood. In addition, the impact of a novel adult LPS challenge (100 μ/kg) was measured on spatial memory (Y-maze test), neurogenesis (doublecortin-positive cell numbers in the hippocampus) and plasma cytokine expression.ResultsFirst, we show in PND14 pups that a peripheral administration of LPS induced the expression of pro- and anti-inflammatory cytokines in the plasma and brain structures that were studied 3 hours after administration. Anxiety-like behavior was altered in adolescent, but not in adult, mice, whereas depressive-like behavior was spared at adolescence and increased at adulthood. This was accompanied by a decreased phosphorylation of the glucocorticoid receptor in the prefrontal cortex, with no effect on corticosterone levels. Second, neonatal LPS treatment had no effect on spatial memory in adolescence and adulthood. However, a second challenge of LPS in adulthood impaired spatial memory performance and neurogenesis and increased circulating levels of CCL2.ConclusionsOur study shows for the first time, in mice, that a peripheral LPS treatment at PND14 differentially alters emotional behaviors, but not spatial memory, at adolescence and adulthood. The behavioral effect of LPS at PND14 could be attributed to HPA axis deregulation and neurogenesis impairment.

Lipopolysaccharide-induced brain activation of the indoleamine 2,3-dioxygenase and depressive-like behavior are impaired in a mouse model of metabolic syndrome.

Although peripheral low-grade inflammation has been associated with a high incidence of mood symptoms in patients with metabolic syndrome (MetS), much less is known about the potential involvement of brain activation of cytokines in that context. Recently we showed in a mouse model of MetS, namely the db/db mice, an enhanced hippocampal inflammation associated with increased anxiety-like behavior (Dinel et al., 2011). However, depressive-like behavior was not affected in db/db mice. Based on the strong association between depressive-like behavior and cytokine-induced brain activation of indoleamine 2,3-dioxygenase (IDO), the enzyme that metabolizes tryptophan along the kynurenine pathway, these results may suggest an impairment of brain IDO activation in db/db mice. To test this hypothesis, we measured the ability of db/db mice and their healthy db/+ littermates to enhance brain IDO activity and depressive-like behavior after a systemic immune challenge with lipopolysaccharide (LPS). Here we show that LPS (5 μg/mouse) significantly increased depressive-like behavior (increased immobility time in a forced-swim test, FST) 24h after treatment in db/+ mice, but not in db/db mice. Interestingly, db/db mice also displayed after LPS treatment blunted increase of brain kynurenine/tryptophan ratio compared to their db/+ counterparts, despite enhanced induction of hippocampal cytokine expression (interleukin-1β, tumor necrosis factor-α). Moreover, this was associated with an impaired effect of LPS on hippocampal expression of the brain-derived neurotrophic factor (BDNF) that contributes to mood regulation, including under inflammatory conditions. Collectively, these data indicate that the rise in brain tryptophan catabolism and depressive-like behavior induced by innate immune system activation is impaired in db/db mice. These findings could have relevance in improving the management and treatment of inflammation-related complications in MetS.

Dairy fat blend improves brain DHA and neuroplasticity and regulates corticosterone in mice

Mimicking the breast milk lipid composition appears to be necessary for infant formula to cover the brains needs in n-3 PUFA. In this study, we evaluated the impact of partial replacement of vegetable oil (VL) in infant formula by dairy fat (DL) on docosahexaenoic acid (DHA) brain level, neuroplasticity and corticosterone in mice. Mice were fed with balanced VL or balanced DL diets enriched or not in DHA and arachidonic acid (ARA) from the first day of gestation. Brain DHA level, microglia number, neurogenesis, corticosterone and glucocorticoid receptor expression were measured in the offsprings. DL diet increased DHA and neuroplasticity in the brain of mice at postnatal day (PND) 14 and at adulthood compared to VL. At PND14, ARA and DHA supplementation increased DHA in VL but not in DL mice brain. Importantly, DHA and ARA supplementation further improved neurogenesis and decreased corticosterone level in DL mice at adulthood. In conclusion, dairy lipids improve brain DHA level and neuroplasticity.

Enriched dairy fat matrix diet prevents early life lipopolysaccharide-induced spatial memory impairment at adulthood

Polyunsaturated fatty acids (PUFAs) are essential fatty acids, which are critical for brain development and later life cognitive functions. The main brain PUFAs are docosahexaenoic acid (DHA) for the n-3 family and arachidonic acid (ARA) for the n-6 family, which are provided to the post-natal brain by breast milk or infant formula. Recently, the use of dairy lipids (DL) in replacement of vegetable lipids (VL) was revealed to potently promote the accretion of DHA in the developing brain. Brain DHA, in addition to be a key component of brain development, display potent anti-inflammatory activities, which protect the brain from adverse inflammatory events. In this work, we evaluated the protective effect of partial replacement of VL by DL, supplemented or not with DHA and ARA, on post-natal inflammation and its consequence on memory. Mice were fed with diets poor in vegetal n-3 PUFA (Def VL), balanced in vegetal n-3/n-6 PUFA (Bal VL), balanced in dairy lipids (Bal DL) or enriched in DHA and ARA (Supp VL; Supp DL) from the first day of gestation until adulthood. At post-natal day 14 (PND14), pups received a single administration of the endotoxin lipopolysaccharide (LPS) and brain cytokine expression, microglia phenotype and neurogenesis were measured. In a second set of experiments, memory and neurogenesis were measured at adulthood. Overall, our data showed that lipid quality of the diet modulates early life LPS effect on microglia phenotype, brain cytokine expression and neurogenesis at PND14 and memory at adulthood. In particular, Bal DL diet protects from the adverse effect of early life LPS exposure on PND14 neurogenesis and adult spatial memory.

The Interest of Adding Micronutrients to Docosahexaenoic Acid Supplementation to Prevent Age-Related Cognitive Decline

Aging is associated to cognitive decline that can lead to neurodegenerative diseases and constitutes one of the main social and economic issues of the 21st century. The loss of memory, orientation and processing abilities associated with aging are involved in the loss of autonomy and in the decline in the quality of life in the elderly. Brain structures involved in memory such as hippocampus, cortex and striatum, are particularly affected by molecular and cellular damage during this period. Lipid metabolism and neurofunctional alterations, including disturbances in synaptic plasticity and neurogenesis, chronic low-grade inflammation and increased oxidative stress, are partly to be involved in age-related cognitive decline. Actually, nutrition represents a strategy of choice to prevent or delay these impairments since many studies have provided valuable data concerning the effect of dietary patterns and specific nutrients on cognitive function. From all nutrients, some of them are particularly attractive. Indeed, n-3 polyunsaturated acids (PUFAs), especially docosahexaenoic acid (DHA), have been identified for their beneficial effects on cognition, notably by acting on brain plasticity (synaptic plasticity, neurogenesis), neuroinflammation and oxidative stress. Other nutrients such as vitamin A, vitamin E, vitamin D, polyphenols as well as pre- and probiotics have aroused a growing interest in decreasing cognitive disorders. As nutrition has to be taken as a whole, we first described the effects of the Mediterranean diet which constitutes the most complete association of nutrients and (DHA from fish, vitamins and polyphenols from fruits and vegetables) represents a global vision of nutrition, then we focused on the interest of combining DHA and micronutrients contained in this diet as well as pre- and probiotics, to prevent age-related cognitive decline and reported the synergistic effects of these associations. Finally, we completed with benefits from dairy products that increase DHA incorporation.

P309: Impact des lipides laitiers et du ratio n-6/n-3 des lipides alimentaires maternels sur la composition en acides gras du cortex préfrontal chez le nouveau-né et la souris à l’âge adulte

Introduction et but de l’etude L’alimentation maternelle au cours de la periode perinatale joue un role essentiel dans la croissance et le developpement cerebral des descendants. L’incorporation adequate d’acide docosahexaenoique (DHA) dans le cerveau est un veritable challenge en nutrition perinatale car le DHA pourrait limiter les processus neuroinflammatoires et attenuer les deficits cognitifs observes a l’âge adulte. L’objectif de l’etude est d’evaluer l’effet de regimes maternels differant par la qualite des lipides, le ratio n-6/n-3 et par l’apport en DHA sur l’incorporation de DHA dans le cortex prefrontal des petits 14 jours apres la naissance (P14) et a l’âge adulte (P90). Materiel et methodes Des souris CD 1 gestantes ont ete nourries des le premier jour de gestation avec un regime equilibre contenant des lipides laitiers supplemente (MGLA DHA/ARA) ou non (MGLA) en DHA (0,2 %) et en acide arachidonique (ARA) (0,5 %). Par comparaison, des souris gestantes ont recu un regime vegetal equilibre supplemente (VEG DHA/ARA) ou non (VEG) en DHA (0,2 %) et en ARA (0,5 %). De plus, un groupe de souris gestantes a recu un regime vegetale carence en n-3 (CAR). Les descendants ont ete nourris avec les memes regimes que leur mere jusqu’a l’âge adulte. Resultats et Analyse statistique A P14, le DHA represente 5–14 % des acides gras totaux et l’ARA 12,5–14,5 % conduisant a un ratio n-6/n-3 entre 1,2 et 1,8. A P90, le DHA est present en plus grande quantite qu’a P14 (8–17,5 %) alors que la teneur en ARA est moins elevee (9–10 %) conduisant a un ratio n-6/n-3 plus faible (0,7–0,9). Ces compositions varient en fonction des regimes maternels. A P14, la deficience en n-3 entraine une diminution significative du taux de DHA (de 11,0 a 4,8 %) compensee par une forte augmentation du taux de 22:5 n-6 (DPAn6) (de 2,6 a 5,9 %) et dans une moindre mesure du taux d’ARA (de 13,2 a 14,3 %) par rapport au groupe VEG. A l’inverse, l’ajout de DHA+ARA au groupe VEG permet d’augmenter le taux de DHA (de 11,0 a 12,7 %) et de diminuer le taux de DPAn6 (de 2,6 a 1,7 %). L’apport en lipides laitiers induit egalement une augmentation du DHA (de 11,0 a 13,0 %) et une diminution du DPAn6 (de 2,6 a 1,4 %), ainsi qu’une diminution d’ARA (de 13,2 a 12,4 %) par rapport au groupe VEG. L’ajout de DHA+ARA dans le regime MGLA entraine une diminution du DPAn6 (de 1,4 a 1,0 %) par rapport au groupe MGLA. A P90, la deficience en n-3 et l’apport en lipides laitiers ont le meme effet qu’a P14. L’ajout de DHA+ARA au regime VEG ne permet pas d’augmenter davantage le taux de DHA mais diminue celui en DPAn6 (de 1,5 a 1,0 %). Par contre l’ajout de DHA+ARA au regime MGLA permet d’augmenter le taux de DHA (de 16,4 a 17,3 %) et de diminuer le taux d’ARA (de 9,3 a 8,9 %) par rapport au groupe MGLA. Conclusion L’apport en lipides laitiers favorise l’incorporation d’AGPI n-3 a longue chaine, precurseurs de metabolites antiinflammatoires au detriment d’AGPI n-6 a longue chaine, precurseurs de metabolites pro-inflammatoires dans le cortex prefrontal chez le nouveau-ne et a l’âge adulte.

SFRP CO-11 – Lipides laitiers en période périnatale : inflammation et cognition

Introduction L’alimentation maternelle joue un role essentiel dans le developpement cerebral du nouveau-ne. Les acides gras omega3 a longue chaine et en particulier l’acide docosahexaenoique (DHA) pourraient limiter les processus neuroinflammatoires et attenuer les deficits cognitifs observes a l’âge adulte. L’objectif de l’etude est d’evaluer l’effet de regimes maternels differant par le ratio n-6/n-3 et par l’apport en DHA sur la reponse inflammatoire chez le petit et les capacites mnesiques a l’âge adulte. Methodes Des le 1er jour de gestation, des souris ont recu des regimes differant par les lipides. Apres induction d’une inflammation a J14, nous avons evalue chez les petits l’expression de cytokines en peripherie et en centrale et chez les adultes les capacites de memoire spatiale. Resultats Le regime laitier a permis de moduler la reponse inflammatoire chez le petit et de proteger l’adulte contre les troubles cognitifs induits par une infection postnatale. Les animaux nourris avec des lipides laitiers + DHA/ARA presentent des deficits de memoire spatiale dans les conditions basales et stimulees. Conclusion La consommation d’un regime contenant des lipides laitiers protege des deficits mnesiques developpes a l’âge adulte a la suite d’une inflammation en periode perinatale.