Short-Term Long Chain Omega3 Diet Protects from Neuroinflammatory Processes and Memory Impairment in Aged Mice

Regular consumption of food enriched in omega3 polyunsaturated fatty acids (ω3 PUFAs) has been shown to reduce risk of cognitive decline in elderly, and possibly development of Alzheimer's disease. Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are the most likely active components of ω3-rich PUFAs diets in the brain. We therefore hypothesized that exposing mice to a DHA and EPA enriched diet may reduce neuroinflammation and protect against memory impairment in aged mice. For this purpose, mice were exposed to a control diet throughout life and were further submitted to a diet enriched in EPA and DHA during 2 additional months. Cytokine expression together with a thorough analysis of astrocytes morphology assessed by a 3D reconstruction was measured in the hippocampus of young (3-month-old) and aged (22-month-old) mice. In addition, the effects of EPA and DHA on spatial memory and associated Fos activation in the hippocampus were assessed. We showed that a 2-month EPA/DHA treatment increased these long-chain ω3 PUFAs in the brain, prevented cytokines expression and astrocytes morphology changes in the hippocampus and restored spatial memory deficits and Fos-associated activation in the hippocampus of aged mice. Collectively, these data indicated that diet-induced accumulation of EPA and DHA in the brain protects against neuroinflammation and cognitive impairment linked to aging, further reinforcing the idea that increased EPA and DHA intake may provide protection to the brain of aged subjects

Etude des voies de signalisation impliquées dans les effets centraux de l'interleukine-1b

Au contact d'un agent pathogène, les monocytes et les macrophages activés synthétisent et libèrent à la périphérie la cytokine inflammatoire interleukine-1 beta (IL-1b). Celle-ci agit au niveau du système nerveux central (SNC) pour induire les manifestations physiologiques (fièvre, activation de l'axe corticotrope) et comportementales (repli de l'individu sur lui-même, anorexie inflammatoire) caractérisant l'état de maladie. Ces phénomènes correspondent à une véritable réorganisation des priorités de l'organisme malade afin d'optimiser ses réactions de défense face à une agression microbienne. Cependant, l'IL-1b, de par son poids moléculaire élevé (21 kDa) ne passe pas passivement la barrière hématoencéphalique (BHE), cette limite physique qui entoure le cerveau et qui correspond à la barrière que forment les cellules endothéliales reliées entre elles par des jonctions serrées. L'IL-1b se fixe alors sur son récepteur fonctionnel, l'IL-1RI, présent au niveau des cellules endothéliales cérébrales et au niveau de structures présentant une BHE lâche, les organes circumventriculaires (OCVs). Ceci serait à l'origine d'une synthèse locale, cérébrale, d'IL-1b et de nombreux intermédiaires moléculaires tels que les prostaglandines et aurait pour fonction de répercuter les effets de l'IL-1b périphérique afin d'induire une modification du fonctionnement cérébral. L'objectif majeur de cette étude a été de déterminer, chez le rat, les cibles d'action directes de l'IL-1b sur le SNC, en terme de mécanismes post-récepteurs, ainsi que l'implication des prostaglandines dans les effets centraux de la cytokine. Par une approche pluridisciplinaire associant étude comportementale, pharmacologique, biochimique et moléculaire, nous avons montré (1) que l'injection d'IL-1b par voie intrapéritonéale induit la translocation de la sous-unité p65 du facteur de transcription NFkB dans le noyau des cellules endothéliales de la vasculature cérébrale, des cellules épendymaires qui bordent les ventricules, des méninges et des astrocytes présents au sein des OXVs ; (2) que cette composante non-neuronale de la réponse cérébrale est essentielle à la mise en place de l'état de maladie puisque l'inhibition pharmacologique de l'activation cérébrale de la voie NFkB prévient la mise en place des effets comportementaux de l'IL-1b ainsi que l'activation cérébrale associée détectée par le marqueur d'activité cellulaire c-Fos ; (3) que la synthèse de l'enzyme Cox-2 des cellules endothéliales de la microvasculature cérébrale dépend de l'activation de ce facteur de transcription ; (4) que l'IL-1b induit parallèlement l'activation de la voie ERK1/2, visualisée par la phosphorylation de la MAPkinase ERK1/2, dans les cellules gliales des OCVs, de l'aire préoptique et du noyau arqué, selon une cinétique établie ; (5) que l'activation de la voie ERK1/2 dans l'aire préoptique est en partie imputable à l'action des prostaglandines sur leurs récepteurs cérébraux puisque celle-ci est réduite après inhibition pharmacologique de Cox-2 cérébrale, ainsi que certaines composantes des effets comportementaux induits par l'IL-1b, de préciser les intermédiaires moléculaires et cellulaires des effets de l'IL-1b dans le cerveau, de connaître l'implication des différentes voies de signalisation de la cytokine dans l'induction de ses effets comportementaux. L'objectif à terme est d'acquérir une bonne connaissance des voies de signalisation activées in vivo dans le cerveau en réponse à l'IL-1 afin d'aider au développement de nouvelles stratégies thérapeutiques pour protéger contre les effets délétères de la neuroinflammation.Interleukin-1b), produced by activated macrophages and monocytes in contact with invading microorganisms, is an important cytokine for the induction of sickness behvior. It evokes a broad spectrim of centrally mediated responses, including fever, somnolence, anorexia and altered metabolic activities. The psychological and behavioral components of sickness represent a highly organized strategy of the organism to fight infection referred to as "sickness behavior". Given its molecular weight and hydrophilic profile, IL-1b cannot passively cross the blood-brain-barrier and its central action is mediated by brain IL-1 receptors (IL-1RI) found to be mainly expressed in brain barrier-related structures like the meninges, the choroid plexus, and vascular endothelium of the whole parenchyma (including the circumventricular organs, or CVOs, that lack a BBB). Acting on its receptor, IL-1b has been proposed to induce the synthesis of small lipophylic mediators such as prostaglandins as the blood brain barrier (BBB), which in turn are thought to diffuse into the brain parenchyma and activate key brain structures mediating behavioral and physiological responses. Our main objective was to determine, in the rat brain, the cerebral cellular targets of IL-1b in term of post-receptor mechanisms, and to evaluate the involvement of prostaglandins in IL-1b central effects...BORDEAUX2-BU Santé (330632101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Microglia–Neuron Crosstalk in Obesity: Melodious Interaction or Kiss of Death?

Diet-induced obesity can originate from the dysregulated activity of hypothalamic neuronal circuits, which are critical for the regulation of body weight and food intake. The exact mechanisms underlying such neuronal defects are not yet fully understood, but a maladaptive cross-talk between neurons and surrounding microglial is likely to be a contributing factor. Functional and anatomical connections between microglia and hypothalamic neuronal cells are at the core of how the brain orchestrates changes in the body’s metabolic needs. However, such a melodious interaction may become maladaptive in response to prolonged diet-induced metabolic stress, thereby causing overfeeding, body weight gain, and systemic metabolic perturbations. From this perspective, we critically discuss emerging molecular and cellular underpinnings of microglia–neuron communication in the hypothalamic neuronal circuits implicated in energy balance regulation. We explore whether changes in this intercellular dialogue induced by metabolic stress may serve as a protective neuronal mechanism or contribute to disease establishment and progression. Our analysis provides a framework for future mechanistic studies that will facilitate progress into both the etiology and treatments of metabolic disorders

Microglia–Neuron Crosstalk in Obesity: Melodious Interaction or Kiss of Death?

Diet-induced obesity can originate from the dysregulated activity of hypothalamic neuronal circuits, which are critical for the regulation of body weight and food intake. The exact mechanisms underlying such neuronal defects are not yet fully understood, but a maladaptive cross-talk between neurons and surrounding microglial is likely to be a contributing factor. Functional and anatomical connections between microglia and hypothalamic neuronal cells are at the core of how the brain orchestrates changes in the body’s metabolic needs. However, such a melodious interaction may become maladaptive in response to prolonged diet-induced metabolic stress, thereby causing overfeeding, body weight gain, and systemic metabolic perturbations. From this perspective, we critically discuss emerging molecular and cellular underpinnings of microglia–neuron communication in the hypothalamic neuronal circuits implicated in energy balance regulation. We explore whether changes in this intercellular dialogue induced by metabolic stress may serve as a protective neuronal mechanism or contribute to disease establishment and progression. Our analysis provides a framework for future mechanistic studies that will facilitate progress into both the etiology and treatments of metabolic disorders.</jats:p

Stress and Microglia: A Double-edged Relationship

Microglia are highly dynamic cells and acquire different activation states to modulate their multiple functions, which are tightly regulated by the central nervous system microenvironment in which they reside. In response to stress, that is to the appearance of non-physiological signals in their vicinity, microglia will adapt their function in order to promote a return to brain homeostasis. However, when these stress signals are chronically present, microglial response may not be adapted and lead to the establishment of a pathological state. The aim of this book chapter is to examine the substantial literature around the ability of acute and chronic stressors to affect microglial structure and function, with a special focus on psychosocial and nutritional stresses. We also discuss the molecular mechanisms known to date that explain the link between exposure to stressors and microglial activation

Female Mice Susceptibility to the Dietary Omega-3/Omega-6 Fatty Acid Ratio: Effects on Adult Hippocampal Neurogenesis and Glia

Maternal intake of the polyunsaturated fatty acids omega-3 (n-3 PUFA) and omega-6 (n-6 PUFA) impacts hippocampal neurogenesis during development, an effect that may extend to adulthood by altering adult hippocampal neurogenesis (AHN). n-3 PUFA and n-6 PUFA are precursors of inflammatory regulators that potentially affect AHN and glia. Additionally, n-3 PUFA dietary supplementation may present a sexually dimorphic action in the brain. Therefore, we postulated that dietary n-6/n-3 PUFA balance shapes the adult DG in a sex-dependent manner influencing AHN and glia. We test our hypothesis by feeding adult female and male mice with n-3 PUFA balanced or deficient diets. To analyze the immunomodulatory potential of the diets, we injected mice with the bacterial endotoxin lipopolysaccharide (LPS). LPS reduced neuroblast number, and its effect was exacerbated by the n-3 PUFA deficient diet. The n-3 PUFA deficient diet reduced the DG volume, AHN, microglia number and surveilled volume. Diet effect on most mature neuroblasts was exclusively significant in female mice. Colocalization and multivariate analysis revealed an association between microglia and AHN, and the sexual dimorphic effect of diet. Our study reveals that female mice are more susceptible than males to the effect of dietary n-6/n-3 PUFA ratio on AHN and microglia.</jats:p

Signaling pathways of interleukin-1 actions in the brain : anatomical distribution of phospho-ERK1/2 in the brain of rat treated systemically with interleukin-1beta

International audienc

Brain cyclooxygenase-2 mediates interleukin-1-induced cellular activation in preoptic and arcuate hypothalamus, but not sickness symptoms

International audienceInterleukin-1ß acts on the CNS to induce fever, neuroendocrine activation, and behavioral changes, but cannot passively cross the blood–brain barrier. According to a widely accepted hypothesis interleukin-1ß induces the synthesis of cyclooxygenase-2 at the blood–brain interface, which produces prostaglandins that diffuse into brain parenchyma to activate neurons. We studied the role of brain cyclooxygenase-2 in interleukin-1ß-induced fever, neuroendocrine and behavioral responses and cellular activation by intracerebroventricular infusion of the cyclooxygenase-2 inhibitor NS-398. Central cyclooxygenase-2 inhibition attenuated extracellular signal-regulated kinase-1/2 phosphorylation and c-Fos induction in the median preoptic area and arcuate hypothalamus, but not in other hypothalamic or brainstem structures, after intraperitoneal interleukin-1ß administration. However, the same treatment did not affect interleukin-1ß-induced fever, rises in corticosterone or anorexia. These findings moderate the prevailing view and indicate that brain cyclooxygenase-2-dependent prostaglandin production is important to activation of the median preoptic and arcuate hypothalamus, but not necessarily involved in fever, rises in plasma corticosterone and anorexia after peripheral interleukin-1ß administration

Inactivation of the cerebral NFKB pathway inhibits interleukin-1 beta-induced sickness behavior and c-Fos expression in various brain nuclei

National audienc

Early-life PUFAs modulate shaping of neuronal circuits by microglia

Early-life PUFAs modulate shaping of neuronal circuits by microglia. 13. European Meeting on Glial Cells in Health and Diseas