Dietary Long‐Chain n‐3 Polyunsaturated Fatty Acid Supplementation Alters Electrophysiological Properties in the Nucleus Accumbens and Emotional Behavior in Naïve and Chronically Stressed Mice

Long‐chain (LC) n‐3 polyunsaturated fatty acids (PUFAs) have drawn attention in the field of neuropsychiatric disorders, in particular depression. However, whether dietary supplementation with LC n‐3 PUFA protects from the development of mood disorders is still a matter of de-bate. In the present study, we studied the effect of a two‐month exposure to isocaloric diets containing n‐3 PUFAs in the form of relatively short‐chain (SC) (6% of rapeseed oil, enriched in α‐linolenic acid (ALA)) or LC (6% of tuna oil, enriched in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) PUFAs on behavior and synaptic plasticity of mice submitted or not to a chronic social defeat stress (CSDS), previously reported to alter emotional and social behavior, as well as synaptic plasticity in the nucleus accumbens (NAc). First, fatty acid content and lipid metabolism gene expression were measured in the NAc of mice fed a SC (control) or LC n‐3 (supplemented) PUFA diet. Our results indicate that LC n‐3 supplementation significantly increased some n‐3 PUFAs, while decreasing some n‐6 PUFAs. Then, in another cohort, control and n‐3 PUFA‐supplemented mice were subjected to CSDS, and social and emotional behaviors were assessed, together with long‐term depression plasticity in accumbal medium spiny neurons. Overall, mice fed with n‐3 PUFA supple-mentation displayed an emotional behavior profile and electrophysiological properties of medium spiny neurons which was distinct from the ones displayed by mice fed with the control diet, and this, independently of CSDS. Using the social interaction index to discriminate resilient and suscep-tible mice in the CSDS groups, n‐3 supplementation promoted resiliency. Altogether, our results pinpoint that exposure to a diet rich in LC n‐3 PUFA, as compared to a diet rich in SC n‐3 PUFA, influences the NAc fatty acid profile. In addition, electrophysiological properties and emotional behavior were altered in LC n‐3 PUFA mice, independently of CSDS. Our results bring new insights about the effect of LC n‐3 PUFA on emotional behavior and synaptic plasticity. © 2022 by the authors. Licensee MDPI, Basel, Switzerland

The Role of Dietary N-6 Polyunsaturated Fatty Acids on Lipid Mediators and Inflammation in the Mouse Brain

N-6 polyunsaturated fatty acids (PUFA) such as arachidonic acid (ARA, 20:4) and n-3 PUFA as docosahexaenoic acid (DHA, 22:6) are precursors to bioactive lipid mediators, which have important roles in many brain functions including inflammation. Previous studies have shown that dietary n-6 PUFA deprivation in pups can change brain ARA and DHA levels. However, the effects of n-6 PUFA deprivation on brain lipid metabolism during maternal stage has yet to be studied. Moreover, n-6 PUFA have been linked to the pathogenesis of many neurological disorders through many mechanisms, including conversion to ARA-derived lipid mediators (pro-inflammatory mediators) in the brain. Though diets low in n-6 PUFA are known to reduce levels of ARA and ARA-derived lipid mediators, no one has yet investigated the effects of lowering dietary n-6 PUFA on modulating brain inflammation and resolution in neuroinflammation. The first objective of this thesis was to examine how lowering dietary n-6 PUFA, from gestation, would change levels of hippocampal n-6 and n-3 PUFA and their lipid mediators in comparison to the offspring period. We found that maternal exposure to an n-6 PUFA deprived diet does not exacerbate the reduction in ARA and ARA-derived lipid mediators within hippocampal phospholipids (PL) relative to offspring exposure, which suggests that offspring exposure is a main regulating factor of these PUFA and their derivatives. Therefore, we used the offspring stage as the feeding period for the subsequent neuroinflammation study. Neuroinflammation was induced using intracerebroventricular injection of lipopolysaccharide (LPS) and the hippocampus was examined at several time points. Following LPS, different pro-inflammatory gene expression was associated with enrichment in gene expression categories associated with inflammation. However, these pro-inflammatory markers were not reduced by lowering dietary n-6 PUFA and importantly did not impair the resolution of neuroinflammation. In conclusion, we found that exposure of the offspring to an n-6 PUFA deprived diet was sufficient to lower the concentrations of ARA and other n-6 PUFA in hippocampal total PL. In a neuroinflammation model, the expression in gene ontology categories associated with inflammation was significantly increased and then resolved in response to LPS administration, however, irrespective of an n-6 PUFA diet.Ph.D

The effects of n-6 polyunsaturated fatty acid deprivation on the inflammatory gene response to lipopolysaccharide in the mouse hippocampus

Abstract Background Neuroinflammation is thought to contribute to psychiatric and neurological disorders such as major depression and Alzheimer’s disease (AD). N-6 polyunsaturated fatty acids (PUFA) and molecules derived from them, including linoleic acid- and arachidonic acid-derived lipid mediators, are known to have pro-inflammatory properties in the periphery; however, this has yet to be tested in the brain. Lowering the consumption of n-6 PUFA is associated with a decreased risk of depression and AD in human observational studies. The purpose of this study was to investigate the inflammation-modulating effects of lowering dietary n-6 PUFA in the mouse hippocampus. Methods C57BL/6 male mice were fed either an n-6 PUFA deprived (2% of total fatty acids) or an n-6 PUFA adequate (23% of total fatty acids) diet from weaning to 12 weeks of age. Animals then underwent intracerebroventricular surgery, in which lipopolysaccharide (LPS) was injected into the left lateral ventricle of the brain. Hippocampi were collected at baseline and following LPS administration (1, 3, 7, and 14 days). A microarray (n = 3 per group) was used to identify candidate genes and results were validated by real-time PCR in a separate cohort of animals (n = 5–8 per group). Results Mice administered with LPS had significantly increased Gene Ontology categories associated with inflammation and immune responses. These effects were independent of changes in gene expression in any diet group. Results were validated for the effect of LPS treatment on astrocyte, cytokine, and chemokine markers, as well as some results of the diets on Ifrd2 and Mfsd2a expression. Conclusions LPS administration increases pro-inflammatory and lipid-metabolizing gene expression in the mouse hippocampus. An n-6 PUFA deprived diet modulated inflammatory gene expression by both increasing and decreasing inflammatory gene expression, without impairing the resolution of neuroinflammation following LPS administration