Polyunsaturated fatty acids (PUFAs) are essential fatty acids which are provided to the body through the diet. The brain is one of the richest organs in the body and has a high need in PUFAs. There ...are 2 main families of PUFAs, n-3 (or omega 3) and n-6 (or omega6). While it is quite easy to find n-6 PUFAs in westernized diets, the need in n-3 PUFAs is poorly reached, leading to decreased level of docosahexaenoic acid (DHA) in the brain. In humans, poor levels of blood n-3 PUFAs and brain DHA are associated to a higher prevalence of cognitive disorders and depression. However, the mechanisms underlying the effect of DHA on brain functions are poorly understood. Using mice models of n-3 PUFAs dietary deficiency or supplementation, we revealed that in the brain, DHA regulate neuroinflammatory pathways, in particular through its effect on microglia, the main innate immune system cell in the brain. In addition, n-3 PUFAs are key actors of ndocannabinoid- dependent synaptic plasticity. While neuroinflammation and eCB-dependent synaptic plasticity are crucial to cognition and emotional behaviour alterations, our results bring to the clinical scene the importance of controlling dietary n-3 PUFAs to protect the brain from the adverse effect of stres or inflammation. Altogether, our work brings a better comprehension of how dietary n-3 PUFAs participate to brain physiology and protect from the development of mood and cognitive disorders. It opens new avenues for the use of these lipids in the protection and treatment of brain diseases.
Disclosure
No significant relationships.
•Fatty acids can modulate microglia function across lifetime.•Lipids influence microglia through direct and indirect mechanisms.•Dietary lipids could represent a novel modifiable factor in diseases ...involving microglial dysfunctions.
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.
Abstract Due to the implication of docosahexaenoic acid (DHA) in neurogenesis, synaptogenesis, neurite outgrowth and to its high incorporation into the brain, this n-3 long chain polyunsaturated ...fatty acid (LCPUFA) is considered as crucial in the development and maintenance of the learning memory performance throughout life. In the present chapter we aimed at reviewing data investigating the relation between DHA and cognition during the perinatal period, young adult- and adulthood and neurodegenerative diseases such as Alzheimer disease (AD). In Humans, dietary DHA supplementation from the perinatal period to adulthood does not reveal a clear and consistent memory improvement whereas it is the case in animal studies. The positive effects observed in animal models may have been enhanced by using n-3 PUFA deficient animal models as controls. In animal models of AD, a general consensus on the beneficial effects of n-3 LCPUFA in attenuating cognitive impairment was established. These studies make DHA a potential suitable micronutrient for the maintenance of cognitive performance at all periods of life.
•Maternal omega-3 deficiency has deleterious effects on pups’ brain development.•Maternal omega-3 deficiency alters fatty acid composition of the fetal and adult offspring brain.•Maternal omega-3 ...deficiency exacerbates maternal and fetal inflammation.•Maternal omega-3 deficiency induces spatial memory deficits in the adult offspring.•There is a strong negative correlation between brain content in omega-3 and cytokines production.
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.
Obesity is characterized by chronic low-grade inflammation that may lead to emotional distress and behavioural symptoms. This study assessed the relationship between adiposity, low-grade ...inflammation, eating behaviour and emotional status in obese women awaiting gastric surgery and investigated the effects of surgery-induced weight loss on this relationship.
A total of 101 women with severe or morbid obesity awaiting gastric surgery were recruited. Assessments were performed before and at 1 year post-surgery and included the measurement of neuroticism and extraversion using the revised Neuroticism-Extraversion-Openness personality inventory (NEO-PI-R) and eating behaviour using the Three-Factor Eating Questionnaire (TFEQ). Blood samples were collected for the measurement of serum inflammatory markers interleukin-6 (IL-6), high-sensitive C-reactive protein (hsCRP) and adipokines (leptin, adiponectin).
At baseline, body mass index (BMI) was positively correlated with inflammatory markers and adipokines. Regression analyses adjusting for age and diabetes revealed that baseline concentrations of IL-6 and hsCRP were associated with the depression and anxiety facets of neuroticism, with higher inflammation predicting higher anxiety and depression. This association remained significant after adjusting for BMI. Gastric surgery induced significant weight loss, which correlated with reduced inflammation. After controlling for BMI variations, decreases in inflammatory markers, notably hsCRP, were associated with reduced anxiety and TFEQ-cognitive restraint scores.
These findings indicate strong associations between adiposity, inflammation and affectivity in obese subjects and show that surgery-induced weight loss is associated concomitantly with reduced inflammation and adipokines and with significant improvement in emotional status and eating behaviour. Inflammatory status appears to represent an important mediator of emotional distress and psychological characteristics of obese individuals.
•Fish hydrolysate contains n-3 LC-PUFAs and low molecular weight peptides.•Fish hydrolysate prevents age-related short-term memory deficits.•Fish hydrolysate affects navigation strategies during ...spatial learning.•Fish hydrolysate possesses immunomodulatory and anxiolytic properties.•Fish hydrolysate is promising for the prevention of age-related cognitive decline.
Brain aging is characterized by a decline in cognitive functions, which can lead to the development of neurodegenerative pathologies. Age-related spatial learning and memory deficits are associated with a chronic low-grade inflammation. Anxiety disorders and stress response alterations, occurring for a part of the elderly, have also been linked to an increased neuroinflammation and thus, an accelerated cognitive decline. Nutrition is an innovative strategy to prevent age-related cognitive impairments. Among the nutrients, n-3 long chain polyunsaturated fatty acids (LC-PUFAs) and low molecular weight peptides from proteins, especially those from marine resources, are good candidates for their immunomodulatory, anxiolytic and neuroprotective properties. The aim of this study is to determine the combined effect of n-3 LC-PUFAs and low molecular weight peptides on cognitive functions, and their mechanism of action. We are the first to show that a dietary supplementation with a fish hydrolysate containing n-3 LC-PUFAs and low molecular weight peptides prevented the age-related spatial short-term memory deficits and modulated navigation strategies adopted during spatial learning. In addition, the fish hydrolysate displayed anxiolytic activities with the reduction of anxiety-like behaviour in aged mice, restored the plasmatic corticosterone levels similar to adult animals following an acute stress and modulated the hypothalamic stress response. These effects on behaviour can be explained by the immunomodulatory and neuroprotective properties of the fish hydrolysate that limited microgliosis in vivo, decreased LPS-induced expression of pro-inflammatory cytokines and increased the expression of growth factors such as BDNF and NGF in vitro. Thus, n-3 LC-PUFAs and low molecular weight peptides contained in the fish hydrolysate can play an important role in the limitation of neuroinflammation and stress response alterations during aging and represent a potential strategy for the prevention of age-related cognitive decline.
Energy-dense food exposure and stress during development have been suggested to contribute to obesity and metabolic disorders later in life. Although these factors are frequently associated, the ...effects of their combination have not yet been investigated. In this study, using an animal model, we examined the long-term impact of maternal high-fat diet (HFD) and early-life stress (ELS) on energy homoeostasis control and food motivation.
Body weight growth under HFD, adipose tissue, body weight control in response to fasting and refeeding, food-motivated behaviour and mesolimbic dopamine function were examined in adult male offspring exposed to maternal HFD (during gestation and lactation) and/or ELS (maternal separation 3 h per day from postnatal day 2 to 14).
Maternal HFD or ELS alone had no significant effect on offspring body weight; however, the combination of these factors exacerbated body weight gain when animals were exposed to HFD after weaning. There are no other significant combinatory effects of these perinatal events. In contrast, independently of the maternal diet, ELS disrupted body weight control during a fasting-refeeding procedure, increased adipose tissue mass and altered lipid metabolism. Finally, maternal HFD and ELS both resulted in exacerbated food-motivated behaviour and blunted dopamine release in the nucleus accumbens during palatable food consumption.
We report a synergistic effect of perinatal HFD exposure and stress on the susceptibility to gain weight under HFD. However, ELS has a stronger impact than maternal HFD exposure on energy homoeostasis and food motivation in adult offspring. Altogether, our results suggest a programming effect of stress and nutrition supporting the hypothesis of the developmental origin of health and disease.
Within the central nervous system the traditional role of microglia has been in brain infection and disease, phagocytosing debris and secreting factors to modify disease progression. More recently, ...microglia have been found to be important for normal brain development, circuit refinement, and synaptic plasticity in ways that were previously unsuspected. Hence, the brain innate immune system appears to be key in all situations, ranging from physiology to pathology. This unique feature of microglia is established by the wide array of receptors it is equipped with to sense molecular patterns. This includes receptors to most if not all neurotransmitters, neuromodulators and purines. We here review novel, yet extensive literature on a new class of microglia modulators, namely bioactive fatty acids. These lipids are issued from metabolism of nutrients and can cross the blood brain barrier to reach the CNS. They appear to be direct modulators of microglial activity, triggering/inhibiting inflammatory processes or enhancing/inhibiting the ability of these cells to respond to hazardous agents.
•Effect of lifelong omega-3 deficiency on sleep in physiology and under inflammation.•Omega-3 deficiency affects the architecture of sleep-wake activity.•Omega-3 deficiency decreases the amplitude of ...delta oscillations during NREM sleep.•Omega-3 deficiency affects the REM sleep response to an acute inflammatory challenge.
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 12 h. 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.
Understanding how malnutrition contributes to depression is building momentum. In the present study we unravel molecular and cellular mechanisms by which nutritional disturbances lead to impaired ...emotional behaviour in mice. Here we report that nutritional n-3 polyunsaturated fatty acids (PUFA) deficiency induces a chronic stress state reflected by disrupted glucocorticoid receptor (GR)-mediated signalling pathway along with hypothalamic-pituitary-adrenal (HPA) axis hyperactivity. This hyperactivity in turn resulted in neuronal atrophy in the dorsolateral (dl)- and dorsomedial (dm)- prefrontal cortex (PFC) and subsequent mood-related behaviour alterations, similarly to chronic social defeat stress. Supplementation of n-3 PUFA prevented detrimental chronic social defeat stress-induced emotional and neuronal impairments by impeding HPA axis hyperactivity. These results indicate a role for dietary n-3 PUFA in the prevention of HPA axis dysfunction associated with the development of some neuropsychiatric disorders including depression.
PDF
