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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.
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Microglía , Estrés Psicológico , Microglía/metabolismo , Microglía/patología , Humanos , Estrés Psicológico/metabolismo , Animales , Encéfalo , Estrés Fisiológico/fisiologíaRESUMEN
Sleep is a natural physiological state, tightly regulated through several neuroanatomical and neurochemical systems, which is essential to maintain physical and mental health. Recent studies revealed that the functions of microglia, the resident immune cells of the brain, differ along the sleep-wake cycle. Inflammatory cytokines, such as interleukin-1ß and tumor necrosis factor-α, mainly produced by microglia in the brain, are also well-known to promote sleep. However, the contributing role of microglia on sleep regulation remains largely elusive, even more so in females. Given the higher prevalence of various sleep disorders in women, we aimed to determine the role of microglia in regulating the sleep-wake cycle specifically in female mice. Microglia were depleted in adult female mice with inhibitors of the colony-stimulating factor 1 receptor (CSF1R) (PLX3397 or PLX5622), which is required for microglial population maintenance. This led to a 65-73% reduction of the microglial population, as confirmed by immunofluorescence staining against IBA1 (marker of microglia/macrophages) and TMEM119 (microglia-specific marker) in the reticular nucleus of the thalamus and primary motor cortex. The spontaneous sleep-wake cycle was evaluated at steady-state, during microglial homeostasis disruption and after complete microglial repopulation, upon cessation of treatment with the inhibitors of CSF1R, using electroencephalography (EEG) and electromyography (EMG). We found that microglia-depleted female mice spent more time in non-rapid eye movement (NREM) sleep and had an increased number of NREM sleep episodes, which was partially restored after microglial total repopulation. To determine whether microglia could regulate sleep locally by modulating synaptic transmission, we used patch clamp to record spontaneous activity of pyramidal neurons in the primary motor cortex, which showed an increase of excitatory synaptic transmission during the dark phase. These changes in neuronal activity were modulated by microglial depletion in a phase-dependent manner. Altogether, our results indicate that microglia are involved in the sleep regulation of female mice, further strengthening their potential implication in the development and/or progression of sleep disorders. Furthermore, our findings indicate that microglial repopulation can contribute to normalizing sleep alterations caused by their partial depletion.
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Movimientos Oculares , Trastornos del Sueño-Vigilia , Femenino , Animales , Ratones , Duración del Sueño , Factor de Necrosis Tumoral alfaRESUMEN
Maternal intake of omega-3 (n-3 PUFAs) and omega-6 (n-6 PUFAs) polyunsaturated fatty acids impacts hippocampal neurogenesis during development, an effect that may extend to adulthood by altering adult hippocampal neurogenesis (AHN). The n-3 PUFAs and n-6 PUFAs 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. The diet effect on most mature neuroblasts was exclusively significant in female mice. Colocalization and multivariate analysis revealed an association between microglia and AHN, as well as 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.
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Ácidos Grasos Omega-3 , Ácidos Grasos Omega-6 , Animales , Dieta , Ácidos Grasos Omega-3/farmacología , Ácidos Grasos Omega-6/farmacología , Ácidos Grasos Insaturados/farmacología , Femenino , Hipocampo , Lipopolisacáridos/toxicidad , Masculino , Ratones , Ratones Endogámicos C57BL , Microglía , NeurogénesisRESUMEN
Over the last century, westernization of dietary habits has led to a dramatic reduction in dietary intake of n-3 polyunsaturated fatty acids (n-3 PUFAs). In particular, low maternal intake of n-3 PUFAs throughout gestation and lactation causes defects in brain myelination. Microglia are recognized for their critical contribution to neurodevelopmental processes, such as myelination. These cells invade the white matter in the first weeks of the post-natal period, where they participate in oligodendrocyte maturation and myelin production. Therefore, we investigated whether an alteration of white matter microglia accompanies the myelination deficits observed in the brain of n-3 PUFA-deficient animals. Macroscopic imaging analysis shows that maternal n-3 PUFA deficiency decreases the density of white matter microglia around post-natal day 10. Microscopic electron microscopy analyses also revealed alterations of microglial ultrastructure, a decrease in the number of contacts between microglia and myelin sheet, and a decreased amount of myelin debris in their cell body. White matter microglia further displayed increased mitochondrial abundance and network area under perinatal n-3 PUFA deficiency. Overall, our data suggest that maternal n-3 PUFA deficiency alters the structure and function of microglial cells located in the white matter of pups early in life, and this could be the key to understand myelination deficits during neurodevelopment.
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Microglia, the brain's resident macrophages, actively contribute to the homeostasis of cerebral parenchyma by sensing neuronal activity and supporting synaptic remodeling and plasticity. While several studies demonstrated different roles for astrocytes in sleep, the contribution of microglia in the regulation of sleep/wake cycle and in the modulation of synaptic activity in the different day phases has not been deeply investigated. Using light as a zeitgeber cue, we studied the effects of microglial depletion with the colony stimulating factor-1 receptor antagonist PLX5622 on the sleep/wake cycle and on hippocampal synaptic transmission in male mice. Our data demonstrate that almost complete microglial depletion increases the duration of NREM sleep and reduces the hippocampal excitatory neurotransmission. The fractalkine receptor CX3CR1 plays a relevant role in these effects, because cx3cr1GFP/GFP mice recapitulate what found in PLX5622-treated mice. Furthermore, during the light phase, microglia express lower levels of cx3cr1 and a reduction of cx3cr1 expression is also observed when cultured microglial cells are stimulated by ATP, a purinergic molecule released during sleep. Our findings suggest that microglia participate in the regulation of sleep, adapting their cx3cr1 expression in response to the light/dark phase, and modulating synaptic activity in a phase-dependent manner.
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Microglía , Transmisión Sináptica , Animales , Receptor 1 de Quimiocinas CX3C/genética , Receptor 1 de Quimiocinas CX3C/metabolismo , Hipocampo/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Microglía/metabolismo , Neuronas/metabolismo , SueñoRESUMEN
Westernization of dietary habits has led to a progressive reduction in dietary intake of n-3 polyunsaturated fatty acids (n-3 PUFAs). Low maternal intake of n-3 PUFAs has been linked to neurodevelopmental disorders, conditions in which myelination processes are abnormal, leading to defects in brain functional connectivity. Only little is known about the role of n-3 PUFAs in oligodendrocyte physiology and white matter development. Here, we show that lifelong n-3 PUFA deficiency disrupts oligodendrocytes maturation and myelination processes during the postnatal period in mice. This has long-term deleterious consequences on white matter organization and hippocampus-prefrontal functional connectivity in adults, associated with cognitive and emotional disorders. Promoting developmental myelination with clemastine, a first-generation histamine antagonist and enhancer of oligodendrocyte precursor cell differentiation, rescues memory deficits in n-3 PUFA deficient animals. Our findings identify a novel mechanism through which n-3 PUFA deficiency alters brain functions by disrupting oligodendrocyte maturation and brain myelination during the neurodevelopmental period.
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Ácidos Grasos Omega-3 , Animales , Encéfalo , Ratones , Vaina de Mielina , Neurogénesis , OligodendroglíaRESUMEN
Memory impairment is one of the disabling manifestations of multiple sclerosis (MS) possibly present from the early stages of the disease and for which there is no specific treatment. Hippocampal synaptic dysfunction and dendritic loss, associated with microglial activation, can underlie memory deficits, yet the molecular mechanisms driving such hippocampal neurodegeneration need to be elucidated. In early-stage experimental autoimmune encephalomyelitis (EAE) female mice, we assessed the expression level of molecules involved in microglia-neuron interactions within the dentate gyrus and found overexpression of genes of the complement pathway. Compared to sham immunized mice, the central element of the complement cascade, C3, showed the strongest and 10-fold upregulation, while there was no increase of downstream factors such as the terminal component C5. The combination of in situ hybridization with immunofluorescence showed that C3 transcripts were essentially produced by activated microglia. Pharmacological inhibition of C3 activity, by daily administration of rosmarinic acid, was sufficient to prevent early dendritic loss, microglia-mediated phagocytosis of synapses in the dentate gyrus, and memory impairment in EAE mice, while morphological markers of microglial activation were still observed. In line, when EAE was induced in C3 deficient mice (C3KO), dendrites and spines of the dentate gyrus as well as memory abilities were preserved. Altogether, these data highlight the central role of microglial C3 in early hippocampal neurodegeneration and memory impairment in EAE and, therefore, pave the way toward new neuroprotective strategies in MS to prevent cognitive deficit using complement inhibitors.
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Complemento C3/metabolismo , Encefalomielitis Autoinmune Experimental/metabolismo , Hipocampo/metabolismo , Trastornos de la Memoria/metabolismo , Degeneración Nerviosa/metabolismo , Animales , Cinamatos/farmacología , Complemento C3/antagonistas & inhibidores , Complemento C3/genética , Convertasas de Complemento C3-C5/farmacología , Dendritas/efectos de los fármacos , Dendritas/metabolismo , Depsidos/farmacología , Encefalomielitis Autoinmune Experimental/patología , Hipocampo/efectos de los fármacos , Hipocampo/patología , Trastornos de la Memoria/patología , Ratones , Ratones Noqueados , Microglía/efectos de los fármacos , Microglía/metabolismo , Molibdoferredoxina , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/patología , Degeneración Nerviosa/patología , Fagocitosis/efectos de los fármacos , Sinapsis/efectos de los fármacos , Sinapsis/metabolismo , Ácido RosmarínicoRESUMEN
Background: Neuroinflammation is a key feature shared by most, if not all, neuropathologies. It involves complex biological processes that act as a protective mechanism to fight against the injurious stimuli, but it can lead to tissue damage if self-perpetuating. In this context, microglia, the main cellular actor of neuroinflammation in the brain, are seen as a double-edged sword. By phagocyting neuronal debris, these cells can not only provide tissue repair but can also contribute to neuronal damage by releasing harmful substances, including inflammatory cytokines. The mechanisms guiding these apparent opposing actions are poorly known. The endocannabinoid system modulates the release of inflammatory factors such as cytokines and could represent a functional link between microglia and neuroinflammatory processes. According to transcriptomic databases and in vitro studies, microglia, the main source of cytokines in pathological conditions, express the cannabinoid type 1 receptor (CB1R). Methods: We thus developed a conditional mouse model of CB1R deletion specifically in microglia, which was subjected to an immune challenge (peripheral lipopolysaccharide injection). Results: Our results reveal that microglial CB1R differentially controls sickness behavior in males and females. Conclusion: These findings add to the comprehension of neuroinflammatory processes and might be of great interest for future studies aimed at developing therapeutic strategies for brain disorders with higher prevalence in men.
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Cannabinoides , Encefalitis , Animales , Masculino , Ratones , Microglía , Enfermedades Neuroinflamatorias , Receptores de Cannabinoides/genéticaRESUMEN
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.
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Microglía/metabolismo , Neuronas/metabolismo , Obesidad/etiología , Animales , Comunicación Celular , Citocinas/metabolismo , Dieta/efectos adversos , Humanos , Red Nerviosa , Obesidad/inmunología , Obesidad/metabolismoRESUMEN
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. © 2020 American Physiological Society. Compr Physiol 10:687-712, 2020.
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Astrocitos/fisiología , Microglía/fisiología , Enfermedades Neurodegenerativas/patología , Neuronas/fisiología , Trastornos del Sueño-Vigilia/patología , Sueño/fisiología , Animales , Astrocitos/citología , Humanos , Microglía/citología , Microglía/patología , Enfermedades Neurodegenerativas/etiología , Neuronas/citologíaRESUMEN
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.
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Trastorno Depresivo Mayor , Ácido Eicosapentaenoico , Encéfalo , Depresión , Trastorno Depresivo Mayor/tratamiento farmacológico , Ácidos Docosahexaenoicos , Humanos , FosfolípidosRESUMEN
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.
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Suplementos Dietéticos , Ácidos Grasos Omega-3/farmacología , Metabolismo de los Lípidos/efectos de los fármacos , Lípidos/análisis , Microglía/efectos de los fármacos , Animales , Células Cultivadas , Ácidos Docosahexaenoicos/metabolismo , Ácidos Grasos Omega-3/administración & dosificación , Femenino , Lactancia , Fenómenos Fisiologicos Nutricionales Maternos , Ratones , Microglía/citología , Microglía/metabolismo , Fosfolípidos/metabolismo , Embarazo , DesteteRESUMEN
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.
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Antiinflamatorios/metabolismo , Antiinflamatorios/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/fisiología , Ácidos Grasos Omega-3/metabolismo , Ácidos Grasos Omega-3/farmacología , Animales , Encéfalo/metabolismo , Humanos , Microglía/efectos de los fármacos , Microglía/metabolismo , Microglía/fisiologíaRESUMEN
Sleep serves crucial learning and memory functions in both nervous and immune systems. Microglia are brain immune cells that actively maintain health through their crucial physiological roles exerted across the lifespan, including phagocytosis of cellular debris and orchestration of neuroinflammation. The past decade has witnessed an explosive growth of microglial research. Considering the recent developments in the field of microglia and sleep, we examine their possible impact on various pathological conditions associated with a gain, disruption, or loss of sleep in this focused mini-review. While there are extensive studies of microglial implication in a variety of neuropsychiatric and neurodegenerative diseases, less is known regarding their roles in sleep disorders. It is timely to stimulate new research in this emergent and rapidly growing field of investigation.
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Cell proliferation and neuroinflammation in the adult hypothalamus may contribute to the pathogenesis of obesity. We tested whether the intertwining of these two processes plays a role in the metabolic changes caused by 3 weeks of a high-saturated fat diet (HFD) consumption. Compared with chow-fed mice, HFD-fed mice had a rapid increase in body weight and fat mass and specifically showed an increased number of microglia in the arcuate nucleus (ARC) of the hypothalamus. Microglia expansion required the adequate presence of fats and carbohydrates in the diet because feeding mice a very high-fat, very low-carbohydrate diet did not affect cell proliferation. Blocking HFD-induced cell proliferation by central delivery of the antimitotic drug arabinofuranosyl cytidine (AraC) blunted food intake, body weight gain, and adiposity. AraC treatment completely prevented the increase in number of activated microglia in the ARC, the expression of the proinflammatory cytokine tumor necrosis factor-α in microglia, and the recruitment of the nuclear factor-κB pathway while restoring hypothalamic leptin sensitivity. Central blockade of cell proliferation also normalized circulating levels of the cytokines leptin and interleukin 1ß and decreased peritoneal proinflammatory CD86 immunoreactive macrophage number. These findings suggest that inhibition of diet-dependent microglia expansion hinders body weight gain while preventing central and peripheral inflammatory responses due to caloric overload.
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Núcleo Arqueado del Hipotálamo/inmunología , Proliferación Celular/efectos de los fármacos , Dieta Alta en Grasa , Ingestión de Alimentos/inmunología , Microglía/inmunología , Obesidad/inmunología , Aumento de Peso/inmunología , Adiposidad/efectos de los fármacos , Adiposidad/inmunología , Animales , Antimitóticos/farmacología , Arabinonucleósidos/farmacología , Núcleo Arqueado del Hipotálamo/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Peso Corporal/inmunología , Citarabina/farmacología , Citidina/farmacología , Ingestión de Alimentos/efectos de los fármacos , Hipotálamo/efectos de los fármacos , Hipotálamo/inmunología , Inflamación , Interleucina-1beta/efectos de los fármacos , Interleucina-1beta/inmunología , Leptina/inmunología , Macrófagos Peritoneales/efectos de los fármacos , Macrófagos Peritoneales/inmunología , Masculino , Ratones , Microglía/efectos de los fármacos , FN-kappa B/efectos de los fármacos , FN-kappa B/inmunología , Factor de Necrosis Tumoral alfa/efectos de los fármacos , Factor de Necrosis Tumoral alfa/inmunología , Aumento de Peso/efectos de los fármacosRESUMEN
The relative amounts of arachidonic acid (AA) and docosahexaenoic acid (DHA) govern the different functions of the brain. Their brain levels depend on structures considered, on fatty acid dietary supply and the age of animals. To have a better overview of the different models available in the literature we here compared the brain fatty acid composition in various mice models (C57BL/6J, CD1, Fat-1, SAMP8 mice) fed with different n-3 PUFA diets (deficient, balanced, enriched) in adults and aged animals. Our results demonstrated that brain AA and DHA content is 1) structure-dependent; 2) strain-specific; 3) differently affected by dietary approaches when compared to genetic model of PUFA modulation; 4) different in n-3 PUFA deficient aged C57BL6/J when compared to SAMP8 mouse model of aging. From these experiments, we highlight the difficulty to compare results obtained in different mouse models, different strains, different brain regions and different ages.
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Ácido Araquidónico/química , Química Encefálica , Grasas Insaturadas en la Dieta/administración & dosificación , Ácidos Docosahexaenoicos/química , Animales , Tronco Encefálico/química , Cerebelo/química , Corteza Cerebral/química , Femenino , Hipocampo/química , Hipotálamo/química , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Teóricos , Corteza Prefrontal/químicaRESUMEN
Several genetic causes of autism spectrum disorder (ASD) have been identified. However, more recent work has highlighted that certain environmental exposures early in life may also account for some cases of autism. Environmental insults during pregnancy, such as infection or malnutrition, seem to dramatically impact brain development. Maternal viral or bacterial infections have been characterized as disruptors of brain shaping, even if their underlying mechanisms are not yet fully understood. Poor nutritional diversity, as well as nutrient deficiency, is strongly associated with neurodevelopmental disorders in children. For instance, imbalanced levels of essential fatty acids, and especially polyunsaturated fatty acids (PUFAs), are observed in patients with ASD and other neurodevelopmental disorders (e.g., attention deficit hyperactivity disorder (ADHD) and schizophrenia). Interestingly, PUFAs, and specifically n-3 PUFAs, are powerful immunomodulators that exert anti-inflammatory properties. These prenatal dietary and immunologic factors not only impact the fetal brain, but also affect the microbiota. Recent work suggests that the microbiota could be the missing link between environmental insults in prenatal life and future neurodevelopmental disorders. As both nutrition and inflammation can massively affect the microbiota, we discuss here how understanding the crosstalk between these three actors could provide a promising framework to better elucidate ASD etiology.
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Trastorno por Déficit de Atención con Hiperactividad/metabolismo , Trastorno del Espectro Autista/metabolismo , Trastorno Autístico/metabolismo , Trastornos Generalizados del Desarrollo Infantil/metabolismo , Ácidos Grasos Omega-3/metabolismo , Microbiota/fisiología , Animales , Trastornos Generalizados del Desarrollo Infantil/complicaciones , Humanos , Estado Nutricional/fisiologíaRESUMEN
[This corrects the article DOI: 10.1371/journal.pbio.1002466.].
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[This corrects the article DOI: 10.1371/journal.pbio.1002466.].