Article

DHA Mitigates Autistic Behaviors Accompanied by Dopaminergic Change in a Gene/Prenatal Stress Mouse Model

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Abstract

Autism Spectrum Disorder (ASD) is characterized by impairments in social interaction, social communication, and repetitive and stereotyped behaviors. Recent work has begun to explore gene x environmental interactions in the etiology of ASD. We previously reported that prenatal stress exposure in stress-susceptible heterozygous serotonin transporter (SERT) KO pregnant dams in a mouse model resulted in autism-like behavior in the offspring (SERT/S mice). The association between prenatal stress and ASD appears to be affected by maternal SERT genotype in clinical populations as well. Using the mouse model, we examined autistic-like behaviors in greater detail, and additionally explored whether diet supplementation with docosahexaenoic acid (DHA) may mitigate the behavioral changes. Only male SERT/S mice showed social impairment and stereotyped behavior, and DHA supplementation ameliorated some of these behaviors. We also measured monoamine levels in the SERT/S mice after three treatment paradigms: DHA rich diet continuously from breeding (DHA diet), DHA rich diet only after weaning (CTL/DHA diet) and control diet only (CTL diet). The dopamine (DA) content in the striatum was significantly increased in the SERT/S mice compared with wild type (WT) mice, whereas no difference was observed with noradrenaline and serotonin content. Moreover, DA content in the striatum was significantly reduced in the SERT/S mice with the DHA-rich diet provided continuously from breeding. The results indicate that autism-associated behaviors and changes in the dopaminergic system in this setting can be mitigated with DHA supplementation.

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... Um dos testes mais utilizados e reconhecidos para avaliação do comportamento animal no TEA é o teste do campo aberto (TCA) o qual foi citado em 13 dos 32 artigos utilizados (40,6%). Trata-se de um teste para avaliação do comportamento exploratório e locomoção dos animais estudados (8,10,13). ...
... O TCA, desenvolvido por Hall em 1934 (14), é realizado em um aparato que consiste em uma arena quadrangular em acrílico transparente, medindo 45 cm × 45 cm, cercada por paredes de, aproximadamente, 22 cm de altura, de modo que o animal em teste não consiga fugir (10). Para facilitar a quantificação da atividade locomotora dos animais, o piso do campo aberto é dividido em nove quadrados idênticos, por entre os quais o animal irá circular, e o número de cruzamentos realizados pelos animais entre os quadrados será quantificado (14,15). ...
... O tempo total empregado no teste depende do objetivo da pesquisa e do avaliador. A literatura consultada apontou duração dos experimentos variando de 5 a 90 minutos (6,10,15). No entanto, o protocolo mais citado utilizou o tempo total de 15 minutos, sendo 5 minutos de habituação e 10 minutos de teste, realizados em um único dia (13). ...
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O transtorno do espectro autista (TEA) é um transtorno do neurodesenvolvimento cujas alterações comportamentaispodem ser investigadas por meio de modelos animais de TEA e pela realização de testes comportamentais para avaliação das alterações. O objetivo deste trabalho foi realizar uma pesquisa bibliográfica sobre os modelos comportamentais animais que têm sido utilizados para o estudo do TEA e a correlação desses modelos com o comportamento humano no TEA. Para esta pesquisa bibliográfica, foi conduzida uma busca nas bases de dados Medline, Web of Science e Clinical Key, no período de junho a setembro de 2019, por artigos científicos na temática de estudo, sendo selecionados artigos publicados entre os anos de 2006 e 2019. No estudo experimental do TEA, são conduzidos testes comportamentais em animais considerando as características clínicas e manifestações do transtorno. Estes modelos experimentais são utilizados para a avaliação do potencial indutor de substâncias para o desenvolvimento do TEA, como para a avaliação de potenciais fármacos ou terapias não farmacológicas para o tratamento do transtorno. Os testes mais comumente utilizados são: teste de campo aberto, teste de enterramento de esferas de vidro, teste de interação social, teste do comportamento repetitivo de autolimpeza, teste do labirinto em cruz elevado, teste de habituação olfativa e odores sociais e teste claro-escuro. Reitera-se a importância desses testes em modelos in vivo de estudo do TEA, possibilitando uma maior compreensão das alterações comportamentais e um melhor entendimento desse transtorno.
... As diffusible factors in blood are a central route by which maternal stress effects are communicated to offspring, it will be important to determine whether prenatal stress induced expression and methylation changes reported in animals [73] are also observed in maternal blood in prenatal stress-associated ASD cases. Furthermore, GABAergic changes observed in ASD [55,56], and the effects of prenatal stress on GABA systems as well as striatal dopamine [62,82], emphasize the importance of epigenetic changes on genes, such as changes on GABAergic genes related to behavioral deficits [83], which may be correctable by psychopharmacology after prenatal stress in mouse models. Such work may be fruitful for establishing biomarkers to monitor responsiveness, as novel therapeutic approaches are developed targeting these mechanisms. ...
... In addition to the aforementioned GABAergic changes observed with exposure to prenatal stress, recent evidence has also revealed that prenatal stress-exposed mice from dams with heterozygous KO of SERT have significantly increased striatal dopamine [82]. It will be of future interest to determine whether ASD patients exposed to prenatal stress also represent a subgroup with significant striatal changes. ...
... It will be of future interest to determine whether ASD patients exposed to prenatal stress also represent a subgroup with significant striatal changes. Notably, administration of 1% docosahexaenoic acid (DHA) omega-3 fatty acid throughout pregnancy in dams, continuing the diet given to pups, reversed repetitive grooming behaviors, social interaction abnormalities, and altered striatal dopamine in mice exposed to prenatal stress born from dams with only one copy of the SERT gene, as compared to offspring that were untreated with DHA or only given DHA after birth [82]. While the clinical implications of this are as of yet unknown, DHA has been of particular interest due to its effects on a range of other neurological conditions due to its effects on a range of anti-oxidant pathways [135], and some evidence suggests synergistic effects with other anti-oxidant agents [136]. ...
Article
Background Genetics are a major etiological contributor to autism spectrum disorder (ASD). Environmental factors, however, also appear to contribute. ASD pathophysiology due to gene x environment is also beginning to be explored. One reason to focus on environmental factors is that they may allow opportunities for intervention or prevention. Methods And Results Herein, we review two such factors that have been associated with a significant proportion of ASD risk, prenatal stress exposure and maternal immune dysregulation. Maternal stress susceptibility appears to interact with prenatal stress exposure to affect offspring neurodevelopment. We also explore how maternal stress may interact with the microbiome in the neurodevelopmental setting. Additionally, understanding of the impact of maternal immune dysfunction on ASD has recently been advanced by recognition of specific fetal brain proteins targeted by maternal autoantibodies, and identification of unique mid-gestational maternal immune profiles. This might also be interrelated with maternal stress exposure. Animal models have been developed to explore pathophysiology targeting each of these factors. Conclusions We are beginning to understand the behavioral, pharmacopathological, and epigenetic effects related to these interactions, and we are beginning to explore potential mitigating factors. Continued growth in understanding of these mechanisms may ultimately allow for the identification of multiple potential targets for prevention or intervention for this subset of environmental-associated ASD cases.
... Two hundred thirteen of them were annotated in the OMIM database. The leading functional target for these genes was the dopaminergic synapse, congruent with our effects on dopamine in the striatum described below in the gene × stress model (86), in addition to pathways associated with addiction and other neurotransmitter systems including glutamate, GABA, the serotonergic system, and the cholinergic system (Table 3). Additionally, DYRK1A was a predicted target for three of these miRNAs (miR-1224-5p, miR-145-5p, and miR-663a). ...
... This is of particular interest with the growing interest in the role of dopamine in social behavior (87), and the potential role for this as a treatment target in this subset of cases with ASD. The effects on dopaminergic synapse targets are also of particular interest given our recent finding that prenatal stress exposure in SERT-het mice resulted in increased striatal DA in offspring brains (86). Furthermore, these dopaminergic changes were reversed with DHA (86). ...
... The effects on dopaminergic synapse targets are also of particular interest given our recent finding that prenatal stress exposure in SERT-het mice resulted in increased striatal DA in offspring brains (86). Furthermore, these dopaminergic changes were reversed with DHA (86). The effects on glutamatergic and GABAergic targets are of particular interest in autism, given the importance of the excitatory/inhibitory imbalance in ASD (88), and the effects on serotonergic targets would be anticipated given the inclusion of maternal SERT genotype in the G × E interaction. ...
Article
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Background: Genetics and environment both are critical in autism spectrum disorder (ASD), but their interaction (G × E) is less understood. Numerous studies have shown higher incidence of stress exposures during pregnancies with children later diagnosed with ASD. However, many stress-exposed mothers have unaffected children. The serotonin transporter ( SERT ) gene affects stress reactivity. Two independent samples have shown that the association between maternal stress exposure and ASD is greatest with maternal presence of the SERT short (S)-allele (deletion in the promoter region). MicroRNAs play a regulatory role in the serotonergic pathway and in prenatal stress and are therefore potential mechanistic targets in this setting. Design/methods: We profiled microRNA expression in blood from mothers of children with ASD, with known stress exposure during pregnancy. Samples were divided into groups based on SERT genotypes (LL/LS/SS) and prenatal stress level (high/low). Results: Two thousand five hundred mature microRNAs were examined. The ANOVA analysis showed differential expression (DE) of 119 microRNAs; 90 were DE in high- vs. low-stress groups (stress-dependent). Two (miR-1224-5p, miR-331-3p) were recently reported by our group to exhibit stress-dependent expression in rodent brain samples from embryos exposed to prenatal stress. Another, miR-145-5p, is associated with maternal stress. Across SERT genotypes, with high stress exposure, 20 significantly DE microRNAs were detected, five were stress-dependent. These microRNAs may be candidates for stress × SERT genotype interactions. This is remarkable as these changes were from mothers several years after stress-exposed pregnancies. Conclusions: Our study provides evidence for epigenetic alterations in relation to a G × E model (prenatal maternal stress × SERT gene) in ASD.
... We should state that we had identified 2 additional prospective experimental studies on this topic (24,25). However, in the first study the intervention (docosahexaenoic acid supplementation) took place both prenatally and postnatally and in this way the true effect of gestational administration could not be really estimated (24). ...
... We should state that we had identified 2 additional prospective experimental studies on this topic (24,25). However, in the first study the intervention (docosahexaenoic acid supplementation) took place both prenatally and postnatally and in this way the true effect of gestational administration could not be really estimated (24). With regard to the second study, the aim of researchers was mainly to show the ability of some factors to induce autistic-like behaviors in an experimental level (pathogenicity proving) rather than investigate the potential treatment effect. ...
... Antioxidant action and calcium metabolism seem to be the key mechanisms of the neuroprotective effects of docosahexaenoic acid, too (39). According to data from animal research, a maternal diet rich in omega-6 and relatively deficient in omega-3 induced autism-associated behaviors in mouse models, while docosahexaenoic acid rescued autismassociated behaviors and brain neurochemistry changes associated with the prenatal stress mouse model (24,25). Furthermore, omega-3 supplementation seems to reverse stereotypical behaviors often observed in autism in rats prenatally exposed to lipopolysaccharides (40). ...
Article
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Nutritional interventions are gaining remarkable attention as complementary management options for autism. Our aim is to provide literature data about the impact of the administration of dietary supplements during pregnancy on the risk of autism spectrum disorder in the offspring. A comprehensive search was undertaken by 2 reviewers independently using PubMed as the medical database source. Prospective clinical and experimental studies were considered and no year-of-publication restriction was placed. We were able to identify 4 basic (conducted in rodents) and 3 clinical research papers fulfilling our selection criteria. Supplements studied included folic acid, iron, multivitamins, choline, vitamin D, and docosahexaenoic acid. Choline and folic acid had a significant impact on the expression of autism-related genes. However, from a clinical point of view, prenatal folate administration did not reduce the risk of autism. Similarly, iron had no significant impact, while the use of multivitamins in moderate frequency had a protective effect. The use of vitamin D and docosahexaenoic acid during gestation decreased the incidence of autism in animal models. In conclusion, available data are controversial and cannot change current routine practice. More large-scale prospective studies are needed to identify the real effect of nutritional supplements and also optimize their administration. • Key teaching points • Multivitamins use during pregnancy can exert a protective effect on the risk of autism, although depending on the frequency of use. Nevertheless, prenatal iron and folate were not shown to have any significant impact. • Research based on animal models showed that choline and folic acid can have a significant impact on the expression of autism-related genes in a sex-specific manner. • Furthermore, the use of vitamin D and docosahexaenoic acid during gestation seem to decrease the incidence of autism in animal offspring. • In the future, more clinical, large-scale prospective and methodologically homogenous clinical studies are needed to further investigate the effect of the periconceptional use of nutritional supplements on autism risk.
... Since understanding the mechanism(s) whereby dietary DHA offers beneficial effects to the human brain is still elusive, recent studies have resorted to answering this question using animal models. There is evidence that maternal diets enriched in n-3 PUFAs can promote neuronal development and synaptic function, alter mental activities, and even modify contents of neurotransmitters, including gamma-aminobutyric acid, dopamine, glutamate, and serotonin, and their metabolites [12][13][14]. Other studies support the ability for DHA to mediate the resolution of inflammation through the production of lipid mediators, such as resolvins and neuroprotectins [15,16]. ...
... Other studies support the ability for DHA to mediate the resolution of inflammation through the production of lipid mediators, such as resolvins and neuroprotectins [15,16]. In a gene/stress mouse model in which autistic behavior was associated with maternal deletion of one copy of the serotonin transporter gene [17], maternal dietary DHA was shown to alter dopamine and mitigate autism-associated behaviors in the pups [13,18]. In fact, the relative deficiency of DHA during pregnancy was sufficient to cause autism-associated behaviors in the pups regardless of whether or not maternal stress was present during pregnancy [18]. ...
... Furthermore, although substantial levels of 4-HNE were present in all pup brain regions, this peroxidation product was apparently not altered by maternal dietary supplement of DHA. In our previous study, maternal DHA supplementation also resulted in an increase in DHA and decrease in ARA levels in the total pup brain [13]. Therefore, the effect of maternal DHA or n-3 PUFA to cause the increase in DHA in pup brain is not surprising, but the fact that this dietary regimen can suppress ARA, as well as n-6 PUFA is intriguing and not well understood. ...
Article
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The abundance of docosahexaenoic acid (DHA) in the mammalian brain has generated substantial interest in the search for its roles in regulating brain functions. Our recent study with a gene/stress mouse model provided evidence to support the ability for the maternal supplement of DHA to alleviate autism-associated behavior in the offspring. DHA and arachidonic acid (ARA) are substrates of enzymatic and non-enzymatic reactions, and lipid peroxidation results in the production of 4-hydroxyhexenal (4-HHE) and 4-hydroxynonenal (4-HNE), respectively. In this study, we examine whether a maternal DHA-supplemented diet alters fatty acids (FAs), as well as lipid peroxidation products in the pup brain, heart and plasma by a targeted metabolite approach. Pups in the maternal DHA-supplemented diet group showed an increase in DHA and a concomitant decrease in ARA in all brain regions examined. However, significant increases in 4-HHE, and not 4-HNE, were found mainly in the cerebral cortex and hippocampus. Analysis of heart and plasma showed large increases in DHA and 4-HHE, but a significant decrease in 4-HNE levels only in plasma. Taken together, the DHA-supplemented maternal diet alters the (n-3)/(n-6) FA ratio, and increases 4-HHE levels in pup brain, heart and plasma. These effects may contribute to the beneficial effects of DHA on neurodevelopment, as well as functional changes in other body organs.
... Our recent study demonstrated the effects of maternal DHA-enriched diet to alleviate stress-induced behavioral deficits in offspring mice (Matsui et al. 2018). Subsequently, a follow-up study using the same dietary regimen showed that administration of the DHA-enriched diet to pregnant mothers resulted in altered fatty acid composition in all brain regions, but increase in 4-HHE levels mainly in the cerebral cortex and hippocampus in the offspring pups (Yang,et al. 2019b). ...
... The reason for the 3-week diet is because this period of time was used in a study in which adult mice fed a fish oil diet with a similar amount of DHA resulted in substantial changes in fatty acids and lipid peroxidation products in different body organs (Nakagawa et al. 2014). The composition of the control and DHA diets have been described previously (Matsui et al. 2018;Yang et al. 2019b) as well as the final fatty acid profiles (Supplemental Tables S1 and S2). The diets were stabilized against auto-oxidation with 0.02 g tertiary-butylhydroquinone/100 g fat. ...
Article
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The abundance of docosahexaenoic acid (DHA) in phospholipids in the brain and retina has generated interest to search for its role in mediating neurological functions. Besides the source of many oxylipins with pro-resolving properties, DHA also undergoes peroxidation, producing 4-hydroxyhexenal (4-HHE), although its function remains elusive. Despite wide dietary consumption, whether supplementation of DHA may alter the peroxidation products and their relationship to phospholipid species in brain and other body organs have not been explored sufficiently. In this study, adult mice were administered a control or DHA-enriched diet for 3 weeks, and phospholipid species and peroxidation products were examined in brain, heart, and plasma. Results demonstrated that this dietary regimen increased (n-3) and decreased (n-6) species to different extent in all major phospholipid classes (PC, dPE, PE-pl, PI and PS) examined. Besides changes in phospholipid species, DHA-enriched diet also showed substantial increases in 4-HHE in brain, heart, and plasma. Among different brain regions, the hippocampus responded to the DHA-enriched diet showing significant increase in 4-HHE. Considering the pro- and anti-inflammatory pathways mediated by the (n-6) and (n-3) polyunsaturated fatty acids, unveiling the ability for DHA-enriched diet to alter phospholipid species and lipid peroxidation products in the brain and in different body organs may be an important step forward towards understanding the mechanism(s) for this (n-3) fatty acid on health and diseases.
... Furthermore, in environmental exposure models for ASD in rodents, n-3 PUFA or DHA supplementation were effective in reversing impairments in social interactions and elevation in social anxiety induced by maternal immune activation or exposure of food allergen during development [63,80,81]. Similarly, genetic models of ASD, including BTBR and serotonin transporter (SERT) knockout, demonstrated that pre-and postnatal n-3 PUFA or DHA supplementation may increase social interest and social preference for novel mice over objects as compared to mice fed n-3 PUFA deprived diets [82,83]. The improvements in social behaviors were observed in conjunction with higher DHA composition in the brain [82][83][84]. ...
... Similarly, genetic models of ASD, including BTBR and serotonin transporter (SERT) knockout, demonstrated that pre-and postnatal n-3 PUFA or DHA supplementation may increase social interest and social preference for novel mice over objects as compared to mice fed n-3 PUFA deprived diets [82,83]. The improvements in social behaviors were observed in conjunction with higher DHA composition in the brain [82][83][84]. Therefore, dietary DHA intervention shows promising results for the prevention of the core behaviors associated with ASD in different animal models. ...
Article
Deficiency in retinoid acid receptor-related orphan receptor alpha (RORα) of staggerer mice results in extensive granule and Purkinje cell loss in the cerebellum as well as in learned motor deficits, cognition impairments and perseverative tendencies that are commonly observed in autistic spectrum disorder (ASD). The effects of RORα on brain lipid metabolism associated with cerebellar atrophy remain unexplored. The aim of this study is to examine the effects of RORα deficiency on brain phospholipid fatty acid concentrations and compositions. Staggerer mice (Rorasg/sg) and wildtype littermates (Rora+/+) were fed n-3 polyunsaturated fatty acids (PUFA) containing diets ad libitum. At 2 months and 7 or more months old, brain total phospholipid fatty acids were quantified by gas chromatography-flame ionization detection. In the cerebellum, all fatty acid concentrations were reduced in 2 months old mice. Since total fatty acid concentrations were significantly different at 2-month-old, we examined changes in fatty acid composition. The composition of ARA was not significantly different between genotypes; though DHA composition remained significantly lowered. Despite cerebellar atrophy at >7-months-old, cerebellar fatty acid concentrations had recovered comparably to wildtype control. Therefore, RORα may be necessary for fatty acid accretions during neurodevelopment. Specifically, the effects of RORα on PUFA metabolisms are region-specific and age-dependent.
... Moreover, increased bioavailability of fatty acids during early development can induce discernable phenotypic changes as early as the weaning point [25]. While no studies have examined the therapeutic potential of perinatal administration in the Fmr1 model, previous studies have supported the potential for prenatal omega-3 fatty acids in the reversal of autisticlike deficits in other ASD rodent models [26][27][28][29][30]. Moreover, interventions during this timeframe provide a higher likelihood for maximal impact, given that administration of omega-3 fatty acids after diagnosis in clinical studies may be too late to improve outcomes [31]. ...
Article
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The current study aimed to further address important questions regarding the therapeutic efficacy of omega-3 fatty acids for various behavioral and neuroimmune aspects of the Fmr1 phenotype. To address these questions, our experimental design utilized two different omega-3 fatty acid administration timepoints, compared to both standard laboratory chow controls (“Standard”) and a diet controlling for the increase in fat content (“Control Fat”). In the first paradigm, post-weaning supplementation (after postnatal day 21) with the omega-3 fatty acid diet (“Omega-3”) reversed deficits in startle threshold, but not deficits in prepulse inhibition, and the effect on startle threshold was not specific to the Omega-3 diet. However, post-weaning supplementation with both experimental diets also impaired acquisition of a fear response, recall of the fear memory and contextual fear conditioning compared to the Standard diet. The post-weaning Omega-3 diet reduced hippocampal expression of IL-6 and this reduction of IL-6 was significantly associated with diminished performance in the fear conditioning task. In the perinatal experimental paradigm, the Omega-3 diet attenuated hyperactivity and acquisition of a fear response. Additionally, perinatal exposure to the Control Fat diet (similar to a “Western” diet) further diminished nonsocial anxiety in the Fmr1 knockout. This study provides significant evidence that dietary fatty acids throughout the lifespan can significantly impact the behavioral and neuroimmune phenotype of the Fmr1 knockout model.
... For example, interaction between the serotonergic gene 5-hydroxytryptamine transporter (5-HTT aka. sodiumdependent serotonin transporter and solute carrier family 6 member 4 (SLC6A4)) and stress was observed for ultrasonic vocalisation 19 and ASD-like stereotypic repetitive grooming behaviour 20 . In addition to maternal stress, early postnatal stress models have been developed with maternal separation being one of the most prominent causes leading to long-lasting increases in anxiety, depressive behaviour and disruption of stress responses. ...
Article
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Perinatal brain injury is a leading cause of death and disability in young children. Recent advances in obstetrics, reproductive medicine and neonatal intensive care have resulted in significantly higher survival rates of preterm or sick born neonates, at the price of increased prevalence of neurological, behavioural and psychiatric problems in later life. Therefore, the current focus of experimental research shifts from immediate injury processes to the consequences for brain function in later life. The aetiology of perinatal brain injury is multi-factorial involving maternal and also labour-associated factors, including not only placental insufficiency and hypoxia–ischaemia but also exposure to high oxygen concentrations, maternal infection yielding excess inflammation, genetic factors and stress as important players, all of them associated with adverse long-term neurological outcome. Several animal models addressing these noxious stimuli have been established in the past to unravel the underlying molecular and cellular mechanisms of altered brain development. In spite of substantial efforts to investigate short-term consequences, preclinical evaluation of the long-term sequelae for the development of cognitive and neuropsychiatric disorders have rarely been addressed. This review will summarise and discuss not only current evidence but also requirements for experimental research providing a causal link between insults to the developing brain and long-lasting neurodevelopmental disorders.
... The possibility that consumption of a DHAenriched diet early in pregnancy may protect against maternal stress-mediated effects on proteomics, immunity, glucocorticoid receptor expression, interactions with estrogen, and stress responsivity in adult offspring are the focus of follow-up studies. This is of additional interest given the finding that DHA reverses social behavior and repetitive behavior changes in adult offspring induced by prenatal stress exposure later in pregnancy in genetically stress susceptible dams, and additionally reverses the increases in striatal dopamine in these offspring exposed to prenatal stress [59]. Given that consumption of a DHA-enriched diet may influence additional tissues, further evaluation will be needed to determine the longterm impact on the brain as well as on other systems by leveraging bulk and single-cell sequencing approaches that may identify programmatic effects of maternal stress and diet in males and females at a cell-type specific resolution. ...
Article
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Early life adversity is widely recognized as a key risk factor for early developmental perturbations and contributes to the presentation of neuropsychiatric disorders in adulthood. Neurodevelopmental disorders exhibit a strong sex bias in susceptibility, presentation, onset, and severity, although the underlying mechanisms conferring vulnerability are not well understood. Environmental perturbations during pregnancy, such as malnutrition or stress, have been associated with sex-specific reprogramming that contribute to increased disease risk in adulthood, whereby stress and nutritional insufficiency may be additive and further exacerbate poor offspring outcomes. To determine whether maternal supplementation of docosahexanoic acid (DHA) exerts an effect on offspring outcome following exposure to early prenatal stress (EPS), dams were fed a purified 10:1 omega-6/omega-3 diet supplemented with either 1.0% preformed DHA/kg feed weight (DHA-enriched) or no additional DHA (denoted as the control diet, CTL). Dams were administered chronic variable stress during the first week of pregnancy (embryonic day, E0.5–7.5), and developmental milestones were assessed at E 12.5. Exposure to early prenatal stress (EPS) decreased placenta and embryo weight in males, but not females, exposed to the CTL diet. DHA enrichment reversed the sex-specific decrease in placenta and embryo weight following EPS. Early prenatal exposure upregulated expression of genes associated with oxygen and nutrient transport, including hypoxia inducible factor 3α (HIF3α), peroxisome proliferator-activated receptor alpha (PPARα), and insulin-like growth binding factor 1 (IGFBP1), in the placenta of CTL diet males exposed to EPS. DHA enrichment in EPS-exposed animals abrogated the male-specific upregulation of PPARα, HIF3α, and IGFBP1. Taken together, these studies suggest that maternal dietary DHA enrichment may buffer against maternal stress programming of sex-specific outcomes during early development.
... It also facilitates serotonergic signaling by increasing serotonin release and promoting serotonin receptor action through cell membrane fluidity in the post synaptic neuron [121]. Another study found that omega-3 can mitigate ASD-like phenotypes by modulating dopaminergic signaling [122]. In a human study, omega-3 supplementation from 10 to 16 weeks gestation until term reduced systemic and placental inflammation in obese pregnant women [118]. ...
Article
There is growing clinical and experimental evidence to suggest that maternal obesity increases children’s susceptibility to neurodevelopmental and neuropsychiatric disorders. Given the worldwide obesity epidemic, it is crucial that we acquire a thorough understanding of the available evidence, identify gaps in knowledge, and develop an agenda for intervention. This review synthesizes human and animal studies investigating the association between maternal obesity and offspring brain health. It also highlights key mechanisms underlying these effects, including maternal and fetal inflammation, alterations to the microbiome, epigenetic modifications of neurotrophic genes, and impaired dopaminergic and serotonergic signaling. Lastly, this review highlights several proposed interventions and priorities for future investigation.
... For instance, dopaminergic mechanisms have also been involved in the positive effects of dietary omega-3 PUFAs on social behavior in mice [53]. Interestingly, DHA supplementation mitigated ASD-like behaviors such as atypical sociability, accompanied by dopaminergic change in a mouse model of autism [54]. ...
Article
Background and objective: Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder for which no treatments exist. Fragile X syndrome (FXS) is the most common form of inherited mental retardation and the most frequent monogenic cause of ASD. Given the lack of pharmacological treatments for ASD, increasing interest is devoted to non-pharmacological approaches, including dietary interventions. Omega-3 polyunsaturated fatty acids (PUFAs) are critical for neurobehavioraldevelopment. This study had two aims: 1. To validatethe recently developed Fmr1-Δexon 8 rat model of FXS; 2. To assess the impact of omega-3 PUFAs dietary supplementation during pregnancy and lactation on the altered behavior displayed by Fmr1-Δexon 8 rats. Methods: Female Fmr1-Δexon 8 and wild-type Sprague–Dawley rats were fed with either an omega-3 PUFAs enriched diet or with an isocaloric control diet during pregnancy and lactation. Behavioral experiments were carried out on the infant (Postnatal days (PNDs) 9 and 13), juvenile (PND 35) and adult (PND 90) male offspring. Results: Fmr1-Δexon 8 pups showed hypolocomotion, reduced ultrasonic vocalizations (USVs) emission and impaired social discrimination compared to wild-type controls. Juvenile and adult Fmr1-Δexon 8 rats showed deficits in the social and cognitive domains, that were counteracted by perinatal omega-3 PUFAs supplementation. Conclusion: Our results support the validity of the Fmr1-Δexon 8 rat model to mimic key autistic-like features and support an important role of omega-3 PUFAs during of neurodevelopment. Although the mechanisms underlying the beneficial effects of omega-3 PUFAs supplementation in ASD needs to be clarified, this dietary intervention holds promise to mitigate core and comorbid autistic features.
... The actions of neurotransmitters are vital for proper brain development and function. DHA has been implicated in the regulation of many neurobiological systems, such as the glutamatergic system, dopaminergic system, noradrenergic system, and serotonergic system (31)(32)(33) and their related receptors. For example, Tang et al. (34) found that maternal DHA deficiency led to a reduction in hippocampal cell proliferation in neonatal female rat pups, in which the brain membrane DHA was positively associated with metabolism and turnover of glutamate and serotonin. ...
Article
Brain development is markedly affected by prenatal alcohol exposure, leading to cognitive and behavioral problems in the children. Protecting neuronal damage from prenatal alcohol could improve neural connections and functioning of the brain. DHA, a n-3 (ω-3) long-chain PUFA, is involved in the development of neurons. Insufficient concentrations of DHA impair neuronal development and plasticity of synaptic junctions and affect neurotransmitter concentrations in the brain. Alcohol consumption during pregnancy decreases the maternal DHA status and reduces the placental transfer of DHA to the fetus, resulting in less DHA being available for brain development. It is important to know whether DHA could induce beneficial effects on various physiological functions that promote neuronal development. This review will discuss the current evidence for the beneficial role of DHA in protecting against neuronal damage and its potential in mitigating the teratogenic effects of alcohol.
... In a study with a gene/stress mouse model, maternal DHA supplementation was shown to mitigate autistic behaviors in offspring pups (181). In order to investigate mechanism(s) whereby DHA supplementation could suppress autistic behavior, Yang et al. examined FAs and peroxidation products in mouse pups from mothers given a control diet or a diet containing 1% DHA (128). ...
Article
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Phospholipids in the central nervous system (CNS) are rich in polyunsaturated fatty acids (PUFAs), particularly arachidonic acid (ARA) and docosahexaenoic acid (DHA). Besides providing physical properties to cell membranes, these PUFAs are metabolically active and undergo turnover through the "deacylation-reacylation (Land's) cycle". Recent studies suggest a Yin-Yang mechanism for metabolism of ARA and DHA, largely due to different phospholipases A2 (PLA2s) mediating their release. ARA and DHA are substrates of cyclooxygenases and lipoxygenases resulting in an array of lipid mediators, which are pro-inflammatory and pro-resolving. The PUFAs are susceptible to peroxidation by oxygen free radicals, resulting in the production of 4-hydroxynonenal (4-HNE) from ARA and 4-hydroxyhexenal (4-HHE) from DHA. These alkenal electrophiles are reactive and capable of forming adducts with proteins, phospholipids and nucleic acids. The perceived cytotoxic and hormetic effects of these hydroxyl-alkenals have impacted cell signaling pathways, glucose metabolism and mitochondrial functions in chronic and inflammatory diseases. Due to the high levels of DHA and ARA in brain phospholipids, this review is aimed at providing information on the Yin-Yang mechanisms for regulating these PUFAs and their lipid peroxidation products in the CNS, and implications of their roles in neurological disorders.
... These observations suggest that alterations in synaptic membrane DHA have an impact on DA synaptic neurotransmission and plasticity (Farooqui 2010). In addition, it has the ability to mitigate stress-induced reductions in serotonin levels (Matsui et al. 2018) and release noradrenaline in cultured SH-SY5Y cells (Mathieu et al. 2008). ...
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... A follow-up to this study made use of docosahexaenoic acid (DHA) as a potential therapeutic intervention. DHA treatment rescued social impairment and reduced ASD-like stereotypic repetitive grooming behavior observed in males that was otherwise increased by interaction of prenatal stress and maternal 5-HTT genotype (Matsui et al., 2017). The consistency of this gene-stress interaction pattern across cohorts in different studies strengthens the significance of maternal serotonin as a stress regulating mechanism. ...
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Purpose of review: While genetic factors are a major etiological contributor to autism spectrum disorder (ASD), evidence also supports a role for environmental factors. Herein, we will discuss two such factors that have been associated with a significant proportion of ASD risk: prenatal stress exposure and maternal immune dysregulation, and how sex and gender relate to these factors. Recent findings: Recent evidence suggests that maternal stress susceptibility interacts with prenatal stress exposure to affect offspring neurodevelopment. Additionally, understanding of the impact of maternal immune dysfunction on ASD has recently been advanced by recognition of specific fetal brain proteins targeted by maternal autoantibodies, and identification of unique mid-gestational maternal immune profiles. Animal models have been developed to explore pathophysiology targeting both of these factors, with limited sex-specific effects observed. While prenatal stress and maternal immune dysregulation are associated with ASD, most cases of these prenatal exposures do not result in ASD, suggesting interaction with multiple other risks. We are beginning to understand the behavioral, pharmacopathological, and epigenetic effects related to these interactions, as well as potential mitigating factors. Sex differences of these risks have been understudied but are crucial for understanding the higher prevalence of ASD in boys. Continued growth in understanding of these mechanisms may ultimately allow for the identification of multiple potential points for prevention or intervention, and for a personalized medicine approach for this subset of environmental-associated ASD cases.
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Prenatal factors influence autism spectrum disorder (ASD) incidence in children and can increase ASD symptoms in offspring of animal models. These may include maternal immune activation (MIA) due to viral or bacterial infection during the first trimesters. Unfortunately, regardless of ASD etiology, existing drugs are poorly effective against core symptoms. For nearly a century a ketogenic diet (KD) has been used to treat seizures, and recent insights into mechanisms of ASD and a growing recognition that immune/inflammatory conditions exacerbate ASD risk has increased interest in KD as a treatment for ASD. Here we studied the effects of KD on core ASD symptoms in offspring exposed to MIA. To produce MIA, pregnant C57Bl/6 mice were injected with the viral mimic polyinosinic-polycytidylic acid; after weaning offspring were fed KD or control diet for three weeks. Consistent with an ASD phenotype of a higher incidence in males, control diet-fed MIA male offspring were not social and exhibited high levels of repetitive self-directed behaviors; female offspring were unaffected. However, KD feeding partially or completely reversed all MIA-induced behavioral abnormalities in males; it had no effect on behavior in females. KD-induced metabolic changes of reduced blood glucose and elevated blood ketones were quantified in offspring of both sexes. Prior work from our laboratory and others demonstrate KDs improve relevant behaviors in several ASD models, and here we demonstrate clear benefits of KD in the MIA model of ASD. Together these studies suggest a broad utility for metabolic therapy in improving core ASD symptoms, and support further research to develop and apply ketogenic and/or metabolic strategies in patients with ASD.
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Autism spectrum disorder (ASD) is a developmental condition that affects approximately four times as many males as females, a strong sex bias that has not yet been fully explained. Understanding the causes of this biased prevalence may highlight novel avenues for treatment development that could benefit patients with diverse genetic backgrounds, and the expertise of sex differences researchers will be invaluable in this endeavor. In this review, I aim to assess current evidence pertaining to the sex difference in ASD prevalence and to identify outstanding questions and remaining gaps in our understanding of how males come to be more frequently affected and/or diagnosed with ASD. Though males consistently outnumber females in ASD prevalence studies, prevalence estimates generated using different approaches report male/female ratios of variable magnitude that suggest that ascertainment or diagnostic biases may contribute to the male skew in ASD. Here, I present the different methods applied and implications of their findings. Additionally, even as prevalence estimations challenge the degree of male bias in ASD, support is growing for the long-proposed female protective effect model of ASD risk, and I review the relevant results from recurrence rate, quantitative trait, and genetic analyses. Lastly, I describe work investigating several sex-differential biological factors and pathways that may be responsible for females’ protection and/or males’ increased risk predicted by the female protective effect model, including sex steroid hormone exposure and regulation and sex-differential activity of certain neural cell types. However, much future work from both the ASD and sex differences research communities will be required to flesh out our understanding of how these factors act to influence the developing brain and modulate ASD risk.
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Dietary supplementation with the long-chain omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) has been shown to have a beneficial effect on reducing the symptoms associated with several neuropsychiatric conditions including anxiety and depression. However, the mechanisms underlying this effect remain largely unknown. Increasing evidence suggests that the vast repertoire of commensal bacteria within the gut plays a critical role in regulating various biological processes in the brain and may contribute to neuropsychiatric disease risk. The present study determined the contribution of DHA on anxiety and depressive-like behaviors through modulation of the gut microbiota in a paradigm of social isolation. Adult male and female mice were subjected to social isolation for 28 days and then placed either on a control diet or a diet supplemented with 0.1% or 1.0% DHA. Fecal pellets were collected both 24 h and 7 days following the introduction of the new diets. Behavioral testing revealed that male mice fed a DHA diet, regardless of dose, exhibited reduced anxiety and depressive-like behaviors compared to control fed mice while no differences were observed in female mice. As the microbiota-brain-axis has been recently implicated in behavior, composition of microbial communities were analyzed to examine if these sex-specific effects of DHA may be associated with changes in the gut microbiota (GM). Clear sex differences were observed with males and females showing distinct microbial compositions prior to DHA supplementation. The introduction of DHA into the diet also induced sex-specific interactions on the GM with the fatty acid producing a significant effect on the microbial profiles in males but not in females. Interestingly, levels of Allobaculum and Ruminococcus were found to significantly correlate with the behavioral changes observed in the male mice. Predictive metagenome analysis using PICRUSt was performed on the fecal samples collected from males and identified enrichment in functional KEGG pathway terms relevant to processes such as the biosynthesis of unsaturated fatty acids and antioxidant metabolism. These results indicate that DHA alters commensal community composition and produces beneficial effects on anxiety and depressive-like behaviors in a sex-specific manner. The present study provides insight into the mechanistic role that gut microbes may play in the regulation of anxiety and depressive-like behaviors and how dietary intervention can modulate these effects.
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A new application for omega-3 fatty acids has recently emerged, concerning the treatment of several mental disorders. This indication is supported by data of neurobiological research, as highly unsaturated fatty acids (HUFAs) are highly concentrated in neural phospholipids and are important components of the neuronal cell membrane. They modulate the mechanisms of brain cell signaling, including the dopaminergic and serotonergic pathways. The aim of this review is to provide a complete and updated account of the empirical evidence of the efficacy and safety that are currently available for omega-3 fatty acids in the treatment of psychiatric disorders. The main evidence for the effectiveness of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) has been obtained in mood disorders, in particular in the treatment of depressive symptoms in unipolar and bipolar depression. There is some evidence to support the use of omega-3 fatty acids in the treatment of conditions characterized by a high level of impulsivity and aggression and borderline personality disorders. In patients with attention deficit hyperactivity disorder, small-to-modest effects of omega-3 HUFAs have been found. The most promising results have been reported by studies using high doses of EPA or the association of omega-3 and omega-6 fatty acids. In schizophrenia, current data are not conclusive and do not allow us either to refuse or support the indication of omega-3 fatty acids. For the remaining psychiatric disturbances, including autism spectrum disorders, anxiety disorders, obsessive-compulsive disorder, eating disorders and substance use disorder, the data are too scarce to draw any conclusion. Concerning tolerability, several studies concluded that omega-3 can be considered safe and well tolerated at doses up to 5 g/day.
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Background: There is evidence that children with Attention Deficit Hyperactivity Disorder (ADHD) and Autistic Spectrum Disorder (ASD) have lower omega-3 polyunsaturated fatty acid (n-3 PUFA) levels compared with controls and conflicting evidence regarding omega-6 (n-6) PUFA levels. Objectives: This study investigated whether erythrocyte n-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were lower and n-6 PUFA arachidonic acid (AA) higher in children with ADHD, ASD and controls, and whether lower n-3 and higher n-6 PUFAs correlated with poorer scores on the Australian Twin Behaviour Rating Scale (ATBRS; ADHD symptoms) and Test of Variable Attention (TOVA) in children with ADHD, and Childhood Autism Rating Scale (CARS) in children with ASD. Methods: Assessments and blood samples of 565 children aged 3-17 years with ADHD (n = 401), ASD (n = 85) or controls (n = 79) were analysed. One-way ANOVAs with Tukey's post-hoc analysis investigated differences in PUFA levels between groups and Pearson's correlations investigated correlations between PUFA levels and ATBRS, TOVA and CARS scores. Results: Children with ADHD and ASD had lower DHA, EPA and AA, higher AA/EPA ratio and lower n-3/n-6 than controls (P<0.001 except AA between ADHD and controls: P = 0.047). Children with ASD had lower DHA, EPA and AA than children with ADHD (P<0.001 for all comparisons). ATBRS scores correlated negatively with EPA (r = -.294, P<0.001), DHA (r = -.424, P<0.001), n-3/n-6 (r = -.477, P<0.001) and positively with AA/EPA (r = .222, P <.01). TOVA scores correlated positively with DHA (r = .610, P<0.001), EPA (r = .418, P<0.001) AA (r = .199, P<0.001), and n-3/n-6 (r = .509, P<0.001) and negatively with AA/EPA (r = -.243, P<0.001). CARS scores correlated significantly with DHA (r = .328, P = 0.002), EPA (r = -.225, P = 0.038) and AA (r = .251, P = 0.021). Conclusions: Children with ADHD and ASD had low levels of EPA, DHA and AA and high ratio of n-6/n-3 PUFAs and these correlated significantly with symptoms. Future research should further investigate abnormal fatty acid metabolism in these disorders.
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The global increase in rates of obesity has been accompanied by a similar surge in the number of autism diagnoses. Accumulating epidemiological evidence suggest a possible link between overweight and the risk for autism spectrum disorders (ASD), as well as autism severity. In laboratory animals, several studies have shown a direct link between various environmental factors, including diet-induced obesity, and the development of autism-related behaviors. However, the effect of high-fat or imbalanced diet on a pre-existing autism-like phenotype is unclear.
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Background: Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by impairment in social communication/interaction and inflexible/repetitive behavior. Several lines of evidence support genetic factors as a predominant cause of ASD. Among those autism susceptibility genes that have been identified, the PTEN tumor suppressor gene, initially identified as predisposing to Cowden heritable cancer syndrome, was found to be mutated in a subset of ASD patients with extreme macrocephaly. However, the ASD-relevant molecular mechanism mediating the effect of PTEN mutations remains elusive. Methods: We developed a Pten knock-in murine model to study the effects of Pten germline mutations, specifically altering subcellular localization, in ASD. Proteins were isolated from the hemispheres of the male littermates, and Western blots were performed to determine protein expression levels of tyrosine hydroxylase (TH). Immunohistochemical stains were carried out to validate the localization of TH and dopamine D2 receptors (D2R). PC12 cells ectopically expressing either wild-type or missense mutant PTEN were then compared for the differences in TH expression. Results: Mice carrying Pten mutations have high TH and D2R in the striatum and prefrontal cortex. They also have increased phosphorylation of cAMP response element-binding protein (CREB) and TH. Mechanistically, PTEN downregulates TH production in PC12 cells via inhibiting the phosphoinositide 3-kinase (PI3K)/CREB signaling pathway, while PTEN reduces TH phosphorylation via suppressing MAPK pathway. Unlike wild-type PTEN but similar to the mouse knock-in mutant Pten, three naturally occurring missense mutations of PTEN that we previously identified in ASD patients, H93R, F241S, and D252G, were not able to suppress TH when overexpressed in PC12 cells. In addition, two other PTEN missense mutations, C124S (pan phosphatase dead) and G129E (lipid phosphatase dead), failed to suppress TH when ectopically expressed in PC12 cells. Conclusions: Our data reveal a non-canonical PTEN-TH pathway in the brain that may work as a core regulator of dopamine signaling, which when dysfunctional is pathogenic in ASD.
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Omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids (PUFA) are essential nutrients for brain development and function. However, whether or not the levels of these fatty acids are altered in individuals with autism remains debatable. In this study, we compared the fatty acid contents between 121 autistic patients and 110 non-autistic, non-developmentally delayed controls, aged 3-17. Analysis of the fatty acid composition of red blood cell (RBC) membrane phospholipids showed that the percentage of total PUFA was lower in autistic patients than in controls; levels of n-6 arachidonic acid (AA) and n-3 docosahexaenoic acid (DHA) were particularly decreased (p < 0.001). In addition, plasma levels of the pro-inflammatory AA metabolite prostaglandin E2 (PGE2) were higher in a subset of the autistic participants (n = 20) compared to controls. Our study demonstrates an alteration in the PUFA profile and increased production of a PUFA-derived metabolite in autistic patients, supporting the hypothesis that abnormal lipid metabolism is implicated in autism.
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Autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting more than 1% of children. It is characterized by social communication deficits and repetitive behaviors/restricted interests. In the absence of any medications known to improve core symptom domains, parents often use complementary alternative treatments, including omega-3 fatty acid supplements. We conducted a 6-month, randomized, placebo controlled trial of omega-3 fatty acid supplements (1.5 g) vs placebo in children 2 to 5 years of age with ASD. Primary outcome measures included the autism composite score of the Pervasive Developmental Disorders Behavioral Inventory (PDDBI) and the externalizing problems score of the Behavior Assessment System for Children (BASC-2). Secondary outcome measures included clinical global improvement (Clinical Global Impression-Improvement (CGI-I)), adaptive function (Vineland Adaptive Behavior Scale (VABS-II)), and language gains (Preschool Language Scale (PLS-4)), as well as safety. Exploratory analysis investigated potential correlations between changes in cytokine profiles and treatment response. Thirty-eight participants were randomized in a 1:1 fashion. There was no significant difference between groups on the 0- to 24-week change in PDDBI autism composite scores (p = 0.5). There was a significant group by week interaction on the BASC-2 externalizing problem score, with participants randomized to the treatment group demonstrating worsening scores (p = 0.02). There was no statistically significant week by group effect on either adaptive function (p = 0.09) or language (p = 0.6). Omega-3s were relatively well tolerated. Changes in cytokines during the study did not significantly correlate with treatment response. This study does not support high dose supplementation of omega-3 fatty acids in young children with ASD. Clinicaltrials.gov NCT01248728. Registered 22 November 2010.
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Although the involvement of genetic abnormalities in autism spectrum disorders (ASD) is well-accepted, recent studies point to an equal contribution by environmental factors, particularly environmental toxicants. However, these toxicant-related studies in ASD have not been systematically reviewed to date. Therefore, we compiled publications investigating potential associations between environmental toxicants and ASD and arranged these publications into the following three categories: (a) studies examining estimated toxicant exposures in the environment during the preconceptional, gestational and early childhood periods; (b) studies investigating biomarkers of toxicants; and (c) studies examining potential genetic susceptibilities to toxicants. A literature search of nine electronic scientific databases through November 2013 was performed. In the first category examining ASD risk and estimated toxicant exposures in the environment, the majority of studies (34/37; 92%) reported an association. Most of these studies were retrospective case-control, ecological or prospective cohort studies, although a few had weaker study designs (for example, case reports or series). Toxicants implicated in ASD included pesticides, phthalates, polychlorinated biphenyls (PCBs), solvents, toxic waste sites, air pollutants and heavy metals, with the strongest evidence found for air pollutants and pesticides. Gestational exposure to methylmercury (through fish exposure, one study) and childhood exposure to pollutants in water supplies (two studies) were not found to be associated with ASD risk. In the second category of studies investigating biomarkers of toxicants and ASD, a large number was dedicated to examining heavy metals. Such studies demonstrated mixed findings, with only 19 of 40 (47%) case-control studies reporting higher concentrations of heavy metals in blood, urine, hair, brain or teeth of children with ASD compared with controls. Other biomarker studies reported that solvent, phthalate and pesticide levels were associated with ASD, whereas PCB studies were mixed. Seven studies reported a relationship between autism severity and heavy metal biomarkers, suggesting evidence of a dose-effect relationship. Overall, the evidence linking biomarkers of toxicants with ASD (the second category) was weaker compared with the evidence associating estimated exposures to toxicants in the environment and ASD risk (the first category) because many of the biomarker studies contained small sample sizes and the relationships between biomarkers and ASD were inconsistent across studies. Regarding the third category of studies investigating potential genetic susceptibilities to toxicants, 10 unique studies examined polymorphisms in genes associated with increased susceptibilities to toxicants, with 8 studies reporting that such polymorphisms were more common in ASD individuals (or their mothers, 1 study) compared with controls (one study examined multiple polymorphisms). Genes implicated in these studies included paraoxonase (PON1, three of five studies), glutathione S-transferase (GSTM1 and GSTP1, three of four studies), δ-aminolevulinic acid dehydratase (one study), SLC11A3 (one study) and the metal regulatory transcription factor 1 (one of two studies). Notably, many of the reviewed studies had significant limitations, including lack of replication, limited sample sizes, retrospective design, recall and publication biases, inadequate matching of cases and controls, and the use of nonstandard tools to diagnose ASD. The findings of this review suggest that the etiology of ASD may involve, at least in a subset of children, complex interactions between genetic factors and certain environmental toxicants that may act synergistically or in parallel during critical periods of neurodevelopment, in a manner that increases the likelihood of developing ASD. Because of the limitations of many of the reviewed studies, additional high-quality epidemiological studies concerning environmental toxicants and ASD are warranted to confirm and clarify many of these findings.
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Dopaminergic function is thought to be altered in major depression and, in animal studies, is reduced in omega-3 polyunsaturated fatty acid (PUFA) deficiency states. Therefore we studied PUFAs and resting prolactin, a marker for dopaminergic tone, and cerebrospinal fluid homovanillic acid (HVA), the chief dopamine metabolite. In medication-free adults (n = 23) with DSM-IV major depressive disorder (MDD), we measured plasma phospholipid levels of omega-3 PUFAs docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), the omega-6 PUFA arachidonic acid (AA), and plasma prolactin levels before and after administration of dl-fenfluramine (FEN). In a subset of patients (n = 14), cerebrospinal fluid levels of HVA and the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were obtained through lumbar puncture. Baseline prolactin was negatively correlated with omega-3 PUFAs (logDHA, F 1,21 = 20.380, p < 0.001; logEPA, F 1,21 = 10.051, p = 0.005) and positively correlated with logAA:DHA (F 1,21 = 15.263, p = 0.001), a measure of omega-6/omega-3 balance. LogDHA was negatively correlated with CSF HVA (Spearman's ρ = -0.675, p = 0.008) but not 5-HIAA (Spearman's ρ = -0.143, p = 0.626) after controlling for sex and HVA - 5-HIAA correlation. PUFAs did not predict the magnitude of the FEN-stimulated change in prolactin, considered to be a serotonin effect. The robust relationship of omega-3 PUFAs with dopaminergic but not serotonergic indices suggests that omega-6:omega-3 balance may impact depression pathophysiology through effects on the dopaminergic system.
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In recent years concern has risen about the increasing prevalence of Autism Spectrum Disorders (ASD). Accumulating evidence shows that exposure to neurotoxic compounds is related to ASD. Neurotransmitters might play a key role, as research has indicated a connection between neurotoxic compounds, neurotransmitters and ASD. In the current review a literature overview with respect to neurotoxic exposure and the effects on neurotransmitter systems is presented. The aim was to identify mechanisms and related factors which together might result in ASD. The literature reported in the current review supports the hypothesis that exposure to neurotoxic compounds can lead to alterations in the GABAergic, glutamatergic, serotonergic and dopaminergic system which have been related to ASD in previous work. However, in several studies findings were reported that are not supportive of this hypothesis. Other factors also might be related, possibly altering the mechanisms at work, such as time and length of exposure as well as dose of the compound. Future research should focus on identifying the pathway through which these factors interact with exposure to neurotoxic compounds making use of human studies.
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Understanding the nature of environmental factors that contribute to behavioral health is critical for successful prevention strategies in individuals at risk for psychiatric disorders. These factors are typically experiential in nature, such as stress and urbanicity, but nutrition-in particular dietary deficiency of omega-3 polyunsaturated fatty acids (n-3 PUFAs)-has increasingly been implicated in the symptomatic onset of schizophrenia and mood disorders, which typically occurs during adolescence to early adulthood. Thus, adolescence might be the critical age range for the negative impact of diet as an environmental insult. A rat model involving consecutive generations of n-3 PUFA deficiency was developed on the basis of the assumption that dietary trends toward decreased consumption of these fats began 4-5 decades ago when the parents of current adolescents were born. Behavioral performance in a wide range of tasks as well as markers of dopamine-related neurotransmission was compared in adolescents and adults fed n-3 PUFA adequate and deficient diets. In adolescents, dietary n-3 PUFA deficiency across consecutive generations produced a modality-selective and task-dependent impairment in cognitive and motivated behavior distinct from the deficits observed in adults. Although this dietary deficiency affected expression of dopamine-related proteins in both age groups in adolescents but not adults, there was an increase in tyrosine hydroxylase expression that was selective to the dorsal striatum. These data support a nutritional contribution to optimal cognitive and affective functioning in adolescents. Furthermore, they suggest that n-3 PUFA deficiency disrupts adolescent behaviors through enhanced dorsal striatal dopamine availability.
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Dietary intervention as a tool for maintaining and improving physical health and wellbeing is a widely researched and discussed topic. Speculation that diet may similarly affect mental health and wellbeing particularly in cases of psychiatric and behavioral symptomatology opens up various avenues for potentially improving quality of life. We examine evidence suggestive that a gluten-free (GF), casein-free (CF), or gluten- and casein-free diet (GFCF) can ameliorate core and peripheral symptoms and improve developmental outcome in some cases of autism spectrum conditions. Although not wholly affirmative, the majority of published studies indicate statistically significant positive changes to symptom presentation following dietary intervention. In particular, changes to areas of communication, attention, and hyperactivity are detailed, despite the presence of various methodological shortcomings. Specific characteristics of best- and non-responders to intervention have not been fully elucidated; neither has the precise mode of action for any universal effect outside of known individual cases of food-related co-morbidity. With the publication of controlled medium- and long-term group studies of a gluten- and casein-free diet alongside more consolidated biological findings potentially linked to intervention, the appearance of a possible diet-related autism phenotype seems to be emerging supportive of a positive dietary effect in some cases. Further debate on whether such dietary intervention should form part of best practice guidelines for autism spectrum conditions (ASCs) and onward representative of an autism dietary-sensitive enteropathy is warranted.
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Lay summary: There is emerging evidence that prenatal maternal stress may increase the risk for Autism Spectrum Disorder (ASD) and contribute to variability in autism-like traits in the general population. Here, we found that more stressful life events experienced during pregnancy was associated with more severe ASD-related symptoms and poorer communication abilities amongst children with ASD. The results from this study suggest that prenatal maternal stress exposure and its sequelae may contribute to variability in symptom severity amongst children with ASD.
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Despite the progress made in understanding the biology of autism spectrum disorder (ASD), effective biological interventions for the core symptoms remain elusive. Because of the etiological heterogeneity of ASD, identification of a "one-size-fits-all" treatment approach will likely continue to be challenging. A meeting was convened at the University of Missouri and the Thompson Center to discuss strategies for stratifying patients with ASD for the purpose of moving toward precision medicine. The "white paper" presented here articulates the challenges involved and provides suggestions for future solutions.
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Aim: Oxytocin presents an exciting potential to target the core symptoms of autism spectrum disorder (ASD) pharmacologically in an easily administered, cost-effective form with possibly minimal adverse effects. But, there are still major gaps in this area of research. This paper reviewed randomized controlled trials (RCTs) examining the effects of oxytocin administration on social cognition and restricted, repetitive behaviors in individuals with an ASD. Method: Electronic literature searches were conducted from PsycINFO, PubMed, Web of Knowledge, and EMBASE for RCTs published through June 2015. Results: 12 RCTs were included in this review. 7 out of the 11 studies that examined social cognition reported improvements. Additionally, one out of the 4 studies on restricted, repetitive behaviors, reported improvements following oxytocin administration. However, results from our meta-analyses suggest that oxytocin has no significant effect on these 2 domains. Conclusion: Previous evidence revealed mixed findings about the effects of oxytocin on ASD. Given the limited number of RCTs, our summary of findings on the effectiveness of oxytocin on ASD should still be considered tentative. © Georg Thieme Verlag KG Stuttgart · New York.
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Stress exposure during gestation is implicated in several neuropsychiatric conditions, including autism spectrum disorder (ASD). Previous research showed that prenatal stress increases risk for ASD with peak exposure during the end of the second and the beginning of the third trimester. However, exposures to prenatal stress do not always result in ASD, suggesting that other factors may interact with environmental stressors to increase ASD risk. The present study examined a maternal genetic variation in the promoter region of the serotonin transporter gene (5-HTTLPR) affecting stress tolerance and its interaction with the effect of environmental stressors on risk for ASD. Two independent cohorts of mothers of ASD children recruited by the University of Missouri and Queen's University were surveyed regarding the prenatal environment and genotyping on 5-HTTLPR was performed to explore this relationship. In both samples, mothers of children with ASD carrying the stress susceptible short allele variant of 5-HTTLPR experienced a greater number of stressors and greater stress severity when compared to mothers carrying the long allele variant. The temporal peak of stressors during gestation in these mothers was consistent with previous findings. Additionally, increased exposure to prenatal stress was not reported in the pregnancies of typically developing siblings from the same mothers, regardless of maternal genotype, suggesting against the possibility that the short allele might increase the recall of stress during pregnancy. The present study provides further evidence of a specific maternal polymorphism that may affect the risk for ASD with exposure to prenatal stress. Autism Res 2016. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.
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This paper reviews current knowledge on the role of the long-chain polyunsaturated fatty acids (LC-PUFA), docosahexaenoic acid (DHA, C22:6n-3) and arachidonic acid (AA, 20:4n-6), in maternal and term infant nutrition as well as infant development. Consensus recommendations and practice guidelines for health-care providers supported by the World Association of Perinatal Medicine, the Early Nutrition Academy, and the Child Health Foundation are provided. The fetus and neonate should receive LC-PUFA in amounts sufficient to support optimal visual and cognitive development. Moreover, the consumption of oils rich in n-3 LC-PUFA during pregnancy reduces the risk for early premature birth. Pregnant and lactating women should aim to achieve an average daily intake of at least 200 mg DHA. For healthy term infants, we recommend and fully endorse breastfeeding, which supplies preformed LC-PUFA, as the preferred method of feeding. When breastfeeding is not possible, we recommend use of an infant formula providing DHA at levels between 0.2 and 0.5 weight percent of total fat, and with the minimum amount of AA equivalent to the contents of DHA. Dietary LC-PUFA supply should continue after the first six months of life, but currently there is not sufficient information for quantitative recommendations.
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Prenatal stress is associated with altered behavioral, cognitive, and psychiatric outcomes in offspring. Due to the importance of GABAergic systems in normal development and in psychiatric disorders, prenatal stress effects on these neurons have been investigated in animal models. Prenatal stress delays GABAergic progenitor migration, but the significance of these early developmental disruptions for the continued development of GABAergic cells in the juvenile brain is unclear. Here, we examined effects of prenatal stress on populations of GABAergic neurons in juvenile and adult medial frontal cortex (mFC) and hippocampus through stereological counting, gene expression, and relevant anxiety-like and social behaviors. Postnatally, the otal GABAergic cell number that peaks in adolescence showed altered trajectories in mFC and hippocampus. Parvalbumin neuron proportion in juvenile brain was altered by prenatal stress, but parvalbumin gene expression showed no differences. In adult brain, parvalbumin neuron proportions were altered by prenatal stress with opposite gene expression changes. Adult prenatally-stressed offspring showed a lack of social preference on a 3-chambered task, increased anxiety-like behavior on the elevated plus maze, and reduced center time in an open field. Despite a lack of significant group differences in adult total GABAergic cell populations, performance on these tasks was correlated with GABAergic populations in mFC and hippocampus. In conclusion, prenatal stress resulted in a delay in GABAergic cell number and maturation of the parvalbumin subtype. Influences of prenatal stress on GABAergic populations during developmentally dynamic periods and during adulthood may be relevant to the anxiety-like behaviors that occur after prenatal stress. This article is protected by copyright. All rights reserved.
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Purpose of review: The purpose of this study is to discuss the role of gluten-free and casein-free diets in the treatment of autism. Recent findings: In a recent UK survey, more than 80% of parents of children with autism spectrum disorder reported some kind of dietary intervention for their child (gluten-free and casein-free diet in 29%). When asked about the effects of the gluten-free and casein-free diet, 20-29% of the parents reported significant improvements on the autism spectrum disorder core dimensions. The findings of this study suggest additional effects of a gluten-free and casein-free diet on comorbid problems of autism such as gastrointestinal symptoms, concentration, and attention. The findings of another recent investigation suggested that age and certain urine compounds may predict the response of autism symptoms to a gluten-free and casein-free diet. Although these results need to be replicated, they highlight the importance of patient subgroup analysis. Intervention trials evaluating the effects of a gluten-free and casein-free diet on autistic symptoms have so far been contradictory and inconclusive. Summary: Most investigations assessing the efficacy of a gluten-free and casein-free diet in the treatment of autism are seriously flawed. The evidence to support the therapeutic value of this diet is limited and weak. A gluten-free and casein-free diet should only be administered if an allergy or intolerance to nutritional gluten or casein is diagnosed.
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Polyunsaturated fatty acids (PUFAs) are not only essential for energy production, but they also exhibit a range of immunomodulatory properties that progress through T cell mediated events. Autoimmunity may have a pathogenic role in a subgroup of autistic children. This study is the first to investigate the relationship between serum levels of anti-myelin basic protein (anti-MBP) brain-specific auto-antibodies and reduced plasma levels of PUFAs in autistic children. Plasma levels of PUFAs (including linoleic, alphalinolenic, arachidonic "AA" and docosahexaenoic "DHA" acids) and serum anti-MBP were measured in 80 autistic children, aged between 4 and 12 years, and 80 healthy-matched children. Autistic patients had significantly lower plasma levels of PUFAs than healthy children. On the other hand, ω6/ω3 ratio (AA/DHA) was significantly higher in autistic patients than healthy children. Low plasma DHA, AA, linolenic and linoleic acids were found in 67.5%, 50%, 40% and 35%, respectively of autistic children. On the other hand, 70% of autistic patients had elevated ω6/ω3 ratio. Autistic patients with increased serum levels of anti-MBP auto-antibodies (75%) had significantly lower plasma DHA (P<0.5) and significantly higher ω6/ω3 ratio (P<0.5) than patients who were seronegative for these antibodies. In conclusions, some autistic children have a significant positive association between reduced levels of plasma DHA and increased serum levels of anti-MBP brain-specific auto-antibodies. However, replication studies of larger samples are recommended to validate whether reduced levels of plasma PUFAs are a mere association or have a role in the induction of the production of anti-MBP in some autistic children. Copyright © 2015 Elsevier B.V. All rights reserved.
Article
Background Prenatal stress is considered a risk factor for several neurodevelopmental disorders including schizophrenia (SZ). An animal model involving restraint stress of pregnant mice suggests that prenatal stress (PRS) induces epigenetic changes in specific GABAergic and glutamatergic genes likely to be implicated in SZ including the gene for brain derived neurotrophic factor (BDNF). Methods Studying adult offspring of pregnant mice subjected to PRS, we explored the long-term effects of PRS on behavior and on the expression of key chromatin remodeling factors including DNA methyltransferase 1 (DNMT1), ten-eleven translocation hydroxylases (TETs), methyl CpG binding protein 2 (MeCP2), histone deacetylases (HDACs), histone methyltransferases (MLL1, SETD1, G9a and EZH1) and demethylase (LSD1) in the frontal cortex (FC) and hippocampus (HP). We also measured the expression of BDNF. Results Adult PRS offspring demonstrate behavioral abnormalities suggestive of SZ and molecular changes similar to SZ postmortem brain: a significant increase in DNMT1 and TET1 in the FC and HP but not in cerebellum, no changes in HDACs, histone methytransferases/demethylases or MeCP2, and a significant decrease in BDNF mRNA variants. The decrease of the corresponding BDNF transcript level was accompanied by an enrichment of 5-methylcytosine and 5-hydroxymethylcytosine at Bdnf gene regulatory regions. In addition, the expression of BDNF transcripts (IV and IX) positively correlated with social approach in both PRS and non-stressed mice. Conclusions Since patients with psychosis and PRS mice show similar epigenetic signature, PRS offspring may be a suitable model for understanding the behavioral and molecular epigenetic changes observed in SZ patients.
Article
Our goal in this study was to determine whether maternal fat intake before or during pregnancy was associated with risk of autism spectrum disorder (ASD) in the offspring. Our primary analysis included 317 mothers who reported a child with ASD and 17,728 comparison mothers from the Nurses' Health Study II (index births in 1991-2007). Dietary information was collected prospectively through a validated food frequency questionnaire. Binomial regression was used to estimate crude and adjusted risk ratios. Maternal intake of linoleic acid was significantly inversely associated with ASD risk in offspring, corresponding to a 34% reduction in risk in the highest versus lowest quartiles of intake. Mothers in the lowest 5% of ω-3 fatty acid intake had a significant increase in offspring ASD risk as compared with the remaining distribution (risk ratio = 1.53, 95% confidence interval: 1.00, 2.32); this association was also seen in the subgroup of women (86 cases and 5,798 noncases) for whom dietary information during pregnancy was available (risk ratio = 2.42, 95% confidence interval: 1.19, 4.91). Thus, variations in intake of polyunsaturated fats within the range commonly observed among US women could affect fetal brain development and ASD risk. Because the number of women with diet assessed during pregnancy was small, however, these results should be interpreted cautiously.
Article
Purpose of review: To provide an updated overview of autism spectrum disorders (ASDs), with particular attention to the pediatrician's role in assessing and managing patients with ASDs. Recent findings: Clinical perspectives on ASDs continue to evolve. The prevalence of ASDs in the United States continues to rise, and pediatricians are being tasked with the responsibility for universal screening. Further changes in its epidemiology will undoubtedly result from anticipated changes in the diagnostic criteria put forth in the upcoming revision to the Diagnostic and Statistical Manual (5th edition). Although there have been considerable advances in identifying a genetic cause in many more cases, the cause remains elusive in most cases. Recent studies of concordant twins suggest there is a stronger environmental component than previously believed. Research suggests earlier diagnosis may be feasible in some cases, and a new treatment approach has been shown to be effective in very young children. Although there have not been any large-scale advances in the medical treatment, some isolated successes have been reported and other promising therapies are now being investigated. Summary: Clinical guidelines for ASDs are evolving, with updated diagnostic criteria expected and revised recommendations for evaluation also imminent. This article provides pediatricians with a clinical overview of ASD - with an emphasis on the clinical considerations relating to screening, evaluation, and management.
Article
Multiple studies have reported prenatal stress as a potential risk factor for the development of autism spectrum disorder (ASD). In rodents, a significant reduction in sociability is seen in prenatally stressed offspring of genetically stress-susceptible dams. Certain dietary factors that contribute to stress reactivity may, therefore, exacerbate prenatal stress-mediated behavioral changes in adult offspring. Adults with a diet rich in omega-6 polyunsaturated fatty acids (PUFAs) display increased stress reactivity. In the current study, the effects of prenatal diet and prenatal stress on social behavior in adult offspring mice were examined. Pregnant C57BL/6J dams received either chronic variable stress or no stress, and were also placed on a control diet or a diet rich in omega-6 PUFAs, in a 2×2 design. We subsequently tested the adult offspring for sociability, anxiety, and locomotor behaviors using a 3-chambered social approach task, an elevated-plus maze, an open field task and a rotarod task. Results indicated that a maternal diet rich in omega-6 PUFAs during gestation and lactation produce changes in sociability consistent with those observed in ASD. Additionally, offspring exposed to a diet rich in omega-6 PUFAs during gestation and lactation had increased levels of anxiety in the elevated-plus maze. Prenatal stress had no effect on offspring behavior. These findings provide evidence for a possible environmental risk factor that contributes to the production of autistic-like behavior in mice.
Article
Serotonin content, serotonin uptake sites, and serotonin receptor binding measured in animal studies are all higher in the developing brain, compared with adult values, and decline before puberty. Furthermore, a disruption of synaptic connectivity in sensory cortical regions can result from experimental increase or decrease of brain serotonin before puberty. The purpose of the present study was to determine whether brain serotonin synthesis capacity is higher in children than in adults and whether there are differences in serotonin synthesis capacity between autistic and nonautistic children. Serotonin synthesis capacity was measured in autistic and nonautistic children at different ages, using α[11C]methyl-L-tryptophan and positron emission tomography. Global brain values for serotonin synthesis capacity (K complex) were obtained for autistic children (n = 30), their nonautistic siblings (n = 8), and epileptic children without autism (n = 16). K-complex values were plotted according to age and fitted to linear and five-parameter functions, to determine developmental changes and differences in serotonin synthesis between groups. For nonautistic children, serotonin synthesis capacity was more than 200% of adult values until the age of 5 years and then declined toward adult values. Serotonin synthesis capacity values declined at an earlier age in girls than in boys. In autistic children, serotonin synthesis capacity increased gradually between the ages of 2 years and 15 years to values 1.5 times adult normal values and showed no sex difference. Significant differences were detected between the autistic and epileptic groups and between the autistic and sibling groups for the change with age in the serotonin synthesis capacity. These data suggest that humans undergo a period of high brain serotonin synthesis capacity during childhood, and that this developmental process is disrupted in autistic children. Ann Neurol 1999;45:287–295
Article
To investigate whether an elevated plus-maze consisting of two open and two closed arms could be used as a model of anxiety in the mouse, NIH Swiss mice were tested in the apparatus immediately after a holeboard test. Factor analysis of data from undrugged animals tested in the holeboard and plus-maze yielded three orthogonal factors interpreted as assessing anxiety, directed exploration and locomotion. Anxiolytic drugs (chlordiazepoxide, sodium pentobarbital and ethanol) increased the proportion of time spent on the open arms, and anxiogenic drugs (FG 7142, caffeine and picrotoxin) reduced this measure. Amphetamine and imipramine failed to alter the indices of anxiety. The anxiolytic effect of chlordiazepoxide was reduced in mice that had previously experienced the plus-maze in an undrugged state. Testing animals in the holeboard immediately before the plus-maze test significantly elevated both the percentage of time spent on the open arms and the total number of arm entries, but did not affect the behavioral response to chlordiazepoxide. The plus-maze appears to be a useful test with which to investigate both anxiolytic and anxiogenic agents.
Article
Stressful events early in life are associated with later psychiatric disorders. We focused on developmental stage and evaluated changes in the corticosterone and serotonergic systems as well as in later anxiety-related behavioral tests. Stressed male Wistar rats were divided into two groups: stressed from postnatal day 11 (PND 11) to 15 and stressed from PND 16 to 20. The rats were exposed to an elevated open platform. Stress increased corticosterone in both experimental groups. In the hypothalamus, amygdala and hippocampus, 5-hydroxytryptamine (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) increased in the rats stressed from PND 11 to 15, and decreased in the rats stressed from PND 16 to 20. In a later behavioral test, rats stressed from PND 11 to 15 traveled shorter distances and tended to spend less time in the center than control rats following restraint stress. There were no significant changes in 5-HT and 5-HIAA in hypothalamus, amygdala and hippocampus after restraint stress in adults. These findings indicate that stress reactions and later effects are different depending on the developmental stage during which the rats were stressed. Stress during the PND 11–15 period may enhance later anxiety-related behaviors without altering 5-HT and 5-HIAA content.
Article
Autism spectrum disorders are a neurodevelopmental disorders with reduced cortical functional connectivity relating to social cognition. Polyunsaturated fatty acids arachidonic acid (ARA) and docosahexaenoic acid (DHA) may have key role in brain network maturation. In particularly, ARA is important in signal transduction related to neuronal maturation. Supplementation with larger ARA doses added to DHA may therefore mitigate social impairment. In a 16-week, double-blind, randomized, placebo-controlled trial, we evaluated the efficacy of supplementation with large doses of ARA added to DHA (n = 7) or placebo (n = 6) in 13 participants (mean age, 14.6 [SD, 5.9] years). To examine underlying mechanisms underlying the effect of our supplementation regimen, we examined plasma levels of antioxidants transferrin and superoxide dismutase, which are useful markers of signal transduction. The outcome measures were the Social Responsiveness Scale and the Aberrant Behavior Checklist-Community. Repeated-measures analysis of variance revealed that our supplementation regimen significantly improved Aberrant Behavior Checklist-Community-measured social withdrawal and Social Responsiveness Scale-measured communication. Treatment effect sizes were more favorable for the treatment group compared with the placebo group (communication: treatment groups, 0.87 vs, placebo, 0.44; social withdrawal: treatment groups, 0.88, vs placebo, 0.54). There was a significant difference in the change in plasma transferrin levels and a trend toward a significant difference in the change in plasma superoxide dismutase levels between the 2 groups. This preliminary study suggests that supplementation with larger ARA doses added to DHA improves impaired social interaction in individuals with autism spectrum disorder by up-regulating signal transduction.
Article
It has been suggested that difficulties associated with ASD may be explained in part by lack of omega-3 fatty acids, and that supplementation of these essential fatty acids may lead to improvement of symptoms. The purpose of this review was to assess the evidence for the effectiveness of omega-3 supplementation for core features of ASD and associated symptoms. We found only two small randomised controlled trials that evaluated omega-3 fatty acids for ASD. There is insufficient evidence that omega-3 fatty acids supplementation is an effective treatment for ASD. However, high quality large randomised controlled trials are needed before definite recommendations about this treatment can be made.
Article
Autism is a pervasive developmental disorder characterized by repetitive stereotyped behavior, social-emotional deficits, and delayed or absent language abilities. There are known neuropathologies in the autism brain affecting limbic, cerebellar, and cortical structures but the neurochemical profile of affected individuals, revealed in postmortem tissue studies, is only recently emerging. One major component that appears highly impacted in autism is the GABAergic system. It is now apparent that there are widespread significant effects in many distributed regions in the autism brain revealed by histochemical, autoradiographic, and biochemical studies. The key synthesizing enzymes for GABA, glutamic acid decarboxylase type 65 and 67 (GAD65 and GAD67), are decreased in the cerebellum and closer examination of mRNA levels revealed that it is largely due to decreases in Purkinje cells and a subpopulation of larger dentate neurons as measured by in situ hybridization studies. Other cell types had either normal GAD levels (Golgi cells, smaller dentate interneurons, and stellate cells) or increased levels (basket cells). GABA receptor density, number, and protein expression are all decreased in the cerebellum and in select cortical areas. GABA(A) and GABA(B) subunit protein expression was significantly reduced in cerebellum, BA 9 and BA 40. Benzodiazepine binding sites were significantly reduced in the hippocampus and anterior cingulate cortex (BA 24). Taken together, data from these studies suggest that there is a marked dysregulation of the inhibitory GABA system in the autism brain affecting particular biomarkers localized to specific cell types and lamina likely influencing circuitry and behavior.
Article
To address how interactions between polyunsaturated fatty acid (PUFA) levels and depressive symptoms were related to proinflammatory cytokine synthesis. Depression and stress promote proinflammatory cytokine production. Dietary intakes of omega-3 (n-3) and omega-6 (n-6) PUFAs also influence inflammation; high n-6:n-3 ratios enhance proinflammatory cytokine production, although n-3 has anti-inflammatory properties. Blood samples from 43 older adults (mean age = 66.67 years, SD = 10.09) provided data on PUFAs and tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-6 soluble receptor (sIL-6r). Depressive symptoms were assessed by the Center for Epidemiological Studies Depression Scale. Depressive symptoms and n-6:n-3 ratios worked together to enhance proinflammatory cytokines beyond the contribution provided by either variable alone, with substantial variance explained by their interaction: 13% for IL-6 and 31% for TNF-alpha, whereas full models accounted for 18% and 40%, respectively. Although predicted cytokine levels were consistent across n-6:n-3 ratios with low depressive symptoms, higher n-6:n-3 ratios were associated with progressively elevated TNF-alpha and IL-6 levels as depressive symptoms increased. Higher levels of sIL-6r were associated with higher n-6:n-3 ratios. Six individuals who met the criteria for major depressive disorder had higher n-6:n-3 ratios and TNF-alpha, IL-6, and sIL-6r levels than those who did not meet the criteria; excluding these six individuals reduced the variance explained by the depressive symptoms and n-6:n-3 ratio interaction. Diets with high n-6:n-3 PUFA ratios may enhance the risk for both depression and inflammatory diseases.