ADHD-like Behaviors Research Articles

Chronic exposure to ethanol of male mice before mating produces attention deficit hyperactivity disorder‐like phenotype along with epigenetic dysregulation of dopamine transporter expression in mouse offspring

Preconception exposure to EtOH through the paternal route may affect neurobehavioral and developmental features of offspring. This study investigates the effects of paternal exposure to EtOH before conception on the hyperactivity, inattention, and impulsivity behavior of male offspring in mice. Sire mice were treated with EtOH in a concentration range approximating human binge drinking (0-4 g/kg/day EtOH) for 7 weeks and mated with untreated females mice to produce offspring. EtOH exposure to sire mice induced attention deficit hyperactivity disorder (ADHD)-like hyperactive, inattentive, and impulsive behaviors in offspring. As a mechanistic link, both protein and mRNA expression of dopamine transporter (DAT), a key determinant of ADHD-like phenotypes in experimental animals and humans, were significantly decreased by paternal EtOH exposure in cerebral cortex and striatum of offspring mice along with increased methylation of a CpG region of the DAT gene promoter. The increase in methylation of DAT gene promoter was also observed in the sperm of sire mice, suggesting germline changes in the epigenetic methylation signature of DAT gene by EtOH exposure. In addition, the expression of two key regulators of methylation-dependent epigenetic regulation of functional gene expression, namely, MeCP2 and DNMT1, was markedly decreased in offspring cortex and striatum sired by EtOH-exposed mice. These results suggest that preconceptional exposure to EtOH through the paternal route induces behavioral changes in offspring, possibly via epigenetic changes in gene expression, which is essential for the regulation of ADHD-like behaviors.

Nutrition, immunological mechanisms and dietary immunomodulation in ADHD

Attention-deficit hyperactivity disorder (ADHD) etiology is not completely understood, but common comorbid dysfunction of the gastrointestinal and immune system suggests that these systems may be affected by a common genetic background and molecular mechanisms. For example, increased levels of specific cytokines were observed in ADHD. Moreover, ADHD has a high comorbidity with both Th1- and Th2-mediated disorders like ear infections, eczema and asthma. A common pathophysiological mechanism was suggested to underlie both asthma and ADHD, while several genes that are linked to ADHD have immune functions. Furthermore, immunological recognition of food provoking ADHD-like behavior was suggested. An immune imbalance, probably requiring a predisposing genetic background, is therefore suggested to contribute to ADHD etiology, with immune dysregulation being more likely than a single subcellular defect. However, next to allergic mechanisms, also pharmacological mechanisms (especially in case of food additives) might be involved. In addition, though cellular (cytokine-related) rather than antibody-mediated immune mechanisms seem involved, specific immune-inflammatory markers other than antibodies have not been systematically studied in ADHD. Substantial alterations implicated in ADHD apparently occur in the immune system and epigenetic regulation of gene expression. As a result, chronic inflammation and oxidative stress could develop, which can lead to ADHD symptoms, for example by chronic T-cell-mediated neuroinflammation. If immune pathways contribute to ADHD, both its diagnosis and treatment should be reconsidered. Modulation of immune system activity might have potential in ADHD treatment, for example by nutritional approaches providing safe and low-cost ADHD therapy, but further research in these fields is implicated.

PCBs and ADHD in Mohawk adolescents

The present study examines the relationship between the levels of persistent polychlorinated biphenyls (PCBs) in adolescents' blood serum and concurrent measures of their ADHD-like behavior derived from ratings provided by parents and teachers. Two measures with demonstrated diagnostic validity, the Conners and ADDES scales, are used. The study was conducted in partnership with the Mohawk Nation at Akwesasne where the St. Lawrence River and surrounding waterways have been contaminated with PCBs that have entered the food chain. This study examines a subset of the data derived from the Mohawk Adolescent Well-Being Study (MAWBS), which was designed to investigate psychosocial and health related outcomes of 271 adolescents aged 10years to 17years and whose mothers were likely to have consumed PCB-contaminated fish and wild game before and during their pregnancy. No evidence of negative effects of adolescent blood PCB levels on ADHD-like behavior was found, and indeed occasional findings were in the unexpected direction. The possibility of negative confounding by SES and breastfeeding history was examined but dismissed.

YY162 prevents ADHD-like behavioral side effects and cytotoxicity induced by Aroclor1254 via interactive signaling between antioxidant potential, BDNF/TrkB, DAT and NET

Methylphenidate (MP) has become the primary drug of choice for treatment of attention-deficit/hyperactivity disorder (ADHD). However, its psychotropic effects severely hamper long-term clinical use. We evaluated the effects of YY162, which consists of terpenoid-strengthened Ginkgo biloba and ginsenoside Rg3, on the ADHD-like condition induced by Aroclor1254, because both components have been suggested to modulate oxidative stress, dopaminergic neurotransmission, and brain-derived neurotrophic factor (BDNF) signaling, which may be critical targets for understanding the pathogenesis of ADHD. YY162 attenuated the increase in reactive oxygen species (ROS) and decrease in BDNF levels induced by Aroclor1254 in SH-SY5Y neuroblastoma cells. YY162 significantly attenuated Aroclor1254-induced ADHD-like behavior and oxidative stress in ICR mice. Furthermore, YY162 attenuated reductions in p-TrkB, BDNF, dopamine transporter (DAT) and norepinephrine transporter (NET) expression. These attenuating effects of YY162 were comparable to those of MP. Importantly, K252a, a TrkB antagonist, counteracted the protective effects of YY162. Our results suggest that YY162 possesses significant protective activities against ADHD-like conditions with negligible behavioral side effects, and that interactive signaling between antioxidant potential and BDNF/TrkB receptor for the positive modulation of the DAT and NET is important for YY162-mediated neuroprotective activity.

Behavioral changes following PCB 153 exposure in the Spontaneously Hypertensive rat – an animal model of Attention-Deficit/Hyperactivity disorder

BackgroundAttention-Deficit/Hyperactivity Disorder (ADHD) is a behavioral disorder affecting 3-5% of children. Although ADHD is highly heritable, environmental factors like exposure during early development to various toxic substances like polychlorinated biphenyls (PCBs) may contribute to the prevalence. PCBs are a group of chemical industrial compounds with adverse effects on neurobiological and cognitive functioning, and may produce behavioral impairments that share significant similarities with ADHD. The present study examined the relation between exposure to PCB 153 and changes in ADHD-like behavior in an animal model of ADHD, the spontaneously hypertensive rats (SHR/NCrl), and in Wistar Kyoto (WKY/NHsd) controls.MethodsSHR/NCrl and WKY/NHsd, males and females, were orally given PCB 153 dissolved in corn oil at around postnatal day (PND) 8, 14, and 20 at a dosage of 1, 3 or 6 mg/kg bodyweight at each exposure. The control groups were orally administered corn oil only. The animals were behaviorally tested for exposure effects from PND 37 to 64 using an operant procedure.ResultsExposure to PCB 153 was associated with pronounced and long-lasting behavioral changes in SHR/NCrl. Exposure effects in the SHR/NCrl depended on dose, where 1 mg/kg tended to reduce ADHD-like behaviors and produce opposite behavioral effects compared to 3 mg/kg and 6 mg/kg, especially in the females. In the WKY/NHsd controls and for the three doses tested, PCB 153 exposure produced a few specific behavioral changes only in males. The data suggest that PCB 153 exposure interacts with strain and sex, and also indicate a non-linear dose–response relation for the behaviors observed.ConclusionsExposure to PCB 153 seems to interact with several variables including strain, sex, dose, and time of testing. To the extent that the present findings can be generalized to humans, exposure effects of PCB 153 on ADHD behavior depends on amount of exposure, where high doses may aggravate ADHD symptoms in genetically vulnerable individuals. In normal controls, exposure may not constitute an environmental risk factor for developing the full range of ADHD symptoms, but can produce specific behavioral changes.

Persistent α1-adrenergic receptor function in the nucleus locus coeruleus causes hyperexcitability in AD/HD model rats

Spontaneously hypertensive rats (SHR) are widely used as a model of attention deficit hyperactivity disorder (ADHD) as their ADHD-like behaviors are restored by methylphenidate. However, a postnatal neural development in SHR is unknown. We performed whole cell patch clamp recordings from locus coeruleus (LC) neurons in neonatal [postnatal day (P) 3-5], juvenile (P21-28), and adult (P 49-56) SHR and age-matched Wistar rats to evaluate α1- and α2-adrenergic receptor (ARs) activities at each developmental period. LC neurons in neonatal Wistar rats and SHR showed no difference in resting membrane potential and spontaneous firing rate, while juvenile and adult SHR LC neurons showed depolarized resting membrane potential and faster spontaneous firing rate than in Wistar rats. Blockade of α1-AR activity by prazosin hyperpolarized the membrane and abolished spontaneous firings in all developmental periods in SHR LC neurons, but not in juvenile and adult Wistar rats. α1-AR stimulation by phenylephrine evoked an inward current in juvenile LC neurons in SHR, but not in juvenile Wistar rats. This phenylephrine-induced inward current was abolished by nonselective cation channel blockers. By contrast, α2-AR stimulation-induced outward currents in the presence of an α1-AR antagonist were equivalent in SHR and Wistar LC neurons. These data suggest that Wistar LC neurons lose α1-AR function during development, whereas α1-ARs remain functional in SHR LC neurons. Thus persistent intrinsic activity of α1-ARs may be a neural mechanism contributing to developmental disorders in juvenile SHRs.

Alpha-2A adrenergic receptor gene variants are associated with increased intra-individual variability in response time

Intra-individual variability in response time has been proposed as an important endophenotype for attention deficit hyperactivity disorder (ADHD). Here we asked whether intra-individual variability is predicted by common variation in catecholamine genes and whether it mediates the relationship between these gene variants and self-reported ADHD symptoms. A total of 402 non-clinical Australian adults of European descent completed a battery of five cognitive tasks and the Conners' Adult ADHD Rating Scale. Exclusion criteria included the presence of major psychiatric or neurologic illnesses and substance dependency. A total of 21 subjects were excluded due to incomplete data or poor quality cognitive or genotyping data. The final sample comprised 381 subjects (201 males; mean age=21.2 years, s.d.=5.1 years). Principal components analysis on variability measures yielded two factors (response selection variability vs selective attention variability). Association of these factors with catecholamine gene variants was tested using single-step linear regressions, with multiple comparisons controlled using permutation analysis. The response selection variability factor was associated with two ADRA2A single-nucleotide polymorphisms (SNPs) (rs1800544, rs602618), p corrected=0.004, 0.012, respectively, whereas the selective attention variability factor was associated with a TH SNP (rs3842727), p corrected=0.024. A bootstrapping analysis indicated that the response selection variability factor mediated the relationship between the ADRA2A SNP rs1800544 and self-reported ADHD symptoms. Thus this study finds evidence that DNA variation in the ADRA2A gene may be causally related to ADHD-like behaviors, in part through its influence on intra-individual variability. Evidence was also found for a novel association between a TH gene variant and intra-individual variability.

Risks from chemical and non-chemical stressors associated with attention deficit hyperactivity disorder (ADHD)-like behavior using structural equation models

Background. ADHD-like behavior – assessed using psychometric tests and behavioral rating scales – is associated with multiple chemical and non-chemical stressors, including sociodemographic charact...

A study of the possible association between adenosine A2A receptor gene polymorphisms and attention‐deficit hyperactivity disorder traits

The adenosine A2A receptor (ADORA2A) is linked to the dopamine neurotransmitter system and is also implicated in the regulation of alertness, suggesting a potential association with attention-deficit hyperactivity disorder (ADHD) traits. Furthermore, animal studies suggest that the ADORA2A may influence ADHD-like behavior. For that reason, the ADORA2A gene emerges as a promising candidate for studying the etiology of ADHD traits. The aim of this study was to examine the relationship between ADORA2A gene polymorphisms and ADHD traits in a large population-based sample. This study was based on the Child and Adolescent Twin Study in Sweden (CATSS), and included 1747 twins. Attention-deficit hyperactivity disorder traits were assessed through parental reports, and samples of DNA were collected. Associations between six single nucleotide polymorphisms (SNPs) and ADHD traits were examined, and results suggested a nominal association between ADHD traits and three of these SNPs: rs3761422, rs5751876 and rs35320474. For one of the SNPs, rs35320474, results remained significant after correction for multiple comparisons. These results indicate the possibility that the ADORA2A gene may be involved in ADHD traits. However, more studies replicating the present results are warranted before this association can be confirmed.

Oroxylin A improves attention deficit hyperactivity disorder-like behaviors in the spontaneously hypertensive rat and inhibits reuptake of dopamine in vitro

In previous studies we have demonstrated that the γ-aminobutryic acid-A (GABA-A) receptor antagonist oroxylin A has an awakening effect and it also represses ADHD-like behaviors (hyperactivity, impulsivity and inattention) in the spontaneously hypertensive rat (SHR) model of attention-deficit hyperactivity disorder (ADHD). We hypothesized that the effects of oroxylin A were exerted via the GABA-A receptor given the important role of the GABAergic system in ADHD. However, it is possible that aside from the GABAergic system, oroxylin A may influence other systems especially those implicated in ADHD (e.g. DAergic, etc.). To test this hypothesis, we evaluated the effects of GABA agonist, or dopamine (DA) antagonist in oroxylin A-induced alleviation of ADHD-like behaviors in SHR. SHR showed inattention and impulsivity as measured by the Y-maze and the electro-foot shock aversive water drinking tests, respectively. Oroxylin A significantly improved these behaviors, furthermore, its effect on SHR impulsivity was attenuated by haloperidol, a DA antagonist, but not by baicalein, an agonist of the GABA-A receptor. In vitro studies showed that oroxylin A inhibited DA uptake similar to methylphenidate, a dopamine transporter blocker, but did not influence norepinephrine uptake unlike atomoxetine, a selective NE reuptake inhibitor. Collectively, the present findings suggest that oroxylin A improves ADHD-like behaviors in SHR via enhancement of DA neurotransmission and not modulation of GABA pathway as previously reported. Importantly, the present study indicates the potential therapeutic value of oroxylin A in the treatment of ADHD.

Review of current evidence on the impact of pesticides, polychlorinated biphenyls and selected metals on attention deficit / hyperactivity disorder in children

The aim of this review was to investigate the association between attention deficit / hyperactivity disorder (ADHD) or ADHD-related symptoms and industrial chemicals, such as organophosphates and organochlorine pesticides, polychlorinated biphenyls (PCBs), lead, mercury and manganese. Medline, PubMed and EBSCO searches were performed to identify the studies that analyzed the association of prenatal and postnatal child exposure to such toxicants and ADHD or ADHD-related symptoms. The review is restricted to human studies published in English in peer-reviewed journals since 2000. Most of the presented studies focused on pesticides, PCB and lead. The impact of mercury and manganese was investigated less frequently. The findings indicate that children's exposure to organophosphate pesticides may cause symptoms consistent with pervasive developmental disorder, ADHD or attention problems. Exposures to organochlorine pesticides and PCBs were associated with ADHD-like behaviors such as alertness, quality of alert response, and cost of attention. The studies provided evidence that blood lead level below 10 μg/dl was associated with ADHD or ADHD-related symptoms. Information on the association between exposure to mercury and neurotoxicity is limited, and requires further confirmation in future research. Two studies indicated that exposure to manganese is related to ADHD; such exposure and its impact on children neurodevelopment need to be further investigated. Future studies should use a prospective design with multiple biological samples collected over time for better assessment of exposure and its critical windows. Additionally, inclusion of potential confounding factors and co-exposures is crucial.

GIT1 is associated with ADHD in humans and ADHD-like behaviors in mice

GIT1 is associated with ADHD in humans and ADHD-like behaviors in mice

Time Spent With Children and Working Parents’ Willingness to Medicate ADHD-Like Behaviors

How much time parents spend with their children is likely to influence their judgments of children’s behaviors and the behaviors themselves. In the diagnosis of children with attention-deficit/hyperactivity disorder (ADHD), parents are key informants and decide whether their children should receive medication. This exploratory study investigates the relationship between working parents’ willingness to medicate ADHD-like behaviors and the time they can spend with their children during a regular workday. The participants (409 parents of 5- to 17- year-old children reporting having no child with emotional or behavioral problems and 87 reporting having such a child) were drawn from a population-based telephone survey of parents stratified by race and ethnicity in two urban Florida counties. Path analysis models, controlling for selected sociodemographic and household variables, showed that spending more time with one’s children during a regular workday and self-identifying as African American were negatively related to willingness to medicate among parents of children with problems. Among parents reporting no children with problems, only the number of children in the household and the parent-type household showed relationships to willingness to medicate, while mothers were more likely than fathers to spend more time with children. These observed relationships were of moderate effect but underscore the importance to initiate studies using valid measures of quantity and quality of parental time spent with ADHD children, and to query parents on these points when assessing the information they provide to clinicians.

Inverse association of intellectual function with very low blood lead but not with manganese exposure in Italian adolescents

BackgroundPediatric lead (Pb) exposure impacts cognitive function and behavior and co-exposure to manganese (Mn) may enhance neurotoxicity. ObjectivesTo assess cognitive and behavioral function in adolescents with environmental exposure to Pb and Mn. MethodsIn this cross sectional study, cognitive function and behavior were examined in healthy adolescents with environmental exposure to metals. The Wechsler Intelligence Scale for Children (WISC) and the Conners-Wells’ Adolescent Self-Report Scale Long Form (CASS:L) were used to assess cognitive and behavioral function, respectively. ALAD polymorphisms rs1800435 and rs1139488 were measured as potential modifiers. ResultsWe examined 299 adolescents (49.2% females) aged 11–14 years. Blood lead (BPb) averaged 1.71μg/dL (median 1.5, range 0.44–10.2), mean Blood Manganese (BMn) was 11.1μg/dL (median 10.9, range 4.00–24.1). Average total IQ was 106.3 (verbal IQ=102, performance IQ=109.3). According to a multiple regression model considering the effect of other covariates, a reduction of about 2.4 IQ points resulted from a two-fold increase of BPb. The Benchmark Level of BPb associated with a loss of 1 IQ-point (BML01) was 0.19μg/dL, with a lower 95% confidence limit (BMLL01) of 0.11μg/dL. A very weak correlation resulted between BPb and the ADHD-like behavior (Kendall's tau rank correlation=0.074, p=0.07). No influence of ALAD genotype was observed on any outcome. Manganese was not associated with cognitive and behavioral outcomes, nor was there any interaction with lead. ConclusionsThese findings demonstrate that very low level of lead exposure has a significant negative impact on cognitive function in adolescent children. Being an essential micro-nutrient, manganese may not cause cognitive effects at these low exposure levels.

Endocrine disrupting compounds, gonadal hormones, and autism

SIR–In his recent review, James provocatively extends the Baron–Cohen theory of autism to suggest that excess maternal testosterone exposure, rather than fetal testosterone exposure, is a potential unifying biological mechanism behind many of the risk factors for autism.1 While James’ extension of the Baron–Cohen hypothesis may oversimplify some aspects of the complex genetic and environmental etiology of autism, I applaud this bold approach. In the face of a growing body of research suggesting that autism has fetal origins, environmental risk factors, and less genetic heritability than previously estimated, such bold theories will be necessary to drive the science forward and identify modifiable risk factors for autism. While the list of potential risk factors discussed by James was quite comprehensive, I propose expanding it to include endocrine disrupting compounds (EDCs) as a set of exposures that may affect the development of autism by disrupting the in utero hormonal milieu directly or changing maternal hormone metabolism or action. I believe there are several reasons to pursue this line of research. First, epidemiological studies have observed that maternal exposure to environmental chemicals during pregnancy, including air pollution, EDCs, and metals has been associated with attention-deficit–hyperactivity disorder (ADHD) and ADHD-like behaviors, autism and autistic-like behaviors, and pervasive developmental disorder–not otherwise specified.2 Second, the developing brain is susceptible to environmental insults and the fetus/child is less efficient at detoxifying environmental chemicals than adults. This implies that the developing fetus/child may be particularly vulnerable to exposures that would be less harmful to an adult. Third, pregnant women are exposed to multiple environmental chemicals, including EDCs.3 Very little is known about the cumulative or synergistic effects of these chemicals on human health. Finally, environmental chemicals may be a modifiable risk factor that would be amenable to public health interventions that could reduce the burden of autism. Phthalates are one illustrative example of an EDC that plausibly fits into the Baron–Cohen hypothesis of autism. Phthalates are a class of chemicals used to retain scents in personal care/beauty products and impart flexibility in polyvinyl chloride plastics. Exposure to phthalates is ubiquitous among persons in industrialized countries and some phthalates have anti-androgenic activity.4 More importantly, the fetus seems to be uniquely sensitive to the anti-androgenic effects of phthalates. Given their anti-androgenic properties, one could hypothesize that phthalate exposures might reduce the risk of autism since higher phthalate exposures could counteract the effect of excess androgen exposure. However, one group of investigators observed increased ADHD-like and autistic-like behaviors in children born to women with higher levels of phthalate exposures.5, 6 These results suggest that EDC action may not act via simplistic agonist-antagonist pathways. Furthermore, the relationship between phthalate exposure (or other environmental chemicals) and child behavior may be modified by child sex, which might be one possible explanation for the excess number of male children with autism. With tens of thousands of chemicals being used in commerce, a single letter to the editor could never do justice to the research being conducted on any one chemical. However, the above example suggesting a potential role for phthalates in the development of autism illustrates why EDCs deserve inclusion in the growing list of potential autism risk factors enumerated by James. Even at the risk of proving James’ hypothesis wrong, the relationships between EDCs, maternal and fetal hormones, and autism deserves further attention.

The ADHD-susceptibility gene lphn3.1 modulates dopaminergic neuron formation and locomotor activity during zebrafish development

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inattention, hyperactivity, increased impulsivity and emotion dysregulation. Linkage analysis followed by fine-mapping identified variation in the gene coding for Latrophilin 3 (LPHN3), a putative adhesion-G protein-coupled receptor, as a risk factor for ADHD. In order to validate the link between LPHN3 and ADHD, and to understand the function of LPHN3 in the etiology of the disease, we examined its ortholog lphn3.1 during zebrafish development. Loss of lphn3.1 function causes a reduction and misplacement of dopamine-positive neurons in the ventral diencephalon and a hyperactive/impulsive motor phenotype. The behavioral phenotype can be rescued by the ADHD treatment drugs methylphenidate and atomoxetine. Together, our results implicate decreased Lphn3 activity in eliciting ADHD-like behavior, and demonstrate its correlated contribution to the development of the brain dopaminergic circuitry.

Effects of Preconceptional Ethanol Consumption on ADHD-Like Symptoms in Sprague-Dawley Rat Offsprings

Ethanol exposure during gestational period is related to growth retardation, morphological abnormality, and even in neurological abnormalities including attention deficit/hyperactivity disorder (ADHD)-like behaviors on offspring. However, relatively little is known about the effects of maternal ethanol consumption prior to conception on their offspring. In this study, we investi-gated whether maternal ethanol administration during preconceptional phase produces ADHD-like behaviors in the rat offspring. Sprague-Dawley (SD) female rats were administrated ethanol via intragastric intubation with dosing regimen of 6 g/kg daily for 10 consecutive days and treated female rats then mated with non-treated male SD rats after 8 weeks. Another group subjected to the same procedure as those conducted on ethanol treated group except the saline administration instead of ethanol. Offspring was tested for their ADHD-like behaviors using open field test, Y maze test and impulsivity test that is performed in the aversive electronic foot shock paradigm. Offspring of preconceptional ethanol treated (EtOH) group showed hyperlocomotive activity, attention deficit and impulsivity. And reduction of striatal dopamine transporter (DAT) level was observed by Western blot in the EtOH group, compared to control (Con) group, while the immunohistochemical analysis exhibited increased expression of norepinephrine transporter (NET) in the frontal cortex. These results suggest that maternal ethanol consumption in the preconceptional phase induces ADHD-like behaviors in offspring that might be related to the abnormal expression of DAT and NET in rat.

Marine omega-3 polyunsaturated fatty acids induce sex-specific changes in reinforcer-controlled behaviour and neurotransmitter metabolism in a spontaneously hypertensive rat model of ADHD

BackgroundPrevious reports suggest that omega-3 (n-3) polyunsaturated fatty acids (PUFA) supplements may reduce ADHD-like behaviour. Our aim was to investigate potential effects of n-3 PUFA supplementation in an animal model of ADHD.MethodsWe used spontaneously hypertensive rats (SHR). SHR dams were given n-3 PUFA (EPA and DHA)-enriched feed (n-6/n-3 of 1:2.7) during pregnancy, with their offspring continuing on this diet until sacrificed. The SHR controls and Wistar Kyoto (WKY) control rats were given control-feed (n-6/n-3 of 7:1). During postnatal days (PND) 25–50, offspring were tested for reinforcement-dependent attention, impulsivity and hyperactivity as well as spontaneous locomotion. The animals were then sacrificed at PND 55–60 and their neostriata were analysed for monoamine and amino acid neurotransmitters with high performance liquid chromatography.Resultsn-3 PUFA supplementation significantly enhanced reinforcement-controlled attention and reduced lever-directed hyperactivity and impulsiveness in SHR males whereas the opposite or no effects were observed in females. Analysis of neostriata from the same animals showed significantly enhanced dopamine and serotonin turnover ratios in the male SHRs, whereas female SHRs showed no change, except for an intermediate increase in serotonin catabolism. In contrast, both male and female SHRs showed n-3 PUFA-induced reduction in non-reinforced spontaneous locomotion, and sex-independent changes in glycine levels and glutamate turnover.ConclusionsFeeding n-3 PUFAs to the ADHD model rats induced sex-specific changes in reinforcement-motivated behaviour and a sex-independent change in non-reinforcement-associated behaviour, which correlated with changes in presynaptic striatal monoamine and amino acid signalling, respectively. Thus, dietary n-3 PUFAs may partly ameliorate ADHD-like behaviour by reinforcement-induced mechanisms in males and partly via reinforcement-insensitive mechanisms in both sexes.

Attention Deficits Predict Phenotypic Outcomes in Syndrome-Specific and Domain-Specific Ways

Attentional difficulties, both at home and in the classroom, are reported across a number of neurodevelopmental disorders. However, exactly how attention influences early socio-cognitive learning remains unclear. We addressed this question both concurrently and longitudinally in a cross-syndrome design, with respect to the communicative domain of vocabulary and to the cognitive domain of early literacy, and then extended the analysis to social behavior. Participants were young children (aged 4–9 years at Time 1) with either Williams syndrome (WS, N = 26) or Down syndrome (DS, N = 26) and typically developing controls (N = 103). Children with WS displayed significantly greater attentional deficits (as indexed by teacher report of behavior typical of attention deficit hyperactivity disorder (ADHD) than children with DS, but both groups had greater attentional problems than the controls. Despite their attention differences, children with DS and those with WS were equivalent in their cognitive abilities of reading single words, both at Time 1 and 12 months later, at Time 2, although they differed in their early communicative abilities in terms of vocabulary. Greater ADHD-like behaviors predicted poorer subsequent literacy for children with DS, but not for children with WS, pointing to syndrome-specific attentional constraints on specific aspects of early development. Overall, our findings highlight the need to investigate more precisely whether and, if so, how, syndrome-specific profiles of behavioral difficulties constrain learning and socio-cognitive outcomes across different domains.

Transcriptome‐wide gene expression in a rat model of attention deficit hyperactivity disorder symptoms: Rats developmentally exposed to polychlorinated biphenyls

Polychlorinated biphenyls (PCB) exposure in rodents provides a useful model for the symptoms of Attention deficit hyperactivity disorder (ADHD). The goal of this study is to identify genes whose expression levels are altered in response to PCB exposure. The brains from 48 rats separated into two age groups of 24 animals each (4 males and 4 females for each PCB exposure level (control, PCB utero, and PCB lactational)) were harvested at postnatal days 23 and 35, respectively. The RNA was isolated from three brain regions of interest and was analyzed for differences in expression of a set of 27,342 transcripts. Two hundred seventy-nine transcripts showed significant differential expression due to PCB exposure mostly due to the difference between PCB lactational and control groups. The cluster analysis applied to these transcripts revealed that significant changes in gene expression levels in PFC area due to PCB lactational exposure. Our pathway analyses implicated 27 significant canonical pathways and 38 significant functional pathways. Our transcriptome-wide analysis of the effects of PCB exposure shows that the expression of many genes is dysregulated by lactational PCB exposure, but not gestational exposure and has highlighted biological pathways that might mediate the effects of PCB exposure on ADHD-like behaviors seen in exposed animals. Our work should further motivate studies of fatty acids in ADHD, and further suggests that another potentially druggable pathway, oxidative stress, may play a role in PCB induced ADHD behaviors.