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Background: Azodicarbonamide is a dough-enhancer used in the process of breadmaking in countries like Nigeria. While there have been suggestions that it is a sensitizer of the respiratory system, there is a dearth of information on its effects on the central nervous system. Aim: This study assessed the effects of azodicarbonamide on the central nervous system (ADA) in rats. Objective: The effects of ADA-containing diet on neurobehaviour, brain antioxidant status, and neuromorphology of selected brain regions in rats were examined. Method: Forty adult rats were randomly-assigned into four groups of ten rats each, and were given standard diet or diet containing ADA at 1, 2 and 4% respectively. Rats were fed a standard diet or ADA-containing diet for a period of 28 days. Weekly body weight assessment and daily estimation of food intake were done. Behavioural tests in the Open field, Y-maze, radial-arm maze, and Elevated Plus Maze (EPM) were conducted on day 29. Twenty-four hours after the last behavioural test, animals were euthanised, whole brains were dissected, weighed, and either homogenised for assessment of lipid peroxidation and antioxidant status; or sectioned and processed for general histology. Results : Consumption of ADA-containing diet was associated with a significant decrease in weight gain/food intake, and significant suppression of horizontal locomotion and rearing behaviours; however, grooming activity increased significantly. Also, there was a significant reduction of open-arm time in the EPM and a significant increase in Y-maze alternation (at the lowest concentration of ADA). ADA-containing diet was not associated with significant changes in brain oxidative status or neuromorphology. Conclusion: The study showed that while ADA-containing diet may alter neurobehaviour in rats; this was not associated with evidence of brain oxidative stress or neuro-histomorphological alterations.

الملخص: أهداف البحث: أظهرت الدراسات الحيوانية والبشرية أن حمض الفوليك ضروري للجهاز العصبي وتطور المخ. في البشر، من المعروف أن انخفاض حمض الفوليك لدى الأمهات يتسبب في عيوب الأنبوب العصبي، وطيف التوحد وغيرها من اضطرابات النمو العصبي لدى الأطفال. تهدف هذه الدراسة إلى تحديد تأثير مكملات حمض الفوليك عند الأمهات على المهارات الحركية النفسية، والتعلم، ووظائف الذاكرة لذريتهن، وخاصة بعد البلوغ. طرق البحث: تم تقسيم ثمانية عشر أنثى من جرذان ويستار بشكل عشوائي إلى ثلاث مجموعات. تم تغذية الفئران على ثلاثة تراكيز مختلفة من حمض الفوليك من قبل الحمل، خلال الحمل وأثناء الرضاعة. بعد البلوغ، تم تقييم النسل للتغيرات السلوكية العصبية والتأكيد النسيجي عن طريق القياس الكمي للخلايا العصبية للحُصَين. النتائج: أظهر تقييم السلوكيات العصبية عددا أقل بكثير من البدائل، والمزيد من التحيز بالنسبة المئوية، وعدد أكبر من أخطاء الذاكرة العاملة والمرجعية. وأشار زيادة الوقت الذي تقضيه في مقصورة مظلمة في مجموعة مكملات حمض الفوليك العجز في ذاكرة التعلم. كما أظهر القياس الكمي العصبي للحصين أن عدد الخلايا العصبية القابلة للحياة في منطقة قرن آمون في المجموعة الضابطة كان أعلى (منطقة قرن آمون ١، ٣١.٢± ٣.٢؛ ومنطقة قرن آمون ٣، ٢٣.٢ ± ٣.٢) مع نواة مميزة في كلا المنطقتين وأقل في مجموعة مكملات حمض الفوليك (منطقة قرن آمون١، ٢٤.٢ ± ٣.١؛ منطقة قرن آمون٣، ١٥.٢± ٢.٢). الاستنتاجات: تدعم دراستنا التأثير السلبي المحتمل لارتفاع مكملات حمض الفوليك للأمهات أثناء الحمل والرضاعة. من المحتمل أن تؤدي مثل هذه التغييرات إلى تغيرات في السلوك العصبي في نسلهم في وقت لاحق. Abstract: Objectives: Animal and human studies have demonstrated that folic acid (FA) is essential for nervous system and brain development. In humans, insufficient maternal FA intake is known to cause neural tube defects, autism spectrum, and other neurodevelopmental disorders in children. The present study aimed to determine the impact of maternal FA supplementation on psychomotor skills and learning and memory functions in their adult offspring. Methods: Eighteen female Wistar rats were randomly divided into three groups. The animals were fed three different concentrations of FA from preconception to pregnancy and during lactation. The adult offspring were assessed for neurobehavioural changes and histological confirmation by hippocampal neuron quantification. Results: Neurobehavioural assessment revealed a significantly smaller number of alternations, a higher percentage bias, and a greater number of working and reference memory errors. The increased time spent in the dark compartment in the FA-supplementation group indicated deficit(s) in learning memory. Hippocampal neuron quantification revealed a higher mean number of viable neurons in the cornu ammonis (CA) region in the control group (CA1 region, 31.2 ± 3.2; CA3 region, 23.2 ± 3.2), with a distinct nucleus in both regions, and least in the FA-supplementation group (CA1 region, 24.2 ± 3.1; CA3 region, 15.2 ± 2.2). Conclusion: Results of this investigation support the possible negative effect of high levels of maternal FA supplementation during pregnancy and lactation. Such alterations potentially lead to neurobehavioural changes in the adult offspring of Wistar rats. الكلمات المفتاحية: السلوك العصبي, حمض الفوليك, الحُصَين, التعلم والذاكرة, Keywords: Folic acid, Hippocampus, Learning and memory, Neurobehaviour

Persons with certain single nucleotide polymorphisms (SNPs) in theCACNA1Dgene (encoding voltage-gated calcium channel subunit alpha 1-D) have increased risk of developing neuropsychiatric disorders such as bipolar, schizophrenia and autism. The molecular consequences of SNPs on gene expression and protein function are not well understood. Thus, the use of animal models to determine genotype-phenotype correlations is critical to understanding disease pathogenesis. Here, we describe the behavioural changes in larval zebrafish carrying an essential splice site mutation (sa17298) incacna1da. Heterozygous mutation resulted in 50% reduction of splice variants 201 and 202 (haploinsufficiency), while homozygosity increased transcript levels of variant 201 above wild type (WT; gain-of-function, GOF). Due to low homozygote viability, we focused primarily on performing the phenotypic analysis on heterozygotes. Indeed,cacna1dasa17298/WTlarvae displayed hyperlocomotion—a behaviour characterised in zebrafish as a surrogate phenotype for epilepsy, anxiety or psychosis-like behaviour. Follow-up tests ruled out anxiety or seizures, however, as neither thigmotaxis defects nor epileptiform-like discharges in larval brains were observed. We therefore focused on testing for potential “psychosis-like” behaviour by assayingcacna1dasa17298/WTlarval locomotor activity under constant light, during light-dark transition and in startle response to dark flashes. Furthermore, exposure of larvae to the antipsychotics, risperidone and haloperidol reversedcacna1da-induced hyperactivity to WT levels while valproate decreased but did not reverse hyperactivity. Together, these findings demonstrate thatcacna1dahaploinsufficiency induces behaviours in larval zebrafish analogous to those observed in rodent models of psychosis. Future studies on homozygous mutants will determine howcacna1dGOF alters behaviour in this context.

This study aimed to examine associations between structural MRI and concurrent motor, neurological and neurobehavioral measures at 30-32 weeks postmenstrual age (PMA; 'Early'), and at term equivalent age ('Term').In this prospective cohort study, infants underwent Early MRI (n = 119; 73 male; median 32 weeks 1 day PMA) and Term MRI (n = 102; 61 male; median 40 weeks 4 days PMA) at 3 T. Structural images were scored generating white matter (WM), cortical gray matter, deep gray matter, cerebellar and global brain abnormality scores. Clinical measures were General Movements Assessment (GMs), Hammersmith Neonatal Neurological Examination (HNNE) and NICU Neonatal Neurobehavioral Scale (NNNS). The Premie-Neuro was administered Early and the Test of Infant Motor Performance (TIMP) and a visual assessment at Term.Early MRI cerebellar scores were strongly associated with neurological components of HNNE (reflexes), NNNS (Hypertonicity), the Premie-Neuro neurological subscale (regression coefficient β = -0.06; 95% confidence interval CI = -0.09, -0.04; p .001) and cramped-synchronized GMs (β = 1.10; 95%CI = 0.57, 1.63; p .001). Term MRI WM and global scores were strongly associated with the TIMP (WM β = -1.02; 95%CI = -1.67, -0.36; p = .002; global β = -1.59; 95%CI = -2.62, -0.56; p = .001).Brain structure on Early and Term MRI was associated with concurrent motor, neurological and neurobehavioral function in very preterm infants.

Introduction: Prematurity (birth before 37+0 weeks’ gestation) is associated with wide-ranging neurodevelopmental impairment. Prognosis among moderate to late (32+0 to +0 weeks’ gestation) preterm infants (MLPT) is better compared to their counterparts born very preterm (+0 weeks’ gestation). However the risk of developmental impairment among MLPT, who make up about 84% of all preterm infants, is 2-3 times higher when compared to infants born at term. Early interventions have aimed to improve outcomes in preterm infants generally, but there are limited data on their need and effect in MLPT specifically. Prioritising research, long-term follow-up and early interventions targeted at ameliorating the impact of preterm birth among MLPT is required. Objectives: To conduct a systematic review of the type of early childhood interventions (from birth until 4 years of age) offered to MLPT children and to evaluate their impact on neurodevelopmental outcomes (cognitive, neurobehavioural and motor) as assessed in these children during childhood (until 18 years of age). Methods and analysis: A systematic literature search in Web of Science, Medline Ovid, PsycINFO, CINAHL and EMBASE will be conducted. Data on MLPT children receiving developmental interventions until the age of 4 years will be evaluated. Interventions may involve parents or primary caregivers. Primary outcomes are cognitive, neurobehavioural and motor development as measured from birth until the age of 18 years. The Cochrane Risk of Bias Assessment Tool will be used to evaluate the methodological quality of randomised controlled trials (RCTs) included in the review and will be graded as low, high or unclear risk of bias. The quality of non-RCTs will be evaluated with the Newcastle-Ottawa Scale. The quality of evidence for each outcome will be evaluated using the Grading of Recommendations Assessment, Development and Evaluation Approach. Publication and reporting bias will be assessed using Egger’s test and funnel plots respectively.

The present study aimed to elucidate the abnormalities in the development of rat brains, livers, kidney and behaviours after drinking desalinated seawater prenatally. Three types of drinking water were employed as an experimental probe (bottled water, filtered desalinated seawater and tap desalinated seawater) to investigate neurobehavioral and morphological changes in the development of pup rats. Female rats from each group were administered water from their birth until gestation and lactation. The 1st and 2nd generation pups were divided into three groups: Group C, mothers and pups administered with bottled drinking water (the control group); Group F, mothers and pups administered with filtered drinking water; Group T, mothers and pups administered with unfiltered desalinated seawater (tap water). Morphological changes (CNS aberration) and neurobehavioral changes were studied. The aberrations recorded in the tissues (brain, liver, kidney and spinal cord) of rats from groups T and F may be due to oxidative stress in these tissues such as reduced glutathione, lipid peroxidation, peroxidase and super oxide dismutase. In conclusion, drinking desalinated seawater for a long time may cause teratogenic effects in the development of New-born rats. Keywords: Oxidative stress, Desalinated water, CNS, Neurobehaviour, Embryotoxicity

Aim Prenatal exposure to cigarettes leads to alterations in brain development during pregnancy. This has an impact on postnatal psychological and behavioural processes, affecting an infant's neurobehavioural profile with little known about which aspects are affected. The evidence was synthesised to assess the effects of prenatal cigarette smoke exposure on neurobehavioural outcomes within the first year of life. Methods Six databases were searched (Web of Science Core Collections, MEDLINE, PsycINFO, CINAHL, EBSCOhost eBook Collection and OpenGrey) in November 2018. Eligible studies (n = 17) had to include a measure of prenatal cigarette exposure and a neurobehavioural assessment ≤1 year of age. Results In the first year of life, specific areas of neurobehavioural functioning are related to prenatal cigarette exposure with eight out of 10 areas of neurobehaviour having significant medium (negative affect, attention, excitability, irritability and orientation) or small (muscle tone, regulation and difficult temperament) pooled effect sizes. Only lethargy and stress did not show any significant pooled effects. Conclusion Prenatal cigarette exposure affects a significant range of behaviours during the first year of life.

Background: This study explored the mechanisms underlying altered neurobehavioural development of female offspring born to mothers with polycystic ovary syndrome (PCOS). Methods: In total, 20 women with PCOS and 32 healthy women who underwent caesarean deliveries with a single female foetus were recruited. Infants were assessed with Dubowitz scoring. Swan71 cell line with stable FOS overexpression was used to verify the regulatory effects of FOS on brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) expression. Learning and memory in female first-generation (F1) and second-generation (F2) offspring in a rat model of PCOS was tested using the Morris water maze at puberty and adulthood. Transcriptome analysis of pubertal hippocampi and hypothalami of female F1 offspring was conducted. Findings: Total score and behaviour subscales of Dubowitz scoring were significantly lower in female infants of women with PCOS. FOS and NGF protein levels were downregulated in placental villi of the PCOS group. FOS played a key role in BDNF inhibition and enhancing NGF in Swan71 cells. PCOS female F1 rats exhibited lower target crossing times during puberty when compared to controls. Transcriptome analysis revealed significant changes in hippocampal and hypothalamic neuronal pathways in female F1 rats at puberty. Interpretation: FOS regulation of neurotrophins in the placenta negatively affects neurobehavioural development of female offspring of PCOS mothers. Funding: This study was funded by the National Key R&D Program of China (2018YFC1004900 to F.Q. and F.W.) and the National Natural Science Foundation of China (81874480 to F.Q.; 81873837 to F.W.).

Background Research on reproductive health effects on children from low-level, long-term exposure to pesticides currently used in the agricultural industry is limited and those on neurobehavioral effects have produced conflicting evidence. We aim at investigating the association between pesticide exposure on the reproductive health and neurobehavior of children in South Africa, by including potential relevant co-exposures from the use of electronic media and maternal alcohol consumption. Methods The design entails a prospective cohort study with a follow-up duration of 2 years starting in 2017, including 1000 school going children between the ages of 9 to 16 years old. Children are enrolled with equal distribution in sex and residence on farms and non-farms in three different agricultural areas (mainly apple, table grapes and wheat farming systems) in the Western Cape, South Africa. The neurobehavior primary health outcome of cognitive functioning was measured through the iPad-based CAmbridge Neuropsychological Test Automated Battery (CANTAB) including domains for attention, memory, and processing speed. The reproductive health outcomes include testicular size in boys and breast size in girls assessed in a physical examination, and blood samples to detect hormone levels and anthropometric measurements. Information on pesticide exposure, co-exposures and relevant confounders are obtained through structured questionnaire interviews with the children and their guardians. Environmental occurrence of pesticides will be determined while using a structured interview with farm owners and review of spraying records and collection of passive water and air samples in all three areas. Pesticide metabolites will be analysed in urine and hair samples collected from the study subjects every 4 months starting at baseline. Discussion The inclusion of three different agricultural areas will yield a wide range of pesticide exposure situations. The prospective longitudinal design is a further strength of this study to evaluate the reproductive and neurobehavioural effects of different pesticides on children. This research will inform relevant policies and regulatory bodies to improve the health, safety and learning environments for children and families in agricultural settings.

The rapid modulation of chromatin organization is thought to play a crucial role in cognitive processes such as memory consolidation. This is supported in part by the dysregulation of many chromatin-remodelling proteins in neurodevelopmental and psychiatric disorders. A key example is ATRX, an X-linked gene commonly mutated in individuals with syndromic and nonsyndromic intellectual disability. The consequences of Atrx inactivation for learning and memory have been difficult to evaluate because of the early lethality of hemizygous-null animals. In this study, we evaluated the outcome of brain-specific Atrx deletion in heterozygous female mice. These mice exhibit a mosaic pattern of ATRX protein expression in the central nervous system attributable to the location of the gene on the X chromosome. Although the hemizygous male mice die soon after birth, heterozygous females survive to adulthood. Body growth is stunted in these animals, and they have low circulating concentrations of insulin growth factor 1. In addition, they are impaired in spatial, contextual fear and novel object recognition memory. Our findings demonstrate that mosaic loss of ATRX expression in the central nervous system leads to endocrine defects and decreased body size and has a negative impact on learning and memory., Summary: Heterozygous expression of the X-linked gene Atrx in the mouse brain causes deficits in spatial, contextual fear and object recognition memory.

The relative safety of antidepressants during pregnancy has received substantial attention, but most syntheses fail to account for mental illness effects. We aimed to evaluate the literature comparing low birth weight (LBW) and neurodevelopmental and neurobehavioural outcomes for children whose mothers took antidepressants in pregnancy compared to those whose mothers had common mental disorders, or symptoms, but who did not take antidepressants during pregnancy. A systematic review was conducted searching PubMed, MEDLINE, PsycINFO and Embase in January 2015. A modified version of the Newcastle Ottawa Scale was used to assess study quality. Eleven cohort studies were included: four reporting a LBW outcome (all with higher risk of bias) and seven reporting a neurodevelopmental outcome (five with higher risk of bias). We found only limited evidence of gestational age-adjusted LBW in exposed children in two studies which had a higher risk of bias and did not control for depressive symptom severity. Only five (7.5%) neurodevelopmental outcomes and one (12.5%) neurobehavioural outcome showed evidence of a statistically significant effect, three out of four were from studies with a higher risk of bias. There is little robust evidence indicating a detrimental effect of antidepressant use during pregnancy on LBW and neurodevelopmental and neurobehavioural outcomes. More rigorous study designs are needed. Electronic supplementary material The online version of this article (10.1007/s00737-017-0780-3) contains supplementary material, which is available to authorized users.