The Effect of Prenatal Hypoxia on Brain Development: Short- and Long-Term Consequences Demonstrated in Rodent Models

ERIC Educational Resources Information Center

Golan, Hava; Huleihel, Mahmoud

2006-01-01

Hypoxia (H) and hypoxia-ischemia (HI) are major causes of foetal brain damage with long-lasting behavioral implications. The effect of hypoxia has been widely studied in human and a variety of animal models. In the present review, we summarize the latest studies testing the behavioral outcomes following prenatal hypoxia/hypoxia-ischemia in rodent…

The Epigenetic Link between Prenatal Adverse Environments and Neurodevelopmental Disorders

PubMed Central

Kundakovic, Marija; Jaric, Ivana

2017-01-01

Prenatal adverse environments, such as maternal stress, toxicological exposures, and viral infections, can disrupt normal brain development and contribute to neurodevelopmental disorders, including schizophrenia, depression, and autism. Increasing evidence shows that these short- and long-term effects of prenatal exposures on brain structure and function are mediated by epigenetic mechanisms. Animal studies demonstrate that prenatal exposure to stress, toxins, viral mimetics, and drugs induces lasting epigenetic changes in the brain, including genes encoding glucocorticoid receptor (Nr3c1) and brain-derived neurotrophic factor (Bdnf). These epigenetic changes have been linked to changes in brain gene expression, stress reactivity, and behavior, and often times, these effects are shown to be dependent on the gestational window of exposure, sex, and exposure level. Although evidence from human studies is more limited, gestational exposure to environmental risks in humans is associated with epigenetic changes in peripheral tissues, and future studies are required to understand whether we can use peripheral biomarkers to predict neurobehavioral outcomes. An extensive research effort combining well-designed human and animal studies, with comprehensive epigenomic analyses of peripheral and brain tissues over time, will be necessary to improve our understanding of the epigenetic basis of neurodevelopmental disorders. PMID:28335457

Prenatal choline supplementation mitigates the adverse effects of prenatal alcohol exposure on development in rats.

PubMed

Thomas, Jennifer D; Abou, Elizabeth J; Dominguez, Hector D

2009-01-01

Prenatal alcohol exposure can lead to a range of physical, neurological, and behavioral alterations referred to as fetal alcohol spectrum disorders (FASD). Variability in outcome observed among children with FASD is likely related to various pre- and postnatal factors, including nutritional variables. Choline is an essential nutrient that influences brain and behavioral development. Recent animal research indicates that prenatal choline supplementation leads to long-lasting cognitive enhancement, as well as changes in brain morphology, electrophysiology and neurochemistry. The present study examined whether choline supplementation during ethanol exposure effectively reduces fetal alcohol effects. Pregnant dams were exposed to 6.0g/kg/day ethanol via intubation from gestational days (GD) 5-20; pair-fed and lab chow controls were included. During treatment, subjects from each group received choline chloride (250mg/kg/day) or vehicle. Physical development and behavioral development (righting reflex, geotactic reflex, cliff avoidance, reflex suspension and hindlimb coordination) were examined. Subjects prenatally exposed to alcohol exhibited reduced birth weight and brain weight, delays in eye opening and incisor emergence, and alterations in the development of all behaviors. Choline supplementation significantly attenuated ethanol's effects on birth and brain weight, incisor emergence, and most behavioral measures. In fact, behavioral performance of ethanol-exposed subjects treated with choline did not differ from that of controls. Importantly, choline supplementation did not influence peak blood alcohol level or metabolism, indicating that choline's effects were not due to differential alcohol exposure. These data indicate early dietary supplements may reduce the severity of some fetal alcohol effects, findings with important implications for children of women who drink alcohol during pregnancy.

Perinatal choline deficiency delays brain development and alters metabolite concentrations in the young pig.

PubMed

Mudd, Austin T; Getty, Caitlyn M; Sutton, Brad P; Dilger, Ryan N

2016-12-01

Adequate choline supply during the perinatal period is critical for proper brain formation, when robust neurogenesis and neuronal maturation occur. Therefore, the objective of this study was to examine the impact of perinatal choline status on neurodevelopment. Sows were fed a choline-deficient (CD) or choline-sufficient (CS) diet during the last half of the gestational period. At 2 days of age, piglets from sows within each prenatal treatment group were further stratified into postnatal treatment groups and provided either a CD or CS milk replacer, resulting in four treatment groups. At 30 days of age, piglets underwent magnetic resonance imaging (MRI) procedures to analyze structural and metabolite differences. Single-voxel spectroscopy (SVS) analysis revealed postnatally CS piglets had higher (P < 0.001) concentrations of glycerophosphocholine-phosphocholine than postnatally CD piglets. Volumetric analysis indicated smaller (P < 0.006) total brain volumes in prenatally CD piglets compared with prenatally CS piglets. Differences (P < 0.05) in the corpus callosum, pons, midbrain, thalamus, and right hippocampus, were observed as larger region-specific volumes proportional to total brain size in prenatally CD piglets compared with CS piglets. Diffusion tensor imaging (DTI) suggested interactions (P < 0.05) between prenatal and postnatal choline status in fractional anisotropy values of the thalamus and right hippocampus. Prenatally CS piglets had lower cerebellar radial diffusivity (P = 0.045) compared with prenatally CD piglets. This study demonstrates that prenatal choline deficiency has profound effects by delaying neurodevelopment as evidenced by structural and metabolic MRI assessments.

Premature brain aging in humans exposed to maternal nutrient restriction during early gestation.

PubMed

Franke, Katja; Gaser, Christian; Roseboom, Tessa J; Schwab, Matthias; de Rooij, Susanne R

2018-06-01

Prenatal exposure to undernutrition is widespread in both developing and industrialized countries, causing irreversible damage to the developing brain, resulting in altered brain structure and decreased cognitive function during adulthood. The Dutch famine in 1944/45 was a humanitarian disaster, now enabling studies of the effects of prenatal undernutrition during gestation on brain aging in late adulthood. We hypothesized that study participants prenatally exposed to maternal nutrient restriction (MNR) would demonstrate altered brain structure resembling premature brain aging in late adulthood, expecting the effect being stronger in men. Utilizing the Dutch famine birth cohort (n = 118; mean age: 67.5 ± 0.9 years), this study implements an innovative biomarker for individual brain aging, using structural neuroimaging. BrainAGE was calculated using state-of-the-art pattern recognition methods, trained on an independent healthy reference sample, then applied to the Dutch famine MRI sample, to evaluate the effects of prenatal undernutrition during early gestation on individual brain aging in late adulthood. Exposure to famine in early gestation was associated with BrainAGE scores indicative of an older-appearing brain in the male sample (mean difference to subjects born before famine: 4.3 years, p < 0.05). Furthermore, in explaining the observed variance in individual BrainAGE scores in the male sample, maternal age at birth, head circumference at birth, medical treatment of hypertension, history of cerebral incidences, actual heart rate, and current alcohol intake emerged to be the most influential variables (adjusted R 2  = 0.63, p < 0.01). The findings of our study on exposure to prenatal undernutrition being associated with a status of premature brain aging during late adulthood, as well as individual brain structure being shaped by birth- and late-life health characteristics, are strongly supporting the critical importance of sufficient nutrient supply during pregnancy. Interestingly, the status of premature brain aging in participants exposed to the Dutch famine during early gestation occurred in the absence of fetal growth restriction at birth as well as vascular pathology in late-life. Additionally, the neuroimaging brain aging biomarker presented in this study will further enable tracking effects of environmental influences or (preventive) treatments on individual brain maturation and aging in epidemiological and clinical studies. Copyright © 2017 Elsevier Inc. All rights reserved.

Maternal Dietary Choline Status Influences Brain Gray and White Matter Development in Young Pigs

PubMed Central

Mudd, Austin T; Getty, Caitlyn M; Dilger, Ryan N

2018-01-01

Abstract Background Choline is an essential nutrient that is pivotal to proper brain development. Research in animal models suggests that perinatal choline deficiency influences neuron development in the hippocampus and cortex, yet these observations require invasive techniques. Objective This study aimed to characterize the effects of perinatal choline deficiency on gray and white matter development with the use of noninvasive neuroimaging techniques in young pigs. Methods During the last 64 d of the 114-d gestation period Yorkshire sows were provided with a choline-sufficient (CS) or choline-deficient (CD) diet, analyzed to contain 1214 mg or 483 mg total choline/kg diet, respectively. Upon farrowing, pigs (Sus scrofa domesticus) were allowed colostrum consumption for ≤48 h, were further stratified into postnatal treatment groups, and were provided either CS or CD milk replacers, analyzed to contain 1591 or 518 mg total choline/kg diet, respectively, for 28 d. At 30 d of age, pigs were subjected to MRI procedures to assess brain development. Gray and white matter development was assessed through voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS) to assess the effects of prenatal and postnatal dietary choline status. Results VBM analysis indicated that prenatally CS pigs exhibited increased (P < 0.01) gray matter in the left and right cortex compared with prenatally CD pigs. Analysis of white matter indicated that prenatally CS pigs exhibited increased (P < 0.01) white matter in the internal capsule, putamen–globus pallidus, and right cortex compared with prenatally CD pigs. No postnatal effects (P > 0.05) of choline status were noted for VBM analyses of gray and white matter. TBSS also showed no significant effects (P > 0.05) of prenatal or postnatal choline status for diffusion values along white matter tracts. Conclusions Observations from this study suggest that prenatal choline deficiency results in altered cortical gray matter and reduced white matter in the internal capsule and putamen of young pigs. With the use of noninvasive neuroimaging techniques, results from our study indicate that prenatal choline deficiency greatly alters gray and white matter development in pigs, thereby providing a translational assessment that may be used in clinical populations.

Neuroimaging is a novel tool to understand the impact of environmental chemicals on neurodevelopment.

PubMed

Horton, Megan K; Margolis, Amy E; Tang, Cheuk; Wright, Robert

2014-04-01

The prevalence of childhood neurodevelopmental disorders has been increasing over the last several decades. Prenatal and early childhood exposure to environmental toxicants is increasingly recognized as contributing to the growing rate of neurodevelopmental disorders. Very little information is known about the mechanistic processes by which environmental chemicals alter brain development. We review the recent advances in brain imaging modalities and discuss their application in epidemiologic studies of prenatal and early childhood exposure to environmental toxicants. Neuroimaging techniques (volumetric and functional MRI, diffusor tensor imaging, and magnetic resonance spectroscopy) have opened unprecedented access to study the developing human brain. These techniques are noninvasive and free of ionization radiation making them suitable for research applications in children. Using these techniques, we now understand much about structural and functional patterns in the typically developing brain. This knowledge allows us to investigate how prenatal exposure to environmental toxicants may alter the typical developmental trajectory. MRI is a powerful tool that allows in-vivo visualization of brain structure and function. Used in epidemiologic studies of environmental exposure, it offers the promise to causally link exposure with behavioral and cognitive manifestations and ultimately to inform programs to reduce exposure and mitigate adverse effects of exposure.

Prenatal Maternal Stress Predicts Methylation of Genes Regulating the Hypothalamic-Pituitary-Adrenocortical System in Mothers and Newborns in the Democratic Republic of Congo

ERIC Educational Resources Information Center

Kertes, Darlene A.; Kamin, Hayley S.; Hughes, David A.; Rodney, Nicole C.; Bhatt, Samarth; Mulligan, Connie J.

2016-01-01

Exposure to stress early in life permanently shapes activity of the hypothalamic-pituitary-adrenocortical (HPA) axis and the brain. Prenatally, glucocorticoids pass through the placenta to the fetus with postnatal impacts on brain development, birth weight (BW), and HPA axis functioning. Little is known about the biological mechanisms by which…

Implications of Prenatal Steroid Perturbations for Neurodevelopment, Behavior, and Autism

PubMed Central

Martien, Katherine M.; Gagnidze, Khatuna; Pfaff, Donald

2014-01-01

The prenatal brain develops under the influence of an ever-changing hormonal milieu that includes endogenous fetal gonadal and adrenal hormones, placental and maternal hormones, and exogenous substances with hormonal activity that can cross the placental barrier. This review discusses the influences of endogenous fetal and maternal hormones on normal brain development and potential consequences of pathophysiological hormonal perturbations to the developing brain, with particular reference to autism. We also consider the effects of hormonal pharmaceuticals used for assisted reproduction, the maintenance of pregnancy, the prevention of congenital adrenal hypertrophy, and hormonal contraceptives continued into an unanticipated pregnancy, among others. These treatments, although in some instances life-saving, may have unintended consequences on the developing fetuses. Additional concern is raised by fetal exposures to endocrine-disrupting chemicals encountered universally by pregnant women from food/water containers, contaminated food, household chemicals, and other sources. What are the potential outcomes of prenatal steroid perturbations on neurodevelopmental and behavioral disorders, including autism-spectrum disorders? Our purposes here are 1) to summarize some consequences of steroid exposures during pregnancy for the development of brain and behavior in the offspring; 2) to summarize what is known about the relationships between exposures and behavior, including autism spectrum disorders; 3) to discuss the molecular underpinnings of such effects, especially molecular epigenetic mechanisms of prenatal steroid manipulations, a field that may explain effects of direct exposures, and even transgenerational effects; and 4) for all of these, to add cautionary notes about their interpretation in the name of scientific rigor. PMID:25211453

Implications of prenatal steroid perturbations for neurodevelopment, behavior, and autism.

PubMed

Gore, Andrea C; Martien, Katherine M; Gagnidze, Khatuna; Pfaff, Donald

2014-12-01

The prenatal brain develops under the influence of an ever-changing hormonal milieu that includes endogenous fetal gonadal and adrenal hormones, placental and maternal hormones, and exogenous substances with hormonal activity that can cross the placental barrier. This review discusses the influences of endogenous fetal and maternal hormones on normal brain development and potential consequences of pathophysiological hormonal perturbations to the developing brain, with particular reference to autism. We also consider the effects of hormonal pharmaceuticals used for assisted reproduction, the maintenance of pregnancy, the prevention of congenital adrenal hypertrophy, and hormonal contraceptives continued into an unanticipated pregnancy, among others. These treatments, although in some instances life-saving, may have unintended consequences on the developing fetuses. Additional concern is raised by fetal exposures to endocrine-disrupting chemicals encountered universally by pregnant women from food/water containers, contaminated food, household chemicals, and other sources. What are the potential outcomes of prenatal steroid perturbations on neurodevelopmental and behavioral disorders, including autism-spectrum disorders? Our purposes here are 1) to summarize some consequences of steroid exposures during pregnancy for the development of brain and behavior in the offspring; 2) to summarize what is known about the relationships between exposures and behavior, including autism spectrum disorders; 3) to discuss the molecular underpinnings of such effects, especially molecular epigenetic mechanisms of prenatal steroid manipulations, a field that may explain effects of direct exposures, and even transgenerational effects; and 4) for all of these, to add cautionary notes about their interpretation in the name of scientific rigor.

Visuo-spatial processing in autism--testing the predictions of extreme male brain theory.

PubMed

Falter, Christine M; Plaisted, Kate C; Davis, Greg

2008-03-01

It has been hypothesised that autism is an extreme version of the male brain, caused by high levels of prenatal testosterone (Baron-Cohen 1999). To test this proposal, associations were assessed between three visuo-spatial tasks and prenatal testosterone, indexed in second-to-fourth digit length ratios (2D:4D). The study included children with Autism Spectrum Disorder, ASD (N = 28), and chronological as well as mental age matched typically-developing children (N = 31). While the group with ASD outperformed the control group at Mental Rotation and Figure-Disembedding, these group differences were not related to differences in prenatal testosterone level. Previous findings of an association between Targeting and 2D:4D were replicated in typically-developing children and children with ASD. The implications of these results for the extreme male brain (EMB) theory of autism are discussed.

The STRONG STAR Multidisciplinary PTSD Research Consortium

DTIC Science & Technology

2013-09-01

prenatal corticosterone exposure mimics the effects of prenatal stress on adult brain stress response systems and fear extinction behavior...stress, prenatal corticosterone reduced TH mRNA, suggesting that prenatal stress produces its effects on TH mRNA through a mechanism dependent on...Exogenous prenatal corticosterone exposure mimics the effects of prenatal stress on adult brain stress response systems and fear extinction behavior

Prenatal diagnosis of holoprosencephaly.

PubMed

Kousa, Youssef A; du Plessis, Adré J; Vezina, Gilbert

2018-05-17

Holoprosencephaly is a spectrum of congenital defects of forebrain development characterized by incomplete separation of the cerebral hemispheres. In vivo diagnosis can be established with prenatal brain imaging and disease severity correlates with extent of abnormally developed brain tissue. Advances in magnetic resonance imaging (MRI) over the past 25 years and their application to the fetus have enabled diagnosis of holoprosencephaly in utero. Here, we report on the prenatal diagnosis of holoprosencephaly using MRI as part of a diagnostic and management evaluation at a tertiary and quaternary referral center. Using an advanced MRI protocol and a 1.5-Tesla magnet, we show radiographic data diagnostic for the holoprosencephaly spectrum, including alobar, semilobar, lobar, middle interhemispheric, and septopreoptic variant. Accurate prenatal evaluation is important because the severity of imaging findings correlates with postnatal morbidity and mortality in holoprosencephaly. Therefore, this work has implications for the evaluation, diagnosis, management, and genetic counseling that families can receive during a pregnancy. © 2018 Wiley Periodicals, Inc.

Dietary choline supplementation to dams during pregnancy and lactation mitigates the effects of in utero stress exposure on adult anxiety-related behaviors.

PubMed

Schulz, Kalynn M; Pearson, Jennifer N; Gasparrini, Mary E; Brooks, Kayla F; Drake-Frazier, Chakeer; Zajkowski, Megan E; Kreisler, Alison D; Adams, Catherine E; Leonard, Sherry; Stevens, Karen E

2014-07-15

Brain cholinergic dysfunction is associated with neuropsychiatric illnesses such as depression, anxiety, and schizophrenia. Maternal stress exposure is associated with these same illnesses in adult offspring, yet the relationship between prenatal stress and brain cholinergic function is largely unexplored. Thus, using a rodent model, the current study implemented an intervention aimed at buffering the potential effects of prenatal stress on the developing brain cholinergic system. Specifically, control and stressed dams were fed choline-supplemented or control chow during pregnancy and lactation, and the anxiety-related behaviors of adult offspring were assessed in the open field, elevated zero maze and social interaction tests. In the open field test, choline supplementation significantly increased center investigation in both stressed and nonstressed female offspring, suggesting that choline-supplementation decreases female anxiety-related behavior irrespective of prenatal stress exposure. In the elevated zero maze, prenatal stress increased anxiety-related behaviors of female offspring fed a control diet (normal choline levels). However, prenatal stress failed to increase anxiety-related behaviors in female offspring receiving supplemental choline during gestation and lactation, suggesting that dietary choline supplementation ameliorated the effects of prenatal stress on anxiety-related behaviors. For male rats, neither prenatal stress nor diet impacted anxiety-related behaviors in the open field or elevated zero maze. In contrast, perinatal choline supplementation mitigated prenatal stress-induced social behavioral deficits in males, whereas neither prenatal stress nor choline supplementation influenced female social behaviors. Taken together, these data suggest that perinatal choline supplementation ameliorates the sex-specific effects of prenatal stress. Published by Elsevier B.V.

Dietary choline supplementation to dams during pregnancy and lactation mitigates the effects of in utero stress exposure on adult anxiety-related behaviors

PubMed Central

Schulz, Kalynn M.; Pearson, Jennifer N.; Gasparrini, Mary E.; Brooks, Kayla F.; Drake-Frazier, Chakeer; Zajkowski, Megan E.; Kreisler, Alison D.; Adams, Catherine E.; Leonard, Sherry; Stevens, Karen E.

2014-01-01

Brain cholinergic dysfunction is associated with neuropsychiatric illnesses such as depression, anxiety, and schizophrenia. Maternal stress exposure is associated with these same illnesses in adult offspring, yet the relationship between prenatal stress and brain cholinergic function is largely unexplored. Thus, using a rodent model, the current study implemented an intervention aimed at buffering the potential effects of prenatal stress on the developing brain cholinergic system. Specifically, control and stressed dams were fed choline-supplemented or control chow during pregnancy and lactation, and the anxiety-related behaviors of adult offspring were assessed in the open field, elevated zero maze and social interaction tests. In the open field test, choline supplementation significantly increased center investigation in both stressed and nonstressed female offspring, suggesting that choline-supplementation decreases female anxiety-related behavior irrespective of prenatal stress exposure. In the elevated zero maze, prenatal stress increased anxiety-related behaviors of female offspring fed a control diet (normal choline levels). However, prenatal stress failed to increase anxiety-related behaviors in female offspring receiving supplemental choline during gestation and lactation, suggesting that dietary choline supplementation ameliorated the effects of prenatal stress on anxiety-related behaviors. For male rats, neither prenatal stress nor diet impacted anxiety-related behaviors in the open field or elevated zero maze. In contrast, perinatal choline supplementation mitigated prenatal stress-induced social behavioral deficits in males, whereas neither prenatal stress nor choline supplementation influenced female social behaviors. Taken together, these data suggest that perinatal choline supplementation ameliorates the sex-specific effects of prenatal stress. PMID:24675162

Prenatal choline and the development of schizophrenia

PubMed Central

FREEDMAN, Robert; ROSS, Randal G.

2015-01-01

Background The primary prevention of illness at the population level, the ultimate aim of medicine, seems out of reach for schizophrenia. Schizophrenia has a strong genetic component, and its pathogenesis begins long before the emergence of psychosis, as early as fetal brain development. Cholinergic neurotransmission at nicotinic receptors is a pathophysiological mechanism related to one aspect of this genetic risk. Choline activates these nicotinic receptors during fetal brain development. Dietary supplementation of maternal choline thus emerges as a possible intervention in pregnancy to alter the earliest developmental course of the illness. Aim Review available literature on the relationship of choline supplementation or choline levels during pregnancy and fetal brain development. Methods A Medline search was used to identify studies assessing effects of choline in human fetal development. Studies of other prenatal risk factors for schizophrenia and the role of cholinergic neurotransmission in its pathophysiology were also identified. Results Dietary requirements for choline are high during pregnancy because of its several uses, including membrane biosynthesis, one-carbon metabolism, and cholinergic neurotransmission. Its ability to act directly at high concentrations as a nicotinic agonist is critical for normal brain circuit development. Dietary supplementation in the second and third trimesters with phosphatidyl-choline supports these functions and is associated generally with better fetal outcome. Improvement in inhibitory neuronal functions whose deficit is associated with schizophrenia and attention deficit disorder has been observed. Conclusion Prenatal dietary supplementation with phosphatidyl-choline and promotion of diets rich in choline-containing foods (meats, soybeans, and eggs) are possible interventions to promote fetal brain development and thereby decrease the risk of subsequent mental illnesses. The low risk and short (sixmonth) duration of the intervention makes it especially conducive to population-wide adoption. Similar findings with folate for the prevention of cleft palate led to recommendations for prenatal pharmacological supplementation and dietary improvement. However, definitive proof of the efficacy of prenatal choline supplementation will not be available for decades (because of the 20-year lag until the onset of schizophrenia), so public health officials need to decide whether or not promoting choline supplementation is justified based on the limited information available. PMID:26120259

Neuroimaging is a novel tool to understand the impact of environmental chemicals on neurodevelopment

PubMed Central

Horton, Megan K.; Margolis, Amy E.; Tang, Cheuk; Wright, Robert

2014-01-01

Purpose of review The prevalence of childhood neurodevelopmental disorders (ND) has been increasing over the last several decades. Prenatal and early childhood exposure to environmental toxicants is increasingly recognized as contributing to the growing rate of NDs. Very little is known about the mechanistic processes by which environmental chemicals alter brain development. We review recent advances in brain imaging modalities and discuss their application in epidemiologic studies of prenatal and early childhood exposure to environmental toxicants. Recent findings Neuroimaging techniques (volumetric and functional magnetic resonance imaging (MRI), diffusor tensor imaging (DTI), magnetic resonance spectroscopy (MRS)) have opened unprecedented access to study the developing human brain. These techniques are non-invasive and free of ionization radiation making them suitable for research applications in children. Using these techniques, we now understand much about structural and functional patterns in the typically developing brain. This knowledge allows us to investigate how prenatal exposure to environmental toxicants may alter the typical developmental trajectory. Summary MRI is a powerful tool that allows in vivo visualization of brain structure and function. Used in epidemiologic studies of environmental exposure, it offers the promise to causally link exposure with behavioral and cognitive manifestations and ultimately to inform programs to reduce exposure and mitigate adverse effects of exposure. PMID:24535497

Sex steroids and human behavior: prenatal androgen exposure and sex-typical play behavior in children.

PubMed

Hines, Melissa

2003-12-01

Gonadal hormones, particularly androgens, direct certain aspects of brain development and exert permanent influences on sex-typical behavior in nonhuman mammals. Androgens also influence human behavioral development, with the most convincing evidence coming from studies of sex-typical play. Girls exposed to unusually high levels of androgens prenatally, because they have the genetic disorder, congenital adrenal hyperplasia (CAH), show increased preferences for toys and activities usually preferred by boys, and for male playmates, and decreased preferences for toys and activities usually preferred by girls. Normal variability in androgen prenatally also has been related to subsequent sex-typed play behavior in girls, and nonhuman primates have been observed to show sex-typed preferences for human toys. These findings suggest that androgen during early development influences childhood play behavior in humans at least in part by altering brain development.

Fetal Brain Behavior and Cognitive Development.

ERIC Educational Resources Information Center

Joseph, R.

2000-01-01

Presents information on prenatal brain development, detailing the functions controlled by the medulla, pons, and midbrain, and the implications for cognitive development. Concludes that fetal cognitive motor activity, including auditory discrimination, orienting, the wake-sleep cycle, fetal heart rate accelerations, and defensive reactions,…

Effects of Unpredictable Variable Prenatal Stress (UVPS) on Bdnf DNA Methylation and Telomere Length in the Adult Rat Brain

NASA Technical Reports Server (NTRS)

Blaze, Jennifer; Asok, A.; Moyer, E. L.; Roth, T. L.; Ronca, A. E.

2015-01-01

In utero exposure to stress can shape neurobiological and behavioral outcomes in offspring, producing vulnerability to psychopathology later in life. Animal models of prenatal stress likewise have demonstrated long-­-term alterations in brain function and behavioral deficits in offspring. For example, using a rodent model of unpredictable variable prenatal stress (UVPS), in which dams are exposed to unpredictable, variable stress across pregnancy, we have found increased body weight and anxiety-­-like behavior in adult male, but not female, offspring. DNA methylation (addition of methyl groups to cytosines which normally represses gene transcription) and changes in telomere length (TTAGGG repeats on the ends of chromosomes) are two molecular modifications that result from stress and could be responsible for the long-­-term effects of UVPS. Here, we measured methylation of brain-­-derived neurotrophic factor (bdnf), a gene important in development and plasticity, and telomere length in the brains of adult offspring from the UVPS model. Results indicate that prenatally stressed adult males have greater methylation in the medial prefrontal cortex (mPFC) compared to non-­-stressed controls, while females have greater methylation in the ventral hippocampus compared to controls. Further, prenatally stressed males had shorter telomeres than controls in the mPFC. These findings demonstrate the ability of UVPS to produce epigenetic alterations and changes in telomere length across behaviorally-­-relevant brain regions, which may have linkages to the phenotypic outcomes.

Prenatal alcohol exposure affects vasculature development in the neonatal brain.

PubMed

Jégou, Sylvie; El Ghazi, Faiza; de Lendeu, Pamela Kwetieu; Marret, Stéphane; Laudenbach, Vincent; Uguen, Arnaud; Marcorelles, Pascale; Roy, Vincent; Laquerrière, Annie; Gonzalez, Bruno José

2012-12-01

In humans, antenatal alcohol exposure elicits various developmental disorders, in particular in the brain. Numerous studies focus on the deleterious effects of alcohol on neural cells. Although recent studies suggest that alcohol can affect angiogenesis in adults, the impact of prenatal alcohol exposure on brain microvasculature remains poorly understood. We used a mouse model to investigate effects of prenatal alcohol exposure on the cortical microvascular network in vivo and ex vivo and the action of alcohol, glutamate, and vascular endothelial growth factor A (VEGF) on activity, plasticity, and survival of microvessels. We used quantitative reverse transcriptase polymerase chain reaction, Western blot, immunohistochemistry, calcimetry, and videomicroscopy. We characterized the effect of prenatal alcohol exposure on the cortical microvascular network in human controls and fetal alcohol syndrome (FAS)/partial FAS (pFAS) patients at different developmental stages. In mice, prenatal alcohol exposure induced a reduction of cortical vascular density, loss of the radial orientation of microvessels, and altered expression of VEGF receptors. Time-lapse experiments performed on brain slices revealed that ethanol inhibited glutamate-induced calcium mobilization in endothelial cells, affected plasticity, and promoted death of microvessels. These effects were prevented by VEGF. In humans, we evidenced a stage-dependent alteration of the vascular network in the cortices of fetuses with pFAS/FAS. Whereas no modification was observed from gestational week 20 (WG20) to WG22, the radial organization of cortical microvessels was clearly altered in pFAS/FAS patients from WG30 to WG38. Prenatal alcohol exposure affects cortical angiogenesis both in mice and in pFAS/FAS patients, suggesting that vascular defects contribute to alcohol-induced brain abnormalities. Copyright © 2012 American Neurological Association.

Maternal enrichment affects prenatal hippocampal proliferation and open-field behaviors in female offspring mice.

PubMed

Maruoka, Takashi; Kodomari, Ikuko; Yamauchi, Rena; Wada, Etsuko; Wada, Keiji

2009-04-17

The maternal environment is thought to be important for fetal brain development. However, the effects of maternal environment are not fully understood. Here, we investigated whether enrichment of the maternal environment can influence prenatal brain development and postnatal behaviors in mice. An enriched environment is a housing condition with several objects such as a running wheel, tube and ladder, which are thought to increase sensory, cognitive and motor stimulation in rodents compared with standard housing conditions. First, we measured the number of BrdU-positive cells in the hippocampal dentate gyrus of fetuses from pregnant dams housed in an enriched environment. Our results revealed that maternal enrichment influences cell proliferation in the hippocampus of female, but not male, fetuses. Second, we used the open-field test to investigate postnatal behaviors in the offspring of dams housed in the enriched environment during pregnancy. We found that maternal enrichment significantly affects the locomotor activity and time spent in the center of the open-field in female, but not male, offspring. These results indicate that maternal enrichment influences prenatal brain development and postnatal behaviors in female offspring.

Intrauterine Exposure to Maternal Stress Alters Bdnf IV DNA Methylation and Telomere Length in the Brain of Adult Rat Offspring

NASA Technical Reports Server (NTRS)

Blaze, Jennifer; Asok, Arun; Borrelli, Kristyn; Tulbert, Christine; Bollinger, Justin; Ronca Finco, April E.; Roth, Tania L.

2017-01-01

DNA methylation (addition of methyl groups to cytosines which normally represses gene transcription) and changes in telomere length (TTAGGG repeats on the ends of chromosomes) are two molecular modifications that result from stress and could contribute to the long-term effects of intrauterine exposure to maternal stress on offspring behavioral outcomes. Here, we measured methylation of Brain-derived neurotrophic factor (Bdnf), a gene important in development and plasticity, and telomere length in the brains of adult rat male and female offspring whose mothers were exposed to unpredictable and variable stressors throughout gestation. Males exposed to prenatal stress had greater methylation (Bdnf IV) in the medial prefrontal cortex (mPFC) compared to non-stressed controls. Further, prenatally-stressed males had shorter telomeres than controls in the mPFC. This study provides the first evidence in a rodent model of an association between prenatal stress exposure and subsequent shorter brain telomere length. Together findings indicate a long-term impact of prenatal stress on DNA methylation and telomere biology with relevance for behavioral and health outcomes, and contribute to a growing literature linking stress to intergenerational epigenetic alterations and changes in telomere length.

Atypical Cortical Gyrification in Adolescents with Histories of Heavy Prenatal Alcohol Exposure

PubMed Central

Infante, M. Alejandra; Moore, Eileen M.; Bischoff-Grethe, Amanda; Migliorini, Robyn; Mattson, Sarah N.; Riley, Edward P.

2015-01-01

Prenatal alcohol exposure can adversely affect brain development, although little is known about the effects of prenatal alcohol exposure on gyrification. Gyrification reflects cortical folding complexity and is a process by which the surface of the brain creates sulci and gyri. Prior studies have shown that prenatal alcohol exposure is associated with reduced gyrification in childhood, but no studies have examined adolescents. Subjects (12–16y) comprised two age-equivalent groups: 30 adolescents with histories of heavy prenatal alcohol exposure (AE) and 19 non-exposed controls (CON). A T1-weighted image was obtained for all participants. Local gyrification index (LGI) was estimated using FreeSurfer. General linear models were used to determine between group differences in LGI controlling for age and sex. Age-by-group interactions were also investigated while controlling for sex. The AE group displayed reduced LGI relative to CON in the bilateral superior parietal region, right postcentral region, and left precentral and lateral occipital regions (ps < .001). Significant age-by-group interactions were observed in the right precentral and lateral occipital regions, and in the left pars opercularis and inferior parietal regions (ps < .01). The AE group showed age-related reductions in gyrification in all regions whereas the CON group showed increased gyrification with age in the lateral occipital region only. While cross-sectional, the age-related reduction in gyrification observed in the AE group suggests alterations in cortical development throughout adolescence and provides further insight into the pathophysiology and brain maturation of adolescents prenatally exposed to alcohol. PMID:26275919

Transcriptional Landscape of the Prenatal Human Brain

PubMed Central

Miller, Jeremy A.; Ding, Song-Lin; Sunkin, Susan M.; Smith, Kimberly A; Ng, Lydia; Szafer, Aaron; Ebbert, Amanda; Riley, Zackery L.; Aiona, Kaylynn; Arnold, James M.; Bennet, Crissa; Bertagnolli, Darren; Brouner, Krissy; Butler, Stephanie; Caldejon, Shiella; Carey, Anita; Cuhaciyan, Christine; Dalley, Rachel A.; Dee, Nick; Dolbeare, Tim A.; Facer, Benjamin A. C.; Feng, David; Fliss, Tim P.; Gee, Garrett; Goldy, Jeff; Gourley, Lindsey; Gregor, Benjamin W.; Gu, Guangyu; Howard, Robert E.; Jochim, Jayson M.; Kuan, Chihchau L.; Lau, Christopher; Lee, Chang-Kyu; Lee, Felix; Lemon, Tracy A.; Lesnar, Phil; McMurray, Bergen; Mastan, Naveed; Mosqueda, Nerick F.; Naluai-Cecchini, Theresa; Ngo, Nhan-Kiet; Nyhus, Julie; Oldre, Aaron; Olson, Eric; Parente, Jody; Parker, Patrick D.; Parry, Sheana E.; Player, Allison Stevens; Pletikos, Mihovil; Reding, Melissa; Royall, Joshua J.; Roll, Kate; Sandman, David; Sarreal, Melaine; Shapouri, Sheila; Shapovalova, Nadiya V.; Shen, Elaine H.; Sjoquist, Nathan; Slaughterbeck, Clifford R.; Smith, Michael; Sodt, Andy J.; Williams, Derric; Zöllei, Lilla; Fischl, Bruce; Gerstein, Mark B.; Geschwind, Daniel H.; Glass, Ian A.; Hawrylycz, Michael J.; Hevner, Robert F.; Huang, Hao; Jones, Allan R.; Knowles, James A.; Levitt, Pat; Phillips, John W.; Sestan, Nenad; Wohnoutka, Paul; Dang, Chinh; Bernard, Amy; Hohmann, John G.; Lein, Ed S.

2014-01-01

Summary The anatomical and functional architecture of the human brain is largely determined by prenatal transcriptional processes. We describe an anatomically comprehensive atlas of mid-gestational human brain, including de novo reference atlases, in situ hybridization, ultra-high resolution magnetic resonance imaging (MRI) and microarray analysis on highly discrete laser microdissected brain regions. In developing cerebral cortex, transcriptional differences are found between different proliferative and postmitotic layers, wherein laminar signatures reflect cellular composition and developmental processes. Cytoarchitectural differences between human and mouse have molecular correlates, including species differences in gene expression in subplate, although surprisingly we find minimal differences between the inner and human-expanded outer subventricular zones. Both germinal and postmitotic cortical layers exhibit fronto-temporal gradients, with particular enrichment in frontal lobe. Finally, many neurodevelopmental disorder and human evolution-related genes show patterned expression, potentially underlying unique features of human cortical formation. These data provide a rich, freely-accessible resource for understanding human brain development. PMID:24695229

Prenatal famine exposure has sex-specific effects on brain size.

PubMed

de Rooij, Susanne R; Caan, Matthan W A; Swaab, Dick F; Nederveen, Aart J; Majoie, Charles B; Schwab, Matthias; Painter, Rebecca C; Roseboom, Tessa J

2016-08-01

Early nutritional deprivation might cause irreversible damage to the brain. Prenatal exposure to undernutrition has been shown to be associated with increased central nervous system anomalies at birth and decreased cognitive function in adulthood. Little is known about the potential effect on the brain in older age. We investigated brain size and structure at age 68 years after prenatal famine exposure. T1-weighted structural magnetic resonance images of the brain were made in 118 Dutch famine birth cohort members. Of these 118 (44% male, age range 65-69 years), 41 had been exposed to famine in early gestation and 77 had been prenatally unexposed. Structural volumes were automatically assessed using FreeSurfer. Diffusion tensor imaging was performed and anisotropy and diffusivity were computed. Fluid attenuated inversion recovery was performed to assess white matter hyperintensities. Exposure to famine in early gestation was associated with smaller intracranial volume in males, but not females. Volumes of total brain, grey and white matter were also smaller in early exposed males, but these differences disappeared after adjusting for intracranial volume. Prenatally exposed males but not females, had a smaller intracranial and total brain volume compared to unexposed subjects. Our findings show that prenatal undernutrition permanently affected brain size.media-1vid110.1093/brain/aww132_video_abstractaww132_video_abstract. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

On the relationship between head circumference, brain size, prenatal long-chain PUFA/5-methyltetrahydrofolate supplementation and cognitive abilities during childhood.

PubMed

Catena, Andrés; Martínez-Zaldívar, Cristina; Diaz-Piedra, Carolina; Torres-Espínola, Francisco J; Brandi, Pilar; Pérez-García, Miguel; Decsi, Tamás; Koletzko, Berthold; Campoy, Cristina

2017-03-29

Head circumference in infants has been reported to predict brain size, total grey matter volume (GMV) and neurocognitive development. However, it is unknown whether it has predictive value on regional and subcortical brain volumes. We aimed to explore the relationship between several head circumference measurements since birth and distributions of GMV and subcortical volumes at later childhood. We examined seventy-four, Caucasian, singleton, term-born infants born to mothers randomised to receive fish oil and/or 5-methyltetrahydrofolate or placebo prenatal supplementation. We assessed head circumference at birth and at 4 and 10 years of age and cognitive abilities at 7 years of age. We obtained brain MRI at 10 years of age, on which we performed voxel-based morphometry, cortical surface extraction and subcortical segmentation. Analyses were controlled for sex, age, height, weight, family status, laterality and total intracranial volume. Prenatal supplementation did not affect head circumference at any age, cognitive abilities or total brain volumes. Head circumference at 4 years presented the highest correlation with total GMV, white matter volume and brain surface area, and was also strongly associated with GMV of frontal, temporal and occipital areas, as well as with caudate nucleus, globus pallidus, putamen and thalamus volumes. As relationships between brain volumes in childhood and several outcomes extend into adulthood, we have found that ages between 0 and 4 years as the optimal time for brain growth; postnatal factors might have the most relevant impact on structural maturation of certain cortical areas and subcortical nuclei, independent of prenatal supplementation.

Effects of nicotine exposure during prenatal or perinatal period on cell numbers in adult rat hippocampus and cerebellum: a stereology study.

PubMed

Chen, Wei-Jung A; King, Karen A; Lee, Ruby E; Sedtal, Christopher S; Smith, Andrew M

2006-11-02

Smoking during pregnancy poses a potential risk to unborn children. The present study examined the long-term effects of early nicotine exposure on the number of pyramidal and granule cells in the hippocampus, and Purkinje cells in the cerebellar vermis. The loss of neurons is the most severe form of brain injury with significant functional implications. In this study, rats were exposed to nicotine during either the prenatal (PRE) period or both the prenatal and early postnatal (PERI) period. It was hypothesized that nicotine treatment would result in long-term decreases in neuronal numbers, and that PERI treatment would be more detrimental to these cell populations than the PRE treatment. The results showed that neither PRE nor PERI nicotine exposure reduces the numbers of pyramidal, granule or Purkinje cells. Neither the regions where these cells reside, nor the cell densities were affected by nicotine. Although no significant cell loss was observed, the current nicotine exposure regimens may lead to alterations in cellular functions or cytoarchitectures. The present results in conjunction with previous reports showing significant cell loss from nicotine exposure during the brain growth spurt suggest that "patch-like" nicotine exposure during prenatal period may alter the sensitivity or the responsiveness of the developing brain to the injurious effects of nicotine during the most vulnerable stage of brain development - the brain growth spurt. Furthermore, the current stereology cell counting results are not in agreement with some reports in the literature, and this discrepancy may simply be a function of different cell counting techniques used.

Early brain development toward shaping of human mind: an integrative psychoneurodevelopmental model in prenatal and perinatal medicine.

PubMed

Hruby, Radovan; Maas, Lili M; Fedor-Freybergh, P G

2013-01-01

The article introduces an integrative psychoneurodevelopmental model of complex human brain and mind development based on the latest findings in prenatal and perinatal medicine in terms of integrative neuroscience. The human brain development is extraordinarily complex set of events and could be influenced by a lot of factors. It is supported by new insights into the early neuro-ontogenic processes with the help of structural 3D magnetic resonance imaging or diffusion tensor imaging of fetal human brain. Various factors and targets for neural development including birth weight variability, fetal and early-life programming, fetal neurobehavioral states and fetal behavioral responses to various stimuli and others are discussed. Molecular biology reveals increasing sets of genes families as well as transcription and neurotropic factors together with critical epigenetic mechanisms to be deeply employed in the crucial neurodevelopmental events. Another field of critical importance is psychoimmuno-neuroendocrinology. Various effects of glucocorticoids as well as other hormones, prenatal stress and fetal HPA axis modulation are thought to be of special importance for brain development. The early postnatal period is characterized by the next intense shaping of complex competences, induced mainly by the very unique mother - newborn´s interactions and bonding. All these mechanisms serve to shape individual human mind with complex abilities and neurobehavioral strategies. Continuous research elucidating these special competences of human fetus and newborn/child supports integrative neuroscientific approach to involve various scientific disciplines for the next progress in human brain and mind research, and opens new scientific challenges and philosophic attitudes. New findings and approaches in this field could establish new methods in science, in primary prevention and treatment strategies, and markedly contribute to the development of modern integrative and personalized medicine.

Minocycline ameliorates prenatal valproic acid induced autistic behaviour, biochemistry and blood brain barrier impairments in rats.

PubMed

Kumar, Hariom; Sharma, Bhupesh

2016-01-01

Autism is a neurodevelopment disorder. One percent worldwide population suffers with autism and males suffer more than females. Microglia plays an important role in neurodevelopment, neuropsychiatric and neurodegenerative disorders. The present study has been designed to investigate the role of minocycline in prenatal valproic acid induced autism in rats. Animals with prenatal valproic acid have reduced social interaction (three chamber social behaviour apparatus), spontaneous alteration (Y-Maze), exploratory activity (Hole board test), intestinal motility, serotonin levels (both in prefrontal cortex and ileum) and prefrontal cortex mitochondrial complex activity (complexes I, II, IV). Furthermore, prenatal valproic acid treated animals have shown an increase in locomotion (actophotometer), anxiety (elevated plus maze), brain oxidative stress (thiobarbituric acid reactive species, glutathione, catalase), nitrosative stress (nitrite/nitrate), inflammation (both in brain and ileum myeloperoxidase activity), calcium and blood brain barrier permeability. Treatment with minocycline significantly attenuated prenatal valproic acid induced reduction in social interaction, spontaneous alteration, exploratory activity intestinal motility, serotonin levels and prefrontal cortex mitochondrial complex activity. Furthermore, minocycline has also attenuated prenatal valproic acid induced increase in locomotion, anxiety, brain oxidative and nitrosative stress, inflammation, calcium and blood brain barrier permeability. Thus, it may be concluded that prenatal valproic acid has induced autistic behaviour, biochemistry and blood brain barrier impairment in animals, which were significantly attenuated by minocycline. Minocycline should be explored further for its therapeutic benefits in autism. Copyright © 2015 Elsevier B.V. All rights reserved.

Prenatal and Neonatal Brain Structure and White Matter Maturation in Children at High Risk for Schizophrenia

PubMed Central

Gilmore, John H.; Kang, Chaeryon; Evans, Dianne D.; Wolfe, Honor M.; Smith, J. Keith; Lieberman, Jeffrey A.; Lin, Weili; Hamer, Robert M.; Styner, Martin; Gerig, Guido

2011-01-01

Objective Schizophrenia is a neurodevelopmental disorder associated with abnormalities of brain structure and white matter, although little is known about when these abnormalities arise. This study was conducted to identify structural brain abnormalities in the prenatal and neonatal periods associated with genetic risk for schizophrenia. Method Prenatal ultrasound scans and neonatal structural magnetic resonance imaging (MRI) and diffusion tensor imaging were prospectively obtained in the offspring of mothers with schizophrenia or schizoaffective disorder (N=26) and matched comparison mothers without psychiatric illness (N=26). Comparisons were made for prenatal lateral ventricle width and head circumference, for neonatal intracranial, CSF, gray matter, white matter, and lateral ventricle volumes, and for neonatal diffusion properties of the genu and splenium of the corpus callosum and corticospinal tracts. Results Relative to the matched comparison subjects, the offspring of mothers with schizophrenia did not differ in prenatal lateral ventricle width or head circumference. Overall, the high-risk neonates had nonsignificantly larger intracranial, CSF, and lateral ventricle volumes. Subgroup analysis revealed that male high-risk infants had significantly larger intracranial, CSF, total gray matter, and lateral ventricle volumes; the female high-risk neonates were similar to the female comparison subjects. There were no group differences in white matter diffusion tensor properties. Conclusions Male neonates at genetic risk for schizophrenia had several larger than normal brain volumes, while females did not. To the authors' knowledge, this study provides the first evidence, in the context of its limitations, that early neonatal brain development may be abnormal in males at genetic risk for schizophrenia. PMID:20516153

Systematic Review of Prenatal Cocaine Exposure and Adolescent Development

PubMed Central

Buckingham-Howes, Stacy; Berger, Sarah Shafer; Scaletti, Laura A.

2013-01-01

BACKGROUND AND OBJECTIVE: Previous research found that prenatal cocaine exposure (PCE) may increase children's vulnerability to behavior and cognition problems. Maturational changes in brain and social development make adolescence an ideal time to reexamine associations. The objective was to conduct a systematic review of published studies examining associations between PCE and adolescent development (behavior, cognition/school outcomes, physiologic responses, and brain morphology/functioning). METHODS: Articles were obtained from PubMed, PsycInfo, Web of Science, and CINAHL databases through July 2012 with search terms: prenatal drug, substance, or cocaine exposure; adolescence/adolescent; and in utero substance/drug exposure. Criteria for inclusion were nonexposed comparison group, human adolescents aged 11 to 19, peer-reviewed, English-language, and adolescent outcomes. RESULTS: Twenty-seven studies representing 9 cohorts met the criteria. Four outcome categories were identified: behavior, cognition/school performance, brain structure/function, and physiologic responses. Eleven examined behavior; 7 found small but significant differences favoring nonexposed adolescents, with small effect sizes. Eight examined cognition/school performance; 6 reported significantly lower scores on language and memory tasks among adolescents with PCE, with varying effect sizes varied. Eight examined brain structure/function and reported morphologic differences with few functional differences. Three examined physiologic responses with discordant findings. Most studies controlled for other prenatal exposures, caregiving environment, and violence exposure; few examined mechanisms. CONCLUSIONS: Consistent with findings among younger children, PCE increases the risk for small but significantly less favorable adolescent functioning. Although the clinical importance of differences is often unknown, the caregiving environment and violence exposure pose additional threats. Future research should investigate mechanisms linking PCE with adolescent functioning. PMID:23713107

Early Exposure to Toxic Substances Damages Brain Architecture. Working Paper #4

ERIC Educational Resources Information Center

National Scientific Council on the Developing Child, 2006

2006-01-01

New science shows that exposure to toxins prenatally or early in life can have a devastating and lifelong effect on the developing architecture of the brain. Exposures to many chemicals have much more severe consequences for embryos, fetuses, and young children, whose brains are still developing, than for adults. Substances that can have a truly…

Neuroimaging and Fetal Alcohol Spectrum Disorders

ERIC Educational Resources Information Center

Norman, Andria L.; Crocker, Nicole; Mattson, Sarah N.; Riley, Edward P.

2009-01-01

The detrimental effects of prenatal alcohol exposure on the developing brain include structural brain anomalies as well as cognitive and behavioral deficits. Initial neuroimaging studies of fetal alcohol spectrum disorders (FASD) using magnetic resonance imaging (MRI) confirmed previous autopsy reports of overall reduction in brain volume and…

Relationships between Head Circumference, Brain Volume and Cognition in Children with Prenatal Alcohol Exposure

PubMed Central

Treit, Sarah; Zhou, Dongming; Chudley, Albert E.; Andrew, Gail; Rasmussen, Carmen; Nikkel, Sarah M.; Samdup, Dawa; Hanlon-Dearman, Ana; Loock, Christine; Beaulieu, Christian

2016-01-01

Head circumference is used together with other measures as a proxy for central nervous system damage in the diagnosis of fetal alcohol spectrum disorders, yet the relationship between head circumference and brain volume has not been investigated in this population. The objective of this study is to characterize the relationship between head circumference, brain volume and cognitive performance in a large sample of children with prenatal alcohol exposure (n = 144) and healthy controls (n = 145), aged 5–19 years. All participants underwent magnetic resonance imaging to yield brain volumes and head circumference, normalized to control for age and sex. Mean head circumference, brain volume, and cognitive scores were significantly reduced in the prenatal alcohol exposure group relative to controls, albeit with considerable overlap between groups. Males with prenatal alcohol exposure had reductions in all three measures, whereas females with prenatal alcohol exposure had reduced brain volumes and cognitive scores, but no difference in head circumference relative to controls. Microcephaly (defined here as head circumference ≤ 3rd percentile) occurred more often in prenatal alcohol exposed participants than controls, but 90% of the exposed sample had head circumferences above this clinical cutoff indicating that head circumference is not a sensitive marker of prenatal alcohol exposure. Normalized head circumference and brain volume were positively correlated in both groups, and subjects with very low head circumference typically had below-average brain volumes. Conversely, over half of the subjects with very low brain volumes had normal head circumferences, which may stem from differential effects of alcohol on the skeletal and nervous systems. There were no significant correlations between head circumference and any cognitive score. These findings confirm group-level reductions in head circumference and increased rates of microcephaly in children with prenatal alcohol exposure, but raise concerns about the predictive value of this metric at an individual-subject level. PMID:26928125

Relationships between Head Circumference, Brain Volume and Cognition in Children with Prenatal Alcohol Exposure.

PubMed

Treit, Sarah; Zhou, Dongming; Chudley, Albert E; Andrew, Gail; Rasmussen, Carmen; Nikkel, Sarah M; Samdup, Dawa; Hanlon-Dearman, Ana; Loock, Christine; Beaulieu, Christian

2016-01-01

Head circumference is used together with other measures as a proxy for central nervous system damage in the diagnosis of fetal alcohol spectrum disorders, yet the relationship between head circumference and brain volume has not been investigated in this population. The objective of this study is to characterize the relationship between head circumference, brain volume and cognitive performance in a large sample of children with prenatal alcohol exposure (n = 144) and healthy controls (n = 145), aged 5-19 years. All participants underwent magnetic resonance imaging to yield brain volumes and head circumference, normalized to control for age and sex. Mean head circumference, brain volume, and cognitive scores were significantly reduced in the prenatal alcohol exposure group relative to controls, albeit with considerable overlap between groups. Males with prenatal alcohol exposure had reductions in all three measures, whereas females with prenatal alcohol exposure had reduced brain volumes and cognitive scores, but no difference in head circumference relative to controls. Microcephaly (defined here as head circumference ≤ 3rd percentile) occurred more often in prenatal alcohol exposed participants than controls, but 90% of the exposed sample had head circumferences above this clinical cutoff indicating that head circumference is not a sensitive marker of prenatal alcohol exposure. Normalized head circumference and brain volume were positively correlated in both groups, and subjects with very low head circumference typically had below-average brain volumes. Conversely, over half of the subjects with very low brain volumes had normal head circumferences, which may stem from differential effects of alcohol on the skeletal and nervous systems. There were no significant correlations between head circumference and any cognitive score. These findings confirm group-level reductions in head circumference and increased rates of microcephaly in children with prenatal alcohol exposure, but raise concerns about the predictive value of this metric at an individual-subject level.

The Modulatory Properties of Chronic Antidepressant Drugs Treatment on the Brain Chemokine - Chemokine Receptor Network: A Molecular Study in an Animal Model of Depression.

PubMed

Trojan, Ewa; Ślusarczyk, Joanna; Chamera, Katarzyna; Kotarska, Katarzyna; Głombik, Katarzyna; Kubera, Marta; Basta-Kaim, Agnieszka

2017-01-01

An increasing number of studies indicate that the chemokine system may be the third major communication system of the brain. Therefore, the role of the chemokine system in the development of brain disorders, including depression, has been recently proposed. However, little is known about the impact of the administration of various antidepressant drugs on the brain chemokine - chemokine receptor axis. In the present study, we used an animal model of depression based on the prenatal stress procedure. We determined whether chronic treatment with tianeptine, venlafaxine, or fluoxetine influenced the evoked by prenatal stress procedure changes in the mRNA and protein levels of the homeostatic chemokines, CXCL12 (SDF-1α), CX3CL1 (fractalkine) and their receptors, in the hippocampus and frontal cortex. Moreover, the impact of mentioned antidepressants on the TGF-β, a molecular pathway related to fractalkine receptor (CX3CR1), was explored. We found that prenatal stress caused anxiety and depressive-like disturbances in adult offspring rats, which were normalized by chronic antidepressant treatment. Furthermore, we showed the stress-evoked CXCL12 upregulation while CXCR4 downregulation in hippocampus and frontal cortex. CXCR7 expression was enhanced in frontal cortex but not hippocampus. Furthermore, the levels of CX3CL1 and CX3CR1 were diminished by prenatal stress in the both examined brain areas. The mentioned changes were normalized with various potency by chronic administration of tested antidepressants. All drugs in hippocampus, while tianeptine and venlafaxine in frontal cortex normalized the CXCL12 level in prenatally stressed offspring. Moreover, in hippocampus only fluoxetine enhanced CXCR4 level, while fluoxetine and tianeptine diminished CXCR7 level in frontal cortex. Additionally, the diminished by prenatal stress levels of CX3CL1 and CX3CR1 in the both examined brain areas were normalized by chronic tianeptine and partially fluoxetine administration. Tianeptine modulate also brain TGF-β signaling in the prenatal stress-induced animal model of depression. Our results provide new evidence that not only prenatal stress-induced behavioral disturbances but also changes of CXCL12 and their receptor and at less extend in CX3CL1-CX3CR1 expression may be normalized by chronic antidepressant drug treatment. In particular, the effect on the CXCL12 and their CXCR4 and CXCR7 receptors requires additional studies to elucidate the possible biological consequences.

PRENATAL INFECTION, MATERNAL IMMUNE ACTIVATION, AND RISK FOR SCHIZOPHRENIA.

PubMed

Canetta, Sarah E; Brown, Alan S

2012-12-01

A body of epidemiological literature has suggested an association between prenatal infection, subsequent maternal immune activation (MIA), and later risk of schizophrenia. These epidemiological studies have inspired preclinical research using rodent and primate models of prenatal infection and MIA. The findings from these preclinical studies indicate that severe infection and immune activation during pregnancy can negatively impact offspring brain development and impair adult behavior. This review aims to summarize the major epidemiological and preclinical findings addressing the connection between prenatal infection and immune activation and later risk of developing schizophrenia, as well as the more limited literature addressing the mechanisms by which this gestational insult might affect offspring neurodevelopment. Finally, directions for future research will be discussed.

Prenatal Cannabis and Tobacco Exposure in Relation to Brain Morphology: A Prospective Neuroimaging Study in Young Children.

PubMed

El Marroun, Hanan; Tiemeier, Henning; Franken, Ingmar H A; Jaddoe, Vincent W V; van der Lugt, Aad; Verhulst, Frank C; Lahey, Benjamin B; White, Tonya

2016-06-15

Cannabis use during pregnancy has been associated with negative behavioral outcomes and psychopathology in offspring. However, there has been little research evaluating alterations in brain structure as a result of maternal cannabis use. In this prospective study, we investigated the association between prenatal cannabis exposure and brain morphology in young children. We matched 96 children prenatally exposed to tobacco only (without cannabis) with 113 unexposed control subjects on the basis of age and gender and subsequently selected 54 children exposed to prenatal cannabis (mostly combined with tobacco exposure). These children (aged 6 to 8 years) were part of a population-based study in the Netherlands, the Generation R Study, and were followed from pregnancy onward. We assessed brain volumetric measures and cortical thickness in magnetic resonance imaging scans using FreeSurfer. We performed vertexwise analyses in FreeSurfer and linear regression analyses adjusting for relevant covariates using Statistical Package for the Social Sciences. Prenatal cannabis exposure was not associated with global brain volumes, such as total brain volume, gray matter volume, or white matter volume. However, prenatal cannabis exposure was associated with differences in cortical thickness: compared with nonexposed control subjects, cannabis-exposed children had thicker frontal cortices. Prenatal tobacco exposure compared with nonexposed control subjects was associated with cortical thinning, primarily in the superior frontal and superior parietal cortices. Our findings suggest an association between prenatal cannabis exposure and cortical thickness in children. Further research is needed to explore the causal nature of this association. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Prenatal and pubertal testosterone affect brain lateralization.

PubMed

Beking, T; Geuze, R H; van Faassen, M; Kema, I P; Kreukels, B P C; Groothuis, T G G

2018-02-01

After decades of research, the influence of prenatal testosterone on brain lateralization is still elusive, whereas the influence of pubertal testosterone on functional brain lateralization has not been investigated, although there is increasing evidence that testosterone affects the brain in puberty. We performed a longitudinal study, investigating the relationship between prenatal testosterone concentrations in amniotic fluid, pubertal testosterone concentrations in saliva, and brain lateralization (measured with functional Transcranial Doppler ultrasonography (fTCD)) of the Mental Rotation, Chimeric Faces and Word Generation tasks. Thirty boys and 30 girls participated in this study at the age of 15 years. For boys, we found a significant interaction effect between prenatal and pubertal testosterone on lateralization of Mental Rotation and Chimeric Faces. In the boys with low prenatal testosterone levels, pubertal testosterone was positively related to the strength of lateralization in the right hemisphere, while in the boys with high prenatal testosterone levels, pubertal testosterone was negatively related to the strength of lateralization. For Word Generation, pubertal testosterone was negatively related to the strength of lateralization in the left hemisphere in boys. For girls, we did not find any significant effects, possibly because their pubertal testosterone levels were in many cases below quantification limit. To conclude, prenatal and pubertal testosterone affect lateralization in a task-specific way. Our findings cannot be explained by simple models of prenatal testosterone affecting brain lateralization in a similar way for all tasks. We discuss alternative models involving age dependent effects of testosterone, with a role for androgen receptor distribution and efficiency. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Adult brain and behavioral pathological markers of prenatal immune challenge during early/middle and late fetal development in mice.

PubMed

Meyer, Urs; Nyffeler, Myriel; Yee, Benjamin K; Knuesel, Irene; Feldon, Joram

2008-05-01

Maternal infection during pregnancy increases the risk for neurodevelopmental disorders such as schizophrenia and autism in the offspring. This association appears to be critically dependent on the precise prenatal timing. However, the extent to which distinct adult psychopathological and neuropathological traits may be sensitive to the precise times of prenatal immune activation remains to be further characterized. Here, we evaluated in a mouse model of prenatal immune challenge by the viral mimic, polyriboinosinic-polyribocytidilic acid (PolyIC), whether prenatal immune activation in early/middle and late gestation may influence the susceptibility to some of the critical cognitive, pharmacological, and neuroanatomical dysfunctions implicated in schizophrenia and autism. We revealed that PolyIC-induced prenatal immune challenge on gestation day (GD) 9 but not GD17 significantly impaired sensorimotor gating and reduced prefrontal dopamine D1 receptors in adulthood, whereas prenatal immune activation specifically in late gestation impaired working memory, potentiated the locomotor reaction to the NMDA-receptor antagonist dizocilpine, and reduced hippocampal NMDA-receptor subunit 1 expression. On the other hand, potentiation of the locomotor reaction to the dopamine-receptor agonist amphetamine and reduction in Reelin- and Parvalbumin-expressing prefrontal neurons emerged independently of the precise times of prenatal immune challenge. Our findings thus highlight that prenatal immune challenge during early/middle and late fetal development in mice leads to distinct brain and behavioral pathological symptom clusters in adulthood. Further examination and evaluation of in utero immune challenge at different times of gestation may provide important new insight into the neuroimmunological and neuropathological mechanisms underlying the segregation of different symptom clusters in heterogeneous neuropsychiatric disorders such as schizophrenia and autism.

Sex Specific Effect of Prenatal Testosterone on Language Lateralization in Children

ERIC Educational Resources Information Center

Lust, J. M.; Geuze, R. H.; Van de Beek, C.; Cohen-Kettenis, P. T.; Groothuis, A. G. G.; Bouma, A.

2010-01-01

Brain lateralization refers to the division of labour between the two hemispheres in controlling a wide array of functions and is remarkably well developed in humans. Based on sex differences in lateralization of handedness and language, several hypotheses have postulated an effect of prenatal exposure to testosterone on human lateralization…

Active coping of prenatally stressed rats in the forced swimming test: involvement of the Nurr1 gene.

PubMed

Montes, Pedro; Ruiz-Sánchez, Elizabeth; Calvillo, Minerva; Rojas, Patricia

2016-09-01

Depending on genetic predisposition, prenatal stress may result in vulnerability or resilience to develop psychiatric disorders in adulthood. Nurr1 is an immediate early gene, important in the brain for the stress response. We tested the hypothesis that prenatal stress and the decrease of hippocampal Nurr1 alter offspring behavioral responses in the forced swimming test (FST). Pregnant Wistar rats were exposed to restraint stress (45 min, thrice daily) from gestation day 14. Prenatally stressed (PS) and non-prenatally stressed (NPS) male offspring were treated bilaterally with a Nurr1 antisense oligodeoxynucleotide (ODN; or control) into the hippocampus at 97 d of age. After 1 h, the rats were exposed to the FST (acute stressor) to analyze their behavioral responses. Thirty minutes after the FST, we analyzed the gene expression of Nurr1, Bdnf and Nr3c1 (genes for Nurr1, brain-derived neurotrophic factor (BDNF) and glucocorticoid receptor (GR), respectively) in the hippocampus, prefrontal cortex (PFC) and hypothalamus. Results showed that the decrease of hippocampal Nurr1 after the antisense ODN in adult NPS rats induces immobility (indicating depressive-like behavior). The PS adult rats, including the group with decreased hippocampal Nurr1, presented low immobility in the FST. This low immobility was concordant with maintenance of Nurr1 and Bdnf expression levels in the three analyzed brain regions; Nr3c1 gene expression was also maintained in the PFC and hypothalamus. These findings suggest that Nurr1 and associated genes could participate in the brain modifications induced by prenatal stress, allowing active coping (resilience) with acute stress in adulthood.

Prenatal Nutritional Deficiency Reprogrammed Postnatal Gene Expression in Mammal Brains: Implications for Schizophrenia

PubMed Central

Xu, Jiawei; He, Guang; Zhu, Jingde; Zhou, Xinyao; St Clair, David; Wang, Teng; Xiang, Yuqian; Zhao, Qingzhu; Xing, Qinghe; Liu, Yun; Wang, Lei; Li, Qiaoli

2015-01-01

Background: Epidemiological studies have identified prenatal exposure to famine as a risk factor for schizophrenia, and animal models of prenatal malnutrition display structural and functional brain abnormalities implicated in schizophrenia. Methods: The offspring of the RLP50 rat, a recently developed animal model of prenatal famine malnutrition exposure, was used to investigate the changes of gene expression and epigenetic modifications in the brain regions. Microarray gene expression analysis was carried out in the prefrontal cortex and the hippocampus from 8 RLP50 offspring rats and 8 controls. MBD-seq was used to test the changes in DNA methylation in hippocampus depending on prenatal malnutrition exposure. Results: In the prefrontal cortex, offspring of RLP50 exhibit differences in neurotransmitters and olfactory-associated gene expression. In the hippocampus, the differentially-expressed genes are related to synaptic function and transcription regulation. DNA methylome profiling of the hippocampus also shows widespread but systematic epigenetic changes; in most cases (87%) this involves hypermethylation. Remarkably, genes encoded for the plasma membrane are significantly enriched for changes in both gene expression and DNA methylome profiling screens (p = 2.37×10–9 and 5.36×10–9, respectively). Interestingly, Mecp2 and Slc2a1, two genes associated with cognitive impairment, show significant down-regulation, and Slc2a1 is hypermethylated in the hippocampus of the RLP50 offspring. Conclusions: Collectively, our results indicate that prenatal exposure to malnutrition leads to the reprogramming of postnatal brain gene expression and that the epigenetic modifications contribute to the reprogramming. The process may impair learning and memory ability and result in higher susceptibility to schizophrenia. PMID:25522397

Acetaldehyde reinforcement and motor reactivity in newborns with or without a prenatal history of alcohol exposure

PubMed Central

March, Samanta M.; Culleré, Marcela E.; Abate, Paula; Hernández, José I.; Spear, Norman E.; Molina, Juan C.

2013-01-01

Animal models have shown that early ontogeny seems to be a period of enhanced affinity to ethanol. Interestingly, the catalase system that transforms ethanol (EtOH) into acetaldehyde (ACD) in the brain, is more active in the perinatal rat compared to adults. ACD has been found to share EtOH's behavioral effects. The general purpose of the present study was to assess ACD motivational and motor effects in newborn rats as a function of prenatal exposure to EtOH. Experiment 1 evaluated if ACD (0.35 μmol) or EtOH (0.02 μmol) supported appetitive conditioning in newborn pups prenatally exposed to EtOH. Experiment 2 tested if prenatal alcohol exposure modulated neonatal susceptibility to ACD's motor effects (ACD dose: 0, 0.35 and 0.52 μmol). Experiment 1 showed that EtOH and ACD supported appetitive conditioning independently of prenatal treatments. In Experiment 2, latency to display motor activity was altered only in neonates prenatally treated with water and challenged with the highest ACD dose. Prenatal EtOH experience results in tolerance to ACD's motor activity effects. These results show early susceptibility to ACD's appetitive effects and attenuation of motor effects as a function of prenatal history with EtOH, within a stage in development where brain ACD production seems higher than later in life. PMID:23785319

Transcriptional landscape of the prenatal human brain.

PubMed

Miller, Jeremy A; Ding, Song-Lin; Sunkin, Susan M; Smith, Kimberly A; Ng, Lydia; Szafer, Aaron; Ebbert, Amanda; Riley, Zackery L; Royall, Joshua J; Aiona, Kaylynn; Arnold, James M; Bennet, Crissa; Bertagnolli, Darren; Brouner, Krissy; Butler, Stephanie; Caldejon, Shiella; Carey, Anita; Cuhaciyan, Christine; Dalley, Rachel A; Dee, Nick; Dolbeare, Tim A; Facer, Benjamin A C; Feng, David; Fliss, Tim P; Gee, Garrett; Goldy, Jeff; Gourley, Lindsey; Gregor, Benjamin W; Gu, Guangyu; Howard, Robert E; Jochim, Jayson M; Kuan, Chihchau L; Lau, Christopher; Lee, Chang-Kyu; Lee, Felix; Lemon, Tracy A; Lesnar, Phil; McMurray, Bergen; Mastan, Naveed; Mosqueda, Nerick; Naluai-Cecchini, Theresa; Ngo, Nhan-Kiet; Nyhus, Julie; Oldre, Aaron; Olson, Eric; Parente, Jody; Parker, Patrick D; Parry, Sheana E; Stevens, Allison; Pletikos, Mihovil; Reding, Melissa; Roll, Kate; Sandman, David; Sarreal, Melaine; Shapouri, Sheila; Shapovalova, Nadiya V; Shen, Elaine H; Sjoquist, Nathan; Slaughterbeck, Clifford R; Smith, Michael; Sodt, Andy J; Williams, Derric; Zöllei, Lilla; Fischl, Bruce; Gerstein, Mark B; Geschwind, Daniel H; Glass, Ian A; Hawrylycz, Michael J; Hevner, Robert F; Huang, Hao; Jones, Allan R; Knowles, James A; Levitt, Pat; Phillips, John W; Sestan, Nenad; Wohnoutka, Paul; Dang, Chinh; Bernard, Amy; Hohmann, John G; Lein, Ed S

2014-04-10

The anatomical and functional architecture of the human brain is mainly determined by prenatal transcriptional processes. We describe an anatomically comprehensive atlas of the mid-gestational human brain, including de novo reference atlases, in situ hybridization, ultra-high-resolution magnetic resonance imaging (MRI) and microarray analysis on highly discrete laser-microdissected brain regions. In developing cerebral cortex, transcriptional differences are found between different proliferative and post-mitotic layers, wherein laminar signatures reflect cellular composition and developmental processes. Cytoarchitectural differences between human and mouse have molecular correlates, including species differences in gene expression in subplate, although surprisingly we find minimal differences between the inner and outer subventricular zones even though the outer zone is expanded in humans. Both germinal and post-mitotic cortical layers exhibit fronto-temporal gradients, with particular enrichment in the frontal lobe. Finally, many neurodevelopmental disorder and human-evolution-related genes show patterned expression, potentially underlying unique features of human cortical formation. These data provide a rich, freely-accessible resource for understanding human brain development.

Variations in brain defects result from cellular mosaicism in the activation of heat shock signalling.

PubMed

Ishii, Seiji; Torii, Masaaki; Son, Alexander I; Rajendraprasad, Meenu; Morozov, Yury M; Kawasawa, Yuka Imamura; Salzberg, Anna C; Fujimoto, Mitsuaki; Brennand, Kristen; Nakai, Akira; Mezger, Valerie; Gage, Fred H; Rakic, Pasko; Hashimoto-Torii, Kazue

2017-05-02

Repetitive prenatal exposure to identical or similar doses of harmful agents results in highly variable and unpredictable negative effects on fetal brain development ranging in severity from high to little or none. However, the molecular and cellular basis of this variability is not well understood. This study reports that exposure of mouse and human embryonic brain tissues to equal doses of harmful chemicals, such as ethanol, activates the primary stress response transcription factor heat shock factor 1 (Hsf1) in a highly variable and stochastic manner. While Hsf1 is essential for protecting the embryonic brain from environmental stress, excessive activation impairs critical developmental events such as neuronal migration. Our results suggest that mosaic activation of Hsf1 within the embryonic brain in response to prenatal environmental stress exposure may contribute to the resulting generation of phenotypic variations observed in complex congenital brain disorders.

Prenatal malnutrition and lead intake produce increased brain lipid peroxidation levels in newborn rats.

PubMed

Maldonado-Cedillo, Brenda Gabriela; Díaz-Ruiz, Araceli; Montes, Sergio; Galván-Arzate, Sonia; Ríos, Camilo; Beltrán-Campos, Vicente; Alcaraz-Zubeldia, Mireya; Díaz-Cintra, Sofia

2016-09-01

Prenatal malnutrition (M) and lead intoxication (Pb) have adverse effects on neuronal development; one of the cellular mechanisms involved is a disruption of the pro- and anti-oxidant balance. In the developing brain, the vulnerability of neuronal membrane phospholipids is variable across the different brain areas. This study assesses the susceptibility of different brain regions to damage by quitar tissue oxidative stress and lead quitar concentrations to determine whether the combined effect of prenatal malnutrition (M) and lead (Pb) intoxication is worse than the effect of either of them individually. M was induced with an isocaloric and hypoproteinic (6% casein) diet 4 weeks before pregnancy. Intoxication was produced with lead acetate in drinking water, from the first gestational day. Both the M and Pb models were continued until the day of birth. Four brain regions (hippocampus, cortex, striatum, and cerebellum) were dissected out to analyze the lipid peroxidation (LP) levels in four groups: normally nourished (C); normally nourished but intoxicated with lead (CPb); malnourished (M); and M intoxicated with lead (MPb). Dam body and brain weights were significantly reduced in the fourth gestational week in the MPb group. Their pups had significantly lower body weights than those in the C and CPb groups. The PbM group exhibited significant increases of lead concentration and LP in all areas evaluated. A potentiation effect of Pb and M on LP was found in the cerebellum. This study provides information on how environmental conditions (intoxication and malnutrition) during the intrauterine period could differentially affect the development of neuronal plasticity and, in consequence, alter adult brain functions such as learning and memory.

Viral infection, inflammation and schizophrenia

PubMed Central

Kneeland, Rachel E.; Fatemi, S. Hossein

2012-01-01

Schizophrenia is a severe neurodevelopmental disorder with genetic and environmental etiologies. Prenatal viral/bacterial infections and inflammation play major roles in the genesis of schizophrenia. In this review, we describe a viral model of schizophrenia tested in mice whereby the offspring of mice prenatally infected with influenza at E7, E9, E16, and E18 show significant gene, protein, and brain structural abnormalities postnatally. Similarly, we describe data on rodents exposed to bacterial infection or injected with a synthetic viral mimic (PolyI:C) also demonstrating brain structural and behavioral abnormalities. Moreover, human serologic data has been indispensible in supporting the viral theory of schizophrenia. Individuals born seropositive for bacterial and viral agents are at a significantly elevated risk of developing schizophrenia. While the specific mechanisms of prenatal viral/bacterial infections and brain disorder are unclear, recent findings suggest that the maternal inflammatory response may be associated with fetal brain injury. Preventive and therapeutic treatment options are also proposed. This review presents data related to epidemiology, human serology, and experimental animal models which support the viral model of schizophrenia. PMID:22349576

PRENATAL INFECTION, MATERNAL IMMUNE ACTIVATION, AND RISK FOR SCHIZOPHRENIA

PubMed Central

Canetta, Sarah E.; Brown, Alan S.

2013-01-01

A body of epidemiological literature has suggested an association between prenatal infection, subsequent maternal immune activation (MIA), and later risk of schizophrenia. These epidemiological studies have inspired preclinical research using rodent and primate models of prenatal infection and MIA. The findings from these preclinical studies indicate that severe infection and immune activation during pregnancy can negatively impact offspring brain development and impair adult behavior. This review aims to summarize the major epidemiological and preclinical findings addressing the connection between prenatal infection and immune activation and later risk of developing schizophrenia, as well as the more limited literature addressing the mechanisms by which this gestational insult might affect offspring neurodevelopment. Finally, directions for future research will be discussed. PMID:23956839

Early-life stress impacts the developing hippocampus and primes seizure occurrence: cellular, molecular, and epigenetic mechanisms

PubMed Central

Huang, Li-Tung

2014-01-01

Early-life stress includes prenatal, postnatal, and adolescence stress. Early-life stress can affect the development of the hypothalamic-pituitary-adrenal (HPA) axis, and cause cellular and molecular changes in the developing hippocampus that can result in neurobehavioral changes later in life. Epidemiological data implicate stress as a cause of seizures in both children and adults. Emerging evidence indicates that both prenatal and postnatal stress can prime the developing brain for seizures and an increase in epileptogenesis. This article reviews the cellular and molecular changes encountered during prenatal and postnatal stress, and assesses the possible link between these changes and increases in seizure occurrence and epileptogenesis in the developing hippocampus. In addititon, the priming effect of prenatal and postnatal stress for seizures and epileptogenesis is discussed. Finally, the roles of epigenetic modifications in hippocampus and HPA axis programming, early-life stress, and epilepsy are discussed. PMID:24574961

Building Your Baby's Brain: A Parent's Guide to the First Five Years = Como estimular el cerebro infantil: Una guia para padres de familia.

ERIC Educational Resources Information Center

Dodge, Diane Trister; Heroman, Cate

Noting that all parents can help their baby's brain to grow, this guide, in English- and Spanish-language versions, explores what science has learned about infant brain development and how parents and caregivers can influence cognitive development. Topics covered include: prenatal care, touching your baby, teaching about feelings and self-control,…

Absence of Prenatal Forebrain Defects in the Dp(16)1Yey/+ Mouse Model of Down Syndrome

PubMed Central

Goodliffe, Joseph W.; Olmos-Serrano, Jose Luis; Aziz, Nadine M.; Pennings, Jeroen L.A.; Guedj, Faycal; Bianchi, Diana W.

2016-01-01

Studies in humans with Down syndrome (DS) show that alterations in fetal brain development are followed by postnatal deficits in neuronal numbers, synaptic plasticity, and cognitive and motor function. This same progression is replicated in several mouse models of DS. Dp(16)1Yey/+ (hereafter called Dp16) is a recently developed mouse model of DS in which the entire region of mouse chromosome 16 that is homologous to human chromosome 21 has been triplicated. As such, Dp16 mice may more closely reproduce neurodevelopmental changes occurring in humans with DS. Here, we present the first comprehensive cellular and behavioral study of the Dp16 forebrain from embryonic to adult stages. Unexpectedly, our results demonstrate that Dp16 mice do not have prenatal brain defects previously reported in human fetal neocortex and in the developing forebrains of other mouse models, including microcephaly, reduced neurogenesis, and abnormal cell proliferation. Nevertheless, we found impairments in postnatal developmental milestones, fewer inhibitory forebrain neurons, and deficits in motor and cognitive performance in Dp16 mice. Therefore, although this new model does not express prenatal morphological phenotypes associated with DS, abnormalities in the postnatal period appear sufficient to produce significant cognitive deficits in Dp16. SIGNIFICANCE STATEMENT Down syndrome (DS) leads to intellectual disability. Several mouse models have increased our understanding of the neuropathology of DS and are currently being used to test therapeutic strategies. A new mouse model that contains an expanded number of DS-related genes, known as Dp(16)1Yey/+ (Dp16), has been generated recently. We sought to determine whether the extended triplication creates a better phenocopy of DS-related brain pathologies. We measured embryonic development, forebrain maturation, and perinatal/adult behavior and revealed an absence of prenatal phenotypes in Dp16 fetal brain, but specific cellular and behavioral deficits after the first 2 postnatal weeks. These results uncover important differences in prenatal phenotype between Dp16 animals and humans with DS and other DS mouse models. PMID:26961948

Behavioral consequences of developmental iron deficiency in infant rhesus monkeys

PubMed Central

Golub, Mari S.; Hogrefe, Casey E.; Germann, Stacey L.; Capitanio, John P.; Lozoff, Betsy

2006-01-01

Human studies have shown that iron deficiency and iron deficiency anemia in infants are associated with behavioral impairment, but the periods of brain development most susceptible to iron deficiency have not been established. In the present study, rhesus monkeys were deprived of iron by dietary iron restriction during prenatal (n = 14, 10 μg Fe/g diet) or early postnatal (n = 12, 1.5 mg Fe/L formula) brain development and compared to controls (n = 12, 100 μg Fe/g diet, 12 mg Fe/L formula) in behavioral evaluations conducted during the first four months of life in the nonhuman primate nursery. Iron deficiency anemia was detected in the pregnant dams in the third trimester and compromised iron status was seen in the prenatally iron-deprived infants at birth, but no iron deficiency was seen in either the prenatally or postnatally iron-deprived infants during the period of behavioral evaluation. Neither prenatal nor postnatal iron deprivation led to significant delays in growth, or gross or fine motor development. Prenatally deprived infants demonstrated a 20% reduced spontaneous activity level, lower inhibitory response to novel environments, and more changes from one behavior to another in weekly observation sessions. Postnatally deprived infants demonstrated poorer performance of an object concept task, and greater emotionality relative to controls. This study indicates that different syndromes of behavioral effects are associated with prenatal and postnatal iron deprivation in rhesus monkey infants and that these effects can occur in the absence of concurrent iron deficiency as reflected in hematological measures. PMID:16343844

Advanced Microscopic Imaging Methods to Investigate Cortical Development and the Etiology of Mental Retardation

ERIC Educational Resources Information Center

Haydar, Tarik F.

2005-01-01

Studies on human patients and animal models of disease have shown that disruptions in prenatal and early postnatal brain development are a root cause of mental retardation. Since proper brain development is achieved by a strict spatiotemporal control of neurogenesis, cell migration, and patterning of synapses, abnormalities in one or more of these…

Approaches to Learning: Supporting Brain Development for School Success

ERIC Educational Resources Information Center

Petersen, Sandra

2012-01-01

Prenatally and in infants and toddlers, the brain is being constructed as a foundation for all later learning. Positive early experiences contribute to the formation of a brain that is capable, early in infancy, of utilizing and strengthening the basic processes of learning. Throughout a lifetime, a person will repeatedly use these approaches to…

Prenatal diagnosis of brain abnormalities in Wolf-Hirschhorn (4p-) syndrome.

PubMed

De Keersmaecker, B; Albert, M; Hillion, Y; Ville, Y

2002-05-01

Although there have been occasional reports of prenatal diagnosis of this syndrome, most cases are diagnosed postnatally. The objective was to evaluate the presence of brain abnormalities in the prenatal diagnosis of Wolf-Hirschhorn syndrome. Prenatal ultrasound and MRI examination of the fetal brain were performed in a case of Wolf-Hirschhorn syndrome. A comprehensive review of Wolf-Hirschhorn syndrome reported between 1960 and 2000 in the literature was carried out. The late diagnosis of a growth-retarded fetus with normal amniotic fluid volume, normal Doppler and negative infection screen calls for a detailed examination of the fetal brain and heart. Multifocal white matter lesions and periventricular cystic changes, which are often attributed to perinatal distress, are possible prenatal features causing suspicion of 4p- syndrome in an IUGR fetus. Subtle abnormalities on ultrasound may suggest a chromosomal problem. Standard cytogenetics cannot always demonstrate a microdeletion. High-resolution banding and molecular analysis can help to confirm the diagnosis. Copyright 2002 John Wiley & Sons, Ltd.

PRENATAL STRESS AND RISK FOR AUTISM

PubMed Central

Kinney, Dennis K.; Munir, Kerim M.; Crowley, David J.; Miller, Andrea M.

2008-01-01

This paper reviews several converging lines of research that suggest that prenatal exposure to environmental stress may increase risk for Autistic Disorder (AD). We first discuss studies finding that prenatal exposure to stressful life events is associated with significantly increased risk of AD, as well as other disorders, such as schizophrenia and depression. We then review evidence from animal and human studies that prenatal stress can produce both (a) abnormal postnatal behaviors that resemble the defining symptoms of AD, and (b) other abnormalities that have elevated rates in AD, such as learning deficits, seizure disorders, perinatal complications, immunologic and neuroinflammatory anomalies, and low postnatal tolerance for stress. We explain why an etiologic role for prenatal stress is compatible with genetic factors in AD, and describe how stress can disrupt fetal brain development. Finally, we discuss implications for understanding underlying processes in AD, including potential gene-environment interactions, and developing new therapies and early prevention programs. PMID:18598714

Perinatal Psychoneuroimmunology: Protocols for the Study of Prenatal Stress and Its Effects on Fetal and Postnatal Brain Development.

PubMed

Frasch, Martin G; Baier, Carlos J; Antonelli, Marta C; Metz, Gerlinde A S

2018-01-01

Prenatal stress (PS) impacts early behavioral, neuroimmune, and cognitive development. Pregnant rat models have been very valuable in examining the mechanisms of such fetal programming. A newer pregnant sheep model of maternal stress offers the unique advantages of chronic in utero monitoring and manipulation. This chapter presents the techniques used to model single and multigenerational stress exposures and their pleiotropic effects on the offspring.

Developmental Implications for Prenatal Exposure to Environmental Toxins: Consumption Habits of Pregnant Women and Prenatal Nicotine Exposure in a Mouse Model

NASA Astrophysics Data System (ADS)

Santiago, Sarah Emily

This dissertation provides a discussion of the effects of maternal consumption of environmental toxins, and will hopefully contribute to the prevention and understanding of developmental disorders and physiological deficits. Developing systems are particularly susceptible to toxic insults, and small changes in utero can result in long-term deficits. Chapter one of this dissertation reviews the potential teratogenicity of nicotine, alcohol, caffeine, MeHg, PCBs, BPA, and tap water contaminants, so as to characterize the current body of literature detailing the effects and implications of prenatal exposure to toxins. In chapter two, research on maternal consumption habits is presented, with an emphasis on commonly-consumed, potentially-teratogenic substances. Occurrences and frequencies of maternal intake of healthy and unhealthy foods, beverages, and medications in a population of predominantly Hispanic women in Southern California were assessed using the Food, Beverage, and Medication Intake Questionnaire (FBMIQ). The described study reveals that a proportion of pregnant women consumed BPA, MeHg, caffeine, and alcohol at varied levels during pregnancy. The following chapters provide an in-depth analysis of the postnatal effects of a particular neuroteratogen, nicotine, which has been shown to impart various detrimental postnatal effects on exposed offspring. A CD-1 mouse model of prenatal nicotine exposure (PNE) was used to analyze aspects of the brain and neocortex that may underly some of the cognitive and behavioral phenotypes seen with PNE. Analyses included postnatal measurements of brain weight, brain widths and lengths, development of neocortical circuitry, and cortical thickness measures. Exposed mice were found to exhibit reduced brain and body weights at birth, a phenotype that recovered by postnatal day 10. No changes in neocortical circuity or thickness in sensory and motor areas were found. PNE also resulted in persistent behavioral effects, including increased anxiety and deficits in sensorimotor integration abilities, in six month old females. Such analyses describe immediate and long-lasting postnatal effects of prenatal nicotine exposure, underscoring the importance of abstaining from nicotine during pregnancy. Hopefully, the works detailed in this dissertation will provide a foundation upon which future researchers can build a better understanding of how prenatal exposures contribute to developmental deficits.

Memantine ameliorates autistic behavior, biochemistry & blood brain barrier impairments in rats.

PubMed

Kumar, Hariom; Sharma, Bhupesh

2016-06-01

Autism spectrum disorder (ASD) is a neurodevelopmental disorder, commonly characterized by altered social behavior, communication, biochemistry and pathological conditions. One percent of the worldwide population suffers from autism and males suffer more than females. NMDA receptors have the important role in neurodevelopment, neuropsychiatric and neurodegenerative disorders. This study has been designed to investigate the role of memantine, a NMDA receptor modulator, in prenatal valproic acid-induced autism in rats. Animals with prenatal valproic acid have shown the reduction in social interaction (three-chamber social behavior apparatus), spontaneous alternation (Y-Maze), exploratory activity (Hole board test), intestinal motility, serotonin levels (both in prefrontal cortex and ileum) and prefrontal cortex mitochondrial complex activity (complex I, II, IV). Furthermore, prenatal valproic acid-treated animals have shown an increase in locomotion (actophotometer), anxiety (elevated plus maze), brain oxidative stress (thiobarbituric acid reactive species, glutathione, catalase), nitrosative stress (nitrite/nitrate), inflammation (both in brain and ileum myeloperoxidase activity), calcium and blood-brain barrier permeability. Treatment with memantine has significantly attenuated prenatal valproic acid-induced reduction in social interaction, spontaneous alteration, exploratory activity intestinal motility, serotonin levels and prefrontal cortex mitochondrial complex activity. Furthermore, memantine has also attenuated the prenatal valproic acid-induced increase in locomotion, anxiety, brain oxidative and nitrosative stress, inflammation, calcium and blood-brain barrier permeability. Thus, it may be concluded that prenatal valproic acid has induced autistic behavior, biochemistry and blood-brain barrier impairment in animals, which were significantly attenuated by memantine. NMDA receptor modulators like memantine should be explored further for the therapeutic benefits in autism. Copyright © 2016 Elsevier Inc. All rights reserved.

A Neurobiological Model for the Effects of Early Brainstem Functioning on the Development of Behavior and Emotion Regulation in Infants: Implications for Prenatal and Perinatal Risk

ERIC Educational Resources Information Center

Geva, Ronny; Feldman, Ruth

2008-01-01

Neurobiological models propose an evolutionary, vertical-integrative perspective on emotion and behavior regulation, which postulates that regulatory functions are processed along three core brain systems: the brainstem, limbic, and cortical systems. To date, few developmental studies applied these models to research on prenatal and perinatal…

The renal effects of prenatal testosterone in rats.

PubMed

Bábíčková, Janka; Borbélyová, Veronika; Tóthová, L'ubomíra; Kubišová, Katarína; Janega, Pavol; Hodosy, Július; Celec, Peter

2015-05-01

Previous studies have shown that prenatal testosterone affects the development of not only reproductive organs but also the brain and even glucose metabolism. Whether prenatal testosterone influences the kidney development is largely unknown. We analyzed whether testosterone modulation during prenatal development would affect renal function and the number of nephrons in adult offspring. Pregnant rats were treated with olive oil, testosterone (2 mg/kg), the androgen receptor blocker flutamide (5 mg/kg) or testosterone plus flutamide via daily intramuscular injections from gestation day 14 until delivery. Renal histology and functional parameters were assessed in male and female adult offspring. Macerated kidneys were used for nephron counting. Prenatal testosterone administration increased proteinuria in male rats by 256%. A similar 134% effect in female rats was not statistically significant. This effect was prevented when flutamide was co-administered. In male rats prenatal testosterone increased blood urea nitrogen. In female rats flutamide increased creatinine clearance. In male rats prenatal testosterone and flutamide led to higher and lower, respectively, interstitial collagen deposition in adulthood. Prenatal testosterone induces proteinuria in adulthood. This effect is mediated via androgen receptor. Additional effects seem to be sex specific. Further studies should focus on the timing and dosing of testosterone as well as the applicability to human development. Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Prenatal isolated mild ventriculomegaly is associated with persistent ventricle enlargement at ages 1 and 2.

PubMed

Lyall, Amanda E; Woolson, Sandra; Wolfe, Honor M; Goldman, Barbara Davis; Reznick, J Steven; Hamer, Robert M; Lin, Weili; Styner, Martin; Gerig, Guido; Gilmore, John H

2012-08-01

Enlargement of the lateral ventricles is thought to originate from abnormal prenatal brain development and is associated with neurodevelopmental disorders. Fetal isolated mild ventriculomegaly (MVM) is associated with the enlargement of lateral ventricle volumes in the neonatal period and developmental delays in early childhood. However, little is known about postnatal brain development in these children. Twenty-eight children with fetal isolated MVM and 56 matched controls were followed at ages 1 and 2 years with structural imaging on a 3T Siemens scanner and assessment of cognitive development with the Mullen Scales of Early Learning. Lateral ventricle, total gray and white matter volumes, and Mullen cognitive composite scores and subscale scores were compared between groups. Compared to controls, children with prenatal isolated MVM had significantly larger lateral ventricle volumes at ages 1 and 2 years. Lateral ventricle volume at 1 and 2 years of age was significantly correlated with prenatal ventricle size. Enlargement of the lateral ventricles was associated with increased intracranial volumes and increased gray and white matter volumes. Children with MVM had Mullen composite scores similar to controls, although there was evidence of delay in fine motor and expressive language skills. Children with prenatal MVM have persistent enlargement of the lateral ventricles through the age of 2 years; this enlargement is associated with increased gray and white matter volumes and some evidence of delay in fine motor and expressive language development. Further study is needed to determine if enlarged lateral ventricles are associated with increased risk for neurodevelopmental disorders. Copyright © 2012 Elsevier Ltd. All rights reserved.

An atlas of the prenatal mouse brain: gestational day 14.

PubMed

Schambra, U B; Silver, J; Lauder, J M

1991-11-01

A prenatal atlas of the mouse brain is presently unavailable and is needed for studies of normal and abnormal development, using techniques including immunocytochemistry and in situ hybridization. This atlas will be especially useful for researchers studying transgenic and mutant mice. This collection of photomicrographs and corresponding drawings of Gestational Day (GD) 14 mouse brain sections is an excerpt from a larger atlas encompassing GD 12-18. In composing this atlas, available published studies on the developing rodent brain were consulted to aid in the detailed labeling of embryonic brain structures. C57Bl/6J mice were mated for 1 h, and the presence of a copulation plug was designated as GD 0. GD 14 embryos were perfused transcardially with 4% paraformaldehyde in 0.1 M phosphate buffer and embedded in paraffin. Serial sections (10 microns thickness) were cut through whole heads in sagittal and horizontal planes. They were stained with hematoxylin and eosin and photographed. Magnifications were 43X and 31X for the horizontal and sagittal sections, respectively. Photographs were traced and line drawings prepared using an Adobe Illustrator on a Macintosh computer.

Sex-dependent programming effects of prenatal glucocorticoid treatment on the developing serotonin system and stress-related behaviors in adulthood

PubMed Central

Hiroi, Ryoko; Carbone, David L.; Zuloaga, Damian G.; Bimonte-Nelson, Heather A.; Handa, Robert J.

2016-01-01

Prenatal stress and overexposure to glucocorticoids (GC) during development may be associated with an increased susceptibility to a number of diseases in adulthood including neuropsychiatric disorders, such as depression and anxiety. In animal models, prenatal overexposure to GC results in hyper-responsiveness to stress in adulthood, and females appear to be more susceptible than males. Here, we tested the hypothesis that overexposure to GC during fetal development has sex-specific programming effects on the brain, resulting in altered behaviors in adulthood. We examined the effects of dexamethasone (DEX; a synthetic GC) during prenatal life on stress-related behaviors in adulthood and on the tryptophan hydroxylase-2 (TpH2) gene expression in the adult dorsal raphe nucleus (DRN). TpH2 is the rate-limiting enzyme for serotonin (5-HT) synthesis and has been implicated in the etiology of human affective disorders. Timed-pregnant rats were treated with DEX from gestational days 18–22. Male and female offspring were sacrificed on the day of birth (postnatal day 0; P0), P7, and in adulthood (P80-84) and brains were examined for changes in TpH2 mRNA expression. Adult animals were also tested for anxiety- and depressive- like behaviors. In adulthood, prenatal DEX increased anxiety- and depressive- like behaviors selectively in females, as measured by decreased time spent in the center of the open field and increased time spent immobile in the forced swim test, respectively. Prenatal DEX increased TpH2 mRNA selectively in the female caudal DRN at P7, whereas it decreased TpH2 mRNA selectively in the female caudal DRN in adulthood. In animals challenged with restraint stress in adulthood, TpH2 mRNA was significantly lower in rostral DRN of prenatal DEX treated females compared to vehicle treated females. These data demonstrated that prenatal overexposure to GC alters the development of TpH2 gene expression and these alterations correlated with lasting behavioral changes found in adult female offspring. PMID:26844389

Brain Lateralization in Mice Is Associated with Zinc Signaling and Altered in Prenatal Zinc Deficient Mice That Display Features of Autism Spectrum Disorder

PubMed Central

Grabrucker, Stefanie; Haderspeck, Jasmin C.; Sauer, Ann Katrin; Kittelberger, Nadine; Asoglu, Harun; Abaei, Alireza; Rasche, Volker; Schön, Michael; Boeckers, Tobias M.; Grabrucker, Andreas M.

2018-01-01

A number of studies have reported changes in the hemispheric dominance in autism spectrum disorder (ASD) patients on functional, biochemical, and morphological level. Since asymmetry of the brain is also found in many vertebrates, we analyzed whether prenatal zinc deficient (PZD) mice, a mouse model with ASD like behavior, show alterations regarding brain lateralization on molecular and behavioral level. Our results show that hemisphere-specific expression of marker genes is abolished in PZD mice on mRNA and protein level. Using magnetic resonance imaging, we found an increased striatal volume in PZD mice with no change in total brain volume. Moreover, behavioral patterns associated with striatal lateralization are altered and the lateralized expression of dopamine receptor 1 (DR1) in the striatum of PZD mice was changed. We conclude that zinc signaling during brain development has a critical role in the establishment of brain lateralization in mice. PMID:29379414

Endogenous Opioids as Substrates for Ethanol Intake in the Neonatal Rat: The impact of prenatal ethanol exposure on the opioid family in the early postnatal period

PubMed Central

Bordner, Kelly; Deak, Terrence

2015-01-01

Background Despite considerable knowledge that prenatal ethanol exposure can lead to devastating effects on the developing fetus, alcohol consumption by pregnant women remains strikingly prevalent. Both clinical and basic research has suggested that, in addition to possible physical, behavioral, and cognitive deficits, gestational exposure to alcohol may lead to an increased risk for the development of later alcohol-related use and abuse disorders. The current work sought to characterize alterations in endogenous opioid signaling peptides and gene expression produced by ethanol exposure during the last days of gestation. Methods Experimental subjects were 4-, 8-, and 12-day old infant rats obtained from pregnant females that were given daily intubations of 0, 1, or 2 g/kg ethanol during the last few days of gestation (GD17-20). Using real-time RT-PCR, western blotting analysis, and enzyme immunoassays, we examined mRNA and protein for three opioid receptors and ligands in the nucleus accumbens, ventral tegmental area, and hypothalamus. Results Three main trends emerged - (1) mRNA for the majority of factors were found to upregulate across each of the three postnatal ages assessed, indicative of escalating ontogenetic expression of opioid-related genes; (2) prenatal ethanol significantly reduced many opioid peptides, suggesting a possible mechanism by which prenatal exposure can affect future responsiveness towards ethanol; and (3) the nucleus accumbens emerged as a key site for ethanol-dependent effects, suggesting a potential target for additional assessment and intervention towards understanding the ethanol's ability to program the developing brain. Conclusion We provide a global assessment of relatively long-term changes in both opioid gene expression and protein following exposure to only moderate amounts of ethanol during a relatively short window in the prenatal period. These results suggest that, while continuing to undergo ontogenetic changes, the infant brain is sensitive to prenatal ethanol exposure and that such exposure may lead to relatively long-lasting changes in the endogenous opioid system within the reward circuitry. These data indicate a potential mechanism and target for additional assessments of ethanol's ability to program the brain, affecting later responsiveness towards the drug. PMID:25662024

Graph theoretical modeling of baby brain networks.

PubMed

Zhao, Tengda; Xu, Yuehua; He, Yong

2018-06-12

The human brain undergoes explosive growth during the prenatal period and the first few postnatal years, establishing an early infrastructure for the later development of behaviors and cognitions. Revealing the developmental rules during the early phrase is essential in understanding the emergence of brain function and the origin of developmental disorders. The graph-theoretical network modeling in combination with multiple neuroimaging probes provides an important research framework to explore early development of the topological wiring and organizational paradigms of the brain. Here, we reviewed studies which employed neuroimaging and graph-theoretical modeling to investigate brain network development from approximately 20 gestational weeks to 2 years of age. Specifically, the structural and functional brain networks have evolved to highly efficient topological architectures in the early stage; where the structural network remains ahead and paves the way for the development of functional network. The brain network develops in a heterogeneous order, from primary to higher-order systems and from a tendency of network segregation to network integration in the prenatal and postnatal periods. The early brain network topologies show abilities in predicting certain cognitive and behavior performance in later life, and their impairments are likely to continue into childhood and even adulthood. These macroscopic topological changes are found to be associated with possible microstructural maturations, such as axonal growth and myelinations. Collectively, this review provides a detailed delineation of the early changes of the baby brains in the graph-theoretical modeling framework, which opens up a new avenue to understand the developmental principles of the connectome. Copyright © 2018. Published by Elsevier Inc.

Epigenetics of the Developing Brain

ERIC Educational Resources Information Center

Champagne, Frances A.

2015-01-01

Advances in understanding of the dynamic molecular interplay between DNA and its surrounding proteins suggest that epigenetic mechanisms are a critical link between early life experiences (e.g., prenatal stress, parent-offspring interactions) and long-term changes in brain and behavior. Although much of this evidence comes from animal studies,…

Effect of histochrome on the severity of delayed effects of prenatal exposure to lead nitrate in the rat brain.

PubMed

Ryzhavsky, B Ya; Lebedko, O A; Belolubskaya, D S

2008-08-01

The effects of histochrome on the severity of delayed effects of prenatal exposure to lead nitrate were studied in the rat brain. Exposure of pregnant rats to lead nitrate during activation of free radical oxidation reduced activity of NADH- and NADPH-dehydrogenases in cortical neurons of their 40-day-old progeny, reduced the number of neurons in a visual field, increased the number of pathologically modified neurons, and stimulated rat motor activity in an elevated plus-maze. Two intraperitoneal injections of histochrome in a dose of 0.1 mg/kg before and after lead citrate challenge attenuated the manifestations of oxidative stress and prevented the changes in some morphological and histochemical parameters of the brain, developing under the effect of lead exposure.

Fractalkine Attenuates Microglial Cell Activation Induced by Prenatal Stress

PubMed Central

Ślusarczyk, Joanna; Trojan, Ewa; Głombik, Katarzyna; Chamera, Katarzyna; Roman, Adam; Budziszewska, Bogusława; Basta-Kaim, Agnieszka

2016-01-01

The potential contribution of inflammation to the development of neuropsychiatric diseases has recently received substantial attention. In the brain, the main immune cells are the microglia. As they are the main source of inflammatory factors, it is plausible that the regulation of their activation may be a potential therapeutic target. Fractalkine (CX3CL1) and its receptor CX3CR1 play a crucial role in the control of the biological activity of the microglia. In the present study, using microglial cultures we investigated whether fractalkine is able to reverse changes in microglia caused by a prenatal stress procedure. Our study found that the microglia do not express fractalkine. Prenatal stress decreases the expression of the fractalkine receptor, which in turn is enhanced by the administration of exogenous fractalkine. Moreover, treatment with fractalkine diminishes the prenatal stress-induced overproduction of proinflammatory factors such as IL-1β, IL-18, IL-6, TNF-α, CCL2, or NO in the microglial cells derived from prenatally stressed newborns. In conclusion, the present results revealed that the pathological activation of microglia in prenatally stressed newborns may be attenuated by fractalkine administration. Therefore, understanding of the role of the CX3CL1-CX3CR1 system may help to elucidate the mechanisms underlying the neuron-microglia interaction and its role in pathological conditions in the brain. PMID:27239349

Postnatal Erythropoietin Mitigates Impaired Cerebral Cortical Development Following Subplate Loss from Prenatal Hypoxia–Ischemia

PubMed Central

Jantzie, Lauren L.; Corbett, Christopher J.; Firl, Daniel J.; Robinson, Shenandoah

2015-01-01

Preterm birth impacts brain development and leads to chronic deficits including cognitive delay, behavioral problems, and epilepsy. Premature loss of the subplate, a transient subcortical layer that guides development of the cerebral cortex and axonal refinement, has been implicated in these neurological disorders. Subplate neurons influence postnatal upregulation of the potassium chloride co-transporter KCC2 and maturation of γ-amino-butyric acid A receptor (GABAAR) subunits. We hypothesized that prenatal transient systemic hypoxia–ischemia (TSHI) in Sprague–Dawley rats that mimic brain injury from extreme prematurity in humans would cause premature subplate loss and affect cortical layer IV development. Further, we predicted that the neuroprotective agent erythropoietin (EPO) could attenuate the injury. Prenatal TSHI induced subplate neuronal loss via apoptosis. TSHI impaired cortical layer IV postnatal upregulation of KCC2 and GABAAR subunits, and postnatal EPO treatment mitigated the loss (n ≥ 8). To specifically address how subplate loss affects cortical development, we used in vitro mechanical subplate ablation in slice cultures (n ≥ 3) and found EPO treatment attenuates KCC2 loss. Together, these results show that subplate loss contributes to impaired cerebral development, and EPO treatment diminishes the damage. Limitation of premature subplate loss and the resultant impaired cortical development may minimize cerebral deficits suffered by extremely preterm infants. PMID:24722771

Toxic effects of prenatal exposure to alcohol, tobacco and other drugs.

PubMed

Scott-Goodwin, A C; Puerto, M; Moreno, I

2016-06-01

Tobacco, alcohol, cannabis and cocaine are the most consumed psychoactive drugs throughout the population. Prenatal exposure to these drugs could alter normal foetal development and could threaten future welfare. The main changes observed in prenatal exposure to tobacco are caused by nicotine and carbon monoxide, which can impede nutrient and oxygen exchange between mother and foetus, restricting foetal growth. Memory, learning processes, hearing and behaviour can also be affected. Alcohol may cause physical and cognitive alterations in prenatally exposed infants, fundamentally caused by altered NMDAR and GABAR activity. Tetrahydrocannabinol, the psychoactive compound of cannabis, is capable of activating CB1R, inducing connectivity deficits during the foetal brain development. This fact could be linked to behavioural and cognitive deficits. Many of the effects from prenatal cocaine exposure are caused by altered cell proliferation, migration, differentiation and dendritic growth processes. Cocaine causes long term behavioural and cognitive alterations and also affects the uteroplacental unit. Copyright © 2016 Elsevier Inc. All rights reserved.

Orbitofrontal cortex and drug use during adolescence: role of prenatal exposure to maternal smoking and BDNF genotype.

PubMed

Lotfipour, Shahrdad; Ferguson, Eamonn; Leonard, Gabriel; Perron, Michel; Pike, Bruce; Richer, Louis; Séguin, Jean R; Toro, Roberto; Veillette, Suzanne; Pausova, Zdenka; Paus, Tomás

2009-11-01

Prenatal exposure to maternal cigarette smoking (PEMCS) may affect brain development and behavior in adolescent offspring. To evaluate the involvement of the orbitofrontal cortex (OFC) in mediating the relationship between PEMCS and substance use. Cross-sectional analyses from the Saguenay Youth Study aimed at evaluating the effects of PEMCS on brain development and behavior among adolescents. Nonexposed adolescents were matched with adolescents exposed prenatally to cigarette smoking by maternal educational level. A French Canadian founder population of the Saguenay-Lac-Saint-Jean region of Quebec, Canada. The behavioral data set included 597 adolescents (275 sibships; 12-18 years of age), half of whom were exposed in utero to maternal cigarette smoking. Analysis of cortical thickness and genotyping were performed using available data from 314 adolescents. The likelihood of substance use was assessed with the Diagnostic Interview Schedule for Children Predictive Scales. The number of different drugs tried by each adolescent was assessed using another questionnaire. Thickness of the OFC was estimated from T1-weighted magnetic resonance images using FreeSurfer software. Prenatal exposure to maternal cigarette smoking is associated with an increased likelihood of substance use. Among exposed adolescents, the likelihood of drug experimentation correlates with the degree of OFC thinning. In nonexposed adolescents, the thickness of the OFC increases as a function of the number of drugs tried. The latter effect is moderated by a brain-derived neurotrophic factor (BDNF) genotype (Val66Met). We speculate that PEMCS interferes with the development of the OFC and, in turn, increases the likelihood of drug use among adolescents. In contrast, we suggest that, among nonexposed adolescents, drug experimentation influences the OFC thickness via processes akin to experience-induced plasticity.

Effects of prenatal methamphetamine exposure: a review of cognitive and neuroimaging studies.

PubMed

Kwiatkowski, Maja A; Roos, Annerine; Stein, Dan J; Thomas, Kevin G F; Donald, Kirsty

2014-06-01

Prenatal methamphetamine exposure (PME) is a significant problem in several parts of the world and poses important health risks for the developing fetus. Research on the short- and long-term outcomes of PME is scarce, however. Here, we summarize present knowledge on the cognitive and behavioral outcomes of PME, based on a review of the neuroimaging, neuropsychology, and neuroscience literature published in the past 15 years. Several studies have reported that the behavioral and cognitive sequelae of PME include broad deficits in the domains of attention, memory, and visual-motor integration. Knowledge regarding brain-behavior relationships is poor, however, in large part because imaging studies are rare. Hence, the effects of PME on developing neurocircuitry and brain architecture remain speculative, and are largely deductive. Some studies have implicated the dopamine-rich fronto-striatal pathways; however, cognitive deficits (e.g., impaired visual-motor integration) that should be associated with damage to those pathways are not manifested consistently across studies. We conclude by discussing challenges endemic to research on prenatal drug exposure, and argue that they may account for some of the inconsistencies in the extant research on PME. Studies confirming predicted brain-behavior relationships in PME, and exploring possible mechanisms underlying those relationships, are needed if neuroscience is to address the urgency of this growing public health problem.

Prenatal cocaine effects on brain structure in early infancy.

PubMed

Grewen, Karen; Burchinal, Margaret; Vachet, Clement; Gouttard, Sylvain; Gilmore, John H; Lin, Weili; Johns, Josephine; Elam, Mala; Gerig, Guido

2014-11-01

Prenatal cocaine exposure (PCE) is related to subtle deficits in cognitive and behavioral function in infancy, childhood and adolescence. Very little is known about the effects of in utero PCE on early brain development that may contribute to these impairments. The purpose of this study was to examine brain structural differences in infants with and without PCE. We conducted MRI scans of newborns (mean age = 5 weeks) to determine cocaine's impact on early brain structural development. Subjects were three groups of infants: 33 with PCE co-morbid with other drugs, 46 drug-free controls and 40 with prenatal exposure to other drugs (nicotine, alcohol, marijuana, opiates, SSRIs) but without cocaine. Infants with PCE exhibited lesser total gray matter (GM) volume and greater total cerebral spinal fluid (CSF) volume compared with controls and infants with non-cocaine drug exposure. Analysis of regional volumes revealed that whole brain GM differences were driven primarily by lesser GM in prefrontal and frontal brain regions in infants with PCE, while more posterior regions (parietal, occipital) did not differ across groups. Greater CSF volumes in PCE infants were present in prefrontal, frontal and parietal but not occipital regions. Greatest differences (GM reduction, CSF enlargement) in PCE infants were observed in dorsal prefrontal cortex. Results suggest that PCE is associated with structural deficits in neonatal cortical gray matter, specifically in prefrontal and frontal regions involved in executive function and inhibitory control. Longitudinal study is required to determine whether these early differences persist and contribute to deficits in cognitive functions and enhanced risk for drug abuse seen at school age and in later life. Copyright © 2014 Elsevier Inc. All rights reserved.

The evolution of Homo sapiens denisova and Homo sapiens neanderthalensis miRNA targeting genes in the prenatal and postnatal brain.

PubMed

Gunbin, Konstantin V; Afonnikov, Dmitry A; Kolchanov, Nikolay A; Derevianko, Anatoly P; Rogaev, Eugeny I

2015-01-01

As the evolution of miRNA genes has been found to be one of the important factors in formation of the modern type of man, we performed a comparative analysis of the evolution of miRNA genes in two archaic hominines, Homo sapiens neanderthalensis and Homo sapiens denisova, and elucidated the expression of their target mRNAs in bain. A comparative analysis of the genomes of primates, including species in the genus Homo, identified a group of miRNA genes having fixed substitutions with important implications for the evolution of Homo sapiens neanderthalensis and Homo sapiens denisova. The mRNAs targeted by miRNAs with mutations specific for Homo sapiens denisova exhibited enhanced expression during postnatal brain development in modern humans. By contrast, the expression of mRNAs targeted by miRNAs bearing variations specific for Homo sapiens neanderthalensis was shown to be enhanced in prenatal brain development. Our results highlight the importance of changes in miRNA gene sequences in the course of Homo sapiens denisova and Homo sapiens neanderthalensis evolution. The genetic alterations of miRNAs regulating the spatiotemporal expression of multiple genes in the prenatal and postnatal brain may contribute to the progressive evolution of brain function, which is consistent with the observations of fine technical and typological properties of tools and decorative items reported from archaeological Denisovan sites. The data also suggest that differential spatial-temporal regulation of gene products promoted by the subspecies-specific mutations in the miRNA genes might have occurred in the brains of Homo sapiens denisova and Homo sapiens neanderthalensis, potentially contributing to the cultural differences between these two archaic hominines.

The evolution of Homo sapiens denisova and Homo sapiens neanderthalensis miRNA targeting genes in the prenatal and postnatal brain

PubMed Central

2015-01-01

Background As the evolution of miRNA genes has been found to be one of the important factors in formation of the modern type of man, we performed a comparative analysis of the evolution of miRNA genes in two archaic hominines, Homo sapiens neanderthalensis and Homo sapiens denisova, and elucidated the expression of their target mRNAs in bain. Results A comparative analysis of the genomes of primates, including species in the genus Homo, identified a group of miRNA genes having fixed substitutions with important implications for the evolution of Homo sapiens neanderthalensis and Homo sapiens denisova. The mRNAs targeted by miRNAs with mutations specific for Homo sapiens denisova exhibited enhanced expression during postnatal brain development in modern humans. By contrast, the expression of mRNAs targeted by miRNAs bearing variations specific for Homo sapiens neanderthalensis was shown to be enhanced in prenatal brain development. Conclusions Our results highlight the importance of changes in miRNA gene sequences in the course of Homo sapiens denisova and Homo sapiens neanderthalensis evolution. The genetic alterations of miRNAs regulating the spatiotemporal expression of multiple genes in the prenatal and postnatal brain may contribute to the progressive evolution of brain function, which is consistent with the observations of fine technical and typological properties of tools and decorative items reported from archaeological Denisovan sites. The data also suggest that differential spatial-temporal regulation of gene products promoted by the subspecies-specific mutations in the miRNA genes might have occurred in the brains of Homo sapiens denisova and Homo sapiens neanderthalensis, potentially contributing to the cultural differences between these two archaic hominines. PMID:26693966

Prepartum and Postpartum Maternal Depressive Symptoms Are Related to Children's Brain Structure in Preschool.

PubMed

Lebel, Catherine; Walton, Matthew; Letourneau, Nicole; Giesbrecht, Gerald F; Kaplan, Bonnie J; Dewey, Deborah

2016-12-01

Perinatal maternal depression is a serious health concern with potential lasting negative consequences for children. Prenatal depression is associated with altered brain gray matter in children, though relations between postpartum depression and children's brains and the role of white matter are unclear. We studied 52 women who provided Edinburgh Postnatal Depression Scale (EPDS) scores during each trimester of pregnancy and at 3 months postpartum and their children who underwent magnetic resonance imaging at age 2.6 to 5.1 years. Associations between maternal depressive symptoms and magnetic resonance imaging measures of cortical thickness and white matter structure in the children were investigated. Women's second trimester EPDS scores negatively correlated with children's cortical thickness in right inferior frontal and middle temporal regions and with radial and mean diffusivity in white matter emanating from the inferior frontal area. Cortical thickness, but not diffusivity, correlations survived correction for postpartum EPDS. Postpartum EPDS scores negatively correlated with children's right superior frontal cortical thickness and with diffusivity in white matter originating from that region, even after correcting for prenatal EPDS. Higher maternal depressive symptoms prenatally and postpartum are associated with altered gray matter structure in children; the observed white matter correlations appear to be uniquely related to the postpartum period. The reduced thickness and diffusivity suggest premature brain development in children exposed to higher maternal perinatal depressive symptoms. These results highlight the importance of ensuring optimal women's mental health throughout the perinatal period, because maternal depressive symptoms appear to increase children's vulnerability to nonoptimal brain development. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

BNDF methylation in mothers and newborns is associated with maternal exposure to war trauma.

PubMed

Kertes, Darlene A; Bhatt, Samarth S; Kamin, Hayley S; Hughes, David A; Rodney, Nicole C; Mulligan, Connie J

2017-01-01

The BDNF gene codes for brain-derived neurotrophic factor, a growth factor involved in neural development, cell differentiation, and synaptic plasticity. Present in both the brain and periphery, BDNF plays critical roles throughout the body and is essential for placental and fetal development. Rodent studies show that early life stress, including prenatal stress, broadly alters BDNF methylation, with presumed changes in gene expression. No studies have assessed prenatal exposure to maternal traumatic stress and BDNF methylation in humans. This study examined associations of prenatal exposure to maternal stress and BDNF methylation at CpG sites across the BDNF gene. Among 24 mothers and newborns in the eastern Democratic Republic of Congo, a region with extreme conflict and violence to women, maternal experiences of war trauma and chronic stress were associated with BDNF methylation in umbilical cord blood, placental tissue, and maternal venous blood. Associations of maternal stress and BDNF methylation showed high tissue specificity. The majority of significant associations were observed in putative transcription factor binding regions. This is the first study in humans to examine BDNF methylation in relation to prenatal exposure to maternal stress in three tissues simultaneously and the first in any mammalian species to report associations of prenatal stress and BDNF methylation in placental tissue. The findings add to the growing body of evidence highlighting the importance of considering epigenetic effects when examining the impacts of trauma and stress, not only for adults but also for offspring exposed via effects transmitted before birth.

Linking prenatal experience to the emerging musical mind.

PubMed

Ullal-Gupta, Sangeeta; Vanden Bosch der Nederlanden, Christina M; Tichko, Parker; Lahav, Amir; Hannon, Erin E

2013-09-03

The musical brain is built over time through experience with a multitude of sounds in the auditory environment. However, learning the melodies, timbres, and rhythms unique to the music and language of one's culture begins already within the mother's womb during the third trimester of human development. We review evidence that the intrauterine auditory environment plays a key role in shaping later auditory development and musical preferences. We describe evidence that externally and internally generated sounds influence the developing fetus, and argue that such prenatal auditory experience may set the trajectory for the development of the musical mind.

Prenatal Immune Challenge Is an Environmental Risk Factor for Brain and Behavior Change Relevant to Schizophrenia: Evidence from MRI in a Mouse Model

PubMed Central

Wei, Ran; Hui, Edward S.; Feldon, Joram; Meyer, Urs; Chung, Sookja; Chua, Siew E.; Sham, Pak C.; Wu, Ed X.; McAlonan, Grainne M.

2009-01-01

Objectives Maternal infection during pregnancy increases risk of severe neuropsychiatric disorders, including schizophrenia and autism, in the offspring. The most consistent brain structural abnormality in patients with schizophrenia is enlarged lateral ventricles. However, it is unknown whether the aetiology of ventriculomegaly in schizophrenia involves prenatal infectious processes. The present experiments tested the hypothesis that there is a causal relationship between prenatal immune challenge and emergence of ventricular abnormalities relevant to schizophrenia in adulthood. Method We used an established mouse model of maternal immune activation (MIA) by the viral mimic PolyI:C administered in early (day 9) or late (day 17) gestation. Automated voxel-based morphometry mapped cerebrospinal fluid across the whole brain of adult offspring and the results were validated by manual region-of-interest tracing of the lateral ventricles. Parallel behavioral testing determined the existence of schizophrenia-related sensorimotor gating abnormalities. Results PolyI:C-induced immune activation, in early but not late gestation, caused marked enlargement of lateral ventricles in adulthood, without affecting total white and grey matter volumes. This early exposure disrupted sensorimotor gating, in the form of prepulse inhibition. Identical immune challenge in late gestation resulted in significant expansion of 4th ventricle volume but did not disrupt sensorimotor gating. Conclusions Our results provide the first experimental evidence that prenatal immune activation is an environmental risk factor for adult ventricular enlargement relevant to schizophrenia. The data indicate immune-associated environmental insults targeting early foetal development may have more extensive neurodevelopmental impact than identical insults in late prenatal life. PMID:19629183

Altered reward processing in adolescents with prenatal exposure to maternal cigarette smoking.

PubMed

Müller, Kathrin U; Mennigen, Eva; Ripke, Stephan; Banaschewski, Tobias; Barker, Gareth J; Büchel, Christian; Conrod, Patricia; Fauth-Bühler, Mira; Flor, Herta; Garavan, Hugh; Heinz, Andreas; Lawrence, Claire; Loth, Eva; Mann, Karl; Martinot, Jean-Luc; Pausova, Zdenka; Rietschel, Marcella; Ströhle, Andreas; Struve, Maren; Walaszek, Bernadeta; Schumann, Gunter; Paus, Tomáš; Smolka, Michael N

2013-08-01

Higher rates of substance use and dependence have been observed in the offspring of mothers who smoked during pregnancy. Animal studies indicate that prenatal exposure to nicotine alters the development of brain areas related to reward processing, which might be a risk factor for substance use and addiction later in life. However, no study has examined the effect of maternal smoking on the offspring's brain response during reward processing. To determine whether adolescents with prenatal exposure to maternal cigarette smoking differ from their nonexposed peers in the response of the ventral striatum to the anticipation or the receipt of a reward. An observational case-control study. Data were obtained from the IMAGEN Study, a European multicenter study of impulsivity, reinforcement sensitivity, and emotional reactivity in adolescents. The IMAGEN sample consists of 2078 healthy adolescents (age range, 13-15 years) recruited from March 1, 2008, through December 31, 2011, in local schools. We assessed an IMAGEN subsample of 177 adolescents with prenatal exposure to maternal cigarette smoking and 177 nonexposed peers (age range, 13-15 years) matched by sex, maternal educational level, and imaging site. Response to reward in the ventral striatum measured with functional magnetic resonance imaging. In prenatally exposed adolescents, we observed a weaker response in the ventral striatum during reward anticipation (left side, F = 14.98 [P < .001]; right side, F = 15.95 [P < .001]) compared with their nonexposed peers. No differences were found regarding the responsivity of the ventral striatum to the receipt of a reward (left side, F = 0.21 [P = .65]; right side, F = 0.47 [P = .49]). The weaker responsivity of the ventral striatum to reward anticipation in prenatally exposed adolescents may represent a risk factor for substance use and development of addiction later in life. This result highlights the need for education and preventive measures to reduce smoking during pregnancy. Future analyses should assess whether prenatally exposed adolescents develop an increased risk for substance use and addiction and which role the reported neuronal differences during reward anticipation plays in this development.

Acute encephalopathy with unilateral cortical-subcortical lesions in two unrelated kindreds treated with glucocorticoids prenatally for congenital adrenal hyperplasia due to 21-hydroxylase deficiency: established facts and novel insight.

PubMed

Grunt, Sebastian; Steinlin, Maja; Weisstanner, Christian; Schöning, Martin; Mullis, Primus E; Flück, Christa E

2013-01-01

Prenatal glucocorticoid (GC) treatment of the female fetus with 21-hydroxylase deficiency (21-OHD) may prevent genital virilization and androgen effects on the brain, but prenatal GC therapy is controversial because of possible adverse effects on fetal programming, the cardiovascular system and the brain. We report 2 patients with congenital adrenal hyperplasia (CAH) due to 21-OHD who were treated prenatally with dexamethasone, suffered from an acute encephalopathy and showed focal and multifocal cortical and subcortical diffusion restrictions in early MRI and signs of permanent alterations in the follow-up neuroimaging studies. Both patients recovered from the acute episode. Whereas the first patient recovered without neurological sequelae the second patient showed hemianopsia and spastic hemiplegia in the neurological follow-up examination. These are 2 children with CAH, both treated prenatally with high doses of dexamethasone to prevent virilization. The question arises whether prenatal high-dose GC treatment in patients with CAH might represent a risk factor for brain lesions in later life. Adverse effects/events should be reported systematically in patients undergoing prenatal GC treatment and long-term follow-up studies involving risk factors for cerebrovascular disease should be performed. Copyright © 2013 S. Karger AG, Basel.

Children with Heavy Prenatal Alcohol Exposure Experience Reduced Control of Isotonic Force

PubMed Central

Nguyen, Tanya T.; Levy, Susan S.; Riley, Edward P.; Thomas, Jennifer D.; Simmons, Roger W.

2013-01-01

Background Heavy prenatal alcohol exposure can result in diverse and extensive damage to the central nervous system, including the cerebellum, basal ganglia, and cerebral cortex. Given that these brain regions are involved in the generation and maintenance of motor force, we predicted that prenatal alcohol exposure would adversely affect this parameter of motor control. We previously reported that children with gestational alcohol exposure experience significant deficits in regulating isometric (i.e., constant) force. The purpose of the present study was to determine if these children exhibit similar deficits when producing isotonic (i.e., graded) force. Methods Children with heavy prenatal alcohol exposure and typically developing children completed a series of isotonic force contractions by exerting force on a load cell to match a criterion target force displayed on a computer monitor. Two levels of target force (5% or 20% of maximum voluntary force) were investigated in combination with varying levels of visual feedback. Results Compared to controls, children with heavy prenatal alcohol exposure generated isotonic force signals that were less accurate, more variable, and less complex in the time domain compared to control children. Specifically, interactions were found between group and visual feedback for response accuracy and signal complexity, suggesting that these children have greater difficulty altering their motor output when visual feedback is low. Conclusions These data suggest that prenatal alcohol exposure produces deficits in regulating isotonic force, which presumably result from alcohol-related damage to developing brain regions involved in motor control. These children will most likely experience difficulty performing basic motor skills and daily functional skills that require coordination of finely graded force. Therapeutic strategies designed to increase feedback and, consequently, facilitate visual-motor integration could improve isotonic force production in these children. PMID:22834891

Prevalence of prenatal brain abnormalities in fetuses with congenital heart disease: a systematic review.

PubMed

Khalil, A; Bennet, S; Thilaganathan, B; Paladini, D; Griffiths, P; Carvalho, J S

2016-09-01

Studies have shown an association between congenital heart defects (CHDs) and postnatal brain abnormalities and neurodevelopmental delay. Recent evidence suggests that some of these brain abnormalities are present before birth. The primary aim of this study was to perform a systematic review to quantify the prevalence of prenatal brain abnormalities in fetuses with CHDs. MEDLINE, EMBASE and The Cochrane Library were searched electronically. Reference lists within each article were hand-searched for additional reports. The outcomes observed included structural brain abnormalities (on magnetic resonance imaging (MRI)) and changes in brain volume (on MRI, three-dimensional (3D) volumetric MRI, 3D ultrasound and phase-contrast MRI), brain metabolism or maturation (on magnetic resonance spectroscopy and phase-contrast MRI) and brain blood flow (on Doppler ultrasound, phase-contrast MRI and 3D power Doppler ultrasound) in fetuses with CHDs. Cohort and case-control studies were included and cases of chromosomal or genetic abnormalities, case reports and editorials were excluded. Proportion meta-analysis was used for analysis. Between-study heterogeneity was assessed using the I(2) test. The search yielded 1943 citations, and 20 studies (n = 1175 cases) were included in the review. Three studies reported data on structural brain abnormalities, while data on altered brain volume, metabolism and blood flow were reported in seven, three and 14 studies, respectively. The three studies (221 cases) reporting on structural brain abnormalities were suitable for inclusion in a meta-analysis. The prevalence of prenatal structural brain abnormalities in fetuses with CHD was 28% (95% CI, 18-40%), with a similar prevalence (25% (95% CI, 14-39%)) when tetralogy of Fallot was considered alone. These abnormalities included ventriculomegaly (most common), agenesis of the corpus callosum, ventricular bleeding, increased extra-axial space, vermian hypoplasia, white-matter abnormalities and delayed brain development. Fetuses with CHD were more likely than those without CHD to have reduced brain volume, delay in brain maturation and altered brain circulation, most commonly in the form of reduced middle cerebral artery pulsatility index and cerebroplacental ratio. These changes were usually evident in the third trimester, but some studies reported them from as early as the second trimester. In the absence of known major aneuploidy or genetic syndromes, fetuses with CHD are at increased risk of brain abnormalities, which are discernible prenatally. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Effects of Moderate Prenatal Alcohol Exposure during Early Gestation in Rats on Inflammation across the Maternal-Fetal-Immune Interface and Later-Life Immune Function in the Offspring

PubMed Central

Terasaki, Laurne S.; Schwarz, Jaclyn M.

2017-01-01

During early brain development, microglial activation can negatively impact long-term neuroimmune and cognitive outcomes. It is well-known that significant alcohol exposure during early gestation results in a number of cognitive deficits associated with fetal alcohol spectrum disorders (FASD). Additionally, microglia are activated following high levels of alcohol exposure in rodent models of FASD. We sought to examine whether moderate prenatal alcohol exposure (70 mg/dL blood alcohol concentration) activates microglia in the fetal rat brain, and whether moderate fetal alcohol exposure has long-term negative consequences for immune function and cognitive function in the rat. We also measured inflammation within the placenta and maternal serum following moderate alcohol exposure to determine whether either could be a source of cytokine production in the fetus. One week of moderate prenatal alcohol exposure produced a sex-specific increase in cytokines and chemokines within the fetal brain. Cytokines were also increased within the placenta, regardless of the sex of the fetus, and independent of the low levels of circulating cytokines within the maternal serum. Adult offspring exposed to alcohol prenatally had exaggerated cytokine production in the brain and periphery in response to lipopolysaccharide (25 μg/kg), as well as significant memory deficits precipitated by this low-level of inflammation. Thus the immune system, including microglia, may be a key link to understanding the etiology of fetal alcohol spectrum disorders and other unexplored cognitive or health risks associated with even low levels of fetal alcohol exposure. PMID:27318824

White matter microstructural alterations in children with prenatal methamphetamine/polydrug exposure

PubMed Central

Colby, John B.; Smith, Lynne; O’Connor, Mary J.; Bookheimer, Susan Y.; Van Horn, John D.; Sowell, Elizabeth R.

2013-01-01

Little is known about the effects of prenatal methamphetamine exposure on white matter microstructure, and the impact of concomitant alcohol exposure. Diffusion tensor imaging and neurocognitive testing were performed on 21 children with prenatal methamphetamine exposure (age 9.8±1.8 years; 17 also exposed to alcohol), 19 children with prenatal alcohol but not methamphetamine exposure (age 10.8±2.3 years), and 27 typically-developing children (age 10.3±3.3 years). Whole-brain maps of fractional anisotropy (FA) were evaluated using tract-based spatial statistics. Relative to unexposed controls, children with prenatal methamphetamine exposure demonstrated higher FA mainly in left-sided regions, including the left anterior corona radiata (LCR) and corticospinal tract (P<0.05, corrected). Post-hoc analyses of these FA differences showed they likely result more from lower radial diffusivity (RD) than higher axial diffusivity (AD). Relative to the methamphetamine-exposed group, children with prenatal alcohol exposure showed lower FA in frontotemporal regions – particularly the right external capsule (P<0.05, corrected). We failed to find any group-performance interaction (on tests of executive functioning and visuomotor integration) in predicting FA; however, FA in the right external capsule was significantly associated with performance on a test of visuomotor integration across groups (P<0.05). This report demonstrates unique diffusion abnormalities in children with prenatal methamphetamine/polydrug exposure that are distinct from those associated with alcohol exposure alone, and illustrates that these abnormalities in brain microstructure are persistent into childhood and adolescence – long after the polydrug exposure in utero. PMID:23149028

Cerebro-oculo-facio-skeletal syndrome.

PubMed

Rafique, Muhammad; Zia, Shumaila

2012-09-01

Cerebro-oculo-facio-skeletal syndrome (COFSS) is a recessively inherited neurodegenerative disorder. We describe an 8 months old Saudi girl, a product of consanguineous parents with unremarkable pre-natal and postnatal history and birth weight 2 kg. She was having microcephaly, micrognathia, micro-ophthalmia, large low set ears, upper lip overhanging the lower lip and congenital contractures. Growth and development were severely retarded. MRI and MRS (magnetic resonance spectrometry) of brain displayed severe brain atrophy and hypo/demyelination of white matter. The relationship between COFSS and differential diagnoses, Cockayne syndrome (CS), Pena-Shokier phenotype (PSP) and Neu-Lexova syndrome (NLS) are discussed. Pre-natal diagnosis followed by appropriate management in time may be helpful to reduce its incidence in the community.

Developmental vitamin D deficiency and autism: Putative pathogenic mechanisms.

PubMed

Ali, Asad; Cui, Xiaoying; Eyles, Darryl

2018-01-01

Autism is a neurodevelopmental disease that presents in early life. Despite a considerable amount of studies, the neurobiological mechanisms underlying autism remain obscure. Both genetic and environmental factors are involved in the development of autism. Vitamin D deficiency is emerging as a consistently reported risk factor in children. One reason for the prominence now being given to this risk factor is that it would appear to interact with several other epidemiological risk factors for autism. Vitamin D is an active neurosteroid and plays crucial neuroprotective roles in the developing brain. It has important roles in cell proliferation and differentiation, immunomodulation, regulation of neurotransmission and steroidogenesis. Animal studies have suggested that transient prenatal vitamin D deficiency is associated with altered brain development. Here we review the potential neurobiological mechanisms linking prenatal vitamin D deficiency and autism and also discuss what future research targets must now be addressed. Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.

A molecular recognizing system of serotonin in rat fetal axonal growth cones: uptake and high affinity binding.

PubMed

Mercado, R; Hernández, J

1992-09-18

Axonal growth cone particles (AGCP) isolated from prenatal and postnatal rat brain had different high-affinity 5-HT uptake characteristics. In postnatal AGCP the uptake behaves as in the adult rat brain, while in the prenatal AGCP the uptake characteristics seem to be in a transitional stage. Also in prenatal AGCP we observed specific, high-affinity 5-HT binding sites. These results support the idea of an important role for 5-HT during axogenesis.

Effects of chronic prenatal MK-801 treatment on object recognition, cognitive flexibility, and drug-induced locomotor activity in juvenile and adult rat offspring.

PubMed

Gallant, S; Welch, L; Martone, P; Shalev, U

2017-06-15

Patients with schizophrenia display impaired cognitive functioning and increased sensitivity to psychomimetic drugs. The neurodevelopmental hypothesis of schizophrenia posits that disruption of the developing brain predisposes neural networks to lasting structural and functional abnormalities resulting in the emergence of such symptoms in adulthood. Given the critical role of the glutamatergic system in early brain development, we investigated whether chronic prenatal exposure to the glutamate NMDA receptor antagonist, MK-801, induces schizophrenia-like behavioural and neurochemical changes in juvenile and adult rats. Pregnant Long-Evans rats were administered saline or MK-801 (0.1mg/kg; s.c.) at gestation day 7-19. Object recognition memory and cognitive flexibility were assessed in the male offspring using a novel object preference task and a maze-based set-shifting procedure, respectively. Locomotor-activating effects of acute amphetamine and MK-801 were also assessed. Adult, but not juvenile, prenatally MK-801-treated rats failed to show novel object preference after a 90min delay, suggesting that object recognition memory may have been impaired. In addition, the set-shifting task revealed impaired acquisition of a new rule in adult prenatally MK-801-treated rats compared to controls. This deficit appeared to be driven by regression to the previously learned behaviour. There were no significant differences in drug-induced locomotor activity in juvenile offspring or in adult offspring following acute amphetamine challenges. Unexpectedly, MK-801-induced locomotor activity in adult prenatally MK-801-treated rats was lower compared to controls. Glutamate transmission dysfunction during early development may modify behavioural parameters in adulthood, though these parameters do not appear to model deficits observed in schizophrenia. Copyright © 2017 Elsevier B.V. All rights reserved.

The long-term effects of prenatal nicotine exposure on response inhibition: an fMRI study of young adults.

PubMed

Longo, Carmelinda A; Fried, Peter A; Cameron, Ian; Smith, Andra M

2013-01-01

The long-term effects of prenatal nicotine exposure on response inhibition were investigated in young adults using functional magnetic resonance imaging (fMRI). Participants were members of the Ottawa Prenatal Prospective Study, a longitudinal study that collected a unique body of information on participants from infancy to young adulthood, which allowed for the measurement of an unprecedented number of potentially confounding drug exposure variables including: prenatal marijuana and alcohol exposure and current marijuana, nicotine and alcohol use. Twelve young adults with prenatal nicotine exposure and 13 non-exposed controls performed a Go/No-Go task while fMRI blood oxygen level-dependent responses were examined. Despite similar task performance, participants prenatally exposed to nicotine demonstrated significantly greater activity in several regions of the brain that typically subserve response inhibition including the inferior frontal gyrus, the inferior parietal lobe, the thalamus and the basal ganglia. In addition, prenatally exposed participants showed greater activity in relatively large posterior regions of the cerebellum. These results suggest that prenatal nicotine exposure leads to altered neural functioning during response inhibition that continues into adulthood. This alteration is compensated for by recruitment of greater neural resources within regions of the brain that subserve response inhibition and the recruitment of additional brain regions to successfully perform the task. Response inhibition is an important executive functioning skill and impairments can impede functioning in much of everyday life. Thus, awareness of the continued long-term neural physiological effects of prenatal nicotine exposure is critical. Copyright © 2013 Elsevier Inc. All rights reserved.

Endogenous opioids as substrates for ethanol intake in the neonatal rat: The impact of prenatal ethanol exposure on the opioid family in the early postnatal period.

PubMed

Bordner, Kelly; Deak, Terrence

2015-09-01

Despite considerable knowledge that prenatal ethanol exposure can lead to devastating effects on the developing fetus, alcohol consumption by pregnant women remains strikingly prevalent. Both clinical and basic research has suggested that, in addition to possible physical, behavioral, and cognitive deficits, gestational exposure to alcohol may lead to an increased risk for the development of later alcohol-related use and abuse disorders. The current work sought to characterize alterations in endogenous opioid signaling peptides and gene expression produced by ethanol exposure during the last days of gestation. Experimental subjects were 4-, 8-, and 12-day old infant rats obtained from pregnant females that were given daily intubations of 0, 1, or 2g/kg ethanol during the last few days of gestation (GDs 17-20). Using real-time RT-PCR, western blotting analysis, and enzyme immunoassays, we examined mRNA and protein for three opioid receptors and ligands in the nucleus accumbens, ventral tegmental area, and hypothalamus. Three main trends emerged - (1) mRNA for the majority of factors was found to upregulate across each of the three postnatal ages assessed, indicative of escalating ontogenetic expression of opioid-related genes; (2) prenatal ethanol significantly reduced many opioid peptides, suggesting a possible mechanism by which prenatal exposure can affect future responsiveness towards ethanol; and (3) the nucleus accumbens emerged as a key site for ethanol-dependent effects, suggesting a potential target for additional assessment and intervention towards understanding the ethanol's ability to program the developing brain. We provide a global assessment of relatively long-term changes in both opioid gene expression and protein following exposure to only moderate amounts of ethanol during a relatively short window in the prenatal period. These results suggest that, while continuing to undergo ontogenetic changes, the infant brain is sensitive to prenatal ethanol exposure and that such exposure may lead to relatively long-lasting changes in the endogenous opioid system within the reward circuitry. These data indicate a potential mechanism and target for additional assessments of ethanol's ability to program the brain, affecting later responsiveness towards the drug. Copyright © 2015 Elsevier Inc. All rights reserved.

Prenatal Stress Disrupts Social Behavior, Cortical Neurobiology and Commensal Microbes in Adult Male Offspring.

PubMed

Gur, Tamar L; Palkar, Aditi Vadodkar; Rajasekera, Therese; Allen, Jacob; Niraula, Anzela; Godbout, Jonathan; Bailey, Michael T

2018-06-24

In utero and early neonatal exposure to maternal stress is linked with psychiatric disorders, and the underlying mechanisms are currently being elucidated. We used a prenatal stressor in pregnant mice to examine novel relationships between prenatal stress exposure, changes in the gut microbiome, and social behavior. Here, we show that males exposed to prenatal stress had a significant reduction in social behavior in adulthood, with increased corticosterone release following social interaction. Male offspring exposed to prenatal stress also had neuroinflammation, decreased oxytocin receptor, and decreased serotonin metabolism in their cortex in adulthood, which are linked to decreased social behavior. Finally, we found a significant difference in commensal microbes, including decreases in Bacteroides and Parabacteroides, in adult male offspring exposed to prenatal stress when compared to non-stressed controls. Our findings indicate that gestation is a critical window where maternal stress contributes to the development of aberrant social behaviors and alterations in cortical neurobiology, and that prenatal stress is sufficient to disrupt the male gut-brain axis into adulthood. Copyright © 2018. Published by Elsevier B.V.

Blockade of D1 dopaminergic transmission alleviates c-fos induction and cleaved caspase-3 expression in the brains of rat pups exposed to prenatal cocaine or perinatal asphyxia.

PubMed

Mitchell, Ellen S; Snyder-Keller, Abigail

2003-07-01

Hypoxia due to uterine vasoconstriction may be an important cause of the teratogenic consequences of prenatal cocaine exposure. We used immediate-early gene and cleaved caspase-3 expression patterns to monitor fetal brain regions affected by intrauterine hypoxia and prenatal cocaine and pretreatment with the D1 dopamine receptor antagonist SCH 23390 to determine how much of the induction observed was due to dopamine. Both cocaine binge (3 x 15 mg/kg) and perinatal asphyxia on embryonic day 22 (E22) induced c-fos in the striatum as well as in several other brain regions within 3 h after treatment. Maternal administration of a D1 dopamine antagonist, SCH 23390, before either cocaine or asphyxia exposure dramatically reduced the numbers of Fos-immunoreactive cells in the striatum as well as in many other brain regions. Cells immunoreactive for cleaved caspase-3 expression were more numerous after perinatal asphyxia than after prenatal cocaine exposure in most brain regions 24 h after C-section. SCH 23390 decreased caspase-3 expression after both birth insults, indicating that the increased incidence of apoptosis is related to overactivation of dopaminergic pathways.

Prenatal pharmacotherapy rescues brain development in a Down's syndrome mouse model.

PubMed

Guidi, Sandra; Stagni, Fiorenza; Bianchi, Patrizia; Ciani, Elisabetta; Giacomini, Andrea; De Franceschi, Marianna; Moldrich, Randal; Kurniawan, Nyoman; Mardon, Karine; Giuliani, Alessandro; Calzà, Laura; Bartesaghi, Renata

2014-02-01

Intellectual impairment is a strongly disabling feature of Down's syndrome, a genetic disorder of high prevalence (1 in 700-1000 live births) caused by trisomy of chromosome 21. Accumulating evidence shows that widespread neurogenesis impairment is a major determinant of abnormal brain development and, hence, of intellectual disability in Down's syndrome. This defect is worsened by dendritic hypotrophy and connectivity alterations. Most of the pharmacotherapies designed to improve cognitive performance in Down's syndrome have been attempted in Down's syndrome mouse models during adult life stages. Yet, as neurogenesis is mainly a prenatal event, treatments aimed at correcting neurogenesis failure in Down's syndrome should be administered during pregnancy. Correction of neurogenesis during the very first stages of brain formation may, in turn, rescue improper brain wiring. The aim of our study was to establish whether it is possible to rescue the neurodevelopmental alterations that characterize the trisomic brain with a prenatal pharmacotherapy with fluoxetine, a drug that is able to restore post-natal hippocampal neurogenesis in the Ts65Dn mouse model of Down's syndrome. Pregnant Ts65Dn females were treated with fluoxetine from embryonic Day 10 until delivery. On post-natal Day 2 the pups received an injection of 5-bromo-2-deoxyuridine and were sacrificed after either 2 h or after 43 days (at the age of 45 days). Untreated 2-day-old Ts65Dn mice exhibited a severe neurogenesis reduction and hypocellularity throughout the forebrain (subventricular zone, subgranular zone, neocortex, striatum, thalamus and hypothalamus), midbrain (mesencephalon) and hindbrain (cerebellum and pons). In embryonically treated 2-day-old Ts65Dn mice, precursor proliferation and cellularity were fully restored throughout all brain regions. The recovery of proliferation potency and cellularity was still present in treated Ts65Dn 45-day-old mice. Moreover, embryonic treatment restored dendritic development, cortical and hippocampal synapse development and brain volume. Importantly, these effects were accompanied by recovery of behavioural performance. The cognitive deficits caused by Down's syndrome have long been considered irreversible. The current study provides novel evidence that a pharmacotherapy with fluoxetine during embryonic development is able to fully rescue the abnormal brain development and behavioural deficits that are typical of Down's syndrome. If the positive effects of fluoxetine on the brain of a mouse model are replicated in foetuses with Down's syndrome, fluoxetine, a drug usable in humans, may represent a breakthrough for the therapy of intellectual disability in Down's syndrome.

Brain glucose metabolism in an animal model of depression.

PubMed

Detka, J; Kurek, A; Kucharczyk, M; Głombik, K; Basta-Kaim, A; Kubera, M; Lasoń, W; Budziszewska, B

2015-06-04

An increasing number of data support the involvement of disturbances in glucose metabolism in the pathogenesis of depression. We previously reported that glucose and glycogen concentrations in brain structures important for depression are higher in a prenatal stress model of depression when compared with control animals. A marked rise in the concentrations of these carbohydrates and glucose transporters were evident in prenatally stressed animals subjected to acute stress and glucose loading in adulthood. To determine whether elevated levels of brain glucose are associated with a change in its metabolism in this model, we assessed key glycolytic enzymes (hexokinase, phosphofructokinase and pyruvate kinase), products of glycolysis, i.e., pyruvate and lactate, and two selected enzymes of the tricarboxylic acid cycle (pyruvate dehydrogenase and α-ketoglutarate dehydrogenase) in the hippocampus and frontal cortex. Additionally, we assessed glucose-6-phosphate dehydrogenase activity, a key enzyme in the pentose phosphate pathway (PPP). Prenatal stress increased the levels of phosphofructokinase, an important glycolytic enzyme, in the hippocampus and frontal cortex. However, prenatal stress had no effect on hexokinase or pyruvate kinase levels. The lactate concentration was elevated in prenatally stressed rats in the frontal cortex, and pyruvate levels remained unchanged. Among the tricarboxylic acid cycle enzymes, prenatal stress decreased the level of pyruvate dehydrogenase in the hippocampus, but it had no effect on α-ketoglutarate dehydrogenase. Like in the case of glucose and its transporters, also in the present study, differences in markers of glucose metabolism between control animals and those subjected to prenatal stress were not observed under basal conditions but in rats subjected to acute stress and glucose load in adulthood. Glucose-6-phosphate dehydrogenase activity was not reduced by prenatal stress but was found to be even higher in animals exposed to all experimental conditions, i.e., prenatal stress, acute stress, and glucose administration. Our data indicate that glycolysis is increased and the Krebs cycle is decreased in the brain of a prenatal stress animal model of depression. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

MicroCT and microMRI imaging of a prenatal mouse model of increased brain size

NASA Astrophysics Data System (ADS)

López, Elisabeth K. N.; Stock, Stuart R.; Taketo, Makoto M.; Chenn, Anjen; Ravosa, Matthew J.

2008-08-01

There are surprisingly few experimental models of neural growth and cranial integration. This and the dearth of information regarding fetal brain development detract from a mechanistic understanding of cranial integration and its relevance to the patterning of skull form, specifically the role of encephalization on basicranial flexion. To address this shortcoming, our research uses transgenic mice expressing a stabilized form of β-catenin to isolate the effects of relative brain size on craniofacial development. These mice develop highly enlarged brains due to an increase in neural precursors, and differences between transgenic and wild-type mice are predicted to result solely from variation in brain size. Comparisons of wild-type and transgenic mice at several prenatal ages were performed using microCT (Scanco Medical MicroCT 40) and microMRI (Avance 600 WB MR spectrometer). Statistical analyses show that the larger brain of the transgenic mice is associated with a larger neurocranium and an altered basicranial morphology. However, body size and postcranial ossification do not seem to be affected by the transgene. Comparisons of the rate of postcranial and cranial ossification using microCT also point to an unexpected effect of neural growth on skull development: increased fetal encephalization may result in a compensatory decrease in the level of cranial ossification. Therefore, if other life history factors are held constant, the ontogeny of a metabolically costly structure such as a brain may occur at the expense of other cranial structures. These analyses indicate the benefits of a multifactorial approach to cranial integration using a mouse model.

Antisera against Neisseria gonorrhoeae cross-react with specific brain proteins of the common marmoset monkey and other nonhuman primate species.

PubMed

Reuss, Bernhard; Asif, Abdul R; Almamy, Abdullah; Schwerk, Christian; Schroten, Horst; Ishikawa, Hiroshi; Drummer, Charis; Behr, Rüdiger

2016-12-15

Prenatal maternal infections with Neisseria gonorrhoeae (NG) correlate with an increased lifetime probability for the offspring to develop psychosis. We could previously demonstrate that in human choroid plexus papilloma cells, anti-NG antibodies (α-NG) bind to mitochondrial proteins HSP60 and ATPB, and interfere with cellular energy metabolism. To assess the in vivo relevance for this, especially during prenatal neural development, we investigated here interactions of NG-specific antisera (α-NG1, α-NG2) with brain, choroid plexus and other non-neural tissues in pre- and perinatal samples of the nonhuman primate (NHP) Callithrix jacchus (CJ), a NHP model for preclinical research. In histological sections at embryonic day E75, immunohistochemistry revealed α-NG1 and -2-staining in choroid plexus, ganglionic hill, optic cup, heart, and liver. Within the cells, organelle-like structures were labeled, which could be identified by immunohistochemical double-labeling as mitochondria. Both one- and two-dimensional Western blot analysis revealed tissue specific patterns of α-NG1 immunoreactive bands and spots, respectively, which were subsequently characterized by mass spectrometry. Thereby we could confirm the interactions of α-NG1 with human HSP60 and ATPB also in CJ choroid plexus and liver. Even more important, in the CJ brain, several new targets, including NCAM1, CRMP2, and SYT1, were identified, which by unrelated studies have been previously suggested to correlate with an increased schizophrenia risk. These findings support the idea that the marmoset monkey is a useful NHP model to investigate the role of maternal bacterial infections during prenatal brain development, and thereby might improve the understanding of this important aspect of schizophrenia pathology. Copyright © 2016 Elsevier B.V. All rights reserved.

The role of gangliosides in brain development and the potential benefits of perinatal supplementation.

PubMed

Ryan, Jennifer M; Rice, Gregory E; Mitchell, Murray D

2013-11-01

The maternal diet provides critical nutrients that can influence fetal and infant brain development and function. This review highlights the potential benefits of maternal dietary ganglioside supplementation on fetal and infant brain development. English-language systematic reviews, preclinical studies, and clinical studies were obtained through searches on PubMed. Reports were selected if they included benefits and harms of maternal ganglioside supplementation during pregnancy or ganglioside-supplemented formula after pregnancy. The potential benefits of ganglioside supplementation were explored by investigating the following: (1) their role in neural development, (2) their therapeutic use in neural injury and disease, (3) their presence in human breast milk, and (4) their use as a dietary supplement during or after pregnancy. Preclinical studies indicate that ganglioside supplementation at high doses (1% of total dietary intake) can significantly increase cognitive development and body weight when given prenatally. However, lower ganglioside supplementation doses have no beneficial cognitive effects, even when given throughout pregnancy and lactation. In human clinical trials, infants given formula supplemented with gangliosides showed increased cognitive development and an increase in ganglioside content. Ganglioside supplementation may promote brain development and function in offspring when administered at the optimum dosage. We propose that prenatal maternal dietary supplementation with gangliosides throughout pregnancy may promote greater long-term effects on brain development and function. Before this concept can be encouraged in preconception clinics, future research and clinical trials are needed to confirm the ability of dietary gangliosides to improve cognitive development, but available results already encourage this area of research. © 2013.

Postnatal exposure to methyl mercury from fish consumption: a review and new data from the Seychelles Child Development Study.

PubMed

Myers, Gary J; Thurston, Sally W; Pearson, Alexander T; Davidson, Philip W; Cox, Christopher; Shamlaye, Conrad F; Cernichiari, Elsa; Clarkson, Thomas W

2009-05-01

Fish is an important source of nutrition worldwide. Fish contain both the neurotoxin methyl mercury (MeHg) and nutrients important for brain development. The developing brain appears to be most sensitive to MeHg toxicity and mothers who consume fish during pregnancy expose their fetus prenatally. Although brain development is most dramatic during fetal life, it continues for years postnatally and additional exposure can occur when a mother breast feeds or the child consumes fish. This raises the possibility that MeHg might influence brain development after birth and thus adversely affect children's developmental outcomes. We reviewed postnatal MeHg exposure and the associations that have been published to determine the issues associated with it and then carried out a series of analyses involving alternative metrics of postnatal MeHg exposure in the Seychelles Child Development Study (SCDS) Main Cohort. The SCDS is a prospective longitudinal evaluation of prenatal MeHg exposure from fish consumption. The Main Cohort includes 779 subjects on whom recent postnatal exposure data were collected at the 6-, 19-, 29-, 66-, and 107-month evaluations. We examined the association of recent postnatal MeHg exposure with multiple 66- and 107-month outcomes and then used three types of alternative postnatal exposure metrics to examine their association with the children's intelligence quotient (IQ) at 107 months of age. Recent postnatal exposure at 107 months of age was adversely associated with four endpoints, three in females only. One alternative postnatal metric was beneficially associated with 9-year IQ in males only. We found several associations between postnatal MeHg biomarkers and children's developmental endpoints. However, as has been the case with prenatal MeHg exposure in the SCDS Main Cohort study, no consistent pattern of associations emerged to support a causal relationship.

Differentiating the Effects of Familial Risk for Alcohol Dependence and Prenatal Exposure to Alcohol on Offspring Brain Morphology.

PubMed

Sharma, Vinod K; Hill, Shirley Y

2017-02-01

Offspring with a family history of alcohol dependence (AD) have been shown to have altered structural and functional integrity of corticolimbic brain structures. Similarly, prenatal exposure to alcohol is associated with a variety of structural and functional brain changes. The goal of this study was to differentiate the brain gray matter volumetric differences associated with familial risk and prenatal exposure to alcohol among offspring while controlling for lifetime personal exposures to alcohol and drugs. A total of 52 high-risk (HR) offspring from maternal multiplex families with a high proportion of AD were studied along with 55 low-risk (LR) offspring. Voxel-based morphometric analysis was performed using statistical parametric mapping (SPM8) software using 3T structural images from these offspring to identify gray matter volume differences associated with familial risk and prenatal exposure. Significant familial risk group differences were seen with HR males showing reduced volume of the left inferior temporal, left fusiform, and left and right insula regions relative to LR males, controlling for prenatal exposure to alcohol drugs and cigarettes. HR females showed a reduction in the right fusiform but also showed a reduction in volume in portions of the cerebellum (left crus I and left lobe 8). Prenatal alcohol exposure effects, assessed within the familial HR group, was associated with reduced right middle cingulum and left middle temporal volume. Even low exposure resulting from mothers drinking in amounts less than the median of those who drank (53 drinks or less over the course of the pregnancy) showed a reduction in volume in the right anterior cingulum and in the left cerebellum (lobes 4 and 5). Familial risk for AD and prenatal exposure to alcohol and other drugs show independent effects on brain morphology. Copyright © 2017 by the Research Society on Alcoholism.

Increased risk of developing schizophrenia in animals exposed to cigarette smoke during the gestational period.

PubMed

Zugno, Alexandra I; Oliveira, Mariana B; Mastella, Gustavo A; Heylmann, Alexandra S A; Canever, Lara; Pacheco, Felipe D; Damazio, Louyse S; Citadin, Sullivan A; de Lucca, Luiz Antonio; Simões, Lutiana Roque; Malgarin, Fernanda; Budni, Josiane; Barichello, Tatiana; Schuck, Patricia F; Quevedo, João

2017-04-03

Cigarette smoking during the prenatal period has been investigated as a causative factor of obstetric abnormalities, which lead to cognitive and behavioural changes associated with schizophrenia. The aim of this study was to investigate behaviour and AChE activity in brain structures in adult rats exposed to cigarette smoke during the prenatal period. Pregnant rats were divided into non-PCSE (non-prenatal cigarette smoke exposure) and PCSE (prenatal cigarette smoke exposure) groups. On post-natal day 60, the rats received saline or ketamine for 7days and were subjected to behavioural tasks. In the locomotor activity task, the non-PCSE+ketamine and PCSE+ketamine groups exhibited increased locomotor activity compared with the saline group. In the social interaction task, the non-PCSE+ketamine and PCSE+ketamine groups exhibited an increased latency compared with the control groups. However, the PCSE+ketamine group exhibited a decreased latency compared with the non-PCSE+ketamine group, which indicates that the cigarette exposure appeared to decrease, the social deficits generated by ketamine. In the inhibitory avoidance task, the non-PCSE+ketamine, PCSE, and PCSE+ketamine groups exhibited impairments in working memory, short-term memory, and long-term memory. In the pre-pulse inhibition (PPI) test, cigarette smoke associated with ketamine resulted in impaired PPI in 3 pre-pulse (PP) intensity groups compared with the control groups. In the biochemical analysis, the AChE activity in brain structures increased in the ketamine groups; however, the PCSE+ketamine group exhibited an exacerbated effect in all brain structures. The present study indicates that exposure to cigarette smoke during the prenatal period may affect behaviour and cerebral cholinergic structures during adulthood. Copyright © 2017 Elsevier Inc. All rights reserved.

Prenatal nicotine exposure enhances Cx43 and Panx1 unopposed channel activity in brain cells of adult offspring mice fed a high-fat/cholesterol diet

PubMed Central

Orellana, Juan A.; Busso, Dolores; Ramírez, Gigliola; Campos, Marlys; Rigotti, Attilio; Eugenín, Jaime; von Bernhardi, Rommy

2014-01-01

Nicotine, the most important neuroteratogen of tobacco smoke, can reproduce brain and cognitive disturbances per se when administered prenatally. However, it is still unknown if paracrine signaling among brain cells participates in prenatal nicotine-induced brain impairment of adult offspring. Paracrine signaling is partly mediated by unopposed channels formed by connexins hemichannels (HCs) and pannexins serving as aqueous pores permeable to ions and small signaling molecules, allowing exchange between the intra- and extracellular milieus. Our aim was to address whether prenatal nicotine exposure changes the activity of those channels in adult mice offspring under control conditions or subjected to a second challenge during young ages: high-fat/cholesterol (HFC) diet. To induce prenatal exposure to nicotine, osmotic minipumps were implanted in CF1 pregnant mice at gestational day 5 to deliver nicotine bitartrate or saline (control) solutions. After weaning, offspring of nicotine-treated or untreated pregnant mice were fed ad libitum with chow or HFC diets for 8 weeks. The functional state of connexin 43 (Cx43) and pannexin 1 (Panx1) unopposed channels was evaluated by dye uptake experiments in hippocampal slices from 11-week-old mice. We found that prenatal nicotine increased the opening of Cx43 HCs in astrocytes, and Panx1 channels in microglia and neurons only if offspring mice were fed with HFC diet. Blockade of inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX2) and prostaglandin E receptor 1 (EP1), ionotropic ATP receptor type 7 (P2X7) and NMDA receptors, showed differential inhibition of prenatal nicotine-induced channel opening in glial cells and neurons. Importantly, inhibition of the above mentioned enzymes and receptors, or blockade of Cx43 and Panx1 unopposed channels greatly reduced adenosine triphosphate (ATP) and glutamate release from hippocampal slices of prenatally nicotine-exposed offspring. We propose that unregulated gliotransmitter release through Cx43 and Panx1 unopposed channels may participate in brain alterations observed in offspring of mothers exposed to tobacco smoke during pregnancy. PMID:25520621

Prenatal Nutrition and Later Education

ERIC Educational Resources Information Center

Evans, T. N.

1972-01-01

Text of an affidavit in the case, Kennedy v. Detroit Board of Education. Reports on a study which established that prenatal nutrition is directly related to brain size and volume determined at 48 hours of infancy and at eight months of age. Pinpoints the relationship between inadequate nutrition in pregnancy, infant brain size, and intellectual…

Low 2D:4D values are associated with video game addiction.

PubMed

Kornhuber, Johannes; Zenses, Eva-Maria; Lenz, Bernd; Stoessel, Christina; Bouna-Pyrrou, Polyxeni; Rehbein, Florian; Kliem, Sören; Mößle, Thomas

2013-01-01

Androgen-dependent signaling regulates the growth of the fingers on the human hand during embryogenesis. A higher androgen load results in lower 2D:4D (second digit to fourth digit) ratio values. Prenatal androgen exposure also impacts brain development. 2D:4D values are usually lower in males and are viewed as a proxy of male brain organization. Here, we quantified video gaming behavior in young males. We found lower mean 2D:4D values in subjects who were classified according to the CSAS-II as having at-risk/addicted behavior (n = 27) compared with individuals with unproblematic video gaming behavior (n = 27). Thus, prenatal androgen exposure and a hyper-male brain organization, as represented by low 2D:4D values, are associated with problematic video gaming behavior. These results may be used to improve the diagnosis, prediction, and prevention of video game addiction.

Low 2D:4D Values Are Associated with Video Game Addiction

PubMed Central

Kornhuber, Johannes; Zenses, Eva-Maria; Lenz, Bernd; Stoessel, Christina; Bouna-Pyrrou, Polyxeni; Rehbein, Florian; Kliem, Sören; Mößle, Thomas

2013-01-01

Androgen-dependent signaling regulates the growth of the fingers on the human hand during embryogenesis. A higher androgen load results in lower 2D:4D (second digit to fourth digit) ratio values. Prenatal androgen exposure also impacts brain development. 2D:4D values are usually lower in males and are viewed as a proxy of male brain organization. Here, we quantified video gaming behavior in young males. We found lower mean 2D:4D values in subjects who were classified according to the CSAS-II as having at-risk/addicted behavior (n = 27) compared with individuals with unproblematic video gaming behavior (n = 27). Thus, prenatal androgen exposure and a hyper-male brain organization, as represented by low 2D:4D values, are associated with problematic video gaming behavior. These results may be used to improve the diagnosis, prediction, and prevention of video game addiction. PMID:24236143

Lifespan analysis of brain development, gene expression and behavioral phenotypes in the Ts1Cje, Ts65Dn and Dp(16)1/Yey mouse models of Down syndrome.

PubMed

Aziz, Nadine M; Guedj, Faycal; Pennings, Jeroen L A; Olmos-Serrano, Jose Luis; Siegel, Ashley; Haydar, Tarik F; Bianchi, Diana W

2018-06-12

Down syndrome (DS) results from triplication of human chromosome 21. Neuropathological hallmarks of DS include atypical central nervous system development that manifests prenatally and extends throughout life. As a result, individuals with DS exhibit cognitive and motor deficits, and have delays in achieving developmental milestones. To determine whether different mouse models of DS recapitulate the human prenatal and postnatal phenotypes, here, we directly compared brain histogenesis, gene expression and behavior over the lifespan of three cytogenetically distinct mouse models of DS: Ts1Cje, Ts65Dn and Dp(16)1/Yey. Histological data indicated that Ts65Dn mice were the most consistently affected with respect to somatic growth, neurogenesis and brain morphogenesis. Embryonic and adult gene expression results showed that Ts1Cje and Ts65Dn brains had considerably more differentially expressed (DEX) genes compared with Dp(16)1/Yey mice, despite the larger number of triplicated genes in the latter model. In addition, DEX genes showed little overlap in identity and chromosomal distribution in the three models, leading to dissimilarities in affected functional pathways. Perinatal and adult behavioral testing also highlighted differences among the models in their abilities to achieve various developmental milestones and perform hippocampal- and motor-based tasks. Interestingly, Dp(16)1/Yey mice showed no abnormalities in prenatal brain phenotypes, yet they manifested behavioral deficits starting at postnatal day 15 that continued through adulthood. In contrast, Ts1Cje mice showed mildly abnormal embryonic brain phenotypes, but only select behavioral deficits as neonates and adults. Altogether, our data showed widespread and unexpected fundamental differences in behavioral, gene expression and brain development phenotypes between these three mouse models. Our findings illustrate unique limitations of each model when studying aspects of brain development and function in DS. This work helps to inform model selection in future studies investigating how observed neurodevelopmental abnormalities arise, how they contribute to cognitive impairment, and when testing therapeutic molecules to ameliorate the intellectual disability associated with DS.This article has an associated First Person interview with the first author of the paper. © 2018. Published by The Company of Biologists Ltd.

Cortical gyrification is abnormal in children with prenatal alcohol exposure.

PubMed

Hendrickson, Timothy J; Mueller, Bryon A; Sowell, Elizabeth R; Mattson, Sarah N; Coles, Claire D; Kable, Julie A; Jones, Kenneth L; Boys, Christopher J; Lim, Kelvin O; Riley, Edward P; Wozniak, Jeffrey R

2017-01-01

Prenatal alcohol exposure (PAE) adversely affects early brain development. Previous studies have shown a wide range of structural and functional abnormalities in children and adolescents with PAE. The current study adds to the existing literature specifically on cortical development by examining cortical gyrification in a large sample of children with PAE compared to controls. Relationships between cortical development and intellectual functioning are also examined. Included were 92 children with PAE and 83 controls ages 9-16 from four sites in the Collaborative Initiative on FASD (CIFASD). All PAE participants had documented heavy PAE. All underwent a formal evaluation of physical anomalies and dysmorphic facial features. MRI data were collected using modified matched protocols on three platforms (Siemens, GE, and Philips). Cortical gyrification was examined using a semi-automated procedure. Whole brain group comparisons using Monte Carlo z-simulation for multiple comparisons showed significantly lower cortical gyrification across a large proportion of the cerebral cortex amongst PAE compared to controls. Whole brain comparisons and ROI based analyses showed strong positive correlations between cortical gyrification and IQ (i.e. less developed cortex was associated with lower IQ). Abnormalities in cortical development were seen across the brain in children with PAE compared to controls. Cortical gyrification and IQ were strongly correlated, suggesting that examining mechanisms by which alcohol disrupts cortical formation may yield clinically relevant insights and potential directions for early intervention.

Early cannabinoid exposure influences neuroendocrine and reproductive functions in male mice: I. Prenatal exposure.

PubMed

Dalterio, S; Steger, R; Mayfield, D; Bartke, A

1984-01-01

Maternal exposure to delta 9-tetrahydrocannabinol (THC), the major psychoactive constituent in marihuana, or to the non-psychoactive cannabinol (CBN) or cannabidiol (CBD) alters endocrine functions and concentrations of brain biogenic amines in their male offspring. Prenatal CBN exposure on day 18 of gestation resulted in decreased plasma FSH levels, testicular testosterone (T) concentrations, and seminal vesicles weights, but increased plasma levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) post-castration in adulthood. Prenatal exposure to THC significantly enhanced the responsiveness of the testes to intratesticular LH injection in vivo and tended to increase human chorionic gonadotropin (hCG)-stimulated T production by decapsulated testes in vitro. In the CBN-exposed mice, hCG-stimulated T production was enhanced, while CBD exposure had no effect. Prenatal THC exposure altered the negative feedback effects of exogenous gonadal steroids in castrated adults, with lower plasma T and FSH levels after 20 micrograms T than in castrated controls. In contrast, CBD-exposed mice had higher levels of LH in plasma post-castration. In CBN-exposed adults, two weeks post-castration the concentration of norepinephrine (NE) and dopamine (DA) in hypothalamus and remaining brain were reduced, while levels of serotonin (5-HT) and its metabolite, 5-HIAA, were elevated compared to that in castrated OIL-controls. Prenatal CBD-exposure also reduced NE and elevated 5-HT and 5-HIAA, but did not affect DA levels post-castration. Concentrations of brain biogenic amines were not influenced by prenatal THC exposure in the present study. A single prenatal exposure to psychoactive or non-psychoactive components of marihuana results in long term alterations in the function of the hypothalamo-pituitary-gonadal axis. Changes in the concentrations of brain biogenic amines may be related to these effects of prenatal cannabinoids on endocrine function in adult male mice.

Effect of prenatal protein malnutrition on long-term potentiation and BDNF protein expression in the rat entorhinal cortex after neocortical and hippocampal tetanization.

PubMed

Hernández, Alejandro; Burgos, Héctor; Mondaca, Mauricio; Barra, Rafael; Núñez, Héctor; Pérez, Hernán; Soto-Moyano, Rubén; Sierralta, Walter; Fernández, Victor; Olivares, Ricardo; Valladares, Luis

2008-01-01

Reduction of the protein content from 25 to 8% casein in the diet of pregnant rats results in impaired neocortical long-term potentiation (LTP) of the offspring together with lower visuospatial memory performance. The present study was aimed to investigate whether this type of maternal malnutrition could result in modification of plastic capabilities of the entorhinal cortex (EC) in the adult progeny. Unlike normal eutrophic controls, 55-60-day-old prenatally malnourished rats were unable to develop LTP in the medial EC to tetanizing stimulation delivered to either the ipsilateral occipital cortex or the CA1 hippocampal region. Tetanizing stimulation of CA1 also failed to increase the concentration of brain-derived neurotrophic factor (BDNF) in the EC of malnourished rats. Impaired capacity of the EC of prenatally malnourished rats to develop LTP and to increase BDNF levels during adulthood may be an important factor contributing to deficits in learning performance having adult prenatally malnourished animals.

Effect of Prenatal Protein Malnutrition on Long-Term Potentiation and BDNF Protein Expression in the Rat Entorhinal Cortex after Neocortical and Hippocampal Tetanization

PubMed Central

Hernández, Alejandro; Burgos, Héctor; Mondaca, Mauricio; Barra, Rafael; Núñez, Héctor; Pérez, Hernán; Soto-Moyano, Rubén; Sierralta, Walter; Fernández, Victor; Olivares, Ricardo; Valladares, Luis

2008-01-01

Reduction of the protein content from 25 to 8% casein in the diet of pregnant rats results in impaired neocortical long-term potentiation (LTP) of the offspring together with lower visuospatial memory performance. The present study was aimed to investigate whether this type of maternal malnutrition could result in modification of plastic capabilities of the entorhinal cortex (EC) in the adult progeny. Unlike normal eutrophic controls, 55–60-day-old prenatally malnourished rats were unable to develop LTP in the medial EC to tetanizing stimulation delivered to either the ipsilateral occipital cortex or the CA1 hippocampal region. Tetanizing stimulation of CA1 also failed to increase the concentration of brain-derived neurotrophic factor (BDNF) in the EC of malnourished rats. Impaired capacity of the EC of prenatally malnourished rats to develop LTP and to increase BDNF levels during adulthood may be an important factor contributing to deficits in learning performance having adult prenatally malnourished animals. PMID:18604298

Non-invasive biomarkers of fetal brain development reflecting prenatal stress: An integrative multi-scale multi-species perspective on data collection and analysis.

PubMed

Frasch, Martin G; Lobmaier, Silvia M; Stampalija, Tamara; Desplats, Paula; Pallarés, María Eugenia; Pastor, Verónica; Brocco, Marcela A; Wu, Hau-Tieng; Schulkin, Jay; Herry, Christophe L; Seely, Andrew J E; Metz, Gerlinde A S; Louzoun, Yoram; Antonelli, Marta C

2018-05-30

Prenatal stress (PS) impacts early postnatal behavioural and cognitive development. This process of 'fetal programming' is mediated by the effects of the prenatal experience on the developing hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS). We derive a multi-scale multi-species approach to devising preclinical and clinical studies to identify early non-invasively available pre- and postnatal biomarkers of PS. The multiple scales include brain epigenome, metabolome, microbiome and the ANS activity gauged via an array of advanced non-invasively obtainable properties of fetal heart rate fluctuations. The proposed framework has the potential to reveal mechanistic links between maternal stress during pregnancy and changes across these physiological scales. Such biomarkers may hence be useful as early and non-invasive predictors of neurodevelopmental trajectories influenced by the PS as well as follow-up indicators of success of therapeutic interventions to correct such altered neurodevelopmental trajectories. PS studies must be conducted on multiple scales derived from concerted observations in multiple animal models and human cohorts performed in an interactive and iterative manner and deploying machine learning for data synthesis, identification and validation of the best non-invasive detection and follow-up biomarkers, a prerequisite for designing effective therapeutic interventions. Copyright © 2018 Elsevier Ltd. All rights reserved.

A review of the serotonin transporter and prenatal cortisol in the development of autism spectrum disorders

PubMed Central

2013-01-01

The diagnosis of autism spectrum disorder (ASD) during early childhood has a profound effect not only on young children but on their families. Aside from the physical and behavioural issues that need to be dealt with, there are significant emotional and financial costs associated with living with someone diagnosed with ASD. Understanding how autism occurs will assist in preparing families to deal with ASD, if not preventing or lessening its occurrence. Serotonin plays a vital role in the development of the brain during the prenatal and postnatal periods, yet very little is known about the serotonergic systems that affect children with ASD. This review seeks to provide an understanding of the biochemistry and physiological actions of serotonin and its termination of action through the serotonin reuptake transporter (SERT). Epidemiological studies investigating prenatal conditions that can increase the risk of ASD describe a number of factors which elevate plasma cortisol levels causing such symptoms during pregnancy such as hypertension, gestational diabetes and depression. Because cortisol plays an important role in driving dysregulation of serotonergic signalling through elevating SERT production in the developing brain, it is also necessary to investigate the physiological functions of cortisol, its action during gestation and metabolic syndromes. PMID:24103554

Altered resting-state whole-brain functional networks of neonates with intrauterine growth restriction.

PubMed

Batalle, Dafnis; Muñoz-Moreno, Emma; Tornador, Cristian; Bargallo, Nuria; Deco, Gustavo; Eixarch, Elisenda; Gratacos, Eduard

2016-04-01

The feasibility to use functional MRI (fMRI) during natural sleep to assess low-frequency basal brain activity fluctuations in human neonates has been demonstrated, although its potential to characterise pathologies of prenatal origin has not yet been exploited. In the present study, we used intrauterine growth restriction (IUGR) as a model of altered neurodevelopment due to prenatal condition to show the suitability of brain networks to characterise functional brain organisation at neonatal age. Particularly, we analysed resting-state fMRI signal of 20 neonates with IUGR and 13 controls, obtaining whole-brain functional networks based on correlations of blood oxygen level-dependent (BOLD) signal in 90 grey matter regions of an anatomical atlas (AAL). Characterisation of the networks obtained with graph theoretical features showed increased network infrastructure and raw efficiencies but reduced efficiency after normalisation, demonstrating hyper-connected but sub-optimally organised IUGR functional brain networks. Significant association of network features with neurobehavioral scores was also found. Further assessment of spatiotemporal dynamics displayed alterations into features associated to frontal, cingulate and lingual cortices. These findings show the capacity of functional brain networks to characterise brain reorganisation from an early age, and their potential to develop biomarkers of altered neurodevelopment. Copyright © 2016 Elsevier Ltd. All rights reserved.

Prenatal SSRI exposure: Effects on later child development.

PubMed

Hermansen, Tone Kristine; Melinder, Annika

2015-01-01

The aim of this review is to integrate research on the pharmacological mechanisms of selective serotonin reuptake inhibitors (SSRIs) and the following effects on fetal brain development and child cognitive function seen in children with prenatal exposure to SSRIs. As antidepressants are transferred from the mother to the fetus through the placenta, the fetus is vulnerable to alterations in neurotransmission and possibly altered neural functioning. Because of this risk, pregnant women suffering from depression are often advised to discontinue their use of antidepressants during pregnancy. Though, maternal untreated depression may also have negative consequences for the fetus and child after birth. In the present review, we find a distinction between studies of early versus late development. Studies on early cognitive development indicate no negative effects, while studies on later development report some cognitive difficulties and behavioral problems, indicating latent effects of exposure. However, the reviewed studies are not all converging, and it is not clear whether and to what extent prenatal SSRI exposure affects cognitive development.

ATTENTION FUNCTIONING IN CHILDREN WITH PRENATAL DRUG EXPOSURE.

PubMed

Jaeger, Dominique A; Suchan, Boris; Schölmerich, Axel; Schneider, Dominik T; Gawehn, Nina

2015-01-01

Children born to drug abusers are exposed to teratogenic influences on intrauterine brain development and undergo postnatal withdrawal. We investigated the interplay of different domains and levels of attention functioning in 24 prenatally exposed and 25 nonexposed children who were 5 to 6 years old. Assessment included parent ratings and neuropsychological and electrophysiological methods. Exposed children had a higher prevalence of attention deficit hyperactivity symptoms, tended to have poorer performance in an attention test battery, and showed EEG alterations in P3 and N2c. Findings suggest long-term effects of prenatal drug exposure on specific domains and on different levels of attention functioning. © 2015 Michigan Association for Infant Mental Health.

Prenatal Organophosphates Exposure Alternates the Cleavage Plane Orientation of Apical Neural Progenitor in Developing Neocortex

PubMed Central

Chen, Xiao-Ping; Chen, Wei-Feng; Wang, Da-Wei

2014-01-01

Prenatal organophosphate exposure elicits long-term brain cytoarchitecture and cognitive function impairments, but the mechanism underlying the onset and development of neural progenitors remain largely unclear. Using precise positioned brain slices, we observed an alternated cleavage plane bias that emerged in the mitotic neural progenitors of embryonal neocortex with diazinion (DZN) and chlorpyrifos (CPF) pretreatment. In comparison with the control, DZN and CPF treatment induced decrease of vertical orientation, increase of oblique orientation, and increase of horizontal orientation. That is, the cleavage plane orientation bias had been rotated from vertical to horizontal after DZN and CPF treatment. Meanwhile, general morphology and mitotic index of the progenitors were unchanged. Acephate (ACP), another common organophosphate, had no significant effects on the cleavage plane orientation, cell morphology and mitotic index. These results represent direct evidence for the toxicity mechanism in onset multiplication of neural progenitors. PMID:24740262

Erythropoietin attenuates loss of potassium chloride co-transporters following prenatal brain injury.

PubMed

Jantzie, L L; Getsy, P M; Firl, D J; Wilson, C G; Miller, R H; Robinson, S

2014-07-01

Therapeutic agents that restore the inhibitory actions of γ-amino butyric acid (GABA) by modulating intracellular chloride concentrations will provide novel avenues to treat stroke, chronic pain, epilepsy, autism, and neurodegenerative and cognitive disorders. During development, upregulation of the potassium-chloride co-transporter KCC2, and the resultant switch from excitatory to inhibitory responses to GABA guide the formation of essential inhibitory circuits. Importantly, maturation of inhibitory mechanisms is also central to the development of excitatory circuits and proper balance between excitatory and inhibitory networks in the developing brain. Loss of KCC2 expression occurs in postmortem samples from human preterm infant brains with white matter lesions. Here we show that late gestation brain injury in a rat model of extreme prematurity impairs the developmental upregulation of potassium chloride co-transporters during a critical postnatal period of circuit maturation in CA3 hippocampus by inducing a sustained loss of oligomeric KCC2 via a calpain-dependent mechanism. Further, administration of erythropoietin (EPO) in a clinically relevant postnatal dosing regimen following the prenatal injury protects the developing brain by reducing calpain activity, restoring oligomeric KCC2 expression and attenuating KCC2 fragmentation, thus providing the first report of a safe therapy to address deficits in KCC2 expression. Together, these data indicate it is possible to reverse abnormalities in KCC2 expression during the postnatal period, and potentially reverse deficits in inhibitory circuit formation central to cognitive impairment and epileptogenesis. Copyright © 2014 Elsevier Inc. All rights reserved.

Foetal asphyxia as a strong stimulator of the sympathetic nervous system in the brain. Case Report.

PubMed

Brucknerová, Ingrid; Ujházy, Eduard

2016-12-18

The aim of the study was to analyse case report of prenatally unknown asphyxia of the foetus (a preterm newborn from the second pregnancy delivered by urgent caesarean section in 31st gestational week; birth weight 850 grams, birth length 41 cm, value of Apgar score 7/8) with signs of respiratory insufficiency immediately after birth with hypotonicity. The authors present the case of postnatal at the 1st day of life assessed cystic malformation in the brain of premature newborn. They emphasize the importance of detailed prenatal investigation as most important in preventing prenatal asphyxia and consequent complications. Central nervous system and especially white matter of the brain of the newborn is most vulnerable area of the brain. Together with oxidative stress after exceeding of antioxidant capacity belong among main factors that play an important role in the pathogenesis of hypoxic-ischemic encephalopathy.

Prenatal maternal infection, neurodevelopment and adult schizophrenia: a systematic review of population-based studies

PubMed Central

Khandaker, G. M.; Zimbron, J.; Lewis, G.; Jones, P. B.

2012-01-01

Background Disruption of foetal development by prenatal maternal infection is consistent with a neurodevelopmental model of schizophrenia. Whether specific prenatal infections are involved, their timing and the mechanisms of any effect are all unknown. We addressed these questions through a systematic review of population-based studies. Method Electronic and manual searches and rigorous quality assessment yielded 21 studies that included an objective assessment of individual-level prenatal maternal infection and standardized psychotic diagnoses in adult offspring. Methodological differences between studies necessitated a descriptive review. Results Results for prenatal maternal non-specific bacterial, respiratory or genital and reproductive infection differed between studies, which reported up to a two- to fivefold increased risk of schizophrenia. Evidence for herpes simplex virus type 2 (HSV-2) and Toxoplasma gondii was mixed; some studies reported up to a doubling of schizophrenia risk. Prenatal HSV-1 or cytomegalovirus (CMV) infections were not associated with increased risk. Exposure to influenza or other infections during early pregnancy may be more harmful than later exposure. Increased proinflammatory cytokines during pregnancy were also associated with risk. Prenatal infection was associated with structural and functional brain abnormalities relevant to schizophrenia. Conclusions Prenatal exposure to a range of infections and inflammatory responses may be associated with risk of adult schizophrenia. Larger samples, mediation and animal models should be used to investigate whether there is a ‘sensitive period’ during development, and the effects of prenatal infections on neurodevelopment. Inclusion of genetic and immunological information should help to elucidate to what extent genetic vulnerability to schizophrenia may be explained by vulnerability to infection. PMID:22717193

Prenatal Glucocorticoid Treatment and Later Mental Health in Children and Adolescents

PubMed Central

Khalife, Natasha; Glover, Vivette; Taanila, Anja; Ebeling, Hanna; Järvelin, Marjo-Riitta; Rodriguez, Alina

2013-01-01

Background Animal studies demonstrate a clear link between prenatal exposure to glucocorticoids (GC) and altered offspring brain development. We aim to examine whether prenatal GC exposure programs long-term mental health in humans. Methods Using propensity-score-matching, children prenatally exposed to synthetic glucocorticoids (sGC), n=37, and controls, n=185, were balanced on important confounders related to sGC treatment - gestational age and pre-pregnancy BMI. We also used mixed-effects modeling to analyse the entire cohort – matching each sGC case, n=37, to all possible controls, n=6079, on gestational age and sex. We obtained data from the Northern Finland Birth Cohort 1986 at four waves – pregnancy, birth, 8 and 16 years. Data on pregnancy and birth outcomes came from medical records. Mental health was assessed at 8 years by teachers with the Rutter B2 scale, and at 16 years by parents with the Strengths and Weaknesses of ADHD symptoms and Normal behavior (SWAN) scale and adolescents by the Youth Self-Report (YSR) scale. Results Prenatal sGC treatment was consistently associated with adverse mental health in childhood and adolescence, as shown by both the propensity-score method and mixed-effects model. Using the propensity-score-matched subsample, linear multiple regression showed prenatal sGC was significantly linked with general psychiatric disturbance (B=8.34 [95% CI: .23-16.45]) and inattention (B= .97 [95% CI: .16-1.80]) at 8 years after control for relevant confounders. Similar findings were obtained at 16 years, but did not reach statistical significance. Mediation by birthweight/placental weight was not detected. Conclusions This study is the first to prospectively investigate the long-term associations between prenatal exposure to sGC treatment and mental health in children and adolescents. We report an association between prenatal exposure to sGC and child mental health, supportive of the idea that sGC has a programming effect on the fetal brain. PMID:24278432

Digit ratio (2D:4D) in primary brain tumor patients: A case-control study.

PubMed

Bunevicius, Adomas; Tamasauskas, Sarunas; Deltuva, Vytenis Pranas; Tamasauskas, Arimantas; Sliauzys, Albertas; Bunevicius, Robertas

2016-12-01

The second-to-fourth digit ratio (2D:4D) reflects prenatal estrogen and testosterone exposure, and is established in utero. Sex steroids are implicated in development and progression of primary brain tumors. To investigate whether there is a link between 2D:4D ratio and primary brain tumors, and age at presentation. Digital images of the right and left palms of 85 primary brain tumor patients (age 56.96±13.68years; 71% women) and 106 (age 54.31±13.68years; 68% women) gender and age matched controls were obtained. The most common brain tumor diagnoses were meningioma (41%), glioblastoma (20%) and pituitary adenoma (16%). Right and left 2D:4D ratios, and right minus left 2D:4D (D r-l ) were compared between patients and controls, and were correlated with age. Right and left 2D:4D ratios were significantly lower in primary brain tumor patients relative to controls (t=-4.28, p<0.001 and t=-3.69, p<0.001, respectively). The D r-l was not different between brain tumor patients and controls (p=0.27). In meningioma and glioma patients, age at presentation correlated negatively with left 2D:4D ratio (rho=-0.42, p=0.01 and rho=-0.36, p=0.02, respectively) and positively with D r-l (rho=0.45, p=0.009 and rho=0.65, p=0.04, respectively). Right and left hand 2D:4D ratios are lower in primary brain tumor patients relative to healthy individuals suggesting greater prenatal testosterone and lower prenatal estrogen exposure in brain tumor patients. Greater age at presentation is associated with greater D r-l and with lower left 2D:4D ratio of meningioma and glioma patients. Due to small sample size our results should be considered preliminary and interpreted with caution. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Cocaine-Induced Neurodevelopmental Deficits and Underlying Mechanisms

PubMed Central

Martin, Melissa M.; Graham, Devon L.; McCarthy, Deirdre M.; Bhide, Pradeep G.; Stanwood, Gregg D.

2017-01-01

Exposure to drugs early in life has complex and long-lasting implications for brain structure and function. This review summarizes work to date on the immediate and long-term effects of prenatal exposure to cocaine. In utero cocaine exposure produces disruptions in brain monoamines, particularly dopamine, during sensitive periods of brain development, and leads to permanent changes in specific brain circuits, molecules, and behavior. Here, we integrate clinical studies and significance with mechanistic preclinical studies, to define our current knowledge base and identify gaps for future investigation. PMID:27345015

Computational Modeling of Resting-State Activity Demonstrates Markers of Normalcy in Children with Prenatal or Perinatal Stroke

PubMed Central

Raja Beharelle, Anjali; Griffa, Alessandra; Hagmann, Patric; Solodkin, Ana; McIntosh, Anthony R.; Small, Steven L.; Deco, Gustavo

2015-01-01

Children who sustain a prenatal or perinatal brain injury in the form of a stroke develop remarkably normal cognitive functions in certain areas, with a particular strength in language skills. A dominant explanation for this is that brain regions from the contralesional hemisphere “take over” their functions, whereas the damaged areas and other ipsilesional regions play much less of a role. However, it is difficult to tease apart whether changes in neural activity after early brain injury are due to damage caused by the lesion or by processes related to postinjury reorganization. We sought to differentiate between these two causes by investigating the functional connectivity (FC) of brain areas during the resting state in human children with early brain injury using a computational model. We simulated a large-scale network consisting of realistic models of local brain areas coupled through anatomical connectivity information of healthy and injured participants. We then compared the resulting simulated FC values of healthy and injured participants with the empirical ones. We found that the empirical connectivity values, especially of the damaged areas, correlated better with simulated values of a healthy brain than those of an injured brain. This result indicates that the structural damage caused by an early brain injury is unlikely to have an adverse and sustained impact on the functional connections, albeit during the resting state, of damaged areas. Therefore, these areas could continue to play a role in the development of near-normal function in certain domains such as language in these children. PMID:26063923

Prenatal enrichment and recovery from perinatal cortical damage: effects of maternal complex housing

PubMed Central

Gibb, Robbin L.; Gonzalez, Claudia L. R.; Kolb, Bryan

2014-01-01

Birth is a particularly vulnerable time for acquiring brain injury. Unfortunately, very few treatments are available for those affected. Here we explore the effectiveness of prenatal intervention in an animal model of early brain damage. We used a complex housing paradigm as a form of prenatal enrichment. Six nulliparous dams and one male rat were placed in complex housing (condomom group) for 12 h per day until the dams' delivered their pups. At parturition the dams were left in their home (standard) cages with their pups. Four dams were housed in standard cages (cagemom group) throughout pregnancy and with their pups until weaning. At postnatal day 3 (P3) infants of both groups received frontal cortex removals or sham surgery. Behavioral testing began on P60 and included the Morris water task and a skilled reaching task. Brains were processed for Golgi analyses. Complex housing of the mother had a significant effect on the behavior of their pups. Control animals from the condomom group outperformed those of the cagemom group in the water task. Condomom animals with lesions performed better than their cagemom cohorts in both the water task and in skilled reaching. Condomom animals showed an increase in cortical thickness at anterior planes and thalamic area at both anterior and posterior regions. Golgi analyses revealed an increase in spine density. These results suggest that prenatal enrichment alters brain organization in manner that is prophylactic for perinatal brain injury. This result could have significant implications for the prenatal management of infants expected to be at risk for difficult birth. PMID:25009478

Exposure to intrauterine inflammation alters metabolomic profiles in the amniotic fluid, fetal and neonatal brain in the mouse

PubMed Central

Barila, Guillermo O.; Hester, Michael S.; Elovitz, Michal A.

2017-01-01

Introduction Exposure to prenatal inflammation is associated with diverse adverse neurobehavioral outcomes in exposed offspring. The mechanism by which inflammation negatively impacts the developing brain is poorly understood. Metabolomic profiling provides an opportunity to identify specific metabolites, and novel pathways, which may reveal mechanisms by which exposure to intrauterine inflammation promotes fetal and neonatal brain injury. Therefore, we investigated whether exposure to intrauterine inflammation altered the metabolome of the amniotic fluid, fetal and neonatal brain. Additionally, we explored whether changes in the metabolomic profile from exposure to prenatal inflammation occurs in a sex-specific manner in the neonatal brain. Methods CD-1, timed pregnant mice received an intrauterine injection of lipopolysaccharide (50 μg/dam) or saline on embryonic day 15. Six and 48 hours later mice were sacrificed and amniotic fluid, and fetal brains were collected (n = 8/group). Postnatal brains were collected on day of life 1 (n = 6/group/sex). Global biochemical profiles were determined using ultra performance liquid chromatography/tandem mass spectrometry (Metabolon Inc.). Statistical analyses were performed by comparing samples from lipopolysaccharide and saline treated animals at each time point. For the P1 brains, analyses were stratified by sex. Results/Conclusions Exposure to intrauterine inflammation induced unique, temporally regulated changes in the metabolic profiles of amniotic fluid, fetal brain and postnatal brain. Six hours after exposure to intrauterine inflammation, the amniotic fluid and the fetal brain metabolomes were dramatically altered with significant enhancements of amino acid and purine metabolites. The amniotic fluid had enhanced levels of several members of the (hypo) xanthine pathway and this compound was validated as a potential biomarker. By 48 hours, the number of altered biochemicals in both the fetal brain and the amniotic fluid had declined, yet unique profiles existed. Neonatal pups exposed to intrauterine inflammation have significant alterations in their lipid metabolites, in particular, fatty acids. These sex-specific metabolic changes within the newborn brain offer an explanation regarding the sexual dimorphism of certain psychiatric and neurobehavioral disorders associated with exposure to prenatal inflammation. PMID:29049352

Familial Dandy-Walker malformation associated with macrocephaly, facial anomalies, developmental delay, and brain stem dysgenesis: prenatal diagnosis and postnatal outcome in brothers. A new syndrome?

PubMed

Chitayat, D; Moore, L; Del Bigio, M R; MacGregor, D; Ben-Zeev, B; Hodgkinson, K; Deck, J; Stothers, T; Ritchie, S; Toi, A

1994-10-01

Brothers are reported with an apparently new constellation of manifestations including Dandy-Walker complex (DWC), migrational brain disorder, macrocephaly, and facial anomalies. The first brother presented at birth, the second was detected prenatally with DWC and the pregnancy terminated. Fetal brain histopathology showed DWC associated with brainstem dysgenesis. Inheritance is likely autosomal or X-linked recessive. An extensive review of the differential diagnosis of DWC is provided.

Visuo-Spatial Processing in Autism--Testing the Predictions of Extreme Male Brain Theory

ERIC Educational Resources Information Center

Falter, Christine M.; Plaisted, Kate C.; Davis, Greg

2008-01-01

It has been hypothesised that autism is an extreme version of the male brain, caused by high levels of prenatal testosterone (Baron-Cohen 1999). To test this proposal, associations were assessed between three visuo-spatial tasks and prenatal testosterone, indexed in second-to-fourth digit length ratios (2D:4D). The study included children with…

COMMENTS ON "EFFECT OF PRENATAL EXPOSURE OF DELTAMETHRIN ON THE ONTOGENY OF XENOBIOTIC METABOLIZING CYTOCHROME P450S IN THE BRAIN AND LIVER OF OFFSPRINGS.

EPA Science Inventory

Comments on: Effect of prenatal exposure of deltamethrin on the ontogeny of xenobiotic metabolizing cytochrome P450s in the brain and liver of offsprings [Johri et al. Toxicol Appl Pharmacol. 214:279-289, 2006]

Johri and colleagues recently reported that maternal exposur...

Zinc in Gut-Brain Interaction in Autism and Neurological Disorders

PubMed Central

Vela, Guillermo; Stark, Peter; Socha, Michael; Sauer, Ann Katrin; Hagmeyer, Simone; Grabrucker, Andreas M.

2015-01-01

A growing amount of research indicates that abnormalities in the gastrointestinal (GI) system during development might be a common factor in multiple neurological disorders and might be responsible for some of the shared comorbidities seen among these diseases. For example, many patients with Autism Spectrum Disorder (ASD) have symptoms associated with GI disorders. Maternal zinc status may be an important factor given the multifaceted effect of zinc on gut development and morphology in the offspring. Zinc status influences and is influenced by multiple factors and an interdependence of prenatal and early life stress, immune system abnormalities, impaired GI functions, and zinc deficiency can be hypothesized. In line with this, systemic inflammatory events and prenatal stress have been reported to increase the risk for ASD. Thus, here, we will review the current literature on the role of zinc in gut formation, a possible link between gut and brain development in ASD and other neurological disorders with shared comorbidities, and tie in possible effects on the immune system. Based on these data, we present a novel model outlining how alterations in the maternal zinc status might pathologically impact the offspring leading to impairments in brain functions later in life. PMID:25878905

Zinc in gut-brain interaction in autism and neurological disorders.

PubMed

Vela, Guillermo; Stark, Peter; Socha, Michael; Sauer, Ann Katrin; Hagmeyer, Simone; Grabrucker, Andreas M

2015-01-01

A growing amount of research indicates that abnormalities in the gastrointestinal (GI) system during development might be a common factor in multiple neurological disorders and might be responsible for some of the shared comorbidities seen among these diseases. For example, many patients with Autism Spectrum Disorder (ASD) have symptoms associated with GI disorders. Maternal zinc status may be an important factor given the multifaceted effect of zinc on gut development and morphology in the offspring. Zinc status influences and is influenced by multiple factors and an interdependence of prenatal and early life stress, immune system abnormalities, impaired GI functions, and zinc deficiency can be hypothesized. In line with this, systemic inflammatory events and prenatal stress have been reported to increase the risk for ASD. Thus, here, we will review the current literature on the role of zinc in gut formation, a possible link between gut and brain development in ASD and other neurological disorders with shared comorbidities, and tie in possible effects on the immune system. Based on these data, we present a novel model outlining how alterations in the maternal zinc status might pathologically impact the offspring leading to impairments in brain functions later in life.

Prenatal air pollution exposure induces neuroinflammation and predisposes offspring to weight gain in adulthood in a sex-specific manner.

PubMed

Bolton, Jessica L; Smith, Susan H; Huff, Nicole C; Gilmour, M Ian; Foster, W Michael; Auten, Richard L; Bilbo, Staci D

2012-11-01

Emerging evidence suggests environmental chemical exposures during critical windows of development may contribute to the escalating prevalence of obesity. We tested the hypothesis that prenatal air pollution exposure would predispose the offspring to weight gain in adulthood. Pregnant mice were exposed to filtered air (FA) or diesel exhaust (DE) on embryonic days (E) 9-17. Prenatal DE induced a significant fetal brain cytokine response at E18 (46-390% over FA). As adults, offspring were fed either a low-fat diet (LFD) or high-fat diet (HFD) for 6 wk. Adult DE male offspring weighed 12% more and were 35% less active than FA male offspring at baseline, whereas there were no differences in females. Following HFD, DE males gained weight at the same rate as FA males, whereas DE females gained 340% more weight than FA females. DE-HFD males had 450% higher endpoint insulin levels than FA-HFD males, and all males on HFD showed decreased activity and increased anxiety, whereas females showed no differences. Finally, both DE males and females fed HFD showed increased microglial activation (30-66%) within several brain regions. Thus, prenatal air pollution exposure can "program" offspring for increased susceptibility to diet-induced weight gain and neuroinflammation in adulthood in a sex-specific manner.

Gestational Exposure to Air Pollution Alters Cortical Volume, Microglial Morphology, and Microglia-Neuron Interactions in a Sex-Specific Manner.

PubMed

Bolton, Jessica L; Marinero, Steven; Hassanzadeh, Tania; Natesan, Divya; Le, Dominic; Belliveau, Christine; Mason, S N; Auten, Richard L; Bilbo, Staci D

2017-01-01

Microglia are the resident immune cells of the brain, important for normal neural development in addition to host defense in response to inflammatory stimuli. Air pollution is one of the most pervasive and harmful environmental toxicants in the modern world, and several large scale epidemiological studies have recently linked prenatal air pollution exposure with an increased risk of neurodevelopmental disorders such as autism spectrum disorder (ASD). Diesel exhaust particles (DEP) are a primary toxic component of air pollution, and markedly activate microglia in vitro and in vivo in adult rodents. We have demonstrated that prenatal exposure to DEP in mice, i.e., to the pregnant dams throughout gestation, results in a persistent vulnerability to behavioral deficits in adult offspring, especially in males, which is intriguing given the greater incidence of ASD in males to females (∼4:1). Moreover, there is a striking upregulation of toll-like receptor (TLR) 4 gene expression within the brains of the same mice, and this expression is primarily in microglia. Here we explored the impact of gestational exposure to DEP or vehicle on microglial morphology in the developing brains of male and female mice. DEP exposure increased inflammatory cytokine protein and altered the morphology of microglia, consistent with activation or a delay in maturation, only within the embryonic brains of male mice; and these effects were dependent on TLR4. DEP exposure also increased cortical volume at embryonic day (E)18, which switched to decreased volume by post-natal day (P)30 in males, suggesting an impact on the developing neural stem cell niche. Consistent with this hypothesis, we found increased microglial-neuronal interactions in male offspring that received DEP compared to all other groups. Taken together, these data suggest a mechanism by which prenatal exposure to environmental toxins may affect microglial development and long-term function, and thereby contribute to the risk of neurodevelopmental disorders.

Gestational Exposure to Air Pollution Alters Cortical Volume, Microglial Morphology, and Microglia-Neuron Interactions in a Sex-Specific Manner

PubMed Central

Bolton, Jessica L.; Marinero, Steven; Hassanzadeh, Tania; Natesan, Divya; Le, Dominic; Belliveau, Christine; Mason, S. N.; Auten, Richard L.; Bilbo, Staci D.

2017-01-01

Microglia are the resident immune cells of the brain, important for normal neural development in addition to host defense in response to inflammatory stimuli. Air pollution is one of the most pervasive and harmful environmental toxicants in the modern world, and several large scale epidemiological studies have recently linked prenatal air pollution exposure with an increased risk of neurodevelopmental disorders such as autism spectrum disorder (ASD). Diesel exhaust particles (DEP) are a primary toxic component of air pollution, and markedly activate microglia in vitro and in vivo in adult rodents. We have demonstrated that prenatal exposure to DEP in mice, i.e., to the pregnant dams throughout gestation, results in a persistent vulnerability to behavioral deficits in adult offspring, especially in males, which is intriguing given the greater incidence of ASD in males to females (∼4:1). Moreover, there is a striking upregulation of toll-like receptor (TLR) 4 gene expression within the brains of the same mice, and this expression is primarily in microglia. Here we explored the impact of gestational exposure to DEP or vehicle on microglial morphology in the developing brains of male and female mice. DEP exposure increased inflammatory cytokine protein and altered the morphology of microglia, consistent with activation or a delay in maturation, only within the embryonic brains of male mice; and these effects were dependent on TLR4. DEP exposure also increased cortical volume at embryonic day (E)18, which switched to decreased volume by post-natal day (P)30 in males, suggesting an impact on the developing neural stem cell niche. Consistent with this hypothesis, we found increased microglial-neuronal interactions in male offspring that received DEP compared to all other groups. Taken together, these data suggest a mechanism by which prenatal exposure to environmental toxins may affect microglial development and long-term function, and thereby contribute to the risk of neurodevelopmental disorders. PMID:28620294

Effect of Gestational Exposure of Cypermethrin on Postnatal Development of Brain Cytochrome P450 2D1 and 3A1 and Neurotransmitter Receptors.

PubMed

Singh, Anshuman; Mudawal, Anubha; Shukla, Rajendra K; Yadav, Sanjay; Khanna, Vinay K; Sethumadhavan, Rao; Parmar, Devendra

2015-08-01

Oral administration of low doses (1.25, 2.5, or 5 mg/kg) of cypermethrin to pregnant Wistar rats from gestation days 5 to 21 led to dose-dependent differences in the induction of cytochrome P450 2D1 (CYP2D1) and 3A1 messenger RNA (mRNA) and protein in brain regions isolated from the offsprings postnatally at 3 weeks that persisted up to adulthood (12 weeks). Similar alterations were observed in the expression of GABAergic, muscarinic, dopaminergic, and serotonergic neurotransmitter receptors in brain regions of rat offsprings. Rechallenge of the prenatally exposed offsprings at adulthood (12 weeks old) with cypermethrin (p.o., 10 mg/kg for 6 days) led to a greater magnitude of alterations in the expression of CYPs, neurotransmitter receptors, and neurotransmitter receptor binding in the brain regions when compared to the control offsprings treated at adulthood with cypermethrin or prenatally exposed offsprings. A greater magnitude of decrease was also observed in the spontaneous locomotor activity (SLA) in prenatally exposed offsprings rechallenged with cypermethrin. The present data indicating similarities in the alterations in the expression of CYPs (2D1 and 3A1) and neurotransmitter receptors in brain has led us to suggest that endogenous function regulating CYPs is possibly associated with neurotransmission processes. A greater magnitude of alterations in CYP2D1, 3A1, neurotransmitter receptors, and SLA in rechallenged animals has further provided evidence that alterations in CYPs are possibly linked with neurotransmission processes.

Abnormal brain activation during working memory in children with prenatal exposure to drugs of abuse: the effects of methamphetamine, alcohol, and polydrug exposure.

PubMed

Roussotte, Florence F; Bramen, Jennifer E; Nunez, S Christopher; Quandt, Lorna C; Smith, Lynne; O'Connor, Mary J; Bookheimer, Susan Y; Sowell, Elizabeth R

2011-02-14

Structural and metabolic abnormalities in fronto-striatal structures have been reported in children with prenatal methamphetamine (MA) exposure. The current study was designed to quantify functional alterations to the fronto-striatal circuit in children with prenatal MA exposure using functional magnetic resonance imaging (fMRI). Because many women who use MA during pregnancy also use alcohol, a known teratogen, we examined 50 children (age range 7-15), 19 with prenatal MA exposure, 15 of whom had concomitant prenatal alcohol exposure (the MAA group), 13 with heavy prenatal alcohol but no MA exposure (ALC group), and 18 unexposed controls (CON group). We hypothesized that MA exposed children would demonstrate abnormal brain activation during a visuospatial working memory (WM) "N-Back" task. As predicted, the MAA group showed less activation than the CON group in many brain areas, including the striatum and frontal lobe in the left hemisphere. The ALC group showed less activation than the MAA group in several regions, including the right striatum. We found an inverse correlation between performance and activity in the striatum in both the CON and MAA groups. However, this relationship was significant in the caudate of the CON group but not the MAA group, and in the putamen of the MAA group but not the CON group. These findings suggest that structural damage in the fronto-striatal circuit after prenatal MA exposure leads to decreased recruitment of this circuit during a WM challenge, and raise the possibility that a rewiring of cortico-striatal networks may occur in children with prenatal MA exposure. Copyright © 2010 Elsevier Inc. All rights reserved.

Late prenatal immune activation causes hippocampal deficits in the absence of persistent inflammation across aging.

PubMed

Giovanoli, Sandra; Notter, Tina; Richetto, Juliet; Labouesse, Marie A; Vuillermot, Stéphanie; Riva, Marco A; Meyer, Urs

2015-11-25

Prenatal exposure to infection and/or inflammation is increasingly recognized to play an important role in neurodevelopmental brain disorders. It has recently been postulated that prenatal immune activation, especially when occurring during late gestational stages, may also induce pathological brain aging via sustained effects on systemic and central inflammation. Here, we tested this hypothesis using an established mouse model of exposure to viral-like immune activation in late pregnancy. Pregnant C57BL6/J mice on gestation day 17 were treated with the viral mimetic polyriboinosinic-polyribocytidilic acid (poly(I:C)) or control vehicle solution. The resulting offspring were first tested using cognitive and behavioral paradigms known to be sensitive to hippocampal damage, after which they were assigned to quantitative analyses of inflammatory cytokines, microglia density and morphology, astrocyte density, presynaptic markers, and neurotrophin expression in the hippocampus throughout aging (1, 5, and 22 months of age). Maternal poly(I:C) treatment led to a robust increase in inflammatory cytokine levels in late gestation but did not cause persistent systemic or hippocampal inflammation in the offspring. The late prenatal manipulation also failed to cause long-term changes in microglia density, morphology, or activation, and did not induce signs of astrogliosis in pubescent, adult, or aged offspring. Despite the lack of persistent inflammatory or glial anomalies, offspring of poly(I:C)-exposed mothers showed marked and partly age-dependent deficits in hippocampus-regulated cognitive functions as well as impaired hippocampal synaptophysin and brain-derived neurotrophic factor (BDNF) expression. Late prenatal exposure to viral-like immune activation in mice causes hippocampus-related cognitive and synaptic deficits in the absence of chronic inflammation across aging. These findings do not support the hypothesis that this form of prenatal immune activation may induce pathological brain aging via sustained effects on systemic and central inflammation. We further conclude that poly(I:C)-based prenatal immune activation models are reliable in their effectiveness to induce (hippocampal) neuropathology across aging, but they appear unsuited for studying the role of chronic systemic or central inflammation in brain aging.

Effects of Prenatal Methylmercury Exposure: From Minamata Disease to Environmental Health Studies.

PubMed

Sakamoto, Mineshi; Itai, Takaaki; Murata, Katsuyuki

2017-01-01

Methylmercury, the causative agent of Minamata disease, can easily penetrate the brain, and adult-type Minamata disease patients showed neurological symptoms according to the brain regions where the neurons, mainly in the cerebrum and cerebellum, were damaged. In addition, fetuses are exposed to methylmercury via the placenta from maternal fish consumption, and high-level exposure to methylmercury causes damage to the brains of infants. Typical patients with fetal-type Minamata disease (i.e., serious poisoning caused by in utero exposure to methylmercury) were born during the period of severe methylmercury pollution in 1955-1959, although they showed no abnormality during gestation nor at delivery. However, they showed difficulties in head control, sitting, and walking, and showed disturbances in mental development, these symptoms that are similar to those of cerebral palsy, during the growth periods after birth. The impaired development of fetal-type Minamata disease patients was one of the most tragic and characteristic feature of Minamata disease. In this review, we first summarize 1) the effects of prenatal methylmercury exposure in Minamata disease. Then, we introduce the studies that were conducted mainly by Sakamoto et al. as follows: 2) a retrospective study on temporal and regional variations of methylmercury pollution in Minamata area using preserved umbilical cord methylmercury, 3) decline in male sex ratio observed in Minamata area, 4) characteristics of hand tremor and postural sway in fetal-type Minamata disease patients, 5) methylmercury transfer from mothers to infants during gestation and lactation (the role of placenta), 6) extrapolation studies using rat models on the effects of prenatal methylmercury exposure on the human brain, and 7) risks and benefits of fish consumption.

[Sex differentiation of central nervous system--brain of man and woman].

PubMed

Arai, Yasumasa

2004-02-01

Sex differentiation of human brain is mostly dependent on the prenatal exposure to androgen(testosterone). Congenital aromatase deficiency does not disturb male brain development in men. This is quite different from experimental evidence from rodents whose brains need intraneuronal aromatization from androgen to estrogen to induce sex differentiation. There is evidence for male-female differences in brain structures. Some of them(INHA-3) appear to be related with sexual orientation. The other(BNST) might participate in forming gender-identity. In addition, sexually dimorphic features are recognized in some cognitive activities. The possible involvement of genetic factors in human brain sex differentiation is also discussed.

Sex differences in methamphetamine pharmacokinetics in adult rats and its transfer to pups through the placental membrane and breast milk.

PubMed

Rambousek, Lukas; Kacer, Petr; Syslova, Kamila; Bumba, Jakub; Bubenikova-Valesova, Vera; Slamberova, Romana

2014-06-01

Methamphetamine (METH) abuse is a growing health problem worldwide, and METH use during pregnancy not only endangers the mother's health but also the developing fetus. To provide better insight into these risks, we performed the following experiments. First, we investigated how sex influences the pharmacokinetics of METH and amphetamine (AMP) in male and female rats. Subsequently, we simulated chronic exposure of prenatal infants to METH abuse by investigating brain and plasma levels of METH and AMP in dams and pups. Finally, we modeled chronic exposure of infants to METH via breast milk and investigated sex differences in pups with regard to drug levels and possible sensitization effect of chronic prenatal METH co-treatment. We observed significantly higher levels of METH and AMP in the plasma and brain of female rats compared to males. Additionally, brain concentrations of METH and AMP in pups exposed to METH prenatally were equivalent to 62.13% and 37.78% relative to dam, respectively. Plasma concentrations of AMP where equivalent to 100% of the concentration in dams, while METH was equivalent to only 36.98%. Finally, we did not observe a significant effect relative to sex with regard to METH/AMP levels or sensitization effects linked to prenatal METH exposure. We demonstrated that female rats display higher levels of METH and AMP, thus indicating a greater risk of addiction and toxicity. Furthermore, our data show that pups are exposed to both METH and AMP following dam exposure. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Brain anomalies in children exposed prenatally to a common organophosphate pesticide

PubMed Central

Rauh, Virginia A.; Perera, Frederica P.; Horton, Megan K.; Whyatt, Robin M.; Bansal, Ravi; Hao, Xuejun; Liu, Jun; Barr, Dana Boyd; Slotkin, Theodore A.; Peterson, Bradley S.

2012-01-01

Prenatal exposure to chlorpyrifos (CPF), an organophosphate insecticide, is associated with neurobehavioral deficits in humans and animal models. We investigated associations between CPF exposure and brain morphology using magnetic resonance imaging in 40 children, 5.9–11.2 y, selected from a nonclinical, representative community-based cohort. Twenty high-exposure children (upper tertile of CPF concentrations in umbilical cord blood) were compared with 20 low-exposure children on cortical surface features; all participants had minimal prenatal exposure to environmental tobacco smoke and polycyclic aromatic hydrocarbons. High CPF exposure was associated with enlargement of superior temporal, posterior middle temporal, and inferior postcentral gyri bilaterally, and enlarged superior frontal gyrus, gyrus rectus, cuneus, and precuneus along the mesial wall of the right hemisphere. Group differences were derived from exposure effects on underlying white matter. A significant exposure × IQ interaction was derived from CPF disruption of normal IQ associations with surface measures in low-exposure children. In preliminary analyses, high-exposure children did not show expected sex differences in the right inferior parietal lobule and superior marginal gyrus, and displayed reversal of sex differences in the right mesial superior frontal gyrus, consistent with disruption by CPF of normal behavioral sexual dimorphisms reported in animal models. High-exposure children also showed frontal and parietal cortical thinning, and an inverse dose–response relationship between CPF and cortical thickness. This study reports significant associations of prenatal exposure to a widely used environmental neurotoxicant, at standard use levels, with structural changes in the developing human brain. PMID:22547821

The biology of human psychosexual differentiation.

PubMed

Gooren, Louis

2006-11-01

Most attempts to identify biological underpinnings of gender identity and sexual orientation in humans have investigated effects of sex steroids, so pivotal in the differentiation of the genitalia, showing strong parallels between animals and the human. The information on humans is derived from the so-called 'experiments of nature', clinical entities with a lesser-than-normal androgen exposure in XY subjects and a higher than normal androgen exposure in XX subjects. Prenatal androgenization appears to predispose to a male gender identity development, but apparently not decisively since 40-50% of 46,XY intersexed children with a history of prenatal androgen exposure do not develop a male gender identity. Obviously, male-to-female transsexuals, with a normal androgen exposure prenatally (there is no serious evidence to the contrary) develop a female gender identity, through unknown biological mechanisms apparently overriding the effects of prenatal androgens. The latest studies in 46, XX subjects exposed to prenatal androgens show that prenatal androgenization of 46,XX fetuses leads to marked masculinization of later gender-related behavior but does not lead to gender confusion/dysphoria. The example of female-to-male transsexuals, without evidence of prenatal androgen exposure, indicates that a male gender identity can develop without a significant androgen stimulus. So we are far away from any comprehensive understanding of hormonal imprinting on gender identity formation. Brain studies in homosexuals have not held up in replication studies or are in need of replication in transsexuals. Genetic studies and the fraternal birth order hypothesis provide indications of familial clustering of homosexuality but in many homosexuals these genetic patterns cannot be identified. The biological explanations advanced for the birth order hypothesis lack any experimental support.

Methylation-reprogrammed Wnt/β-catenin signalling mediated prenatal hypoxia-induced brain injury in foetal and offspring rats.

PubMed

Zhang, Yingying; Zhang, Mengshu; Li, Lingjun; Wei, Bin; He, Axin; Lu, Likui; Li, Xiang; Zhang, Lubo; Xu, Zhice; Sun, Miao

2018-05-28

Prenatal hypoxia (PH) is a common pregnancy complication, harmful to brain development. This study investigated whether and how PH affected Wnt pathway in the brain. Pregnant rats were exposed to hypoxia (10.5% O 2 ) or normoxia (21% O 2 ; Control). Foetal brain weight and body weight were decreased in the PH group, the ratio of brain weight to body weight was increased significantly. Prenatal hypoxia increased mRNA expression of Wnt3a, Wnt7a, Wnt7b and Fzd4, but not Lrp6. Activated β-catenin protein and Fosl1 expression were also significantly up-regulated. Increased Hif1a expression was found in the PH group associated with the higher Wnt signalling. Among 5 members of the Sfrp family, Sfrp4 was down-regulated. In the methylation-regulating genes, higher mRNA expressions of Dnmt1 and Dnmt3b were found in the PH group. Sodium bisulphite and sequencing revealed hyper-methylation in the promoter region of Sfrp4 gene in the foetal brain, accounting for its decreased expression and contributing to the activation of the Wnt-Catenin signalling. The study of PC12 cells treated with 5-aza further approved that decreased methylation could result in the higher Sfrp4 expression. In the offspring hippocampus, protein levels of Hif1a and mRNA expression of Sfrp4 were unchanged, whereas Wnt signal pathway was inhibited. The data demonstrated that PH activated the Wnt pathway in the foetal brain, related to the hyper-methylation of Sfrp4 as well as Hif1a signalling. Activated Wnt signalling might play acute protective roles to the foetal brain in response to hypoxia, also would result in disadvantageous influence on the offspring in long-term. © 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Prenatal choline supplementation attenuates spatial learning deficits of offspring rats exposed to low-protein diet during fetal period.

PubMed

Zhu, Cui-Hong; Wu, Ting; Jin, Yu; Huang, Bi-Xia; Zhou, Rui-Fen; Wang, Yi-Qin; Luo, Xiao-Lin; Zhu, Hui-Lian

2016-06-01

Prenatal intake of choline has been reported to lead to enhanced cognitive function in offspring, but little is known about the effects on spatial learning deficits. The present study examined the effects of prenatal choline supplementation on developmental low-protein exposure and its potential mechanisms. Pregnant female rats were fed either a normal or low-protein diet containing sufficient choline (1.1g/kg choline chloride) or supplemented choline (5.0g/kg choline chloride) until delivery. The Barnes maze test was performed at postnatal days 31-37. Choline and its metabolites, the synaptic structural parameters of the CA1 region in the brain of the newborn rat, were measured. The Barnes maze test demonstrated that prenatal low-protein pups had significantly greater error scale values, hole deviation scores, strategy scores and spatial search strategy and had lesser random search strategy values than normal protein pups (all P<.05). These alterations were significantly reversed by choline supplementation. Choline supplementation increased the brain levels of choline, betaine, phosphatidylethanolamine and phosphatidylcholine of newborns by 51.35% (P<.05), 33.33% (P<.001), 28.68% (P<.01) and 23.58% (P<.05), respectively, compared with the LPD group. Prenatal choline supplementation reversed the increased width of the synaptic cleft (P<.05) and decreased the curvature of the synaptic interface (P<.05) induced by a low-protein diet. Prenatal choline supplementation could attenuate the spatial learning deficits caused by prenatal protein malnutrition by increasing brain choline, betaine and phospholipids and by influencing the hippocampus structure. Copyright © 2016 Elsevier Inc. All rights reserved.

Altered brain functional connectivity and behaviour in a mouse model of maternal alcohol binge-drinking.

PubMed

Cantacorps, Lídia; González-Pardo, Héctor; Arias, Jorge L; Valverde, Olga; Conejo, Nélida M

2018-06-08

Prenatal and perinatal alcohol exposure caused by maternal alcohol intake during gestation and lactation periods can have long-lasting detrimental effects on the brain development and behaviour of offspring. Children diagnosed with Foetal Alcohol Spectrum Disorders (FASD) display a wide range of cognitive, emotional and motor deficits, together with characteristic morphological abnormalities. Maternal alcohol binge drinking is particularly harmful for foetal and early postnatal brain development, as it involves exposure to high levels of alcohol over short periods of time. However, little is known about the long-term effects of maternal alcohol binge drinking on brain function and behaviour. To address this issue, we used pregnant C57BL/6 female mice with time-limited access to a 20% v/v alcohol solution as a procedure to model alcohol binge drinking during gestation and lactational periods. Male offspring were behaviourally tested during adolescence (30 days) and adulthood (60 days), and baseline neural metabolic capacity of brain regions sensitive to alcohol effects were also evaluated in adult animals from both groups. Our results show that prenatal and postnatal alcohol exposure caused age-dependent changes in spontaneous locomotor activity, increased anxiety-like behaviour and attenuated alcohol-induced conditioned place preference in adults. Also, significant changes in neural metabolic capacity using cytochrome c oxidase (CCO) quantitative histochemistry were found in the hippocampal dentate gyrus, the mammillary bodies, the ventral tegmental area, the lateral habenula and the central lobules of the cerebellum in adult mice with prenatal and postnatal alcohol exposure. In addition, the analysis of interregional CCO activity correlations in alcohol-exposed adult mice showed disrupted functional brain connectivity involving the limbic, brainstem, and cerebellar regions. Finally, increased neurogenesis was found in the dentate gyrus of the hippocampus of alcohol-exposed offspring, suggesting neuroadaptive effects due to early alcohol exposure. Our results demonstrate that maternal binge-like alcohol drinking causes long-lasting effects on motor and emotional-related behaviours associated with impaired neuronal metabolic capacity and altered functional brain connectivity. Copyright © 2018 Elsevier Inc. All rights reserved.

Early neurotrophic pharmacotherapy rescues developmental delay and Alzheimer’s-like memory deficits in the Ts65Dn mouse model of Down syndrome

PubMed Central

Kazim, Syed Faraz; Blanchard, Julie; Bianchi, Riccardo; Iqbal, Khalid

2017-01-01

Down syndrome (DS), caused by trisomy 21, is the most common genetic cause of intellectual disability and is associated with a greatly increased risk of early-onset Alzheimer’s disease (AD). The Ts65Dn mouse model of DS exhibits several key features of the disease including developmental delay and AD-like cognitive impairment. Accumulating evidence suggests that impairments in early brain development caused by trisomy 21 contribute significantly to memory deficits in adult life in DS. Prenatal genetic testing to diagnose DS in utero, provides the novel opportunity to initiate early pharmacological treatment to target this critical period of brain development. Here, we report that prenatal to early postnatal treatment with a ciliary neurotrophic factor (CNTF) small-molecule peptide mimetic, Peptide 021 (P021), rescued developmental delay in pups and AD-like hippocampus-dependent memory impairments in adult life in Ts65Dn mice. Furthermore, this treatment prevented pre-synaptic protein deficit, decreased glycogen synthase kinase-3beta (GSK3β) activity, and increased levels of synaptic plasticity markers including brain derived neurotrophic factor (BNDF) and phosphorylated CREB, both in young (3-week-old) and adult (~ 7-month-old) Ts65Dn mice. These findings provide novel evidence that providing neurotrophic support during early brain development can prevent developmental delay and AD-like memory impairments in a DS mouse model. PMID:28368015

Roles of heat shock factor 1 in neuronal response to fetal environmental risks and its relevance to brain disorders.

PubMed

Hashimoto-Torii, Kazue; Torii, Masaaki; Fujimoto, Mitsuaki; Nakai, Akira; El Fatimy, Rachid; Mezger, Valerie; Ju, Min J; Ishii, Seiji; Chao, Shih-Hui; Brennand, Kristen J; Gage, Fred H; Rakic, Pasko

2014-05-07

Prenatal exposure of the developing brain to various environmental challenges increases susceptibility to late onset of neuropsychiatric dysfunction; still, the underlying mechanisms remain obscure. Here we show that exposure of embryos to a variety of environmental factors such as alcohol, methylmercury, and maternal seizure activates HSF1 in cerebral cortical cells. Furthermore, Hsf1 deficiency in the mouse cortex exposed in utero to subthreshold levels of these challenges causes structural abnormalities and increases seizure susceptibility after birth. In addition, we found that human neural progenitor cells differentiated from induced pluripotent stem cells derived from schizophrenia patients show higher variability in the levels of HSF1 activation induced by environmental challenges compared to controls. We propose that HSF1 plays a crucial role in the response of brain cells to prenatal environmental insults and may be a key component in the pathogenesis of late-onset neuropsychiatric disorders. Copyright © 2014 Elsevier Inc. All rights reserved.

Alterations in the Vaginal Microbiome by Maternal Stress Are Associated With Metabolic Reprogramming of the Offspring Gut and Brain.

PubMed

Jašarević, Eldin; Howerton, Christopher L; Howard, Christopher D; Bale, Tracy L

2015-09-01

The neonate is exposed to the maternal vaginal microbiota during parturition, providing the primary source for normal gut colonization, host immune maturation, and metabolism. These early interactions between the host and microbiota occur during a critical window of neurodevelopment, suggesting early life as an important period of cross talk between the developing gut and brain. Because perturbations in the prenatal environment such as maternal stress increase neurodevelopmental disease risk, disruptions to the vaginal ecosystem could be a contributing factor in significant and long-term consequences for the offspring. Therefore, to examine the hypothesis that changes in the vaginal microbiome are associated with effects on the offspring gut microbiota and on the developing brain, we used genomic, proteomic and metabolomic technologies to examine outcomes in our mouse model of early prenatal stress. Multivariate modeling identified broad proteomic changes to the maternal vaginal environment that influence offspring microbiota composition and metabolic processes essential for normal neurodevelopment. Maternal stress altered proteins related to vaginal immunity and abundance of Lactobacillus, the prominent taxa in the maternal vagina. Loss of maternal vaginal Lactobacillus resulted in decreased transmission of this bacterium to offspring. Further, altered microbiota composition in the neonate gut corresponded with changes in metabolite profiles involved in energy balance, and with region- and sex-specific disruptions of amino acid profiles in the developing brain. Taken together, these results identify the vaginal microbiota as a novel factor by which maternal stress may contribute to reprogramming of the developing brain that may predispose individuals to neurodevelopmental disorders.

Human Brain Abnormalities Associated With Prenatal Alcohol Exposure and Fetal Alcohol Spectrum Disorder

PubMed Central

Jarmasz, Jessica S.; Basalah, Duaa A.; Chudley, Albert E.; Del Bigio, Marc R.

2017-01-01

Abstract Fetal alcohol spectrum disorder (FASD) is a common neurodevelopmental problem, but neuropathologic descriptions are rare and focused on the extreme abnormalities. We conducted a retrospective survey (1980–2016) of autopsies on 174 individuals with prenatal alcohol exposure or an FASD diagnosis. Epidemiologic details and neuropathologic findings were categorized into 5 age groups. Alcohol exposure was difficult to quantify. When documented, almost all mothers smoked tobacco, many abused other substances, and prenatal care was poor or nonexistent. Placental abnormalities were common (68%) in fetal cases. We identified micrencephaly (brain weight <5th percentile) in 31, neural tube defects in 5, isolated hydrocephalus in 6, corpus callosum defects in 6 (including some with complex anomalies), probable prenatal ischemic lesions in 5 (excluding complications of prematurity), minor subarachnoid heterotopias in 4, holoprosencephaly in 1, lissencephaly in 1, and cardiac anomalies in 26 cases. The brain abnormalities associated with prenatal alcohol exposure are varied; cause–effect relationships cannot be determined. FASD is likely not a monotoxic disorder. The animal experimental literature, which emphasizes controlled exposure to ethanol alone, is therefore inadequate. Prevention must be the main societal goal, however, a clear understanding of the neuropathology is necessary for provision of care to individuals already affected. PMID:28859338

Prenatal ethanol exposure differentially affects hippocampal neurogenesis in the adolescent and aged brain.

PubMed

Gil-Mohapel, J; Titterness, A K; Patten, A R; Taylor, S; Ratzlaff, A; Ratzlaff, T; Helfer, J; Christie, B R

2014-07-25

Exposure to ethanol in utero is associated with a myriad of sequelae for the offspring. Some of these effects are morphological in nature and noticeable from birth, while others involve more subtle changes to the brain that only become apparent later in life when the individuals are challenged cognitively. One brain structure that shows both functional and structural deficits following prenatal ethanol exposure is the hippocampus. The hippocampus is composed of two interlocking gyri, the cornu ammonis (CA) and the dentate gyrus (DG), and they are differentially affected by prenatal ethanol exposure. The CA shows a more consistent loss in neuronal numbers, with different ethanol exposure paradigms, than the DG, which in contrast shows more pronounced and consistent deficits in synaptic plasticity. In this study we show that significant deficits in adult hippocampal neurogenesis are apparent in aged animals following prenatal ethanol exposure. Deficits in hippocampal neurogenesis were not apparent in younger animals. Surprisingly, even when ethanol exposure occurred in conjunction with maternal stress, deficits in neurogenesis did not occur at this young age, suggesting that the capacity for neurogenesis is highly conserved early in life. These findings are unique in that they demonstrate for the first time that deficits in neurogenesis associated with prenatal ethanol consumption appear later in life. Copyright © 2014. Published by Elsevier Ltd.

Direct and Passive Prenatal Nicotine Exposure and the Development of Externalizing Psychopathology

ERIC Educational Resources Information Center

Gatzke-Kopp, Lisa M.; Beauchaine, Theodore P.

2007-01-01

The association between maternal smoking during pregnancy and childhood antisocial outcomes has been demonstrated repeatedly across a variety of outcomes. Yet debate continues as to whether this association reflects a direct programming effect of nicotine on fetal brain development, or a phenotypic indicator of heritable liability passed from…

Cognitive Developmental Biology: History, Process and Fortune's Wheel

ERIC Educational Resources Information Center

Balaban, Evan

2006-01-01

Biological contributions to cognitive development continue to be conceived predominantly along deterministic lines, with proponents of different positions arguing about the preponderance of gene-based versus experience-based influences that organize brain circuits irreversibly during prenatal or early postnatal life, and evolutionary influences…

Computational modeling of resting-state activity demonstrates markers of normalcy in children with prenatal or perinatal stroke.

PubMed

Adhikari, Mohit H; Raja Beharelle, Anjali; Griffa, Alessandra; Hagmann, Patric; Solodkin, Ana; McIntosh, Anthony R; Small, Steven L; Deco, Gustavo

2015-06-10

Children who sustain a prenatal or perinatal brain injury in the form of a stroke develop remarkably normal cognitive functions in certain areas, with a particular strength in language skills. A dominant explanation for this is that brain regions from the contralesional hemisphere "take over" their functions, whereas the damaged areas and other ipsilesional regions play much less of a role. However, it is difficult to tease apart whether changes in neural activity after early brain injury are due to damage caused by the lesion or by processes related to postinjury reorganization. We sought to differentiate between these two causes by investigating the functional connectivity (FC) of brain areas during the resting state in human children with early brain injury using a computational model. We simulated a large-scale network consisting of realistic models of local brain areas coupled through anatomical connectivity information of healthy and injured participants. We then compared the resulting simulated FC values of healthy and injured participants with the empirical ones. We found that the empirical connectivity values, especially of the damaged areas, correlated better with simulated values of a healthy brain than those of an injured brain. This result indicates that the structural damage caused by an early brain injury is unlikely to have an adverse and sustained impact on the functional connections, albeit during the resting state, of damaged areas. Therefore, these areas could continue to play a role in the development of near-normal function in certain domains such as language in these children. Copyright © 2015 the authors 0270-6474/15/358914-11$15.00/0.

Prenatal Testosterone, Visual-Spatial Memory, and Numerical Skills in Young Children

ERIC Educational Resources Information Center

Bull, Rebecca; Davidson, Wendy Anne; Nordmann, Emily

2010-01-01

Lateralization of the brain is strongly influenced by prenatal androgens, with differential exposure thought to account for cognitive sex differences. This study investigated sex and individual differences and relationships between 2D:4D (the ratio of the 2nd to 4th digit [digit ratio] as a proxy indicator of prenatal testosterone exposure),…

Spatial learning impairment in prepubertal guinea pigs prenatally exposed to the organophosphorus pesticide chlorpyrifos: Toxicological implications

PubMed Central

Mamczarz, Jacek; Pescrille, Joseph D.; Gavrushenko, Lisa; Burke, Richard D.; Fawcett, William P.; DeTolla, Louis J.; Chen, Hegang; Pereira, Edna F.R.; Albuquerque, Edson X.

2017-01-01

Exposure of the developing brain to chlorpyrifos (CPF), an organophosphorus (OP) pesticide used extensively in agriculture worldwide, has been associated with increased prevalence of cognitive deficits in children, particularly boys. The present study was designed to test the hypothesis that cognitive deficits induced by prenatal exposure to sub-acute doses of CPF can be reproduced in precocial small species. To address this hypothesis, pregnant guinea pigs were injected daily with CPF (25 mg/kg, s.c.) or vehicle (peanut oil) for 10 days starting on presumed gestation day (GD) 53–55. Offspring were born around GD 65, weaned on postnatal day (PND) 20, and subjected to behavioral tests starting around PND 30. On the day of birth, butyrylcholinesterase (BuChE), an OP bioscavenger used as a biomarker of OP exposures, and acetylcholinesterase (AChE), a major molecular target of OP compounds, were significantly inhibited in the blood of CPF-exposed offspring. In their brains, BuChE, but not AChE, was significantly inhibited. Prenatal CPF exposure had no significant effect on locomotor activity or on locomotor habituation, a form of non-associative memory assessed in open fields. Spatial navigation in the Morris water maze (MWM) was found to be sexually dimorphic among guinea pigs, with males outperforming females. Prenatal CPF exposure impaired spatial learning more significantly among male than female guinea pigs and, consequently, reduced the sexual dimorphism of the task. The results presented here, which strongly support the test hypothesis, reveal that the guinea pig is a valuable animal model for preclinical assessment of the developmental neurotoxicity of OP pesticides. These findings are far reaching as they lay the groundwork for future studies aimed at identifying therapeutic interventions to treat and/or prevent the neurotoxic effects of CPF in the developing brain. PMID:27296654

Prenatal NMDA Receptor Antagonism Impaired Proliferation of Neuronal Progenitor, Leading to Fewer Glutamatergic Neurons in the Prefrontal Cortex

PubMed Central

Toriumi, Kazuya; Mouri, Akihiro; Narusawa, Shiho; Aoyama, Yuki; Ikawa, Natsumi; Lu, Lingling; Nagai, Taku; Mamiya, Takayoshi; Kim, Hyoung-Chun; Nabeshima, Toshitaka

2012-01-01

N-methyl--aspartate (NMDA) receptor is a glutamate receptor which has an important role on mammalian brain development. We have reported that prenatal treatment with phencyclidine (PCP), a NMDA receptor antagonist, induces long-lasting behavioral deficits and neurochemical changes. However, the mechanism by which the prenatal antagonism of NMDA receptor affects neurodevelopment, resulting in behavioral deficits, has remained unclear. Here, we report that prenatal NMDA receptor antagonism impaired the proliferation of neuronal progenitors, leading to a decrease in the progenitor pool in the ventricular and the subventricular zone. Furthermore, using a PCR array focused on neurogenesis and neuronal stem cells, we evaluated changes in gene expression causing the impairment of neuronal progenitor proliferation and found aberrant gene expression, such as Notch2 and Ntn1, in prenatal PCP-treated mice. Consequently, the density of glutamatergic neurons in the prefrontal cortex was decreased, probably resulting in glutamatergic hypofunction. Prenatal PCP-treated mice displayed behavioral deficits in cognitive memory and sensorimotor gating until adulthood. These findings suggest that NMDA receptors regulate the proliferation and maturation of progenitor cells for glutamatergic neuron during neurodevelopment, probably via the regulation of gene expression. PMID:22257896

CYP3A5 Mediates Effects of Cocaine on Human Neocorticogenesis: Studies using an In Vitro 3D Self-Organized hPSC Model with a Single Cortex-Like Unit.

PubMed

Lee, Chun-Ting; Chen, Jia; Kindberg, Abigail A; Bendriem, Raphael M; Spivak, Charles E; Williams, Melanie P; Richie, Christopher T; Handreck, Annelie; Mallon, Barbara S; Lupica, Carl R; Lin, Da-Ting; Harvey, Brandon K; Mash, Deborah C; Freed, William J

2017-02-01

Because of unavoidable confounding variables in the direct study of human subjects, it has been difficult to unravel the effects of prenatal cocaine exposure on the human fetal brain, as well as the cellular and biochemical mechanisms involved. Here, we propose a novel approach using a human pluripotent stem cell (hPSC)-based 3D neocortical organoid model. This model retains essential features of human neocortical development by encompassing a single self-organized neocortical structure, without including an animal-derived gelatinous matrix. We reported previously that prenatal cocaine exposure to rats during the most active period of neural progenitor proliferation induces cytoarchitectural changes in the embryonic neocortex. We also identified a role of CYP450 and consequent oxidative ER stress signaling in these effects. However, because of differences between humans and rodents in neocorticogenesis and brain CYP metabolism, translation of the research findings from the rodent model to human brain development is uncertain. Using hPSC 3D neocortical organoids, we demonstrate that the effects of cocaine are mediated through CYP3A5-induced generation of reactive oxygen species, inhibition of neocortical progenitor cell proliferation, induction of premature neuronal differentiation, and interruption of neural tissue development. Furthermore, knockdown of CYP3A5 reversed these cocaine-induced pathological phenotypes, suggesting CYP3A5 as a therapeutic target to mitigate the deleterious neurodevelopmental effects of prenatal cocaine exposure in humans. Moreover, 3D organoid methodology provides an innovative platform for identifying adverse effects of abused psychostimulants and pharmaceutical agents, and can be adapted for use in neurodevelopmental disorders with genetic etiologies.

Effects of prenatal stress and neonatal handling on anxiety, spatial learning and serotonergic system of male offspring mice.

PubMed

Akatsu, Shigemi; Ishikawa, Chihiro; Takemura, Kaori; Ohtani, Akiko; Shiga, Takashi

2015-12-01

Environmental factors during perinatal period have various effects on behavior. The present study examined the effects of prenatal stress and neonatal handling on anxiety and spatial learning of offspring. Prenatal stress increased anxiety-related behavior of adult offspring, whereas neonatal handling had no effect. In contrast, spatial learning was not affected by prenatal stress, but improved by neonatal handling in both prenatally stressed and non-stressed mice. Next, to elucidate possible brain mechanisms mediating effects of environmental factors on behavior, we focused on serotonin (5-HT) system in the frontal cortex and hippocampus which is involved in anxiety and learning. We examined effects of environmental factors on the mRNA expression of 5-HT1A, 5-HT2A and 5-HT2C receptors in the frontal cortex and hippocampus during postnatal period and adulthood. Both prenatal stress and neonatal handling altered the mRNA expression of 5-HT receptors. These effects were dependent on environmental factors, brain regions and developmental stages. In summary, the present study revealed that prenatal stress and neonatal handling had differential effects on anxiety and spatial learning of offspring, and concomitantly the expression of 5-HT receptors. It was also shown that the effects of prenatal stress on 5-HT system were recovered partially by neonatal handling. Copyright © 2015 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

Prenatal zinc prevents communication impairments and BDNF disturbance in a rat model of autism induced by prenatal lipopolysaccharide exposure.

PubMed

Kirsten, Thiago B; Queiroz-Hazarbassanov, Nicolle; Bernardi, Maria M; Felicio, Luciano F

2015-06-01

Aims: Previous investigations by our group have shown that prenatal exposure to lipopolysaccharide (LPS),which mimics infections by Gram-negative bacteria, induced autistic-like behavior. No effective treatment yet exists for autism. Therefore, we used our rat model to test a possible treatment for autism.We selected zinc as the prenatal treatment to prevent or ease the impairments induced by LPS because LPS induces hypozincaemia.Materials and methods:We evaluated the effects of LPS and zinc on female reproductive performance. Communication,which is impaired in autism,was tested in pups by ultrasonic vocalizations. Plasma levels of brain-derived neurotrophic factor (BDNF) were determined because it has been considered an autism important biomarker.Key findings: Prenatal LPS exposure reduced offspring number and treatment with zinc prevented this reduction.Moreover, pups that were prenatally exposed to LPS spent longer periods without calling their mothers, and posttreatment with zinc prevented this impairment induced by LPS to the same levels as controls. Prenatal LPS also increased BDNF levels in adult offspring, and posttreatment with zinc reduced the elevation of BDNF to the same levels as controls.Significance: BDNF hyperactivity was also found in several studies of autistic patients. Together with our previous studies, our model of prenatal LPS induced autistic-like behavioral, brain, and immune disturbances. This suggests that it is a valid rat model of autism. Prenatal zinc prevented reproductive, communication, and BDNF impairments.The present study revealed a potential beneficial effect of prenatal zinc administration for the prevention of autism with regard to the BDNF pathway.

Prenatal methylmercury exposure hampers glutathione antioxidant system ontogenesis and causes long-lasting oxidative stress in the mouse brain

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stringari, James; Nunes, Adriana K.C.; Franco, Jeferson L.

2008-02-15

During the perinatal period, the central nervous system (CNS) is extremely sensitive to metals, including methylmercury (MeHg). Although the mechanism(s) associated with MeHg-induced developmental neurotoxicity remains obscure, several studies point to the glutathione (GSH) antioxidant system as an important molecular target for this toxicant. To extend our recent findings of MeHg-induced GSH dyshomeostasis, the present study was designed to assess the developmental profile of the GSH antioxidant system in the mouse brain during the early postnatal period after in utero exposure to MeHg. Pregnant mice were exposed to different doses of MeHg (1, 3 and 10 mg/l, diluted in drinkingmore » water, ad libitum) during the gestational period. After delivery, pups were killed at different time points - postnatal days (PND) 1, 11 and 21 - and the whole brain was used for determining biochemical parameters related to the antioxidant GSH system, as well as mercury content and the levels of F{sub 2}-isoprostane. In control animals, cerebral GSH levels significantly increased over time during the early postnatal period; gestational exposure to MeHg caused a dose-dependent inhibition of this developmental event. Cerebral glutathione peroxidase (GPx) and glutathione reductase (GR) activities significantly increased over time during the early postnatal period in control animals; gestational MeHg exposure induced a dose-dependent inhibitory effect on both developmental phenomena. These adverse effects of prenatal MeHg exposure were corroborated by marked increases in cerebral F{sub 2}-isoprostanes levels at all time points. Significant negative correlations were found between F{sub 2}-isoprostanes and GSH, as well as between F{sub 2}-isoprostanes and GPx activity, suggesting that MeHg-induced disruption of the GSH system maturation is related to MeHg-induced increased lipid peroxidation in the pup brain. In utero MeHg exposure also caused a dose-dependent increase in the cerebral levels of mercury at birth. Even though the cerebral mercury concentration decreased to nearly basal levels at postnatal day 21, GSH levels, GPx and GR activities remained decreased in MeHg-exposed mice, indicating that prenatal exposure to MeHg affects the cerebral GSH antioxidant systems by inducing biochemical alterations that endure even when mercury tissue levels decrease and become indistinguishable from those noted in pups born to control dams. This study is the first to show that prenatal exposure to MeHg disrupts the postnatal development of the glutathione antioxidant system in the mouse brain, pointing to an additional molecular mechanism by which MeHg induces pro-oxidative damage in the developing CNS. Moreover, our experimental observation corroborates previous reports on the permanent functional deficits observed after prenatal MeHg exposure.« less

Prenatal methylmercury exposure hampers glutathione antioxidant system ontogenesis and causes long-lasting oxidative stress in the mouse brain

PubMed Central

Stringari, James; Nunes, Adriana KC; Franco, Jeferson L; Bohrer, Denise; Garcia, Solange C; Dafre, Alcir L; Milatovic, Dejan; Souza, Diogo O; Rocha, João BT; Aschner, Michael; Farina, Marcelo

2010-01-01

During the perinatal period, the central nervous system (CNS) is extremely sensitive to metals, including methylmercury (MeHg). Although the mechanism(s) associated with MeHg-induced developmental neurotoxicity remains obscure, several studies point to the glutathione (GSH) antioxidant system as an important molecular target for this toxicant. To extend our recent findings of MeHg-induced GSH dyshomeostasis, the present study was designed to assess the developmental profile of the GSH antioxidant system in the mouse brain during the early postnatal period after in utero exposure to MeHg. Pregnant mice were exposed to different doses of MeHg (1, 3 and 10 mg/L, diluted in drinking water, ad libitum) during the gestational period. After delivery, pups were killed at different time points - postnatal days (PNDs) 1, 11 and 21 - and the whole brain was used for determining biochemical parameters related to the antioxidant GSH system, as well as mercury content and the levels of F2-isoprostane. In control animals, cerebral GSH levels significantly increased over time during the early postnatal period; gestational exposure to MeHg caused a dose-dependent inhibition of this developmental event. Cerebral glutathione peroxidase (GPx) and glutathione reductase (GR) activities significantly increased over time during the early postnatal period in control animals; gestational MeHg exposure induced a dose-dependent inhibitory effect on both developmental phenomena. These adverse effects of prenatal MeHg exposure were corroborated by marked increases in cerebral F2-isoprostanes levels at all time points. Significant negative correlations were found between F2-isoprostanes and GSH, as well as between F2-isoprostanes and GPx activity, suggesting that MeHg-induced disruption of the GSH system maturation is related to MeHg-induced increased lipid peroxidation in the pup brain. In utero MeHg exposure also caused a dose-dependent increase in the cerebral levels of mercury at birth. Even though the cerebral mercury concentration decreased to nearly basal levels at postnatal day 21, GSH levels, GPx and GR activities remained decreased in MeHg-exposed mice, indicating that prenatal exposure to MeHg affects the cerebral GSH antioxidant systems by inducing biochemical alterations that endure even when mercury tissue levels decrease and become indistinguishable from those noted in pups born to control dams. This study is the first to show that prenatal exposure to MeHg disrupts the postnatal development of the glutathione antioxidant system in the mouse brain, pointing to an additional molecular mechanism by which MeHg induces pro-oxidative damage in the developing CNS. Moreover, our experimental observation corroborates previous reports on the permanent functional deficits observed after prenatal MeHg exposure. PMID:18023834

Frontostriatal connectivity in children during working memory and the effects of prenatal methamphetamine, alcohol, and polydrug exposure.

PubMed

Roussotte, Florence F; Rudie, Jeffrey D; Smith, Lynne; O'Connor, Mary J; Bookheimer, Susan Y; Narr, Katherine L; Sowell, Elizabeth R

2012-01-01

Various abnormalities in frontal and striatal regions have been reported in children with prenatal alcohol and/or methamphetamine exposure. In a recent fMRI study, we observed a correlation between accuracy on a working-memory task and functional activation in the putamen in children with prenatal methamphetamine and polydrug exposure. Because the putamen is part of the corticostriatal motor loop whereas the caudate is involved in the executive loop, we hypothesized that a loss of segregation between distinct corticostriatal networks may occur in these participants. The current study was designed to test this hypothesis using functional connectivity MRI. We examined 50 children ranging in age from 7 to 15, including 19 with prenatal methamphetamine exposure (15 of whom had concomitant prenatal alcohol exposure), 13 with prenatal exposure to alcohol but not methamphetamine, and 18 unexposed controls. We measured the coupling between blood oxygenation level dependent (BOLD) fluctuations during a working-memory task in four striatal seed regions and those in the rest of the brain. We found that the putamen seeds showed increased connectivity with frontal brain regions involved in executive functions while the caudate seeds showed decreased connectivity with some of these regions in both groups of exposed subjects compared to controls. These findings suggest that localized brain abnormalities resulting from prenatal exposure to alcohol and/or methamphetamine lead to a partial rewiring of corticostriatal networks. These results represent important progress in the field, and could have substantial clinical significance in helping devise more targeted treatments and remediation strategies designed to better serve the needs of this population. Copyright © 2012 S. Karger AG, Basel.

Developmental fluoxetine and prenatal stress effects on serotonin, dopamine, and synaptophysin density in the PFC and hippocampus of offspring at weaning.

PubMed

Gemmel, Mary; Rayen, Ine; Lotus, Tiffany; van Donkelaar, Eva; Steinbusch, Harry W; De Lacalle, Sonsoles; Kokras, Nikolaos; Dalla, Christina; Pawluski, Jodi L

2016-04-01

Selective serotonin reuptake inhibitor medication exposure during the perinatal period can have a long term impact in adult offspring on neuroplasticity and the serotonergic system, but the impact of these medications during early development is poorly understood. The aim of this study was to determine the effects of developmental exposure to the SSRI, fluoxetine, on the serotonergic system, dopaminergic system, and synaptophysin density in the prefrontal cortex and hippocampus, as well as number of immature neurons in the dentate gyrus, in juvenile rat offspring at weaning. To model aspects of maternal depression, prenatal restraint stress was used. Sprague-Dawley rat offspring were exposed to either prenatal stress and/or fluoxetine. Main findings show that developmental fluoxetine exposure to prenatally stressed offspring decreased 5-HT and 5-HIAA levels and altered the dopaminergic system in the hippocampus. Prenatal stress, regardless of fluoxetine, increased synaptophysin density in the PFC. This work indicates that early exposure to maternal stress and SSRI medication can alter brain monoamine levels and synaptophysin density in offspring at weaning. © 2015 Wiley Periodicals, Inc.

Prenatal androgen exposure alters girls' responses to information indicating gender-appropriate behaviour

PubMed Central

Hines, Melissa; Pasterski, Vickie; Spencer, Debra; Neufeld, Sharon; Patalay, Praveetha; Hindmarsh, Peter C.; Hughes, Ieuan A.; Acerini, Carlo L.

2016-01-01

Individual variability in human gender-related behaviour is influenced by many factors, including androgen exposure prenatally, as well as self-socialization and socialization by others postnatally. Many studies have looked at these types of influences in isolation, but little is known about how they work together. Here, we report that girls exposed to high concentrations of androgens prenatally, because they have the genetic condition congenital adrenal hyperplasia, show changes in processes related to self-socialization of gender-related behaviour. Specifically, they are less responsive than other girls to information that particular objects are for girls and they show reduced imitation of female models choosing particular objects. These findings suggest that prenatal androgen exposure may influence subsequent gender-related behaviours, including object (toy) choices, in part by changing processes involved in the self-socialization of gendered behaviour, rather than only by inducing permanent changes in the brain during early development. In addition, the findings suggest that some of the behavioural effects of prenatal androgen exposure might be subject to alteration by postnatal socialization processes. The findings also suggest a previously unknown influence of early androgen exposure on later processes involved in self-socialization of gender-related behaviour, and thus expand understanding of the developmental systems regulating human gender development. PMID:26833843

Prenatal androgen exposure alters girls' responses to information indicating gender-appropriate behaviour.

PubMed

Hines, Melissa; Pasterski, Vickie; Spencer, Debra; Neufeld, Sharon; Patalay, Praveetha; Hindmarsh, Peter C; Hughes, Ieuan A; Acerini, Carlo L

2016-02-19

Individual variability in human gender-related behaviour is influenced by many factors, including androgen exposure prenatally, as well as self-socialization and socialization by others postnatally. Many studies have looked at these types of influences in isolation, but little is known about how they work together. Here, we report that girls exposed to high concentrations of androgens prenatally, because they have the genetic condition congenital adrenal hyperplasia, show changes in processes related to self-socialization of gender-related behaviour. Specifically, they are less responsive than other girls to information that particular objects are for girls and they show reduced imitation of female models choosing particular objects. These findings suggest that prenatal androgen exposure may influence subsequent gender-related behaviours, including object (toy) choices, in part by changing processes involved in the self-socialization of gendered behaviour, rather than only by inducing permanent changes in the brain during early development. In addition, the findings suggest that some of the behavioural effects of prenatal androgen exposure might be subject to alteration by postnatal socialization processes. The findings also suggest a previously unknown influence of early androgen exposure on later processes involved in self-socialization of gender-related behaviour, and thus expand understanding of the developmental systems regulating human gender development. © 2016 The Author(s).

Chromatin Switches during Neural Cell Differentiation and Their Dysregulation by Prenatal Alcohol Exposure.

PubMed

Gavin, David P; Grayson, Dennis R; Varghese, Sajoy P; Guizzetti, Marina

2017-05-11

Prenatal alcohol exposure causes persistent neuropsychiatric deficits included under the term fetal alcohol spectrum disorders (FASD). Cellular identity emerges from a cascade of intrinsic and extrinsic (involving cell-cell interactions and signaling) processes that are partially initiated and maintained through changes in chromatin structure. Prenatal alcohol exposure influences neuronal and astrocyte development, permanently altering brain connectivity. Prenatal alcohol exposure also alters chromatin structure through histone and DNA modifications. However, the data linking alcohol-induced differentiation changes with developmental alterations in chromatin structure remain to be elucidated. In the first part of this review, we discuss the sequence of chromatin structural changes involved in neural cell differentiation during normal development. We then discuss the effects of prenatal alcohol on developmental histone modifications and DNA methylation in the context of neurogenesis and astrogliogenesis. We attempt to synthesize the developmental literature with the FASD literature, proposing that alcohol-induced changes to chromatin structure account for altered neurogenesis and astrogliogenesis as well as altered neuron and astrocyte differentiation. Together these changes may contribute to the cognitive and behavioral abnormalities in FASD. Future studies using standardized alcohol exposure paradigms at specific developmental stages will advance the understanding of how chromatin structural changes impact neural cell fate and maturation in FASD.

Chromatin Switches during Neural Cell Differentiation and Their Dysregulation by Prenatal Alcohol Exposure

PubMed Central

Gavin, David P.; Grayson, Dennis R.; Varghese, Sajoy P.; Guizzetti, Marina

2017-01-01

Prenatal alcohol exposure causes persistent neuropsychiatric deficits included under the term fetal alcohol spectrum disorders (FASD). Cellular identity emerges from a cascade of intrinsic and extrinsic (involving cell-cell interactions and signaling) processes that are partially initiated and maintained through changes in chromatin structure. Prenatal alcohol exposure influences neuronal and astrocyte development, permanently altering brain connectivity. Prenatal alcohol exposure also alters chromatin structure through histone and DNA modifications. However, the data linking alcohol-induced differentiation changes with developmental alterations in chromatin structure remain to be elucidated. In the first part of this review, we discuss the sequence of chromatin structural changes involved in neural cell differentiation during normal development. We then discuss the effects of prenatal alcohol on developmental histone modifications and DNA methylation in the context of neurogenesis and astrogliogenesis. We attempt to synthesize the developmental literature with the FASD literature, proposing that alcohol-induced changes to chromatin structure account for altered neurogenesis and astrogliogenesis as well as altered neuron and astrocyte differentiation. Together these changes may contribute to the cognitive and behavioral abnormalities in FASD. Future studies using standardized alcohol exposure paradigms at specific developmental stages will advance the understanding of how chromatin structural changes impact neural cell fate and maturation in FASD. PMID:28492482

Functional connectivity abnormalities and associated cognitive deficits in fetal alcohol Spectrum disorders (FASD).

PubMed

Wozniak, Jeffrey R; Mueller, Bryon A; Mattson, Sarah N; Coles, Claire D; Kable, Julie A; Jones, Kenneth L; Boys, Christopher J; Lim, Kelvin O; Riley, Edward P; Sowell, Elizabeth R

2017-10-01

Consistent with well-documented structural and microstructural abnormalities in prenatal alcohol exposure (PAE), recent studies suggest that functional connectivity (FC) may also be disrupted. We evaluated whole-brain FC in a large multi-site sample, examined its cognitive correlates, and explored its potential to objectively identify neurodevelopmental abnormality in individuals without definitive dysmorphic features. Included were 75 children with PAE and 68 controls from four sites. All participants had documented heavy prenatal alcohol exposure. All underwent a formal evaluation of physical anomalies and dysmorphic facial features. MRI data were collected using modified matched protocols on three platforms (Siemens, GE, and Philips). Resting-state FC was examined using whole-brain graph theory metrics to characterize each individual's connectivity. Although whole-brain FC metrics did not discriminate prenatally-exposed from unexposed overall, atypical FC (> 1 standard deviation from the grand mean) was significantly more common (2.7 times) in the PAE group vs. In a subset of 55 individuals (PAE and controls) whose dysmorphology examination could not definitively characterize them as either Fetal Alcohol Syndrome (FAS) or non-FAS, atypical FC was seen in 27 % of the PAE group, but 0 % of controls. Across participants, a 1 % difference in local network efficiency was associated with a 36 point difference in global cognitive functioning. Whole-brain FC metrics have potential to identify individuals with objective neurodevelopmental abnormalities from prenatal alcohol exposure. When applied to individuals unable to be classified as FAS or non-FAS from dysmorphology alone, these measures separate prenatally-exposed from non-exposed with high specificity.

Gender-specific effects of prenatal and adolescent exposure to tobacco smoke on auditory and visual attention.

PubMed

Jacobsen, Leslie K; Slotkin, Theodore A; Mencl, W Einar; Frost, Stephen J; Pugh, Kenneth R

2007-12-01

Prenatal exposure to active maternal tobacco smoking elevates risk of cognitive and auditory processing deficits, and of smoking in offspring. Recent preclinical work has demonstrated a sex-specific pattern of reduction in cortical cholinergic markers following prenatal, adolescent, or combined prenatal and adolescent exposure to nicotine, the primary psychoactive component of tobacco smoke. Given the importance of cortical cholinergic neurotransmission to attentional function, we examined auditory and visual selective and divided attention in 181 male and female adolescent smokers and nonsmokers with and without prenatal exposure to maternal smoking. Groups did not differ in age, educational attainment, symptoms of inattention, or years of parent education. A subset of 63 subjects also underwent functional magnetic resonance imaging while performing an auditory and visual selective and divided attention task. Among females, exposure to tobacco smoke during prenatal or adolescent development was associated with reductions in auditory and visual attention performance accuracy that were greatest in female smokers with prenatal exposure (combined exposure). Among males, combined exposure was associated with marked deficits in auditory attention, suggesting greater vulnerability of neurocircuitry supporting auditory attention to insult stemming from developmental exposure to tobacco smoke in males. Activation of brain regions that support auditory attention was greater in adolescents with prenatal or adolescent exposure to tobacco smoke relative to adolescents with neither prenatal nor adolescent exposure to tobacco smoke. These findings extend earlier preclinical work and suggest that, in humans, prenatal and adolescent exposure to nicotine exerts gender-specific deleterious effects on auditory and visual attention, with concomitant alterations in the efficiency of neurocircuitry supporting auditory attention.

The Relationship between the Second-to-Fourth Digit Ratio and Behavioral Sexual Dimorphism in School-Aged Children.

PubMed

Mitsui, Takahiko; Araki, Atsuko; Miyashita, Chihiro; Ito, Sachiko; Ikeno, Tamiko; Sasaki, Seiko; Kitta, Takeya; Moriya, Kimihiko; Cho, Kazutoshi; Morioka, Keita; Kishi, Reiko; Shinohara, Nobuo; Takeda, Masayuki; Nonomura, Katsuya

2016-01-01

Sexually dimorphic brain development and behavior are known to be influenced by sex hormones exposure in prenatal periods. On the other hand, second-to forth digit ratio (2D/4D) has been used as an indirect method to investigate the putative effects of prenatal exposure to androgen. In the present study, we herein investigated the relationship between gender-role play behavior and the second-to-fourth digit ratio (2D/4D), which has been used as an indirect method to investigate the putative effects of prenatal exposure to androgens, in school-aged children. Among 4981 children who became 8 years old by November 2014 and were contactable for this survey by The Hokkaido Study of Environment and Children's Health, 1631 (32.7%), who had data for 2D/4D and Pre-school Activities Inventory (PSAI) as well as data for the survey at baseline, were available for analysis. Parents sent reports of PSAI on the sex-typical characteristics, preferred toys, and play activities of children, and black and white photocopies of the left and right hand palms via mail. PSAI consisted of 12 masculine items and 12 feminine items, and a composite score was created by subtracting the feminine score from the masculine score, with higher scores representing masculine-typical behavior. While composite scores in PSAI were significantly higher in boys than in girls, 2D/4D was significantly lower in boys than in girls. Although the presence or absence of brothers or sisters affected the composite, masculine, and feminine scored of PSAI, a multivariate regression model revealed that 2D/4D negatively correlated with the composite scores of PSAI in boys, whereas no correlation was found in girls. Although 2D/4D negatively correlated with the masculine score in boys and girls, no correlation was observed between 2D/4D and the feminine score. In conclusion, although social factors, such as the existence of brother or sisters, affect dimorphic brain development and behavior in childhood, the present study revealed that the prenatal hormonal environment was an important factor influencing masculine-typical dimorphic brain development and behavior in school-aged children.

Webinar Presentation: Prenatal Residential Proximity to Agricultural Pesticide Applications and IQ in Children

EPA Pesticide Factsheets

This presentation, Prenatal Residential Proximity to Agricultural Pesticide Applications and IQ in Children, was given at the NIEHS/EPA Children's Centers 2015 Webinar Series: Brain Health held on Aug. 12, 2015.

Fetal cerebral imaging - ultrasound vs. MRI: an update.

PubMed

Blondiaux, Eléonore; Garel, Catherine

2013-11-01

The purpose of this article is to analyze the advantages and limitations of prenatal ultrasonography (US) and magnetic resonance imaging (MRI) in the evaluation of the fetal brain. These imaging modalities should not be seen as competitive but rather as complementary. There are wide variations in the world regarding screening policies, technology, skills, and legislation about termination of pregnancy, and these variations markedly impact on the way of using prenatal imaging. According to the contribution expected from each technique and to local working conditions, one should choose the most appropriate imaging modality on a case-by-case basis. The advantages and limitations of US and MRI in the setting of fetal brain imaging are displayed. Different anatomical regions (midline, ventricles, subependymal area, cerebral parenchyma, pericerebral space, posterior fossa) and pathological conditions are analyzed and illustrated in order to compare the respective contribution of each technique. An accurate prenatal diagnosis of cerebral abnormalities is of utmost importance for prenatal counseling.

Prenatal Bisphenol A Exposure Alters Sex-Specific Estrogen Receptor Expression in the Neonatal Rat Hypothalamus and Amygdala

PubMed Central

Patisaul, Heather B.

2013-01-01

Bisphenol A (BPA) exposure is ubiquitous, and in laboratory animals, early-life BPA exposure has been shown to alter sex-specific neural organization, neuroendocrine physiology, and behavior. The specific mechanisms underlying these brain-related outcomes, however, remain largely unknown, constraining the capacity to ascertain the potential human relevance of neural effects observed in animal models. In the perinatal rat brain, estrogen is masculinizing, suggesting that BPA-induced perturbation of estrogen receptor (ESR) expression may underpin later in-life neuroendocrine effects. We hypothesized that prenatal BPA exposure alters sex-specific ESR1 (ERα) and ESR2 (ERβ) expression in postnatal limbic nuclei. Sprague Dawley rats were mated and gavaged on gestational days (GDs) 6–21 with vehicle, 2.5 or 25 μg/kg bw/day BPA, or 5 or 10 μg/kg bw/day ethinyl estradiol. An additional group was restrained but not gavaged (naïve control). Offspring were sacrificed the day after birth to quantify ESR gene expression throughout the hypothalamus and amygdala by in situ hybridization. Relative to the vehicle group, significant effects of BPA were observed on ESR1 and ESR2 expression throughout the mediobasal hypothalamus and amygdala in both sexes. Significant differences in ESR expression were also observed in the mediobasal hypothalamus and amygdala of the naïve control group compared with the vehicle group, highlighting the potential for gavage to influence gene expression in the developing brain. These results indicate that ESR expression in the neonatal brain of both sexes can be altered by low-dose prenatal BPA exposure. PMID:23457122

Decreased serotonin level during pregnancy alters morphological and functional characteristics of tonic nociceptive system in juvenile offspring of the rat.

PubMed

Butkevich, Irina P; Khozhai, Ludmila I; Mikhailenko, Victor A; Otellin, Vladimir A

2003-11-13

Serotonin (5-HT) contributes to the prenatal development of the central nervous system, acting as a morphogen in the young embryo and later as a neurotransmitter. This biologically active agent influences both morphological and biochemical differentiation of raphe neurons, which give rise to the descending serotonergic paths that regulate the processing of acutely evoked nociceptive inputs. The involvement of 5-HT in the prenatal development of tonic nociceptive system has not been studied. In the present study we evaluated the effects of a single injection (400 mg/kg, 2 ml, i.p.) of the 5-HT synthesis inhibitor, para-chlorophenylalanine (pCPA), given to pregnant rats during the critical period fetal serotonin development. The functional integrity of the tonic nociceptive response was investigated in 25 day old rats using the classic formalin test. Morphological analysis of brain structures involved in formalin-induced pain and 5-HT levels in the heads of 12-day embryos were also evaluated. Embryonic levels of 5-HT were significantly lowered by the treatment. The juvenile rats from pCPA-treated females showed altered brain morphology and cell differentiation in the developing cortex, hippocampus, raphe nuclei, and substantia nigra. In the formalin test, there were significant decreases in the intensity and duration of the second phase of the formalin-induced response, characterizing persistent, tonic pain. The extent of impairments in the brain structures correlated positively with the level of decrease in the behavioral responses. The data demonstrate the involvement of 5-HT in the prenatal development of the tonic nociceptive system. The decreased tonic component of the behavioral response can be explained by lower activity of the descending excitatory serotonergic system originating in the raphe nuclei, resulting in decreased tonic pain processing organized at the level of the dorsal horn of the spinal cord.

Sex-Typical Play: Masculinization/Defeminization in Girls with an Autism Spectrum Condition

ERIC Educational Resources Information Center

Knickmeyer, Rebecca C.; Wheelwright, Sally; Baron-Cohen, Simon B.

2008-01-01

We tested the hypothesis that prenatal masculinization of the brain by androgens increases risk of developing an autism spectrum condition (ASC). Sex-typical play was measured in n = 66 children diagnosed with an ASC and n = 55 typically developing age-matched controls. Consistent with the hypothesis, girls with autism did not show the…

Differentiating prenatal exposure to methamphetamine and alcohol versus alcohol and not methamphetamine using tensor based brain morphometry and discriminant analysis

PubMed Central

Sowell, Elizabeth R.; Leow, Alex D.; Bookheimer, Susan Y.; Smith, Lynne M.; O’Connor, Mary J.; Kan, Eric; Rosso, Carly; Houston, Suzanne; Dinov, Ivo D.; Thompson, Paul M.

2010-01-01

Here we investigate the effects of prenatal exposure to methamphetamine (MA) on local brain volume using magnetic resonance imaging. Because many who use MA during pregnancy also use alcohol, a known teratogen, we examined whether local brain volumes differed among 61 children (ages 5 to 15), 21 with prenatal MA exposure, 18 with concomitant prenatal alcohol exposure (the MAA group), 13 with heavy prenatal alcohol but not MA exposure (ALC group), and 27 unexposed controls (CON group). Volume reductions were observed in both exposure groups relative to controls in striatal and thalamic regions bilaterally, and right prefrontal and left occipitoparietal cortices. Striatal volume reductions were more severe in the MAA group than in the ALC group, and within the MAA group, a negative correlation between full-scale IQ (FSIQ) scores and caudate volume was observed. Limbic structures including the anterior and posterior cingulate, the inferior frontal gyrus (IFG) and ventral and lateral temporal lobes bilaterally were increased in volume in both exposure groups. Further, cingulate and right IFG volume increases were more pronounced in the MAA than ALC group. Discriminant function analyses using local volume measurements and FSIQ were used to predict group membership, yielding factor scores that correctly classified 72% of participants in jackknife analyses. These findings suggest that striatal and limbic structures, known to be sites of neurotoxicity in adult MA abusers, may be more vulnerable to prenatal MA exposure than alcohol exposure, and that more severe striatal damage is associated with more severe cognitive deficit. PMID:20237258

Nicotine during pregnancy: changes induced in neurotransmission, which could heighten proclivity to addict and induce maladaptive control of attention.

PubMed

Kohlmeier, K A

2015-06-01

Prenatal exposure to nicotine, occurring either via maternal smoking or via use of transdermal nicotine patches to facilitate cigarette abstinence by pregnant women, is associated with ∼ 13% of pregnancies worldwide. Nicotine exposure during gestation has been correlated with several negative physiological and psychosocial outcomes, including heightened risk for aberrant behaviors involving alterations in processing of attention as well as an enhanced liability for development of drug dependency. Nicotine is a terotogen, altering neuronal development of various neurotransmitter systems, and it is likely these alterations participate in postnatal deficits in attention control and facilitate development of drug addiction. This review discusses the alterations in neuronal development within the brain's major neurotransmitter systems, with special emphasis placed on alterations within the laterodorsal tegmental nucleus, in light of the role this cholinergic nucleus plays in attention and addiction. Changes induced within this nucleus by gestational exposure to nicotine, in combination with changes induced in other brain regions, are likely to contribute to the transgenerational burden imposed by nicotine. Although neuroplastic changes induced by nicotine are not likely to act in isolation, and are expected to interact with epigenetic changes induced by preconception exposure to drugs of abuse, unraveling these changes within the developing brain will facilitate eventual development of targeted treatments for the unique vulnerability for arousal disorders and development of addiction within the population of individuals who have been prenatally exposed to nicotine.

Effects of prenatal stress on differentiation of the sexually dimorphic nucleus of the preoptic area (SDN-POA) of the rat brain.

PubMed

Anderson, D K; Rhees, R W; Fleming, D E

1985-04-15

The present study was designed to determine the effects of prenatal malnutrition or environmental stress on the development of the sexually dimorphic nucleus of the preoptic area (SDN-POA). Pregnant rats were divided into a control group and two treatment groups (immobilization-illumination-heat or environmental stress, and nutritional stress). The two forms of stress were administered during the third trimester of gestation (days 14-20). Male and female offspring were sacrificed at birth, 20, and 60 days postnatally. The cross-sectional area of the SDN-POA was identified under light microscopy and was measured. The data confirm previous studies by showing a significant sex difference in the SDN-POA between control male and female rats. Prenatally stressed males sacrificed 20 and 60 days after birth showed SDN-POA areas 50% smaller than the nuclear areas of control males. The size of the SDN-POA of female offspring, however, was not significantly altered by prenatal treatments.

Fetal endocrine therapy for congenital adrenal hyperplasia should not be done.

PubMed

Miller, Walter L

2015-06-01

Prenatal treatment of congenital adrenal hyperplasia by administering dexamethasone to a woman presumed to be carrying an at-risk fetus remains a controversial experimental treatment. Review of data from animal experimentation and human trials indicates that dexamethasone cannot be considered safe for the fetus. In animals, prenatal dexamethasone decreases birth weight, affects renal, pancreatic beta cell and brain development, increases anxiety and predisposes to adult hypertension and hyperglycemia. In human studies, prenatal dexamethasone is associated with orofacial clefts, decreased birth weight, poorer verbal working memory, and poorer self-perception of scholastic and social competence. Numerous medical societies have cautioned that prenatal treatment of adrenal hyperplasia with dexamethasone is not appropriate for routine clinical practice and should only be done in Institutional Review Board approved, prospective clinical research settings with written informed consent. The data indicate that this treatment is inconsistent with the classic medical ethical maxim to 'first do no harm'. Copyright © 2015 Elsevier Ltd. All rights reserved.

Testing the prenatal hormone hypothesis of tic-related disorders: gender identity and gender role behavior.

PubMed

Alexander, Gerianne M; Peterson, Bradley S

2004-01-01

The hypothesis that prenatal masculinization of the brain increases risk of tic disorders in postnatal life was tested by measuring gender and gender role behavior in 89 children and adults with a clinical diagnosis of Tourette syndrome or obsessive compulsive disorder and 67 healthy, unaffected children and adults. Consistent with this hypothesis, a tic disorder in females was associated with more gender dysphoria, increased masculine play preferences, and a more typically "masculine" pattern of performance on two sex-typed spatial tasks. Males with tic disorders reported increased masculine play preferences, and the strength of these preferences was positively associated with the severity of tic symptoms. In addition, unlike their female counterparts, males with tic disorders showed a relative impairment in mental rotation ability. These behavioral profiles are consistent with those of children who have verifiable elevations in prenatal androgen levels. These findings therefore support the hypothesis that an altered androgen-dependent process of sexual differentiation during prenatal life may contribute to the development of tic-related disorders.

Molecular mechanisms of maternal cannabis and cigarette use on human neurodevelopment

PubMed Central

Morris, Claudia V.; DiNieri, Jennifer A.; Szutorisz, Henrietta; Hurd, Yasmin L.

2011-01-01

Prenatal development is highly sensitive to maternal drug use due to the vulnerability for disruption of the fetal brain where the ongoing neurodevelopmental, resulting in lifelong consequences that can enhance risk for psychiatric disorders. Cannabis and cigarettes are the most commonly used illicit and licit substances, respectively, among pregnant women. While the behavioral consequences of prenatal cannabis and cigarette exposure have been well-documented in epidemiological and clinical studies, only recently have investigations into the molecular mechanisms associated with the developmental impact of early drug exposure been addressed. This article reviews the literature relevant to long-term gene expression disturbances in the human fetal brain in relation to maternal cannabis and cigarette use. To provide translational insights, we discuss animal models in which protracted molecular consequences of prenatal cannabis and cigarette exposure can be better explored and enable future evaluation of epigenetic pathways such as DNA methylation and histone modification that could potentially maintain abnormal gene regulation and related behavioral disturbances. Altogether, this information may help to address the current gaps of knowledge regarding the impact of early drug exposure that set in motion lifelong molecular disturbances that underlie vulnerability to psychiatric disorders. PMID:22103415

Neuroimaging findings of congenital Zika virus infection: a pictorial essay.

PubMed

Zare Mehrjardi, Mohammad; Poretti, Andrea; Huisman, Thierry A G M; Werner, Heron; Keshavarz, Elham; Araujo Júnior, Edward

2017-03-01

Zika virus (ZIKV) is a mosquito-borne arbovirus from the Flaviviridae family. It had caused several epidemics since its discovery in 1947, but there was no significant attention to this virus until the recent outbreak in Brazil in 2015. The main concern is the causal relationship between prenatal ZIKV infection and congenital microcephaly, which has been confirmed recently. Moreover, ZIKV may cause other central nervous system abnormalities such as brain parenchymal atrophy with secondary ventriculomegaly, intracranial calcification, malformations of cortical development (such as polymicrogyria, and lissencephaly-pachygyria), agenesis/hypoplasia of the corpus callosum, cerebellar and brainstem hypoplasia, sensorineural hearing-loss, and ocular abnormalities as well as arthrogryposis in the infected fetuses. Postnatal (acquired) ZIKV infection usually has an asymptomatic or mildly symptomatic course, while prenatal (congenital) ZIKV infection has a more severe course and may cause severe brain anomalies that are described as congenital Zika syndrome. In this pictorial essay, we aim to illustrate the prenatal and postnatal neuroimaging findings that may be seen in fetuses and neonates with congenital Zika syndrome, and will discuss possible radiological differential diagnoses. A detailed knowledge of these findings is paramount for an early correct diagnosis, prognosis determination, and counseling of the affected children and families.

Systemic Prenatal Insults Disrupt Telencephalon Development

PubMed Central

Robinson, Shenandoah

2006-01-01

Infants born prematurely are prone to chronic neurologic deficits including cerebral palsy (CP), epilepsy, cognitive delay, behavioral problems, and neurosensory impairments. In affected children, imaging and neuropathological findings demonstrate significant damage to white matter. The extent of cortical damage has been less obvious. Advances in the understanding of telencephalon development provide insights into how systemic intrauterine insults affect the developing white matter, subplate and cortex, and lead to multiple neurologic impairments. In addition to white matter oligodendrocytes and axons, other elements at risk for perinatal brain injury include subplate neurons, GABAergic neurons migrating through white matter and subplate, and afferents of maturing neurotransmitter systems. Common insults including hypoxia-ischemia and infection often affect the developing brain differently than the mature brain, and insults precipitate a cascade of damage to multiple neural lineages. Insights from development can identify potential targets for therapies to repair the damaged neonatal brain before it has matured. PMID:16061421

Prenatal caffeine intake differently affects synaptic proteins during fetal brain development.

PubMed

Mioranzza, Sabrina; Nunes, Fernanda; Marques, Daniela M; Fioreze, Gabriela T; Rocha, Andréia S; Botton, Paulo Henrique S; Costa, Marcelo S; Porciúncula, Lisiane O

2014-08-01

Caffeine is the psychostimulant most consumed worldwide. However, little is known about its effects during fetal brain development. In this study, adult female Wistar rats received caffeine in drinking water (0.1, 0.3 and 1.0 g/L) during the active cycle in weekdays, two weeks before mating and throughout pregnancy. Cerebral cortex and hippocampus from embryonic stages 18 or 20 (E18 or E20, respectively) were collected for immunodetection of the following synaptic proteins: brain-derived neurotrophic factor (BDNF), TrkB receptor, Sonic Hedgehog (Shh), Growth Associated Protein 43 (GAP-43) and Synaptosomal-associated Protein 25 (SNAP-25). Besides, the estimation of NeuN-stained nuclei (mature neurons) and non-neuronal nuclei was verified in both brain regions and embryonic periods. Caffeine (1.0 g/L) decreased the body weight of embryos at E20. Cortical BDNF at E18 was decreased by caffeine (1.0 g/L), while it increased at E20, with no major effects on TrkB receptors. In the hippocampus, caffeine decreased TrkB receptor only at E18, with no effects on BDNF. Moderate and high doses of caffeine promoted an increase in Shh in both brain regions at E18, and in the hippocampus at E20. Caffeine (0.3g/L) decreased GAP-43 only in the hippocampus at E18. The NeuN-stained nuclei increased in the cortex at E20 by lower dose and in the hippocampus at E18 by moderate dose. Our data revealed that caffeine transitorily affect synaptic proteins during fetal brain development. The increased number of NeuN-stained nuclei by prenatal caffeine suggests a possible acceleration of the telencephalon maturation. Although some modifications in the synaptic proteins were transient, our data suggest that caffeine even in lower doses may alter the fetal brain development. Copyright © 2014 ISDN. Published by Elsevier Ltd. All rights reserved.

Early prenatal vitamin D concentrations and social-emotional development in infants.

PubMed

Chawla, Devika; Fuemmeler, Bernard; Benjamin-Neelon, Sara E; Hoyo, Cathrine; Murphy, Susan; Daniels, Julie L

2017-12-04

Many pregnant women in the United States have suboptimal vitamin D, but the impact on infant development is unclear. Moreover, no pregnancy-specific vitamin D recommendations have been widely accepted. Given the ubiquitous expression of vitamin D receptors in the brain, we investigated the association between early prenatal plasma 25-hydroxyvitamin D (25(OH)D) concentrations and children's social and emotional development in the Newborn Epigenetic Study, a prospective study of pregnancies from 2009 to 2011 in Durham, North Carolina. We measured 25(OH)D concentrations in first or second trimester plasma samples and categorized 25(OH)D concentrations into quartiles. Covariates were derived from maternal questionnaires. Mothers completed the Infant Toddler Social-Emotional Development Assessment when children were 12-24 months of age. We used multivariable linear regression to evaluate associations between 25(OH)D and specific behavior scores, adjusted for season of blood draw, maternal age, education, parity, smoking, marital status, prepregnancy BMI, and infant gender. We investigated effect-measure modification by race/ethnicity. Of the 218 mother-infant pairs with complete data, Black mothers had much lower 25(OH)D concentrations as compared to White and Hispanic mothers. After adjustment, lower prenatal 25(OH)D was associated with slightly higher (less favorable) Internalizing scores among White children, but lower (more favorable) Internalizing scores among Black and Hispanic children. Lower prenatal 25(OH)D also appears to be associated with higher (less favorable) dysregulation scores, though only among White and Hispanic children. Though imprecise, preliminary results warrant further investigation regarding a role for prenatal vitamin D on children's early social and emotional development.

Fetal alcohol spectrum disorders: an overview.

PubMed

Riley, Edward P; Infante, M Alejandra; Warren, Kenneth R

2011-06-01

When fetal alcohol syndrome (FAS) was initially described, diagnosis was based upon physical parameters including facial anomalies and growth retardation, with evidence of developmental delay or mental deficiency. Forty years of research has shown that FAS lies towards the extreme end of what are now termed fetal alcohol spectrum disorders (FASD). The most profound effects of prenatal alcohol exposure are on the developing brain and the cognitive and behavioral effects that ensue. Alcohol exposure affects brain development via numerous pathways at all stages from neurogenesis to myelination. For example, the same processes that give rise to the facial characteristics of FAS also cause abnormal brain development. Behaviors as diverse as executive functioning to motor control are affected. This special issue of Neuropsychology Review addresses these changes in brain and behavior highlighting the relationship between the two. A diagnostic goal is to recognize FAS as a disorder of brain rather than one of physical characteristics.

Volumetric MRI study of brain in children with intrauterine exposure to cocaine, alcohol, tobacco, and marijuana.

PubMed

Rivkin, Michael J; Davis, Peter E; Lemaster, Jennifer L; Cabral, Howard J; Warfield, Simon K; Mulkern, Robert V; Robson, Caroline D; Rose-Jacobs, Ruth; Frank, Deborah A

2008-04-01

The objective of this study was to use volumetric MRI to study brain volumes in 10- to 14-year-old children with and without intrauterine exposure to cocaine, alcohol, cigarettes, or marijuana. Volumetric MRI was performed on 35 children (mean age: 12.3 years; 14 with intrauterine exposure to cocaine, 21 with no intrauterine exposure to cocaine) to determine the effect of prenatal drug exposure on volumes of cortical gray matter; white matter; subcortical gray matter; cerebrospinal fluid; and total parenchymal volume. Head circumference was also obtained. Analyses of each individual substance were adjusted for demographic characteristics and the remaining 3 prenatal substance exposures. Regression analyses adjusted for demographic characteristics showed that children with intrauterine exposure to cocaine had lower mean cortical gray matter and total parenchymal volumes and smaller mean head circumference than comparison children. After adjustment for other prenatal exposures, these volumes remained smaller but lost statistical significance. Similar analyses conducted for prenatal ethanol exposure adjusted for demographics showed significant reduction in mean cortical gray matter; total parenchymal volumes; and head circumference, which remained smaller but lost statistical significance after adjustment for the remaining 3 exposures. Notably, prenatal cigarette exposure was associated with significant reductions in cortical gray matter and total parenchymal volumes and head circumference after adjustment for demographics that retained marginal significance after adjustment for the other 3 exposures. Finally, as the number of exposures to prenatal substances grew, cortical gray matter and total parenchymal volumes and head circumference declined significantly with smallest measures found among children exposed to all 4. CONCLUSIONS; These data suggest that intrauterine exposures to cocaine, alcohol, and cigarettes are individually related to reduced head circumference; cortical gray matter; and total parenchymal volumes as measured by MRI at school age. Adjustment for other substance exposures precludes determination of statistically significant individual substance effect on brain volume in this small sample; however, these substances may act cumulatively during gestation to exert lasting effects on brain size and volume.

Fish consumption and prenatal methylmercury exposure: cognitive and behavioral outcomes in the main cohort at 17 years from the Seychelles child development study.

PubMed

Davidson, Philip W; Cory-Slechta, Deborah A; Thurston, Sally W; Huang, Li-Shan; Shamlaye, Conrad F; Gunzler, Douglas; Watson, Gene; van Wijngaarden, Edwin; Zareba, Grazyna; Klein, Jonathan D; Clarkson, Thomas W; Strain, J J; Myers, Gary J

2011-12-01

People worldwide depend upon daily fish consumption as a major source of protein and other nutrients. Fish are high in nutrients essential for normal brain development, but they also contain methylmercury (MeHg), a neurotoxicant. Our studies in a population consuming fish daily have indicated no consistent pattern of adverse associations between prenatal MeHg and children's development. For some endpoints we found performance improved with increasing prenatal exposure to MeHg. Follow up studies indicate this association is related to the beneficial nutrients present in fish. To determine if the absence of adverse outcomes and the presence of beneficial associations between prenatal MeHg and developmental outcomes previously reported persists into adolescence. This study was conducted on the Main Cohort of the Seychelles Child Development Study (SCDS). We examined the association between prenatal MeHg exposure and subjects' performance at 17 years of age on 27 endpoints. The test battery included the Wisconsin Card Sorting Test (WCST), the California Verbal Learning Test (CVLT), the Woodcock-Johnson (W-J-II) Achievement Test, subtests of the Cambridge Neuropsychological Test Automated Battery (CANTAB), and measures of problematic behaviors. Analyses for all endpoints were adjusted for postnatal MeHg, sex, socioeconomic status, maternal IQ, and child's age at testing and the child's IQ was added for problematic behavioral endpoints. Mean prenatal MeHg exposure was 6.9 ppm. There was no association between prenatal MeHg and 21 endpoints. Increasing prenatal MeHg was associated with better scores on four endpoints (higher W-J-II math calculation scores, reduced numbers of trials on the Intra-Extradimensional Shift Set of the CANTAB), fewer reports of substance use and incidents of and referrals for problematic behaviors in school. Increasing prenatal MeHg was adversely associated with one level of referrals to a school counselor. At age 17 years there was no consistent pattern of adverse associations present between prenatal MeHg exposure and detailed domain specific neurocognitive and behavioral testing. There continues to be evidence of improved performance on some endpoints as prenatal MeHg exposure increases in the range studied, a finding that appears to reflect the role of beneficial nutrients present in fish as demonstrated previously in younger subjects. These findings suggest that ocean fish consumption during pregnancy is important for the health and development of children and that the benefits are long lasting. Copyright © 2011 Elsevier Inc. All rights reserved.

Fish Consumption and Prenatal Methylmercury Exposure: Cognitive and Behavioral Outcomes in the Main Cohort at 17 Years from the Seychelles Child Development Study

PubMed Central

Davidson, Philip W.; Cory-Slechta, Deborah A.; Thurston, Sally W.; Huang, Li-Shan; Shamlaye, Conrad F.; Gunzler, Douglas; Watson, Gene; van Wijngaarden, Edwin; Zareba, Grazyna; Klein, Jonathan D.; Clarkson, Thomas W.; Strain, J.J.; Myers, Gary J.

2011-01-01

Introduction People worldwide depend upon daily fish consumption as a major source of protein and other nutrients. Fish are high in nutrients essential for normal brain development, but they also contain methylmercury (MeHg), a neurotoxicant. Our studies in a population consuming fish daily have indicated no consistent pattern of adverse associations between prenatal MeHg and children’s development. For some endpoints we found performance improved with increasing prenatal exposure to MeHg. Follow up studies indicate this association is related to the beneficial nutrients present in fish. Objectives To determine if the absence of adverse outcomes and the presence of beneficial associations between prenatal MeHg and developmental outcomes previously reported persists into adolescence. Methods This study was conducted on the Main Cohort of the Seychelles Child Development Study (SCDS). We examined the association between prenatal MeHg exposure and subjects’ performance at 17 years of age on 27 endpoints. The test battery included the Wisconsin Card Sorting Test (WCST), the California Verbal Learning Test (CVLT), the Woodcock-Johnson (W-J-II) Achievement Test, subtests of the Cambridge Neuropsychological Test Automated Battery (CANTAB), and measures of problematic behaviors. Analyses for all endpoints were adjusted for postnatal MeHg, sex, socioeconomic status, maternal IQ, and child’s age at testing and the child’s IQ was added for problematic behavioral endpoints. Results Mean prenatal MeHg exposure was 6.9 ppm. There was no association between prenatal MeHg and 21 endpoints. Increasing prenatal MeHg was associated with better scores on four endpoints (higher W-J-II math calculation scores, reduced numbers of trials on the Intra-Extradimensional Shift Set of the CANTAB, fewer reports of substance use and incidents of and referrals for problematic behaviors in school. Increasing prenatal MeHg was adversely associated with one level of referrals to a school counselor. Conclusions At age 17 years there was no consistent pattern of adverse associations present between prenatal MeHg exposure and detailed domain specific neurocognitive and behavioral testing. There continues to be evidence of improved performance on some endpoints as prenatal MeHg exposure increases in the range studied, a finding that appears to reflect the role of beneficial nutrients present in fish as demonstrated previously in younger subjects. These findings suggest that ocean fish consumption during pregnancy is important for the health and development of children and that the benefits are long lasting. PMID:21889535

Effects of early-life adversity on immune function are mediated by prenatal environment: Role of prenatal alcohol exposure.

PubMed

Raineki, Charlis; Bodnar, Tamara S; Holman, Parker J; Baglot, Samantha L; Lan, Ni; Weinberg, Joanne

2017-11-01

The contribution of the early postnatal environment to the pervasive effects of prenatal alcohol exposure (PAE) is poorly understood. Moreover, PAE often carries increased risk of exposure to adversity/stress during early life. Dysregulation of immune function may play a role in how pre- and/or postnatal adversity/stress alters brain development. Here, we combine two animal models to examine whether PAE differentially increases vulnerability to immune dysregulation in response to early-life adversity. PAE and control litters were exposed to either limited bedding (postnatal day [PN] 8-12) to model early-life adversity or normal bedding, and maternal behavior and pup vocalizations were recorded. Peripheral (serum) and central (amygdala) immune (cytokines and C-reactive protein - CRP) responses of PAE animals to early-life adversity were evaluated at PN12. Insufficient bedding increased negative maternal behavior in both groups. Early-life adversity increased vocalization in all animals; however, PAE pups vocalized less than controls. Early-life adversity reduced serum TNF-α, KC/GRO, and IL-10 levels in control but not PAE animals. PAE increased serum CRP, and levels were even higher in pups exposed to adversity. Finally, PAE reduced KC/GRO and increased IL-10 levels in the amygdala. Our results indicate that PAE alters immune system development and both behavioral and immune responses to early-life adversity, which could have subsequent consequences for brain development and later life health. Copyright © 2017 Elsevier Inc. All rights reserved.

The role of glucocorticoid, interleukin-1β, and antioxidants in prenatal stress effects on embryonic microglia.

PubMed

Bittle, Jada; Stevens, Hanna E

2018-02-16

Maternal stress during pregnancy is associated with an increased risk of psychopathology in offspring. Resident immune cells of the brain, microglia, may be mediators of prenatal stress and altered neurodevelopment. Here, we demonstrate that neither the exogenous pro-inflammatory cytokine, interleukin-1β (IL-1β), nor the glucocorticoid hormone, corticosterone, recapitulated the full effects of prenatal stress on the morphology of microglial cells in the cortical plate of embryonic mice; IL-1β effects showed greater similarity to prenatal stress effects on microglia. Unexpectedly, oil vehicle alone, which has antioxidant properties, moderated the effects of prenatal stress on microglia. Microglia changes with prenatal stress were also sensitive to the antioxidant, N-acetylcysteine, suggesting redox dysregulation as a mechanism of prenatal stress.

Prenatal testosterone and gender-related behaviour.

PubMed

Hines, Melissa

2006-11-01

Testosterone plays an important role in mammalian brain development. In neural regions with appropriate receptors testosterone, or its metabolites, influences patterns of cell death and survival, neural connectivity and neurochemical characterization. Consequently, testosterone exposure during critical periods of early development produces permanent behavioural changes. In humans, affected behaviours include childhood play behaviour, sexual orientation, core gender identity and other characteristics that show sex differences (i.e. differ on average between males and females). These influences have been demonstrated primarily in individuals who experienced marked prenatal hormone abnormalities and associated ambiguities of genital development (e.g. congenital adrenal hyperplasia). However, there is also evidence that testosterone works within the normal range to make some individuals within each sex more sex-typical than others. The size of testosterone-related influences, and perhaps even their existence, varies from one sex-typed characteristic to another. For instance: prenatal exposure to high levels of testosterone has a substantial influence on sex-typical play behaviour, including sex-typed toy preferences, whereas influences on core gender identify and sexual orientation are less dramatic. In addition: there appears to be little or no influence of prenatal testosterone on mental rotations ability, although mental rotations ability shows a marked sex difference. These findings have implications for basic understanding of the role of testosterone in normative gender development, as well as for the clinical management of individuals with disorders of sex development (formerly called intersex syndromes).

Associations of maternal long-chain polyunsaturated fatty acids, methyl mercury, and infant development in the Seychelles Child Development Nutrition Study.

PubMed

Strain, J J; Davidson, Philip W; Bonham, Maxine P; Duffy, Emeir M; Stokes-Riner, Abbie; Thurston, Sally W; Wallace, Julie M W; Robson, Paula J; Shamlaye, Conrad F; Georger, Lesley A; Sloane-Reeves, Jean; Cernichiari, Elsa; Canfield, Richard L; Cox, Christopher; Huang, Li Shan; Janciuras, Joanne; Myers, Gary J; Clarkson, Thomas W

2008-09-01

Fish consumption during gestation can provide the fetus with long-chain polyunsaturated fatty acids (LCPUFA) and other nutrients essential for growth and development of the brain. However, fish consumption also exposes the fetus to the neurotoxicant, methyl mercury (MeHg). We studied the association between these fetal exposures and early child development in the Seychelles Child Development Nutrition Study (SCDNS). Specifically, we examined a priori models of Omega-3 and Omega-6 LCPUFA measures in maternal serum to test the hypothesis that these LCPUFA families before or after adjusting for prenatal MeHg exposure would reveal associations with child development assessed by the BSID-II at ages 9 and 30 months. There were 229 children with complete outcome and covariate data available for analysis. At 9 months, the PDI was positively associated with total Omega-3 LCPUFA and negatively associated with the ratio of Omega-6/Omega-3 LCPUFA. These associations were stronger in models adjusted for prenatal MeHg exposure. Secondary models suggested that the MeHg effect at 9 months varied by the ratio of Omega-6/Omega-3 LCPUFA. There were no significant associations between LCPUFA measures and the PDI at 30 months. There were significant adverse associations, however, between prenatal MeHg and the 30-month PDI when the LCPUFA measures were included in the regression analysis. The BSID-II mental developmental index (MDI) was not associated with any exposure variable. These data support the potential importance to child development of prenatal availability of Omega-3 LCPUFA present in fish and of LCPUFA in the overall diet. Furthermore, they indicate that the beneficial effects of LCPUFA can obscure the determination of adverse effects of prenatal MeHg exposure in longitudinal observational studies.

Associations of maternal long chain polyunsaturated fatty acids, methyl mercury, and infant development in the Seychelles Child Development Nutrition Study

PubMed Central

Strain, J.J.; Davidson, Philip W.; Bonham, Maxine P.; Duffy, Emeir M.; Stokes-Riner, Abbie; Thurston, Sally W.; Wallace, Julie M.W.; Robson, Paula J.; Shamlaye, Conrad F.; Georger, Lesley A.; Sloane-Reeves, Jean; Cernichiari, Elsa; Canfield, Richard L.; Cox, Christopher; Huang, Li Shan; Janciuras, Joanne; Myers, Gary J.; Clarkson, Thomas W.

2008-01-01

Fish consumption during gestation can provide the fetus with long chain polyunsaturated fatty acids (LCPUFA) and other nutrients essential for growth and development of the brain. However, fish consumption also exposes the fetus to the neurotoxicant, methyl mercury (MeHg). We studied the association between these fetal exposures and early child development in the Seychelles Child Development Nutrition Study (SCDNS). Specifically, we examined a priori models of Ω-3 and Ω-6 LCPUFA measures in maternal serum to test the hypothesis that these LCPUFA families before or after adjusting for prenatal MeHg exposure would reveal associations with child development assessed by the BSID-II at ages 9 and 30 months. There were 229 children with complete outcome and covariate data available for analysis. At 9 months, the PDI was positively associated with total Ω-3 LCPUFA and negatively associated with the ratio of Ω-6/Ω-3 LCPUFA. These associations were stronger in models adjusted for prenatal MeHg exposure. Secondary models suggested that the MeHg effect at 9 months varied by the ratio of Ω-6/Ω-3 LCPUFA. There were no significant associations between LCPUFA measures and the PDI at 30 months. There were significant adverse associations, however, between prenatal MeHg and the 30 month PDI when the LCPUFA measures were included in the regression analysis. The BSID-II Mental Developmental Index (MDI) was not associated with any exposure variable. These data support the potential importance to child development of prenatal availability of Ω-3 LCPUFA present in fish and of LCPUFA in the overall diet. Furthermore, they indicate that the beneficial effects of LCPUFA can obscure the determination of adverse effects of prenatal MeHg exposure in longitudinal observational studies. PMID:18590765

Fetal Origins of Child Non-Right-Handedness and Mental Health

ERIC Educational Resources Information Center

Rodriguez, Alina; Waldenstrom, Ulla

2008-01-01

Background: Environmental risk during fetal development for non-right-handedness, an index of brain asymmetry, and its relevance for child mental health is not fully understood. Methods: A Swedish population-based prospective pregnancy-offspring cohort was followed-up when children were five years old (N = 1714). Prenatal environmental risk…

A prenatal interruption of DISC1 function in the brain exhibits a lasting impact on adult behaviors, brain metabolism, and interneuron development.

PubMed

Deng, Dazhi; Jian, Chongdong; Lei, Ling; Zhou, Yijing; McSweeney, Colleen; Dong, Fengping; Shen, Yilun; Zou, Donghua; Wang, Yonggang; Wu, Yuan; Zhang, Limin; Mao, Yingwei

2017-10-17

Mental illnesses like schizophrenia (SCZ) and major depression disorder (MDD) are devastating brain disorders. The SCZ risk gene, disrupted in schizophrenia 1 ( DISC1 ), has been associated with neuropsychiatric conditions. However, little is known regarding the long-lasting impacts on brain metabolism and behavioral outcomes from genetic insults on fetal NPCs during early life. We have established a new mouse model that specifically interrupts DISC1 functions in NPCs in vivo by a dominant-negative DISC1 (DN-DISC1) with a precise temporal and spatial regulation. Interestingly, prenatal interruption of mouse Disc1 function in NPCs leads to abnormal depression-like deficit in adult mice. Here we took a novel unbiased metabonomics approach to identify brain-specific metabolites that are significantly changed in DN-DISC1 mice. Surprisingly, the inhibitory neurotransmitter, GABA, is augmented. Consistently, parvalbumin (PV) interneurons are increased in the cingulate cortex, retrosplenial granular cortex, and motor cortex. Interestingly, somatostatin (SST) positive and neuropeptide Y (NPY) interneurons are decreased in some brain regions, suggesting that DN-DISC1 expression affects the localization of interneuron subtypes. To further explore the cellular mechanisms that cause this change, DN-DISC1 suppresses proliferation and promotes the cell cycle exit of progenitors in the medial ganglionic eminence (MGE), whereas it stimulates ectopic proliferation of neighboring cells through cell non-autonomous effect. Mechanistically, it modulates GSK3 activity and interrupts Dlx2 activity in the Wnt activation. In sum, our results provide evidence that specific genetic insults on NSCs at a short period of time could lead to prolonged changes of brain metabolism and development, eventually behavioral defects.

Second-to-fourth digit ratio predicts success among high-frequency financial traders

PubMed Central

Coates, John M.; Gurnell, Mark; Rustichini, Aldo

2009-01-01

Prenatal androgens have important organizing effects on brain development and future behavior. The second-to-fourth digit length ratio (2D:4D) has been proposed as a marker of these prenatal androgen effects, a relatively longer fourth finger indicating higher prenatal androgen exposure. 2D:4D has been shown to predict success in highly competitive sports. Yet, little is known about the effects of prenatal androgens on an economically influential class of competitive risk taking—trading in the financial world. Here, we report the findings of a study conducted in the City of London in which we sampled 2D:4D from a group of male traders engaged in what is variously called “noise” or “high-frequency” trading. We found that 2D:4D predicted the traders' long-term profitability as well as the number of years they remained in the business. 2D:4D also predicted the sensitivity of their profitability to increases both in circulating testosterone and in market volatility. Our results suggest that prenatal androgens increase risk preferences and promote more rapid visuomotor scanning and physical reflexes. The success and longevity of traders exposed to high levels of prenatal androgens further suggests that financial markets may select for biological traits rather than rational expectations. PMID:19139402

Second-to-fourth digit ratio predicts success among high-frequency financial traders.

PubMed

Coates, John M; Gurnell, Mark; Rustichini, Aldo

2009-01-13

Prenatal androgens have important organizing effects on brain development and future behavior. The second-to-fourth digit length ratio (2D:4D) has been proposed as a marker of these prenatal androgen effects, a relatively longer fourth finger indicating higher prenatal androgen exposure. 2D:4D has been shown to predict success in highly competitive sports. Yet, little is known about the effects of prenatal androgens on an economically influential class of competitive risk taking-trading in the financial world. Here, we report the findings of a study conducted in the City of London in which we sampled 2D:4D from a group of male traders engaged in what is variously called "noise" or "high-frequency" trading. We found that 2D:4D predicted the traders' long-term profitability as well as the number of years they remained in the business. 2D:4D also predicted the sensitivity of their profitability to increases both in circulating testosterone and in market volatility. Our results suggest that prenatal androgens increase risk preferences and promote more rapid visuomotor scanning and physical reflexes. The success and longevity of traders exposed to high levels of prenatal androgens further suggests that financial markets may select for biological traits rather than rational expectations.

Prenatal Exposure to Arsenic Impairs Behavioral Flexibility and Cortical Structure in Mice

PubMed Central

Aung, Kyaw H.; Kyi-Tha-Thu, Chaw; Sano, Kazuhiro; Nakamura, Kazuaki; Tanoue, Akito; Nohara, Keiko; Kakeyama, Masaki; Tohyama, Chiharu; Tsukahara, Shinji; Maekawa, Fumihiko

2016-01-01

Exposure to arsenic from well water in developing countries is suspected to cause developmental neurotoxicity. Although, it has been demonstrated that exposure to sodium arsenite (NaAsO2) suppresses neurite outgrowth of cortical neurons in vitro, it is largely unknown how developmental exposure to NaAsO2 impairs higher brain function and affects cortical histology. Here, we investigated the effect of prenatal NaAsO2 exposure on the behavior of mice in adulthood, and evaluated histological changes in the prelimbic cortex (PrL), which is a part of the medial prefrontal cortex that is critically involved in cognition. Drinking water with or without NaAsO2 (85 ppm) was provided to pregnant C3H mice from gestational days 8 to 18, and offspring of both sexes were subjected to cognitive behavioral analyses at 60 weeks of age. The brains of female offspring were subsequently harvested and used for morphometrical analyses. We found that both male and female mice prenatally exposed to NaAsO2 displayed an impaired adaptation to repetitive reversal tasks. In morphometrical analyses of Nissl- or Golgi-stained tissue sections, we found that NaAsO2 exposure was associated with a significant increase in the number of pyramidal neurons in layers V and VI of the PrL, but not other layers of the PrL. More strikingly, prenatal NaAsO2 exposure was associated with a significant decrease in neurite length but not dendrite spine density in all layers of the PrL. Taken together, our results indicate that prenatal exposure to NaAsO2 leads to behavioral inflexibility in adulthood and cortical disarrangement in the PrL might contribute to this behavioral impairment. PMID:27064386

Maternal DHA supplementation protects rat offspring against impairment of learning and memory following prenatal exposure to valproic acid.

PubMed

Gao, Jingquan; Wu, Hongmei; Cao, Yonggang; Liang, Shuang; Sun, Caihong; Wang, Peng; Wang, Ji; Sun, Hongli; Wu, Lijie

2016-09-01

Docosahexaenoic acid (22:6n-3; DHA) is known to play a critical role in postnatal brain development. However, there have been no studies investigating the preventive effect of DHA on prenatal valproic acid (VPA)-induced behavioral and molecular alterations in offspring. The present study was to evaluate the neuroprotective effects in offspring using maternal feeding of DHA to rats exposed to VPA in pregnancy. In the present study, rats were exposed to VPA on day 12.5 of pregnancy; DHA was administered at the dosages of 100, 300 and 500 mg/kg/day for 3 weeks from day 1 to 21 of pregnancy. The results showed that maternal feeding of DHA to the prenatal exposed to VPA (1) prevented VPA-induced learning and memory impairment but did not change social-related behavior, (2) increased total DHA content in offspring plasma and hippocampus, (3) rescued VPA-induced neuronal loss and apoptosis of pyramidal cells in hippocampal CA1, (4) influenced the content of malondialdehyde and glutathione and the activities of superoxide dismutase and glutathione in the hippocampus, (5) altered levels of apoptosis-related proteins (Bcl-2, Bax and caspase-3) and inhibited the activity of caspase-3 in offspring hippocampus and (6) enhanced relative levels of p-CaMKII and p-CREB proteins in the hippocampus. These findings suggest that maternal feeding with DHA may prevent prenatal VPA-induced impairment of learning and memory, normalize several different molecules associated with oxidative stress and apoptosis in the hippocampus of offspring, and exert preventive effects on prenatal VPA-induced brain dysfunction. Copyright © 2016 Elsevier Inc. All rights reserved.

Docosahexaenoic acid partially ameliorates deficits in social behavior and ultrasonic vocalizations caused by prenatal ethanol exposure.

PubMed

Wellmann, Kristen A; George, Finney; Brnouti, Fares; Mooney, Sandra M

2015-06-01

Prenatal ethanol exposure disrupts social behavior in humans and rodents. One system particularly important for social behavior is the somatosensory system. Prenatal ethanol exposure alters the structure and function of this area. Docosahexaenoic acid (DHA), an omega 3 polyunsaturated fatty acid, is necessary for normal brain development and brains from ethanol-exposed animals are DHA deficient. Thus, we determined whether postnatal DHA supplementation ameliorated behavioral deficits induced by prenatal ethanol exposure. Timed pregnant Long-Evans rats were assigned to one of three groups: ad libitum access to an ethanol-containing liquid diet, pair fed an isocaloric isonutritive non-alcohol liquid diet, or ad libitum access to chow and water. Pups were assigned to one of two postnatal treatment groups; gavaged intragastrically once per day between postnatal day (P)11 and P20 with DHA (10 mg/kg in artificial rat milk) or artificial rat milk. A third group was left untreated. Isolation-induced ultrasonic vocalizations (iUSVs) were recorded on P14. Social behavior and play-induced USVs were tested on P28 or P42. Somatosensory performance was tested with a gap crossing test around P33 or on P42. Anxiety was tested on elevated plus maze around P35. Animals exposed to ethanol prenatally vocalized less, play fought less, and crossed a significantly shorter gap than control-treated animals. Administration of DHA ameliorated these ethanol-induced deficits such that the ethanol-exposed animals given DHA were no longer significantly different to control-treated animals. Thus, DHA administration may have therapeutic value to reverse some of ethanol's damaging effects. Copyright © 2015 Elsevier B.V. All rights reserved.

Ultrasound evaluation of cortical brain development in fetuses with intrauterine growth restriction.

PubMed

Businelli, Caterina; de Wit, Charlotte; Visser, Gerard H A; Pistorius, Lourens R

2014-09-10

Abstract Objective: We evaluated the ultrasound appearance of brain volume and cortical development in fetuses with early growth restriction and placental insufficiency. Methods: We examined a cohort of 20 fetuses with severe intrauterine growth restriction (IUGR) and evidence of placental insufficiency by three-dimensional (3D) ultrasound between 24 and 34 weeks. We graded cortical development and measured the supratentorial intracranial volume. The cortical grading and volume were compared to data obtained from a reference population of 28 adequate for gestational age (AGA) fetuses. Results: Ultrasound examinations were performed in 20 fetuses with IUGR. The biometry and brain volume were significantly reduced in IUGR fetuses. There was evidence of accelerated cortical development in IUGR fetuses. Conclusion: This study confirms that the smaller brain volume in IUGR fetuses, with normal or accelerated cortical maturation as previously depicted with postnatal MRI examination, can be demonstrated by prenatal 3D ultrasound.

Fetal Alcohol Spectrum Disorder-associated depression: evidence for reductions in the levels of brain-derived neurotrophic factor in a mouse model

PubMed Central

Caldwell, Kevin K.; Sheema, S.; Paz, Rodrigo D; Samudio-Ruiz, Sabrina L.; Laughlin, Mary H.; Spence, Nathan E.; Roehlk, Michael J; Alcon, Sara N.; Allan, Andrea M.

2009-01-01

Prenatal ethanol exposure is associated with an increased incidence of depressive disorders in patient populations. However, the mechanisms that link prenatal ethanol exposure and depression are unknown. Several recent studies have implicated reduced brain-derived neurotrophic factor (BDNF) levels in the hippocampal formation and frontal cortex as important contributors to the etiology of depression. In the present studies, we sought to determine whether prenatal ethanol exposure is associated with behaviors that model depression, as well as with reduced BDNF levels in the hippocampal formation and/or medial frontal cortex, in a mouse model of fetal alcohol spectrum disorder (FASD). Compared to control adult mice, prenatal ethanol-exposed adult mice displayed increased learned helplessness behavior and increased immobility in the Porsolt forced swim test. Prenatal ethanol exposure was associated with decreased BDNF protein levels in the medial frontal cortex, but not the hippocampal formation, while total BDNF mRNA and BDNF transcripts containing exon III, IV or VI were reduced in both the medial frontal cortex and the hippocampal formation of prenatal ethanol-exposed mice. These results identify reduced BDNF levels in the medial frontal cortex and hippocampal formation as potential mediators of depressive disorders associated with FASD. PMID:18558427

Universal characteristics of evolution and development are inherent in fetal autonomic brain maturation.

PubMed

Schmidt, Alexander; Schukat-Talamazzini, Ernst G; Zöllkau, Janine; Pytlik, Adelina; Leibl, Sophia; Kumm, Kathrin; Bode, Franziska; Kynass, Isabelle; Witte, Otto W; Schleussner, Ekkehard; Schneider, Uwe; Hoyer, Dirk

2018-07-01

Adverse prenatal environmental influences to the developing fetus are associated with mental and cardiovascular disease in later life. Universal developmental characteristics such as self-organization, pattern formation, and adaptation in the growing information processing system have not yet been sufficiently analyzed with respect to description of normal fetal development and identification of developmental disturbances. Fetal heart rate patterns are the only non-invasive order parameter of the developing autonomic brain available with respect to the developing complex organ system. The objective of the present study was to investigate whether universal indices, known from evolution and phylogeny, describe the ontogenetic fetal development from 20 weeks of gestation onwards. By means of a 10-fold cross-validated data-driven multivariate regression modeling procedure, relevant indices of heart rate variability (HRV) were explored using 552 fetal heart rate recordings, each lasting over 30 min. We found that models which included HRV indices of increasing fluctuation amplitude, complexity and fractal long-range dependencies largely estimated the maturation age (coefficients of determination 0.61-0.66). Consideration of these characteristics in prenatal care may not only have implications for early identification of developmental disturbances, but also for the development of system-theory-based therapeutic strategies. Copyright © 2018 Elsevier B.V. All rights reserved.

Prenatal lipopolysaccharide exposure affects maternal behavior and male offspring sexual behavior in adulthood.

PubMed

Bernardi, Maria M; Kirsten, Thiago B; Matsuoka, Suzana M; Teodorov, Elizabeth; Habr, Soraya F; Penteado, Sandra H W N; Palermo-Neto, João

2010-01-01

This study investigates the effects of prenatal lipopolysaccharide (LPS) exposure on the maternal behavior of pregnant rats and the physical development and sexual behavior of their male offspring in adulthood. For two experiments, pregnant rats were injected with LPS (250 microg/kg, i.p.) on gestation day (GD) 21. In the first experiment, the maternal behavior (postnatal day, PND, 6) and the dam's open-field general activity (PND7) were evaluated. In the second experiment, the maternal pre- and postnatal parameters, the pup's development, the offspring's sexual behavior in adulthood, and the pup's organ weights were assessed. Compared to the control group, the LPS-treated dams presented reduced maternal behavior, decreased general activity, a smaller body weight difference between GD21 and PND1, a greater number of perinatal deaths, and smaller litters. For the male pups, LPS treatment resulted in a decreased body weight on PND2, whereas the anogenital distance and the day of testis descent were not modified. The male sexual behavior was impaired by prenatal LPS. Particularly the number of ejaculating animals was reduced. The testis weight was also lower in the prenatally LPS-treated rats than in the control rats. We propose that prenatal LPS exposure on GD21 acts as an imprinting factor that interferes with the programming of brain sexual determination in offspring. Copyright 2009 S. Karger AG, Basel.

Maternal vitamin C deficiency does not reduce hippocampal volume and β-tubulin III intensity in prenatal Guinea pigs.

PubMed

Hansen, Stine N; Schjoldager, Janne G; Paidi, Maya D; Lykkesfeldt, Jens; Tveden-Nyborg, Pernille

2016-07-01

Marginal vitamin C (vitC) deficiency affects 5% to 10% of adults including subpopulations such as pregnant women and newborns. Animal studies link vitC deficiency to deleterious effects on the developing brain, but exactly how the brain adapts to vitC deficiency and the mechanisms behind the observed deficits remain largely unknown. We hypothesized that vitC deficiency in utero may lead to a decreased neuronal maturation and increased cellular death giving rise to alterations of the hippocampal morphology in a guinea pig model. Brains from prenatal guinea pig pups (n=9-10 in each group) subjected to either a sufficient (918mg vitC/kg feed) or deficient (100mg vitC/kg feed) maternal dietary regimen were assessed with regards to hippocampal volume and β-tubulin isotype III staining intensity at 2 gestational time points (45 and 56). We found a distinct differential regional growth pattern of the hippocampus with a clear effect of gestational age, whereas vitC status did not affect either investigated parameters. Within hippocampal subdivisions, the overall expansion of the hippocampus from gestational day 45 to 56 was found to reside in the dentate gyrus. In conclusion, the present study found that hippocampal volume and β-tubulin isotype III intensity in the prenatal guinea pig were influenced by gestational day but not by maternal vitC intake. Copyright © 2016 Elsevier Inc. All rights reserved.

Prenatal exposure to psychostimulants increases impulsivity, compulsivity, and motivation for rewards in adult mice.

PubMed

Lloyd, S A; Oltean, C; Pass, H; Phillips, B; Staton, K; Robertson, C L; Shanks, R A

2013-07-02

Given the widespread use and misuse of methamphetamine (METH) and methylphenidate (MPD), especially in relation to women of childbearing age, it is important to consider the long-lasting effects of these drugs on the brain of the developing fetus. Male and female C57Bl/6J mice were prenatally exposed to METH (5mg/kg), MPD (10mg/kg), or saline. Following a 3-month washout, behavioral analysis using the 5-Choice Serial Reaction Time Task (5CSRTT) was performed on adult mice. After reaching training criteria, performance on a pseudo-random intertrial interval test session revealed decrements in 5CSRTT behavior. Prenatally-treated METH and MPD mice demonstrated significant increases in impulsivity, compulsivity, and motivation for reward compared to their saline controls. There were sex by drug interactions indicating a possible sexually dimorphic response to these prenatal drug exposures. Of particular clinical interest, we find that mice prenatally exposed to METH or MPD express characteristics of both inhibitory control decrements and heightened motivation for rewards, which represent core symptoms of addiction and other impulse control disorders. Copyright © 2013 Elsevier Inc. All rights reserved.

Prenatal Stress and Peripubertal Stimulation of the Endocannabinoid System Differentially Regulate Emotional Responses and Brain Metabolism in Mice

PubMed Central

Macrì, Simone; Ceci, Chiara; Canese, Rossella; Laviola, Giovanni

2012-01-01

The central endocannabinoid system (ECS) and the hypothalamic-pituitary-adrenal-axis mediate individual responses to emotionally salient stimuli. Their altered developmental adjustment may relate to the emergence of emotional disturbances. Although environmental influences regulate the individual phenotype throughout the entire lifespan, their effects may result particularly persistent during plastic developmental stages (e.g. prenatal life and adolescence). Here, we investigated whether prenatal stress – in the form of gestational exposure to corticosterone supplemented in the maternal drinking water (100 mg/l) during the last week of pregnancy – combined with a pharmacological stimulation of the ECS during adolescence (daily fatty acid amide hydrolase URB597 i.p. administration - 0.4 mg/kg - between postnatal days 29–38), influenced adult mouse emotional behaviour and brain metabolism measured through in vivo quantitative magnetic resonance spectroscopy. Compared to control mice, URB597-treated subjects showed, in the short-term, reduced locomotion and, in the long term, reduced motivation to execute operant responses to obtain palatable rewards paralleled by reduced levels of inositol and taurine in the prefrontal cortex. Adult mice exposed to prenatal corticosterone showed increased behavioural anxiety and reduced locomotion in the elevated zero maze, and altered brain metabolism (increased glutamate and reduced taurine in the hippocampus; reduced inositol and N-Acetyl-Aspartate in the hypothalamus). Present data further corroborate the view that prenatal stress and pharmacological ECS stimulation during adolescence persistently regulate emotional responses in adulthood. Yet, whilst we hypothesized these factors to be interactive in nature, we observed that the consequences of prenatal corticosterone administration were independent from those of ECS drug-induced stimulation during adolescence. PMID:22848620

Lipopolysaccharide Exposure Induces Maternal Hypozincemia, and Prenatal Zinc Treatment Prevents Autistic-Like Behaviors and Disturbances in the Striatal Dopaminergic and mTOR Systems of Offspring

PubMed Central

Kirsten, Thiago Berti; Chaves-Kirsten, Gabriela P.; Bernardes, Suene; Scavone, Cristoforo; Sarkis, Jorge E.; Bernardi, Maria Martha; Felicio, Luciano F.

2015-01-01

Autism is characterized by social deficits, repetitive behaviors, and cognitive inflexibility. The risk factors appear to include genetic and environmental conditions, such as prenatal infections and maternal dietary factors. Previous investigations by our group have demonstrated that prenatal exposure to lipopolysaccharide (LPS), which mimics infection by gram-negative bacteria, induces autistic-like behaviors. To understand the causes of autistic-like behaviors, we evaluated maternal serum metal concentrations, which are involved in intrauterine development and infection/inflammation. We identified reduced maternal levels of zinc, magnesium, selenium and manganese after LPS exposure. Because LPS induced maternal hypozincemia, we treated dams with zinc in an attempt to prevent or ease the impairments in the offspring. We evaluated the social and cognitive autistic-like behaviors and brain tissues of the offspring to identify the central mechanism that triggers the development of autism. Prenatal LPS exposure impaired play behaviors and T-maze spontaneous alternations, i.e., it induced autistic-like behaviors. Prenatal LPS also decreased tyrosine hydroxylase levels and increased the levels of mammalian target of rapamycin (mTOR) in the striatum. Thus, striatal dopaminergic impairments may be related to autism. Moreover, excessive signaling through the mTOR pathway has been considered a biomarker of autism, corroborating our rat model of autism. Prenatal zinc treatment prevented these autistic-like behaviors and striatal dopaminergic and mTOR disturbances in the offspring induced by LPS exposure. The present findings revealed a possible relation between maternal hypozincemia during gestation and the onset of autism. Furthermore, prenatal zinc administration appears to have a beneficial effect on the prevention of autism. PMID:26218250

Lipopolysaccharide Exposure Induces Maternal Hypozincemia, and Prenatal Zinc Treatment Prevents Autistic-Like Behaviors and Disturbances in the Striatal Dopaminergic and mTOR Systems of Offspring.

PubMed

Kirsten, Thiago Berti; Chaves-Kirsten, Gabriela P; Bernardes, Suene; Scavone, Cristoforo; Sarkis, Jorge E; Bernardi, Maria Martha; Felicio, Luciano F

2015-01-01

Autism is characterized by social deficits, repetitive behaviors, and cognitive inflexibility. The risk factors appear to include genetic and environmental conditions, such as prenatal infections and maternal dietary factors. Previous investigations by our group have demonstrated that prenatal exposure to lipopolysaccharide (LPS), which mimics infection by gram-negative bacteria, induces autistic-like behaviors. To understand the causes of autistic-like behaviors, we evaluated maternal serum metal concentrations, which are involved in intrauterine development and infection/inflammation. We identified reduced maternal levels of zinc, magnesium, selenium and manganese after LPS exposure. Because LPS induced maternal hypozincemia, we treated dams with zinc in an attempt to prevent or ease the impairments in the offspring. We evaluated the social and cognitive autistic-like behaviors and brain tissues of the offspring to identify the central mechanism that triggers the development of autism. Prenatal LPS exposure impaired play behaviors and T-maze spontaneous alternations, i.e., it induced autistic-like behaviors. Prenatal LPS also decreased tyrosine hydroxylase levels and increased the levels of mammalian target of rapamycin (mTOR) in the striatum. Thus, striatal dopaminergic impairments may be related to autism. Moreover, excessive signaling through the mTOR pathway has been considered a biomarker of autism, corroborating our rat model of autism. Prenatal zinc treatment prevented these autistic-like behaviors and striatal dopaminergic and mTOR disturbances in the offspring induced by LPS exposure. The present findings revealed a possible relation between maternal hypozincemia during gestation and the onset of autism. Furthermore, prenatal zinc administration appears to have a beneficial effect on the prevention of autism.

Impact of Low Dose Oral Exposure to Bisphenol A (BPA) on the Neonatal Rat Hypothalamic and Hippocampal Transcriptome: A CLARITY-BPA Consortium Study

PubMed Central

Arambula, Sheryl E.; Belcher, Scott M.; Planchart, Antonio; Turner, Stephen D.

2016-01-01

Bisphenol A (BPA) is an endocrine disrupting, high volume production chemical found in a variety of products. Evidence of prenatal exposure has raised concerns that developmental BPA may disrupt sex-specific brain organization and, consequently, induce lasting changes on neurophysiology and behavior. We and others have shown that exposure to BPA at doses below the no-observed-adverse-effect level can disrupt the sex-specific expression of estrogen-responsive genes in the neonatal rat brain including estrogen receptors (ERs). The present studies, conducted as part of the Consortium Linking Academic and Regulatory Insights of BPA Toxicity program, expanded this work by examining the hippocampal and hypothalamic transcriptome on postnatal day 1 with the hypothesis that genes sensitive to estrogen and/or sexually dimorphic in expression would be altered by prenatal BPA exposure. NCTR Sprague-Dawley dams were gavaged from gestational day 6 until parturition with BPA (0-, 2.5-, 25-, 250-, 2500-, or 25 000-μg/kg body weight [bw]/d). Ethinyl estradiol was used as a reference estrogen (0.05- or 0.5-μg/kg bw/d). Postnatal day 1 brains were microdissected and gene expression was assessed with RNA-sequencing (0-, 2.5-, and 2500-μg/kg bw BPA groups only) and/or quantitative real-time PCR (all exposure groups). BPA-related transcriptional changes were mainly confined to the hypothalamus. Consistent with prior observations, BPA induced sex-specific effects on hypothalamic ERα and ERβ (Esr1 and Esr2) expression and hippocampal and hypothalamic oxytocin (Oxt) expression. These data demonstrate prenatal BPA exposure, even at doses below the current no-observed-adverse-effect level, can alter gene expression in the developing brain. PMID:27571134

Impact of Low Dose Oral Exposure to Bisphenol A (BPA) on the Neonatal Rat Hypothalamic and Hippocampal Transcriptome: A CLARITY-BPA Consortium Study.

PubMed

Arambula, Sheryl E; Belcher, Scott M; Planchart, Antonio; Turner, Stephen D; Patisaul, Heather B

2016-10-01

Bisphenol A (BPA) is an endocrine disrupting, high volume production chemical found in a variety of products. Evidence of prenatal exposure has raised concerns that developmental BPA may disrupt sex-specific brain organization and, consequently, induce lasting changes on neurophysiology and behavior. We and others have shown that exposure to BPA at doses below the no-observed-adverse-effect level can disrupt the sex-specific expression of estrogen-responsive genes in the neonatal rat brain including estrogen receptors (ERs). The present studies, conducted as part of the Consortium Linking Academic and Regulatory Insights of BPA Toxicity program, expanded this work by examining the hippocampal and hypothalamic transcriptome on postnatal day 1 with the hypothesis that genes sensitive to estrogen and/or sexually dimorphic in expression would be altered by prenatal BPA exposure. NCTR Sprague-Dawley dams were gavaged from gestational day 6 until parturition with BPA (0-, 2.5-, 25-, 250-, 2500-, or 25 000-μg/kg body weight [bw]/d). Ethinyl estradiol was used as a reference estrogen (0.05- or 0.5-μg/kg bw/d). Postnatal day 1 brains were microdissected and gene expression was assessed with RNA-sequencing (0-, 2.5-, and 2500-μg/kg bw BPA groups only) and/or quantitative real-time PCR (all exposure groups). BPA-related transcriptional changes were mainly confined to the hypothalamus. Consistent with prior observations, BPA induced sex-specific effects on hypothalamic ERα and ERβ (Esr1 and Esr2) expression and hippocampal and hypothalamic oxytocin (Oxt) expression. These data demonstrate prenatal BPA exposure, even at doses below the current no-observed-adverse-effect level, can alter gene expression in the developing brain.

Experimental methods for testing the effects of neurotrophic peptide, ADNF-9, against alcohol-induced apoptosis during pregnancy in c57bl/6 mice.

PubMed

Sari, Youssef

2013-04-24

Experimental designs for investigating the effects of prenatal alcohol exposure during early embryonic stages in fetal brain growth are challenging. This is mostly due to the difficulty of microdissection of fetal brains and their sectioning for determination of apoptotic cells caused by prenatal exposure to alcohol. The experiments described here provide visualized techniques from mice breeding to the identification of cell death in fetal brain tissue. This study used C57BL/6 mice as the animal model for studying fetal alcohol exposure and the role of trophic peptide against alcohol-induced apoptosis. The breeding consists of a 2-hr matting window to determine the exact stage of embryonic age. An established fetal alcohol exposure model has been used in this study to determine the effects of prenatal alcohol exposure in fetal brains. This involves free access to alcohol or pair-fed liquid diets as the sole source of nutrients for the pregnant mice. The techniques involving dissection of fetuses and microdissection of fetal brains are described carefully, since the latter can be challenging. Microdissection requires a stereomicroscope and ultra-fine forceps. Step-by-step procedures for dissecting the fetal brains are provided visually. The fetal brains are dissected from the base of the primordium olfactory bulb to the base of the metencephalon. For investigating apoptosis, fetal brains are first embedded in gelatin using a peel-away mold to facilitate their sectioning with a vibratome apparatus. Fetal brains embedded and fixed in paraformaldehyde are easily sectioned, and the free floating sections can be mounted in superfrost plus slides for determination of apoptosis or cell death. TUNEL (TdT-mediated dUTP Nick End Labeling; TdT: terminal deoxynucleotidyl transferase) assay has been used to identify cell death or apoptotic cells. It is noteworthy that apoptosis and cell-mediated cytotoxicity are characterized by DNA fragmentation. Thus, the visualized TUNEL-positive cells are indicative of cell death or apoptotic cells. The experimental designs here provide information about the use of an established liquid diet for studying the effects of alcohol and the role of neurotrophic peptides during pregnancy in fetal brains. This involves breeding and feeding pregnant mice, microdissecting fetal brains, and determining apoptosis. Together, these visual and textual techniques might be a source for investigating prenatal exposure of harmful agents in fetal brains.

Fetal Alcohol Spectrum Disorders: An Overview from the Glia Perspective.

PubMed

Wilhelm, Clare J; Guizzetti, Marina

2015-01-01

Alcohol consumption during pregnancy can produce a variety of central nervous system (CNS) abnormalities in the offspring resulting in a broad spectrum of cognitive and behavioral impairments that constitute the most severe and long-lasting effects observed in fetal alcohol spectrum disorders (FASD). Alcohol-induced abnormalities in glial cells have been suspected of contributing to the adverse effects of alcohol on the developing brain for several years, although much research still needs to be done to causally link the effects of alcohol on specific brain structures and behavior to alterations in glial cell development and function. Damage to radial glia due to prenatal alcohol exposure may underlie observations of abnormal neuronal and glial migration in humans with Fetal Alcohol Syndrome (FAS), as well as primate and rodent models of FAS. A reduction in cell number and altered development has been reported for several glial cell types in animal models of FAS. In utero alcohol exposure can cause microencephaly when alcohol exposure occurs during the brain growth spurt a period characterized by rapid astrocyte proliferation and maturation; since astrocytes are the most abundant cells in the brain, microenchephaly may be caused by reduced astrocyte proliferation or survival, as observed in in vitro and in vivo studies. Delayed oligodendrocyte development and increased oligodendrocyte precursor apoptosis has also been reported in experimental models of FASD, which may be linked to altered myelination/white matter integrity found in FASD children. Children with FAS exhibit hypoplasia of the corpus callosum and anterior commissure, two areas requiring guidance from glial cells and proper maturation of oligodendrocytes. Finally, developmental alcohol exposure disrupts microglial function and induces microglial apoptosis; given the role of microglia in synaptic pruning during brain development, the effects of alcohol on microglia may be involved in the abnormal brain plasticity reported in FASD. The consequences of prenatal alcohol exposure on glial cells, including radial glia and other transient glial structures present in the developing brain, astrocytes, oligodendrocytes and their precursors, and microglia contributes to abnormal neuronal development, reduced neuron survival and disrupted brain architecture and connectivity. This review highlights the CNS structural abnormalities caused by in utero alcohol exposure and outlines which abnormalities are likely mediated by alcohol effects on glial cell development and function.

Histological study on hippocampus, amygdala and cerebellum following low lead exposure during prenatal and postnatal brain development in rats.

PubMed

Barkur, Rajashekar Rao; Bairy, Laxminarayana K

2016-06-01

Neuropsychological studies in children who are exposed to lead during their early brain development have shown to develop behavioural and cognitive deficit. The aim of the present study was to assess the cellular damage in hippocampus, amygdala and cerebellum of rat pups exposed to lead during different periods of early brain development. Five groups of rat pups were investigated. (a) Control group (n = 8) (mothers of these rats were given normal drinking water throughout gestation and lactation), (b) pregestation lead-exposed group (n = 8) (mothers of these rats were exposed to 0.2% lead acetate in the drinking water for one month before conception), (c) gestation lead-exposed group (n = 8) (exposed to 0.2% lead acetate in the drinking water through the mother throughout gestation [gestation day 01 to day 21]), (d) lactation lead-exposed group (n = 8) (exposed to 0.2% lead acetate in the drinking water through the mother throughout lactation [postnatal day 01 to day 21]) and (e) gestation and lactation lead-exposed group (n = 8) (exposed to 0.2% lead acetate throughout gestation and lactation). On postnatal day 30, rat pups of all the groups were killed. Numbers of surviving neurons in the hippocampus, amygdala and cerebellum regions were counted using cresyl violet staining technique. Histological data indicate that lead exposure caused significant damage to neurons of hippocampus, amygdala and cerebellum regions in all lead-exposed groups except lactation lead-exposed group. The extent of damage to neurons of hippocampus, amygdala and cerebellum regions in lactation lead-exposed group was comparable to gestation and lactation groups even though the duration of lead exposure was much less in lactation lead-exposed group. To conclude, the postnatal period of brain development seems to be more vulnerable to lead neurotoxicity compared to prenatal period of brain development. © The Author(s) 2014.

Prenatal Exposure of Guinea Pigs to the Organophosphorus Pesticide Chlorpyrifos Disrupts the Structural and Functional Integrity of the Brain

PubMed Central

Mullins, Roger J.; Xu, Su; Pereira, Edna F.R.; Pescrille, Joseph D.; Todd, Spencer W.; Mamczarz, Jacek; Albuquerque, Edson X.; Gullapalli, Rao P.

2015-01-01

This study was designed to test the hypothesis that prenatal exposure of guinea pigs to the organophosphorus (OP) pesticide chlorpyrifos (CPF) disrupts the structural and functional integrity of the brain. Pregnant guinea pigs were injected with chlorpyrifos (20 mg/kg, s.c.) or vehicle (peanut oil) once per day for ten consecutive days, starting approximately on the 50th day of gestation. Cognitive behavior of female offspring was examined starting at 40–45 post-natal days (PND) using the Morris Water Maze (MWM), and brain structural integrity was analyzed at PND 70 using magnetic resonance imaging (MRI) methods, including T2-weighted anatomical scans and Diffusion Kurtosis Imaging (DKI). The offspring of exposed mothers had significantly decreased body weight and brain volume, particularly in the frontal regions of the brain including the striatum. Furthermore, the offspring demonstrated significant spatial learning deficits in MWM recall compared to the vehicle group. Diffusion measures revealed reduced white matter integrity within the striatum and amygdala that correlated with spatial learning performance. These findings reveal the lasting effect of pre-natal exposure to CPF as well as the danger of mother to child transmission of CPF in the environment. PMID:25704171

Prenatal exposure to cannabinoids evokes long-lasting functional alterations by targeting CB1 receptors on developing cortical neurons.

PubMed

de Salas-Quiroga, Adán; Díaz-Alonso, Javier; García-Rincón, Daniel; Remmers, Floortje; Vega, David; Gómez-Cañas, María; Lutz, Beat; Guzmán, Manuel; Galve-Roperh, Ismael

2015-11-03

The CB1 cannabinoid receptor, the main target of Δ(9)-tetrahydrocannabinol (THC), the most prominent psychoactive compound of marijuana, plays a crucial regulatory role in brain development as evidenced by the neurodevelopmental consequences of its manipulation in animal models. Likewise, recreational cannabis use during pregnancy affects brain structure and function of the progeny. However, the precise neurobiological substrates underlying the consequences of prenatal THC exposure remain unknown. As CB1 signaling is known to modulate long-range corticofugal connectivity, we analyzed the impact of THC exposure on cortical projection neuron development. THC administration to pregnant mice in a restricted time window interfered with subcerebral projection neuron generation, thereby altering corticospinal connectivity, and produced long-lasting alterations in the fine motor performance of the adult offspring. Consequences of THC exposure were reminiscent of those elicited by CB1 receptor genetic ablation, and CB1-null mice were resistant to THC-induced alterations. The identity of embryonic THC neuronal targets was determined by a Cre-mediated, lineage-specific, CB1 expression-rescue strategy in a CB1-null background. Early and selective CB1 reexpression in dorsal telencephalic glutamatergic neurons but not forebrain GABAergic neurons rescued the deficits in corticospinal motor neuron development of CB1-null mice and restored susceptibility to THC-induced motor alterations. In addition, THC administration induced an increase in seizure susceptibility that was mediated by its interference with CB1-dependent regulation of both glutamatergic and GABAergic neuron development. These findings demonstrate that prenatal exposure to THC has long-lasting deleterious consequences in the adult offspring solely mediated by its ability to disrupt the neurodevelopmental role of CB1 signaling.

Sexual orientation, fraternal birth order, and the maternal immune hypothesis: a review.

PubMed

Bogaert, Anthony F; Skorska, Malvina

2011-04-01

In 1996, psychologists Ray Blanchard and Anthony Bogaert found evidence that gay men have a greater number of older brothers than do heterosexual men. This "fraternal birth order" (FBO) effect has been replicated numerous times, including in non-Western samples. More recently, strong evidence has been found that the FBO effect is of prenatal origin. Although there is no direct support for the exact prenatal mechanism, the most plausible explanation may be immunological in origin, i.e., a mother develops an immune reaction against a substance important in male fetal development during pregnancy, and that this immune effect becomes increasingly likely with each male gestation. This immune effect is hypothesized to cause an alteration in (some) later born males' prenatal brain development. The target of the immune response may be molecules (i.e., Y-linked proteins) on the surface of male fetal brain cells, including in sites of the anterior hypothalamus, which has been linked to sexual orientation in other research. Antibodies might bind to these molecules and thus alter their role in typical sexual differentiation, leading some later born males to be attracted to men as opposed to women. Here we review evidence in favor of this hypothesis, including recent research showing that mothers of boys develop an immune response to one Y-linked protein (i.e., H-Y antigen; SMCY) important in male fetal development, and that this immune effect becomes increasingly likely with each additional boy to which a mother gives birth. We also discuss other Y-linked proteins that may be relevant if this hypothesis is correct. Finally, we discuss issues in testing the maternal immune hypothesis of FBO. Copyright © 2011 Elsevier Inc. All rights reserved.

Sex-Specific Alterations of White Matter Developmental Trajectories in Infants With Prenatal Exposure to Methamphetamine and Tobacco.

PubMed

Chang, Linda; Oishi, Kenichi; Skranes, Jon; Buchthal, Steven; Cunningham, Eric; Yamakawa, Robyn; Hayama, Sara; Jiang, Caroline S; Alicata, Daniel; Hernandez, Antonette; Cloak, Christine; Wright, Tricia; Ernst, Thomas

2016-12-01

Methamphetamine is a common illicit drug used worldwide. Methamphetamine and/or tobacco use by pregnant women remains prevalent. However, little is known about the effect of comorbid methamphetamine and tobacco use on human fetal brain development. To investigate whether microstructural brain abnormalities reported in children with prenatal methamphetamine and/or tobacco exposure are present at birth before childhood environmental influences. A prospective, longitudinal study was conducted between September 17, 2008, and February 28, 2015, at an ambulatory academic medical center. A total of 752 infant-mother dyads were screened and 139 of 195 qualified neonates were evaluated (36 methamphetamine/tobacco exposed, 32 tobacco exposed, and 71 unexposed controls). They were recruited consecutively from the community. Prenatal methamphetamine and/or tobacco exposure. Quantitative neurologic examination and diffusion tensor imaging performed 1 to 3 times through age 4 months; diffusivities and fractional anisotropy (FA) assessed in 7 white matter tracts and 4 subcortical brain regions using an automated atlas-based method. Of the 139 infants evaluated, 72 were female (51.8%); the mean (SE) postmenstrual age at baseline was 41.5 (0.27) weeks. Methamphetamine/tobacco-exposed infants showed delayed developmental trajectories on active muscle tone (group × age, P < .001) and total neurologic scores (group × age, P = .01) that normalized by ages 3 to 4 months. Only methamphetamine/tobacco-exposed boys had lower FA (group × age, P = .02) and higher diffusivities in superior (SCR) and posterior corona radiatae (PCR) (group × age × sex, P = .002; group × age × sex, P = .01) at baseline that normalized by age 3 months. Only methamphetamine/tobacco- and tobacco-exposed girls showed persistently lower FA in anterior corona radiata (ACR) (group, P = .04; group × age × sex, P = .01). Tobacco-exposed infants showed persistently lower axial diffusion in the thalamus and internal capsule across groups (P = .02). Prenatal methamphetamine/tobacco exposure may lead to delays in motor development, with less coherent fibers and less myelination in SCR and PCR only in male infants, but these abnormalities may normalize by ages 3 to 4 months after cessation of stimulant exposure. In contrast, persistently less coherent ACR fibers were observed in methamphetamine/tobacco- and tobacco-exposed girls, possibly from increased dendritic branching or spine density due to epigenetic influences. Persistently lower diffusivity in the thalamus and internal capsule of all tobacco-exposed infants suggests aberrant axonal development. Collectively, prenatal methamphetamine and/or tobacco exposure may lead to delayed motor development and white matter maturation in sex- and regional-specific manners.

A physical multifield model predicts the development of volume and structure in the human brain

NASA Astrophysics Data System (ADS)

Rooij, Rijk de; Kuhl, Ellen

2018-03-01

The prenatal development of the human brain is characterized by a rapid increase in brain volume and a development of a highly folded cortex. At the cellular level, these events are enabled by symmetric and asymmetric cell division in the ventricular regions of the brain followed by an outwards cell migration towards the peripheral regions. The role of mechanics during brain development has been suggested and acknowledged in past decades, but remains insufficiently understood. Here we propose a mechanistic model that couples cell division, cell migration, and brain volume growth to accurately model the developing brain between weeks 10 and 29 of gestation. Our model accurately predicts a 160-fold volume increase from 1.5 cm3 at week 10 to 235 cm3 at week 29 of gestation. In agreement with human brain development, the cortex begins to form around week 22 and accounts for about 30% of the total brain volume at week 29. Our results show that cell division and coupling between cell density and volume growth are essential to accurately model brain volume development, whereas cell migration and diffusion contribute mainly to the development of the cortex. We demonstrate that complex folding patterns, including sinusoidal folds and creases, emerge naturally as the cortex develops, even for low stiffness contrasts between the cortex and subcortex.

Perinatal exposure to methadone affects central cholinergic activity in the weanling rat.

PubMed

Robinson, S E; Mo, Q; Maher, J R; Wallace, M J; Kunko, P M

1996-06-01

Pregnant rats were implanted with osmotic minipumps containing either methadone hydrochloride (initial dose, 9 mg/kg/day) or sterile water. Their offspring were cross-fostered so that they were exposed to methadone prenatally and/or postnatally. Perinatal methadone exposure disrupted cholinergic activity on postnatal day 21 as measured by the turnover rate of acetylcholine (TRACh) in both female and male rats, although there were some sexually-dimorphic responses. The most profoundly affected brain region was the striatum, where prenatal exposure to methadone increased ACh turnover, whether or not the rats continued to be exposed to methadone postnatally. It appears unlikely that neonatal withdrawal contributes to brain regional changes in ACh turnover, as continued postnatal exposure to methadone did not prevent the prenatal methadone induced changes.

Prenatal zinc reduces stress response in adult rat offspring exposed to lipopolysaccharide during gestation.

PubMed

Galvão, Marcella C; Chaves-Kirsten, Gabriela P; Queiroz-Hazarbassanov, Nicolle; Carvalho, Virgínia M; Bernardi, Maria M; Kirsten, Thiago B

2015-01-01

Previous investigations by our group have shown that prenatal treatment with lipopolysaccharide (LPS; 100 μg/kg, intraperitoneally) on gestation day (GD) 9.5 in rats, which mimics infections by Gram-negative bacteria, induces short- and long-term behavioral and neuroimmune changes in the offspring. Because LPS induces hypozincemia, dams were treated with zinc after LPS in an attempt to prevent or ameliorate the impairments induced by prenatal LPS exposure. LPS can also interfere with hypothalamic-pituitary-adrenal (HPA) axis development; thus, behavioral and neuroendocrine parameters linked to HPA axis were evaluated in adult offspring after a restraint stress session. We prenatally exposed Wistar rats to LPS (100 μg/kg, intraperitoneally, on GD 9.5). One hour later they received zinc (ZnSO4, 2 mg/kg, subcutaneously). Adult female offspring that were in metestrus/diestrus were submitted to a 2 h restraint stress session. Immediately after the stressor, 22 kHz ultrasonic vocalizations, open field behavior, serum corticosterone and brain-derived neurotrophic factor (BDNF) levels, and striatal and hypothalamic neurotransmitter and metabolite levels were assessed. Offspring that received prenatal zinc after LPS presented longer periods in silence, increased locomotion, and reduced serum corticosterone and striatal norepinephrine turnover compared with rats treated with LPS and saline. Prenatal zinc reduced acute restraint stress response in adult rats prenatally exposed to LPS. Our findings suggest a potential beneficial effect of prenatal zinc, in which the stress response was reduced in offspring that were stricken with infectious/inflammatory processes during gestation. Copyright © 2014 Elsevier Inc. All rights reserved.

Two-hit exposure to polychlorinated biphenyls at gestational and juvenile life stages: 2. Sex-specific neuromolecular effects in the brain

PubMed Central

Bell, Margaret R.; Hart, Bethany G.; Gore, Andrea C.

2015-01-01

Exposures to polychlorinated biphenyls (PCBs) during early development have long-lasting, sexually dimorphic consequences on adult brain and behavior. However, few studies have investigated their effects during juvenile development, a time when increases in pubertal hormones influence brain maturation. Here, male and female Sprague Dawley rats were exposed to PCBs (Aroclor 1221, 1 mg/kg/day) or vehicle prenatally, during juvenile development, or both, and their effects on serum hormone concentrations, gene expression, and DNA methylation were assessed in adulthood. Gene expression in male but not female brains was affected by 2-hits of PCBs, a result that paralleled behavioral effects of PCBs. Furthermore, the second hit often changed the effects of a first hit in complex ways. Thus, PCB exposures during critical fetal and juvenile developmental periods result in unique neuromolecular phenotypes, with males most vulnerable to the treatments. PMID:26620572

Prenatal stress and inhibitory neuron systems: implications for neuropsychiatric disorders

PubMed Central

Fine, Rebecca; Zhang, Jie; Stevens, Hanna E.

2014-01-01

Prenatal stress is a risk factor for several psychiatric disorders in which inhibitory neuron pathology is implicated. A growing body of research demonstrates that inhibitory circuitry in the brain is directly and persistently affected by prenatal stress. This review synthesizes research that elucidates how this early, developmental risk factor impacts inhibitory neurons and how these findings intersect with research on risk factors and inhibitory neuron pathophysiology in schizophrenia, anxiety, autism and Tourette syndrome. The specific impact of prenatal stress on inhibitory neurons, particularly developmental mechanisms, may elucidate further the pathophysiology of these disorders. PMID:24751963

Effects of prenatal methamphetamine exposure on verbal memory revealed with fMRI

PubMed Central

Lu, Lisa H.; Johnson, Arianne; O’Hare, Elizabeth D.; Bookheimer, Susan Y.; Smith, Lynne M.; O’Connor, Mary J.; Sowell, Elizabeth R.

2009-01-01

Objective Efforts to understand specific effects of prenatal methamphetamine exposure on cognitive processing are hampered by high rates of concomitant alcohol use during pregnancy. We examined whether neurocognitive systems differed among children with differing prenatal teratogenic exposures when they engaged in a verbal memory task. Patients and Methods Participants (7-15 years old) engaged in a verbal paired associate learning task while undergoing functional magnetic resonance imaging. The MA group included 14 children with prenatal methamphetamine exposure, 12 of whom had concomitant alcohol exposure. They were compared to 9 children with prenatal alcohol but not methamphetamine exposure (ALC) and 20 unexposed controls (CON). Groups did not differ in age, gender, or socioeconomic status. Participants’ IQ and verbal learning performance were measured using standardized instruments. Results The MA group activated more diffuse brain regions, including bilateral medial temporal structures known to be important for memory, than both the ALC and the CON groups. These group differences remained after IQ was covaried. More activation in medial temporal structures by the MA group compared to the ALC group cannot be explained by performance differences because both groups performed at similar levels on the verbal memory task. Conclusions More diffuse activation in the MA group during verbal memory may reflect recruitment of compensatory systems to support a weak verbal memory network. Differences in activation patterns between the MA and ALC groups suggest that prenatal MA exposure influences the development of the verbal memory system above and beyond effects of prenatal alcohol exposure. PMID:19525715

Neuroimaging effects of prenatal alcohol exposure on the developing human brain: a magnetic resonance imaging review.

PubMed

Donald, Kirsten Ann; Eastman, Emma; Howells, Fleur Margaret; Adnams, Colleen; Riley, Edward Patrick; Woods, Roger Paul; Narr, Katherine Louise; Stein, Dan Joseph

2015-10-01

This paper reviews the magnetic resonance imaging (MRI) literature on the effects of prenatal alcohol exposure on the developing human brain. A literature search was conducted through the following databases: PubMed, PsycINFO and Google Scholar. Combinations of the following search terms and keywords were used to identify relevant studies: 'alcohol', 'fetal alcohol spectrum disorders', 'fetal alcohol syndrome', 'FAS', 'FASD', 'MRI', 'DTI', 'MRS', 'neuroimaging', 'children' and 'infants'. A total of 64 relevant articles were identified across all modalities. Overall, studies reported smaller total brain volume as well as smaller volume of both the white and grey matter in specific cortical regions. The most consistently reported structural MRI findings were alterations in the shape and volume of the corpus callosum, as well as smaller volume in the basal ganglia and hippocampi. The most consistent finding from diffusion tensor imaging studies was lower fractional anisotropy in the corpus callosum. Proton magnetic resonance spectroscopy studies are few to date, but showed altered neurometabolic profiles in the frontal and parietal cortex, thalamus and dentate nuclei. Resting-state functional MRI studies reported reduced functional connectivity between cortical and deep grey matter structures. Discussion There is a critical gap in the literature of MRI studies in alcohol-exposed children under 5 years of age across all MRI modalities. The dynamic nature of brain maturation and appreciation of the effects of alcohol exposure on the developing trajectory of the structural and functional network argue for the prioritisation of studies that include a longitudinal approach to understanding this spectrum of effects and potential therapeutic time points.

Motor impairments related to brain injury timing in early hemiparesis. Part II: abnormal upper extremity joint torque synergies.

PubMed

Sukal-Moulton, Theresa; Krosschell, Kristin J; Gaebler-Spira, Deborah J; Dewald, Julius P A

2014-01-01

Extensive neuromotor development occurs early in human life, and the timing of brain injury may affect the resulting motor impairment. In Part I of this series, it was demonstrated that the distribution of weakness in the upper extremity depended on the timing of brain injury in individuals with childhood-onset hemiparesis. The goal of this study was to characterize how timing of brain injury affects joint torque synergies, or losses of independent joint control. Twenty-four individuals with hemiparesis were divided into 3 groups based on the timing of their injury: before birth (PRE-natal, n = 8), around the time of birth (PERI-natal, n = 8), and after 6 months of age (POST-natal, n = 8). Individuals with hemiparesis and 8 typically developing peers participated in maximal isometric shoulder, elbow, wrist, and finger torque generation tasks while their efforts were recorded by a multiple degree-of-freedom load cell. Motor output in 4 joints of the upper extremity was concurrently measured during 8 primary torque generation tasks to quantify joint torque synergies. There were a number of significant coupling patterns identified in individuals with hemiparesis that differed from the typically developing group. POST-natal differences were most noted in the coupling of shoulder abductors with elbow, wrist, and finger flexors, while the PRE-natal group demonstrated significant distal joint coupling with elbow flexion. The torque synergies measured provide indirect evidence for the use of bulbospinal pathways in the POST-natal group, while those with earlier injury may use relatively preserved ipsilateral corticospinal motor pathways.

Altered brain morphology and functional connectivity reflect a vulnerable affective state after cumulative multigenerational stress in rats.

PubMed

McCreary, J Keiko; Truica, L Sorina; Friesen, Becky; Yao, Youli; Olson, David M; Kovalchuk, Igor; Cross, Albert R; Metz, Gerlinde A S

2016-08-25

Prenatal stress is a risk factor for abnormal neuroanatomical, cognitive, behavioral and mental health outcomes with potentially transgenerational consequences. Females in general seem more resilient to the effects of prenatal stress than males. Here, we examined if repeated stress across generations may diminish stress resiliency and cumulatively enhance the susceptibility for adverse health outcomes in females. Pregnant female rats of three successive generations were exposed to stress from gestational days 12-18 to generate multigenerational prenatal stress (MPS) in the maternal lineage. Stress response was measured by plasma corticosterone levels and open-field exploration in each generation. Neuromorphological consequences of MPS were investigated in the F3 generation using in vivo manganese-enhanced magnetic resonance imaging (MEMRI), T2-relaxometry, and cytoarchitectonics in relation to candidate gene expression involved in brain plasticity and mental health. Each additional generation of prenatal stress incrementally elevated hypothalamic-pituitary-adrenal axis activation, anxiety-like and aversive behaviors in adult female offspring. Elevated stress responses in the MPS F3 generation were accompanied by reduced neural density in prefrontal cortex, hippocampus and whole brain along with altered brain activation patterns in in vivo MEMRI. MPS increased ephrin receptor A5 (Epha5), neuronal growth regulator (Negr1) and synaptosomal-associated protein 25 (Snap25) gene expression and reduced fibroblast growth factor 12 (Fgf12) in prefrontal cortex. These genes regulate neuronal maturation, arborization and synaptic plasticity and may explain altered brain cytoarchitectonics and connectivity. These findings emphasize that recurrent stress across generations may cumulatively increase stress vulnerability and the risk of adverse health outcomes through perinatal programing in females. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Duloxetine prevents the effects of prenatal stress on depressive-like and anxiety-like behavior and hippocampal expression of pro-inflammatory cytokines in adult male offspring rats.

PubMed

Zhang, Xiaosong; Wang, Qi; Wang, Yan; Hu, Jingmin; Jiang, Han; Cheng, Wenwen; Ma, Yuchao; Liu, Mengxi; Sun, Anji; Zhang, Xinxin; Li, Xiaobai

2016-12-01

Stress during pregnancy may cause neurodevelopmental and psychiatric disorders. However, the mechanisms are largely unknown. Currently, pro-inflammatory cytokines have been identified as a risk factor for depression and anxiety disorder. Unfortunately, there is very little research on the long-term effects of prenatal stress on the neuroinflammatory system of offspring. Moreover, the relationship between antidepressant treatment and cytokines in the central nervous system, especially in the hippocampus, an important emotion modulation center, is unclear. Therefore, the aim of this study was to determine the effects of prenatal chronic mild stress during development on affective-like behaviors and hippocampal cytokines in adult offspring, and to verify whether antidepressant (duloxetine) administration from early adulthood could prevent the harmful consequences. To do so, prenatally stressed and non-stressed Sprague-Dawley rats were treated with either duloxetine (10mg/kg/day) or vehicle from postnatal day 60 for 21days. Adult offspring were divided into four groups: 1) prenatal stress+duloxetine treatment, 2) prenatal stress+vehicle, 3) duloxetine treatment alone, and 4) vehicle alone. Adult offspring were assessed for anxiety-like behavior using the open field test and depression-like behavior using the forced swim test. Brains were analyzed for pro-inflammatory cytokine markers in the hippocampus via real-time PCR. Results demonstrate that prenatal stress-induced anxiety- and depression-like behaviors are associated with an increase in hippocampal inflammatory mediators, and duloxetine administration prevents the increased hippocampal pro-inflammatory cytokine interleukin-6 and anxiety- and depression-like behavior in prenatally stressed adult offspring. This research provides important evidence on the long-term effect of PNS exposure during development in a model of maternal adversity to study the pathogenesis of depression and its therapeutic interventions. Copyright © 2016 ISDN. Published by Elsevier Ltd. All rights reserved.

Responsiveness of cerebral and hepatic cytochrome P450s in rat offspring prenatally exposed to lindane

DOE Office of Scientific and Technical Information (OSTI.GOV)

Johri, Ashu; Yadav, Sanjay; Dhawan, Alok

2008-08-15

ABSTRACT: Prenatal exposure to low doses of lindane has been shown to affect the ontogeny of xenobiotic metabolizing cytochrome P450s (CYPs), involved in the metabolism and neurobehavioral toxicity of lindane. Attempts were made in the present study to investigate the responsiveness of CYPs in offspring prenatally exposed to lindane (0.25 mg/kg b. wt.; 1/350th of LD{sub 50}; p. o. to mother) when challenged with 3-methylcholanthrene (MC) or phenobarbital (PB), inducers of CYP1A and 2B families or a sub-convulsant dose of lindane (30 mg/kg b. wt., p. o.) later in life. Prenatal exposure to lindane was found to produce an increasemore » in the mRNA and protein expression of CYP1A1, 1A2, 2B1, 2B2 isoforms in brain and liver of the offspring at postnatal day 50. The increased expression of the CYPs in the offspring suggests the sensitivity of the CYPs during postnatal development, possibly, to low levels of lindane, which may partition into mother's milk. A higher increase in expression of CYP1A and 2B isoenzymes and their catalytic activity was observed in animals pretreated prenatally with lindane and challenged with MC (30 mg/kg, i. p. x 5 days) or PB (80 mg/kg, i. p. x 5 days) when young at age (approx. 7 weeks) compared to animals exposed to MC or PB alone. Further, challenge of the control and prenatally exposed offspring with a single sub-convulsant dose of lindane resulted in an earlier onset and increased incidence of convulsions in the offspring prenatally exposed to lindane have demonstrated sensitivity of the CYPs in the prenatally exposed offspring. Our data assume significance as the subtle changes in the expression profiles of hepatic and cerebral CYPs in rat offspring during postnatal development could modify the adult response to a later exposure to xenobiotics.« less

Quantitative and Qualitative Analysis of Transient Fetal Compartments during Prenatal Human Brain Development

PubMed Central

Vasung, Lana; Lepage, Claude; Radoš, Milan; Pletikos, Mihovil; Goldman, Jennifer S.; Richiardi, Jonas; Raguž, Marina; Fischi-Gómez, Elda; Karama, Sherif; Huppi, Petra S.; Evans, Alan C.; Kostovic, Ivica

2016-01-01

The cerebral wall of the human fetal brain is composed of transient cellular compartments, which show characteristic spatiotemporal relationships with intensity of major neurogenic events (cell proliferation, migration, axonal growth, dendritic differentiation, synaptogenesis, cell death, and myelination). The aim of the present study was to obtain new quantitative data describing volume, surface area, and thickness of transient compartments in the human fetal cerebrum. Forty-four postmortem fetal brains aged 13–40 postconceptional weeks (PCW) were included in this study. High-resolution T1 weighted MR images were acquired on 19 fetal brain hemispheres. MR images were processed using in-house software (MNI-ACE toolbox). Delineation of fetal compartments was performed semi-automatically by co-registration of MRI with histological sections of the same brains, or with the age-matched brains from Zagreb Neuroembryological Collection. Growth trajectories of transient fetal compartments were reconstructed. The composition of telencephalic wall was quantitatively assessed. Between 13 and 25 PCW, when the intensity of neuronal proliferation decreases drastically, the relative volume of proliferative (ventricular and subventricular) compartments showed pronounced decline. In contrast, synapse- and extracellular matrix-rich subplate compartment continued to grow during the first two trimesters, occupying up to 45% of telencephalon and reaching its maximum volume and thickness around 30 PCW. This developmental maximum coincides with a period of intensive growth of long cortico-cortical fibers, which enter and wait in subplate before approaching the cortical plate. Although we did not find significant age related changes in mean thickness of the cortical plate, the volume, gyrification index, and surface area of the cortical plate continued to exponentially grow during the last phases of prenatal development. This cortical expansion coincides developmentally with the transformation of embryonic cortical columns, dendritic differentiation, and ingrowth of axons. These results provide a quantitative description of transient human fetal brain compartments observable with MRI. Moreover, they will improve understanding of structural-functional relationships during brain development, will enable correlation between in vitro/in vivo imaging and fine structural histological studies, and will serve as a reference for study of perinatal brain injuries. PMID:26941612

In Six-month-old Infants, Prenatal Exposure to Maternal Anxiety is Associated with Less Developed Smooth Pursuit Eye Movements: An Initial Study.

PubMed

Pellegrino, Laurel; Ross, Randal G; Hunter, Sharon K

2013-01-01

There are an increasing number of reports suggesting an association between maternal anxiety experienced during pregnancy and adverse outcomes of the offspring. However, exploration of the biological changes in the brain that mediate that relationship has been hampered by the lack of appropriate biomarkers. This report represents an initial step exploring whether a potential infant biomarker, smooth pursuit eye movements, may be associated with prenatal exposure to maternal anxiety. Blinded cross-sectional study. Department of Psychiatry, University of Colorado School of Medicine. Data collected from July 2011 to May 2012. Forty-three infants including 34 whose prenatal maternal anxiety status was identified (12 with a known maternal prenatal anxiety diagnosis and 22 without) had eye movements recorded during a smooth pursuit eye movement task at four and/or six months of age. At 6 months of age, infants with prenatal exposure to maternal anxiety, compared to infants without such exposure, spent a higher percentage of time utilizing smooth pursuit (t=2.7, df=24, P =.013), had longer duration of smooth pursuit uninterrupted by saccades (t=2.5, df=24, P =.019), and had decreased frequency of forward saccades (t=3.8, df=24, P =.001). No differences between groups were identified at 4 months of age. Smooth pursuit abnormalities may, at six months of age, be a potential biomarker for prenatal maternal anxiety exposure.

Peptidergic Agonists of Activity-Dependent Neurotrophic Factor Protect Against Prenatal Alcohol-Induced Neural Tube Defects and Serotonin Neuron Loss

PubMed Central

Zhou, Feng C.; Fang, Yuan; Goodlett, Charles

2009-01-01

Introduction Prenatal alcohol exposure via maternal liquid diet consumption by C57BL/6 (B6) mice causes conspicuous midline neural tube deficit (dysraphia) and disruption of genesis and development of serotonin (5-HT) neurons in the raphe nuclei, together with brain growth retardation. The current study tested the hypothesis that concurrent treatment with either an activity-dependent neurotrophic factor (ADNF) agonist peptide [SALLRSIPA, (SAL)] or an activity-dependent neurotrophic protein (ADNP) agonist peptide [NAPVSIPQ, (NAP)] would protect against these alcohol-induced deficits in brain development. Methods Timed-pregnant B6 dams consumed alcohol from embryonic day 7 (E7, before the onset of neurulation) until E15. Fetuses were obtained on E15 and brain sections processed for 5-HT immunocytochemistry, for evaluation of morphologic development of the brainstem raphe and its 5-HT neurons. Additional groups were treated either with SAL or NAP daily from E7 to E15 to assess the potential protective effects of these peptides. Measures of incomplete occlusion of the ventral canal and the frequency and extent of the openings in the rhombencephalon were obtained to assess fetal dysraphia. Counts of 5-HT-immunostained neurons were also obtained in the rostral and caudal raphe. Results Prenatal alcohol exposure resulted in abnormal openings along the midline and delayed closure of ventral canal in the brainstem. This dysraphia was associated with reductions in the number of 5-HT neurons both in the rostral raphe nuclei (that gives rise to ascending 5-HT projections) and in the caudal raphe (that gives rise to the descending 5-HT projections). Concurrent treatment of the alcohol-consuming dams with SAL prevented dysraphia and protected against the alcohol-induced reductions in 5-HT neurons in both the rostral and caudal raphe. NAP was less effective in protecting against dysraphia and did not protect against 5-HT loss in the rostral raphe, but did protect against loss in the caudal raphe. Conclusions These findings further support the potential usefulness of these peptides for therapeutic interventions in pregnancies at risk for alcohol-induced developmental deficits. Notably, the ascending 5-HT projections of the rostral raphe have profound effects in regulating forebrain development and function, and the descending 5-HT projections of the caudal raphe are critical for regulating respiration. Protection of the rostral 5-HT-system may help prevent structural and functional deficits linked to abnormal forebrain development, and protection of the caudal systems may also reduce the increased risk for sudden infant death syndrome associated with prenatal alcohol exposure. PMID:18565153

Maternal Stress and Effects of Prenatal Air Pollution on Offspring Mental Health Outcomes in Mice

PubMed Central

Huff, Nicole C.; Smith, Susan H.; Mason, S. Nicholas; Foster, W. Michael; Auten, Richard L.; Bilbo, Staci D.

2013-01-01

Background: Low socioeconomic status is consistently associated with reduced physical and mental health, but the mechanisms remain unclear. Increased levels of urban air pollutants interacting with parental stress have been proposed to explain health disparities in respiratory disease, but the impact of such interactions on mental health is unknown. Objectives: We aimed to determine whether prenatal air pollution exposure and stress during pregnancy act synergistically on offspring to induce a neuroinflammatory response and subsequent neurocognitive disorders in adulthood. Methods: Mouse dams were intermittently exposed via oropharyngeal aspiration to diesel exhaust particles (DEP; 50 μg × 6 doses) or vehicle throughout gestation. This exposure was combined with standard housing or nest material restriction (NR; a novel model of maternal stress) during the last third of gestation. Results: Adult (postnatal day 60) offspring of dams that experienced both stressors (DEP and NR) displayed increased anxiety, but only male offspring of this group had impaired cognition. Furthermore, maternal DEP exposure increased proinflammatory interleukin (IL)-1β levels within the brains of adult males but not females, and maternal DEP and NR both decreased anti-inflammatory IL-10 in male, but not female, brains. Similarly, only DEP/NR males showed increased expression of the innate immune recognition gene toll-like receptor 4 (Tlr4) and its downstream effector, caspase-1. Conclusions: These results show that maternal stress during late gestation increases the susceptibility of offspring—particularly males—to the deleterious effects of prenatal air pollutant exposure, which may be due to a synergism of these factors acting on innate immune recognition genes and downstream neuroinflammatory cascades within the developing brain. Citation: Bolton JL, Huff NC, Smith SH, Mason SN, Foster WM, Auten RL, Bilbo SD. 2013. Maternal stress and effects of prenatal air pollution on offspring mental health outcomes in mice. Environ Health Perspect 121:1075–1082; http://dx.doi.org/10.1289/ehp.1306560 PMID:23823752

Subcortical and cortical structural central nervous system changes and attention processing deficits in preschool-aged children with prenatal methamphetamine and tobacco exposure.

PubMed

Derauf, Chris; Lester, Barry M; Neyzi, Nurunisa; Kekatpure, Minal; Gracia, Luis; Davis, James; Kallianpur, Kalpana; Efird, Jimmy T; Kosofsky, Barry

2012-01-01

To examine the independent contributions of prenatal methamphetamine exposure (PME) and prenatal tobacco exposure (PTE) on brain morphology among a sample of nonalcohol-exposed 3- to 5-year-old children followed prospectively since birth. The sample included 20 children with PME (19 with PTE) and 15 comparison children (7 with PTE), matched on race, birth weight, maternal education and type of insurance. Subcortical and cortical volumes and cortical thickness measures were derived through an automated segmentation procedure from T1-weighted structural magnetic resonance images obtained on unsedated children. Attention was assessed using the computerized Conners' Kiddie Continuous Performance Test Version 5 (K-CPT™ V.5). PME effects on subcortical and cortical brain volumes and cortical thickness were tested by general linear model with type III sum of squares, adjusting for PTE, prenatal marijuana exposure, age at time of scan, gender, handedness, pulse sequence and total intracranial volume (for volumetric outcomes). A similar analysis was done for PTE effects on subcortical and cortical brain volumes and thickness, adjusting for PME and the above covariates. Children with PME had significantly reduced caudate nucleus volumes and cortical thickness increases in perisylvian and orbital-frontal cortices. In contrast, children with PTE showed cortical thinning in perisylvian and lateral occipital cortices and volumetric increases in frontal regions and decreases in anterior cingulate. PME was positively related and caudate volume was inversely related to K-CPT reaction time by inter-stimulus interval, a measure of the ability to adjust to changing task demands, suggesting that children with PME may have subtle attentional deficits mediated by caudate volume reductions. Our results suggest that PME and PTE may have distinct differential cortical effects on the developing central nervous system. Additionally, PME may be associated with subtle deficits in attention mediated by caudate volume reductions. Copyright © 2012 S. Karger AG, Basel.

Gender development and the human brain.

PubMed

Hines, Melissa

2011-01-01

Convincing evidence indicates that prenatal exposure to the gonadal hormone, testosterone, influences the development of children's sex-typical toy and activity interests. In addition, growing evidence shows that testosterone exposure contributes similarly to the development of other human behaviors that show sex differences, including sexual orientation, core gender identity, and some, though not all, sex-related cognitive and personality characteristics. In addition to these prenatal hormonal influences, early infancy and puberty may provide additional critical periods when hormones influence human neurobehavioral organization. Sex-linked genes could also contribute to human gender development, and most sex-related characteristics are influenced by socialization and other aspects of postnatal experience, as well. Neural mechanisms underlying the influences of gonadal hormones on human behavior are beginning to be identified. Although the neural mechanisms underlying experiential influences remain largely uninvestigated, they could involve the same neural circuitry as that affected by hormones.

Changes in Dpysl2 expression are associated with prenatally stressed rat offspring and susceptibility to schizophrenia in humans

PubMed Central

LEE, HWAYOUNG; JOO, JAESOON; NAH, SEONG-SU; KIM, JONG WOO; KIM, HYUNG-KI; KWON, JUN-TACK; LEE, HWA-YOUNG; KIM, YOUNG OCK; KIM, HAK-JAE

2015-01-01

Exposure to stress during critical periods of fetal brain development is an environmental risk factor for the development of schizophrenia in adult offspring. In the present study, a repeated-variable stress paradigm was applied to pregnant rats during the last week of gestation, which is analogous to the second trimester of brain development in humans. Behavioral and proteomic analyses were conducted in prenatally-stressed (PNS) adult offspring and non-stressed (NS) adult controls. In the behavioral tests, grooming behavior in the social interaction test, line-crossing behavior in the open field test, and swimming behavior in the forced swimming test were decreased in the PNS group. Western blot analysis and immunohistochemical analysis revealed that the expression of dihydropyrimidinase-like 2 (Dpysl2) or collapsin response mediator protein 2 (Crmp2) was downregulated in the prefrontal cortex and hippocampus of rats in the PNS group. Subsequently, single-nucleotide polymorphisms (SNPs) of the human dihydropyrimidinase-like 2 (DPYSL2) gene were analyzed in a population. Two functional SNPs (rs9886448 in the promoter region and rs2289593 in the exon region) were associated with susceptibility to schizophrenia. The present findings demonstrated that the downregulation of genes such as Dpysl2 and Dypsl3 in a rat model of prenatal stress may affect subsequent behavioral changes and that polymorphisms of the DPYSL2 gene in humans may be associated with the development of schizophrenia. Taken together with previous studies investigating the association between the DPYSL2 gene and schizophrenia, the present findings may contribute additional evidence regarding developmental theories of the pathophysiology of schizophrenia. PMID:25847191

Effects of dopaminergic genes, prenatal adversities, and their interaction on attention-deficit/hyperactivity disorder and neural correlates of response inhibition.

PubMed

van der Meer, Dennis; Hartman, Catharina A; van Rooij, Daan; Franke, Barbara; Heslenfeld, Dirk J; Oosterlaan, Jaap; Faraone, Stephen V; Buitelaar, Jan K; Hoekstra, Pieter J

2017-03-01

Attention-deficit/hyperactivity disorder (ADHD) is often accompanied by impaired response inhibition; both have been associated with aberrant dopamine signalling. Given that prenatal exposure to alcohol or smoking is known to affect dopamine-rich brain regions, we hypothesized that individuals carrying the ADHD risk alleles of the dopamine receptor D4 ( DRD4 ) and dopamine transporter ( DAT1 ) genes may be especially sensitive to their effects. Functional MRI data, information on prenatal adversities and genetic data were available for 239 adolescents and young adults participating in the multicentre ADHD cohort study NeuroIMAGE (average age 17.3 yr). We analyzed the effects of DRD4 and DAT1 , prenatal exposure to alcohol and smoking and their interactions on ADHD severity, response inhibition and neural activity. We found no significant gene × environment interaction effects. We did find that the DRD4 7-repeat allele was associated with less superior frontal and parietal brain activity and with greater activity in the frontal pole and occipital cortex. Prenatal exposure to smoking was also associated with lower superior frontal activity, but with greater activity in the parietal lobe. Further, those exposed to alcohol had more activity in the lateral orbitofrontal cortex, and the DAT1 risk variant was associated with lower cerebellar activity. Retrospective reports of maternal substance use and the cross-sectional study design restrict causal inference. While we found no evidence of gene × environment interactions, the risk factors under investigation influenced activity of brain regions associated with response inhibition, suggesting they may add to problems with inhibiting behaviour.

Associations between prenatal, childhood, and adolescent stress and variations in white-matter properties in young men.

PubMed

Jensen, Sarah K G; Pangelinan, Melissa; Björnholm, Lassi; Klasnja, Anja; Leemans, Alexander; Drakesmith, Mark; Evans, C J; Barker, Edward D; Paus, Tomáš

2017-10-21

Previous studies have shown that both pre- and post-natal adversities, the latter including exposures to stress during childhood and adolescence, explain variation in structural properties of white matter (WM) in the brain. While previous studies have examined effects of independent stress exposures within one developmental period, such as childhood, we examine effects of stress across development using data from a prospective longitudinal study. More specifically, we ask how stressful events during prenatal development, childhood, and adolescence relate to variation in WM properties in early adulthood in young men recruited from a birth cohort. Using data from 393 mother-son pairs from a community-based birth cohort from England (Avon Longitudinal Study of Parents and Children), we examined how stressful life events relate to variation in different structural properties of WM in the corpus callosum and across the whole brain in early adulthood in men aged 18-21 years. We distinguish between stress occurring during three developmental periods: a) prenatal maternal stress, b) postnatal stress within the first four years of life, c) stress during adolescence (age 12-16 years). To obtain a comprehensive quantification of variation in WM, we assess structural properties of WM using four different measures, namely fractional anisotropy (FA), mean diffusivity (MD), magnetization transfer ratio (MTR) and myelin water fraction (MWF). The developmental model shows that prenatal stress is associated with lower MTR and MWF in the genu and/or splenium of the corpus callosum, and with lower MTR in global (lobar) WM. Stress during early childhood is associated with higher MTR in the splenium, and stress during adolescence is associated with higher MTR in the genu and lower MD in the splenium. We see no associations between postnatal stress and variation in global (lobar) WM. The current study found evidence for independent effects of stress on WM properties during distinct neurodevelopmental periods. We speculate that these independent effects are due to differences in the developmental processes unfolding at different developmental time points. We suggest that associations between prenatal stress and WM properties may relate to abnormalities in neurogenesis, affecting the number and density of axons, while postnatal stress may interfere with processes related to myelination or radial growth of axons. Potential consequences of prenatal glucocorticoid exposure should be considered in obstetric care. Copyright © 2017 Elsevier Inc. All rights reserved.

Neurobehavioral Disorder Associated With Prenatal Alcohol Exposure

PubMed Central

Hagan, Joseph F.; Balachova, Tatiana; Bertrand, Jacquelyn; Chasnoff, Ira; Dang, Elizabeth; Fernandez-Baca, Daniel; Kable, Julie; Kosofsky, Barry; Senturias, Yasmin N.; Singh, Natasha; Sloane, Mark; Weitzman, Carol; Zubler, Jennifer

2017-01-01

Children and adolescents affected by prenatal exposure to alcohol who have brain damage that is manifested in functional impairments of neurocognition, self-regulation, and adaptive functioning may most appropriately be diagnosed with neurobehavioral disorder associated with prenatal exposure. This Special Article outlines clinical implications and guidelines for pediatric medical home clinicians to identify, diagnose, and refer children regarding neurobehavioral disorder associated with prenatal exposure. Emphasis is given to reported or observable behaviors that can be identified as part of care in pediatric medical homes, differential diagnosis, and potential comorbidities. In addition, brief guidance is provided on the management of affected children in the pediatric medical home. Finally, suggestions are given for obtaining prenatal history of in utero exposure to alcohol for the pediatric patient. PMID:27677572

A review on neuroimaging studies of genetic and environmental influences on early brain development.

PubMed

Gao, Wei; Grewen, Karen; Knickmeyer, Rebecca C; Qiu, Anqi; Salzwedel, Andrew; Lin, Weili; Gilmore, John H

2018-04-16

The past decades witnessed a surge of interest in neuroimaging study of normal and abnormal early brain development. Structural and functional studies of normal early brain development revealed massive structural maturation as well as sequential, coordinated, and hierarchical emergence of functional networks during the infancy period, providing a great foundation for the investigation of abnormal early brain development mechanisms. Indeed, studies of altered brain development associated with either genetic or environmental risks emerged and thrived. In this paper, we will review selected studies of genetic and environmental risks that have been relatively more extensively investigated-familial risks, candidate risk genes, and genome-wide association studies (GWAS) on the genetic side; maternal mood disorders and prenatal drug exposures on the environmental side. Emerging studies on environment-gene interactions will also be reviewed. Our goal was not to perform an exhaustive review of all studies in the field but to leverage some representative ones to summarize the current state, point out potential limitations, and elicit discussions on important future directions. Copyright © 2018 Elsevier Inc. All rights reserved.

Using sex differences in the developing brain to identify nodes of influence for seizure susceptibility and epileptogenesis.

PubMed

Kight, Katherine E; McCarthy, Margaret M

2014-12-01

Sexual differentiation of the developing brain organizes the neural architecture differently between males and females, and the main influence on this process is exposure to gonadal steroids during sensitive periods of prenatal and early postnatal development. Many molecular and cellular processes are influenced by steroid hormones in the developing brain, including gene expression, cell birth and death, neurite outgrowth and synaptogenesis, and synaptic activity. Perturbations in these processes can alter neuronal excitability and circuit activity, leading to increased seizure susceptibility and the promotion of pathological processes that constitute epileptogenesis. In this review, we will provide a general overview of sex differences in the early developing brain that may be relevant for altered seizure susceptibility in early life, focusing on limbic areas of the brain. Sex differences that have the potential to alter the progress of epileptogenesis are evident at molecular and cellular levels in the developing brain, and include differences in neuronal excitability, response to environmental insult, and epigenetic control of gene expression. Knowing how these processes differ between the sexes can help us understand fundamental mechanisms underlying gender differences in seizure susceptibility and epileptogenesis. Copyright © 2014 Elsevier Inc. All rights reserved.

Prenatal and Neonatal Thyroid Stimulating Hormone Levels and Autism Spectrum Disorders

ERIC Educational Resources Information Center

Yau, Vincent M.; Lutsky, Marta; Yoshida, Cathleen K.; Lasley, Bill; Kharrazi, Martin; Windham, Gayle; Gee, Nancy; Croen, Lisa A.

2015-01-01

Thyroid hormones are critical for normal brain development. This study examined autism spectrum disorders (ASD) and thyroid stimulating hormone (TSH) levels measured in mid-pregnancy maternal serum and infant blood after birth. Three groups of children born in Orange County, CA in 2000-2001 were identified: ASD (n = 78), developmental delay…

The Impact of Ultrasound on Developing Brain Neurons. Science Briefs

ERIC Educational Resources Information Center

National Scientific Council on the Developing Child, 2007

2007-01-01

"Science Briefs" summarize the findings and implications of a recent study in basic science or clinical research. This brief reports on the study. This Brief summarizes the findings and implications of "Prenatal Exposure to Ultrasound Waves Impacts Neuronal Migration in Mice" (E. S. B. C. Ang, Jr.; V. Gluncic; A. Duque; M. E. Schafer; and P.…

Antiepileptic drugs and brain maturation: fetal exposure to lamotrigine generates cortical malformations in rats.

PubMed

Manent, Jean-Bernard; Jorquera, Isabel; Franco, Valentina; Ben-Ari, Yehezkel; Perucca, Emilio; Represa, Alfonso

2008-02-01

Intake of antiepileptic drugs (AEDs) during pregnancy can provoke severe and subtle fetal malformations associated with deleterious sequelae, reflecting the need for experimental investigations on the comparative teratogenic potential of these agents. We recently reported that prenatal exposure to vigabatrin and valproate, two AEDs which act through GABAergic mechanisms, induces hippocampal and cortical dysplasias in rodents. We have now investigated the effects of phenobarbital (PB, 30 mg/kg day) i.p.), a drug also endowed with GABAergic effects, and the new generation AEDs lamotrigine (LTG, 5-20mg/kg/day i.p.), topiramate (TPM, 10mg/kg/day i.p.), and levetiracetam (LEV, 50mg/kg/day i.p.) on brain development. Prenatal exposure to LTG induced hippocampal and cortical malformations in a dose-dependent manner, at maternal plasma concentrations within the clinically occurring range. These abnormalities were not observed after exposure to PB, TP and LEV. These observations raise concerns about potential clinical correlates and call for detailed comparative investigations on the consequences of AED use during pregnancy.

Prenatal stress-immune programming of sex differences in comorbidity of depression and obesity/metabolic syndrome.

PubMed

Goldstein, Jill M; Holsen, Laura; Huang, Grace; Hammond, Bradley D; James-Todd, Tamarra; Cherkerzian, Sara; Hale, Taben M; Handa, Robert J

2016-12-01

Major depressive disorder (MDD) is the number one cause of disability worldwide and is comorbid with many chronic diseases, including obesity/metabolic syndrome (MetS). Women have twice as much risk for MDD and comorbidity with obesity/MetS as men, although pathways for understanding this association remain unclear. On the basis of clinical and preclinical studies, we argue that prenatal maternal stress (ie, excess glucocorticoid expression and associated immune responses) that occurs during the sexual differentiation of the fetal brain has sex-dependent effects on brain development within highly sexually dimorphic regions that regulate mood, stress, metabolic function, the autonomic nervous system, and the vasculature. Furthermore, these effects have lifelong consequences for shared sex-dependent risk of MDD and obesity/MetS. Thus, we propose that there are shared biologic substrates at the anatomical, molecular, and/or genetic levels that produce the comorbid risk for MDD-MetS through sex-dependent fetal origins.

Maternal stress and effects of prenatal air pollution on offspring mental health outcomes in mice.

PubMed

Bolton, Jessica L; Huff, Nicole C; Smith, Susan H; Mason, S Nicholas; Foster, W Michael; Auten, Richard L; Bilbo, Staci D

2013-09-01

Low socioeconomic status is consistently associated with reduced physical and mental health, but the mechanisms remain unclear. Increased levels of urban air pollutants interacting with parental stress have been proposed to explain health disparities in respiratory disease, but the impact of such interactions on mental health is unknown. We aimed to determine whether prenatal air pollution exposure and stress during pregnancy act synergistically on offspring to induce a neuroinflammatory response and subsequent neurocognitive disorders in adulthood. Mouse dams were intermittently exposed via oropharyngeal aspiration to diesel exhaust particles (DEP; 50 μg × 6 doses) or vehicle throughout gestation. This exposure was combined with standard housing or nest material restriction (NR; a novel model of maternal stress) during the last third of gestation. Adult (postnatal day 60) offspring of dams that experienced both stressors (DEP and NR) displayed increased anxiety, but only male offspring of this group had impaired cognition. Furthermore, maternal DEP exposure increased proinflammatory interleukin (IL)-1β levels within the brains of adult males but not females, and maternal DEP and NR both decreased anti-inflammatory IL-10 in male, but not female, brains. Similarly, only DEP/NR males showed increased expression of the innate immune recognition gene toll-like receptor 4 (Tlr4) and its downstream effector, caspase-1. These results show that maternal stress during late gestation increases the susceptibility of offspring-particularly males-to the deleterious effects of prenatal air pollutant exposure, which may be due to a synergism of these factors acting on innate immune recognition genes and downstream neuroinflammatory cascades within the developing brain.

Fluoxetine during development reverses the effects of prenatal stress on depressive-like behavior and hippocampal neurogenesis in adolescence.

PubMed

Rayen, Ine; van den Hove, Daniël L; Prickaerts, Jos; Steinbusch, Harry W; Pawluski, Jodi L

2011-01-01

Depression during pregnancy and the postpartum period is a growing health problem, which affects up to 20% of women. Currently, selective serotonin reuptake inhibitor (SSRIs) medications are commonly used for treatment of maternal depression. Unfortunately, there is very little research on the long-term effect of maternal depression and perinatal SSRI exposure on offspring development. Therefore, the aim of this study was to determine the role of exposure to fluoxetine during development on affective-like behaviors and hippocampal neurogenesis in adolescent offspring in a rodent model of maternal depression. To do this, gestationally stressed and non-stressed Sprague-Dawley rat dams were treated with either fluoxetine (5 mg/kg/day) or vehicle beginning on postnatal day 1 (P1). Adolescent male and female offspring were divided into 4 groups: 1) prenatal stress+fluoxetine exposure, 2) prenatal stress+vehicle, 3) fluoxetine exposure alone, and 4) vehicle alone. Adolescent offspring were assessed for anxiety-like behavior using the Open Field Test and depressive-like behavior using the Forced Swim Test. Brains were analyzed for endogenous markers of hippocampal neurogenesis via immunohistochemistry. Results demonstrate that maternal fluoxetine exposure reverses the reduction in immobility evident in prenatally stressed adolescent offspring. In addition, maternal fluoxetine exposure reverses the decrease in hippocampal cell proliferation and neurogenesis in maternally stressed adolescent offspring. This research provides important evidence on the long-term effect of fluoxetine exposure during development in a model of maternal adversity.

Reading Development in Typically Developing Children and Children with Prenatal or Perinatal Brain Lesions: Differential School Year and Summer Growth

ERIC Educational Resources Information Center

Demir-Lira, Özlem Ece; Levine, Susan C.

2016-01-01

Summer slide, uneven growth of academic skills during the calendar year, captures the fact that the learning gains children make during the school year do not continue at the same pace over the summer, when children are typically not in school. We compared growth of reading skills during the school year and during the summer months in children…

Otoacoustic emissions, auditory evoked potentials and self-reported gender in people affected by disorders of sex development (DSD).

PubMed

Wisniewski, Amy B; Espinoza-Varas, Blas; Aston, Christopher E; Edmundson, Shelagh; Champlin, Craig A; Pasanen, Edward G; McFadden, Dennis

2014-08-01

Both otoacoustic emissions (OAEs) and auditory evoked potentials (AEPs) are sexually dimorphic, and both are believed to be influenced by prenatal androgen exposure. OAEs and AEPs were collected from people affected by 1 of 3 categories of disorders of sex development (DSD) - (1) women with complete androgen insensitivity syndrome (CAIS); (2) women with congenital adrenal hyperplasia (CAH); and (3) individuals with 46,XY DSD including prenatal androgen exposure who developed a male gender despite initial rearing as females (men with DSD). Gender identity (GI) and role (GR) were measured both retrospectively and at the time of study participation, using standardized questionnaires. The main objective of this study was to determine if patterns of OAEs and AEPs correlate with gender in people affected by DSD and in controls. A second objective was to assess if OAE and AEP patterns differed according to degrees of prenatal androgen exposure across groups. Control males, men with DSD, and women with CAH produced fewer spontaneous OAEs (SOAEs) - the male-typical pattern - than control females and women with CAIS. Additionally, the number of SOAEs produced correlated with gender development across all groups tested. Although some sex differences in AEPs were observed between control males and females, AEP measures did not correlate with gender development, nor did they vary according to degrees of prenatal androgen exposure, among people with DSD. Thus, OAEs, but not AEPs, may prove useful as bioassays for assessing early brain exposure to androgens and predicting gender development in people with DSD. Copyright © 2014 Elsevier Inc. All rights reserved.

Otoacoustic Emissions, Auditory Evoked Potentials and Self-Reported Gender in People Affected by Disorders of Sex Development (DSD)

PubMed Central

Wisniewski, Amy B.; Espinoza-Varas, Blas; Aston, Christopher E.; Edmundson, Shelagh; Champlin, Craig A.; Pasanen, Edward G.; McFadden, Dennis

2014-01-01

Both otoacoustic emissions (OAEs) and auditory evoked potentials (AEPs) are sexually dimorphic, and both are believed to be influenced by prenatal androgen exposure. OAEs and AEPs were collected from people affected by 1 of 3 categories of disorders of sex development (DSD) – (1) women with complete androgen insensitivity syndrome (CAIS); (2) women with congenital adrenal hyperplasia (CAH); and (3) individuals with 46, XY DSD including prenatal androgen exposure who developed a male gender despite initial rearing as females (men with DSD). Gender identity (GI) and role (GR) were measured both retrospectively and at the time of study participation, using standardized questionnaires. The main objective of this study was to determine if patterns of OAEs and AEPs correlate with gender in people affected by DSD and in controls. A second objective was to assess if OAE and AEP patterns differed according to degrees of prenatal androgen exposure across groups. Control males, men with DSD, and women with CAH produced fewer spontaneous OAEs (SOAEs) – the male-typical pattern – than control females and women with CAIS. Additionally, the number of SOAEs produced correlated with gender development across all groups tested. Although some sex differences in AEPs were observed between control males and females, AEP measures did not correlate with gender development, nor did they vary according to degrees of prenatal androgen exposure, among people with DSD. Thus, OAEs, but not AEPs, may prove useful as bioassays for assessing early brain exposure to androgens and predicting gender development in people with DSD. PMID:25038289

Early Developmental Disturbances of Cortical Inhibitory Neurons: Contribution to Cognitive Deficits in Schizophrenia

PubMed Central

Volk, David W.; Lewis, David A.

2014-01-01

Cognitive dysfunction is a disabling and core feature of schizophrenia. Cognitive impairments have been linked to disturbances in inhibitory (gamma-aminobutyric acid [GABA]) neurons in the prefrontal cortex. Cognitive deficits are present well before the onset of psychotic symptoms and have been detected in early childhood with developmental delays reported during the first year of life. These data suggest that the pathogenetic process that produces dysfunction of prefrontal GABA neurons in schizophrenia may be related to altered prenatal development. Interestingly, adult postmortem schizophrenia brain tissue studies have provided evidence consistent with a disease process that affects different stages of prenatal development of specific subpopulations of prefrontal GABA neurons. Prenatal ontogeny (ie, birth, proliferation, migration, and phenotypic specification) of distinct subpopulations of cortical GABA neurons is differentially regulated by a host of transcription factors, chemokine receptors, and other molecular markers. In this review article, we propose a strategy to investigate how alterations in the expression of these developmental regulators of subpopulations of cortical GABA neurons may contribute to the pathogenesis of cortical GABA neuron dysfunction and consequently cognitive impairments in schizophrenia. PMID:25053651

Altered hippocampal plasticity by prenatal kynurenine administration, kynurenine-3-monoxygenase (KMO) deletion or galantamine.

PubMed

Forrest, C M; McNair, K; Pisar, M; Khalil, O S; Darlington, L G; Stone, T W

2015-12-03

Glutamate receptors sensitive to N-methyl-D-aspartate (NMDA) are involved in embryonic brain development but their activity may be modulated by the kynurenine pathway of tryptophan metabolism which includes an agonist (quinolinic acid) and an antagonist (kynurenic acid) at these receptors. Our previous work has shown that prenatal inhibition of the pathway produces abnormalities of brain development. In the present study kynurenine and probenecid (both 100mg/kg, doses known to increase kynurenic acid levels in the brain) were administered to female Wistar rats on embryonic days E14, E16 and E18 of gestation and the litter was allowed to develop to post-natal day P60. Western blotting revealed no changes in hippocampal expression of several proteins previously found to be altered by inhibition of the kynurenine pathway including the NMDA receptor subunits GluN1, GluN2A and GluN2B, as well as doublecortin, Proliferating Cell Nuclear Antigen (PCNA), sonic hedgehog and unco-ordinated (unc)-5H1 and 5H3. Mice lacking the enzyme kynurenine-3-monoxygenase (KMO) also showed no changes in hippocampal expression of several of these proteins or the 70-kDa and 100-kDa variants of Disrupted in Schizophrenia-1 (DISC1). Electrical excitability of pyramidal neurons in the CA1 region of hippocampal slices was unchanged, as was paired-pulse facilitation and inhibition. Long-term potentiation was decreased in the kynurenine-treated rats and in the KMO(-/-) mice, but galantamine reversed this effect in the presence of nicotinic receptor antagonists, consistent with evidence that it can potentiate glutamate at NMDA receptors. It is concluded that interference with the kynurenine pathway in utero can have lasting effects on brain function of the offspring, implying that the kynurenine pathway is involved in the regulation of early brain development. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Altered hippocampal plasticity by prenatal kynurenine administration, kynurenine-3-monoxygenase (KMO) deletion or galantamine

PubMed Central

Forrest, C.M.; McNair, K.; Pisar, M.; Khalil, O.S.; Darlington, L.G.; Stone, T.W.

2015-01-01

Glutamate receptors sensitive to N-methyl-d-aspartate (NMDA) are involved in embryonic brain development but their activity may be modulated by the kynurenine pathway of tryptophan metabolism which includes an agonist (quinolinic acid) and an antagonist (kynurenic acid) at these receptors. Our previous work has shown that prenatal inhibition of the pathway produces abnormalities of brain development. In the present study kynurenine and probenecid (both 100 mg/kg, doses known to increase kynurenic acid levels in the brain) were administered to female Wistar rats on embryonic days E14, E16 and E18 of gestation and the litter was allowed to develop to post-natal day P60. Western blotting revealed no changes in hippocampal expression of several proteins previously found to be altered by inhibition of the kynurenine pathway including the NMDA receptor subunits GluN1, GluN2A and GluN2B, as well as doublecortin, Proliferating Cell Nuclear Antigen (PCNA), sonic hedgehog and unco-ordinated (unc)-5H1 and 5H3. Mice lacking the enzyme kynurenine-3-monoxygenase (KMO) also showed no changes in hippocampal expression of several of these proteins or the 70-kDa and 100-kDa variants of Disrupted in Schizophrenia-1 (DISC1). Electrical excitability of pyramidal neurons in the CA1 region of hippocampal slices was unchanged, as was paired-pulse facilitation and inhibition. Long-term potentiation was decreased in the kynurenine-treated rats and in the KMO(−/−) mice, but galantamine reversed this effect in the presence of nicotinic receptor antagonists, consistent with evidence that it can potentiate glutamate at NMDA receptors. It is concluded that interference with the kynurenine pathway in utero can have lasting effects on brain function of the offspring, implying that the kynurenine pathway is involved in the regulation of early brain development. PMID:26365611

Relations between prospective memory, cognitive abilities, and brain structure in adolescents who vary in prenatal drug exposure

PubMed Central

Robey, Alison; Buckingham-Howes, Stacy; Salmeron, Betty Jo; Black, Maureen M.; Riggins, Tracy

2014-01-01

This investigation examined how prospective memory (PM) relates to cognitive abilities (i.e., executive function, attention, working memory, and retrospective memory), and brain structure in adolescents who vary in prenatal drug exposure (PDE). The sample included 105 (55 female, 50 male) urban, primarily African American adolescents (mean age 15.5 years) from low socioeconomic status (SES) families; 56% (n=59) were prenatally exposed to drugs (heroin and/or cocaine) and 44% (n=46) were not prenatally exposed, but similar in age, gender, race, and SES. Executive functioning, attentional control, working memory, retrospective memory, and overall cognitive ability were assessed by validated performance measures. Executive functioning was also measured by caregiver report. A subset of 52 adolescents completed MRI scans, which provided measures of subcortical gray matter volumes and thickness of prefrontal, parietal and temporal cortices. Results revealed no differences in PM performance by PDE status, even after adjusting for age and IQ. Executive function, retrospective memory, cortical thickness in frontal and parietal regions, and volume of subcortical regions (i.e., putamen and hippocampus) were related to PM performance in the sample overall, even after adjusting for age, IQ, and total gray matter volume. Findings suggest that variations in PM ability during adolescence are robustly related to individual differences in cognitive abilities, in particular executive function and retrospective memory, and brain structure, but do not vary by PDE status. PMID:24630759

A milk-based wolfberry preparation prevents prenatal stress-induced cognitive impairment of offspring rats, and inhibits oxidative damage and mitochondrial dysfunction in vitro.

PubMed

Feng, Zhihui; Jia, Haiqun; Li, Xuesen; Bai, Zhuanli; Liu, Zhongbo; Sun, Lijuan; Zhu, Zhongliang; Bucheli, Peter; Ballèvre, Olivier; Wang, Junkuan; Liu, Jiankang

2010-05-01

Lycium barbarum (Fructus Lycii, Wolfberry, or Gouqi) belongs to the Solanaceae. The red-colored fruits of L. barbarum have been used for a long time as an ingredient in Chinese cuisine and brewing, and also in traditional Chinese herbal medicine for improving health. However, its effects on cognitive function have not been well studied. In the present study, prevention of a milk-based wolfberry preparation (WP) on cognitive dysfunction was tested in a prenatal stress model with rats and the antioxidant mechanism was tested by in vitro experiments. We found that prenatal stress caused a significant decrease in cognitive function (Morris water maze test) in female offspring. Pretreatment of the mother rats with WP significantly prevented the prenatal stress-induced cognitive dysfunction. In vitro studies showed that WP dose-dependently scavenged hydroxyl and superoxide radicals (determined by an electron spin resonance spectrometric assay), and inhibited FeCl(2)/ascorbic acid-induced dysfunction in brain tissue and tissue mitochondria, including increases in reactive oxygen species and lipid peroxidation and decreases in the activities of complex I, complex II, and glutamate cysteine ligase. These results suggest that dietary supplementation with WP may be an effective strategy for preventing the brain oxidative mitochondrial damage and cognitive dysfunction associated with prenatal stress.

The evolution of modern human brain shape

PubMed Central

Neubauer, Simon; Hublin, Jean-Jacques; Gunz, Philipp

2018-01-01

Modern humans have large and globular brains that distinguish them from their extinct Homo relatives. The characteristic globularity develops during a prenatal and early postnatal period of rapid brain growth critical for neural wiring and cognitive development. However, it remains unknown when and how brain globularity evolved and how it relates to evolutionary brain size increase. On the basis of computed tomographic scans and geometric morphometric analyses, we analyzed endocranial casts of Homo sapiens fossils (N = 20) from different time periods. Our data show that, 300,000 years ago, brain size in early H. sapiens already fell within the range of present-day humans. Brain shape, however, evolved gradually within the H. sapiens lineage, reaching present-day human variation between about 100,000 and 35,000 years ago. This process started only after other key features of craniofacial morphology appeared modern and paralleled the emergence of behavioral modernity as seen from the archeological record. Our findings are consistent with important genetic changes affecting early brain development within the H. sapiens lineage since the origin of the species and before the transition to the Later Stone Age and the Upper Paleolithic that mark full behavioral modernity. PMID:29376123

The evolution of modern human brain shape.

PubMed

Neubauer, Simon; Hublin, Jean-Jacques; Gunz, Philipp

2018-01-01

Modern humans have large and globular brains that distinguish them from their extinct Homo relatives. The characteristic globularity develops during a prenatal and early postnatal period of rapid brain growth critical for neural wiring and cognitive development. However, it remains unknown when and how brain globularity evolved and how it relates to evolutionary brain size increase. On the basis of computed tomographic scans and geometric morphometric analyses, we analyzed endocranial casts of Homo sapiens fossils ( N = 20) from different time periods. Our data show that, 300,000 years ago, brain size in early H. sapiens already fell within the range of present-day humans. Brain shape, however, evolved gradually within the H. sapiens lineage, reaching present-day human variation between about 100,000 and 35,000 years ago. This process started only after other key features of craniofacial morphology appeared modern and paralleled the emergence of behavioral modernity as seen from the archeological record. Our findings are consistent with important genetic changes affecting early brain development within the H. sapiens lineage since the origin of the species and before the transition to the Later Stone Age and the Upper Paleolithic that mark full behavioral modernity.

Magnetic resonance imaging of the kinked fetal brain stem: a sign of severe dysgenesis.

PubMed

Stroustrup Smith, Annemarie; Levine, Deborah; Barnes, Patrick D; Robertson, Richard L

2005-12-01

Magnetic resonance imaging (MRI) allows visualization of the fetal brain stem in a manner not previously possible. A "kinked" brain stem is a sign of severe neurodysgenesis. The purpose of this series was to describe cases of a kinked brain stem detected on prenatal MRI and to discuss the possible genetic and syndromic etiologies. Seven cases of a kinked brain stem on fetal MRI (gestational age range, 18-34 weeks) were reviewed and correlated with other clinical, genetic, imaging, and autopsy findings. In all cases, there was associated cerebellar hypogenesis. Additional findings were ventriculomegaly (4 cases), cerebral hypogenesis (3 cases), microcephaly (4 cases), schizencephaly (1 case), cephalocele (1 case), hypogenesis of the corpus callosum (1 case), and hydrocephalus (1 case). In 2 cases, prenatal sonography misidentified the kinked brain stem as the cerebellum. A kinked brain stem is an indicator of severe neurodysgenesis arising early in gestation. Magnetic resonance imaging provides the necessary resolution to detect this sign and delineate any associated anomalies in utero to assist with further genetic evaluation, management, and counseling.

Comprehensive transcriptional map of primate brain development

PubMed Central

Bakken, Trygve E.; Miller, Jeremy A.; Ding, Song-Lin; Sunkin, Susan M.; Smith, Kimberly A.; Ng, Lydia; Szafer, Aaron; Dalley, Rachel A.; Royall, Joshua J.; Lemon, Tracy; Shapouri, Sheila; Aiona, Kaylynn; Arnold, James; Bennett, Jeffrey L.; Bertagnolli, Darren; Bickley, Kristopher; Boe, Andrew; Brouner, Krissy; Butler, Stephanie; Byrnes, Emi; Caldejon, Shiella; Carey, Anita; Cate, Shelby; Chapin, Mike; Chen, Jefferey; Dee, Nick; Desta, Tsega; Dolbeare, Tim A.; Dotson, Nadia; Ebbert, Amanda; Fulfs, Erich; Gee, Garrett; Gilbert, Terri L.; Goldy, Jeff; Gourley, Lindsey; Gregor, Ben; Gu, Guangyu; Hall, Jon; Haradon, Zeb; Haynor, David R.; Hejazinia, Nika; Hoerder-Suabedissen, Anna; Howard, Robert; Jochim, Jay; Kinnunen, Marty; Kriedberg, Ali; Kuan, Chihchau L.; Lau, Christopher; Lee, Chang-Kyu; Lee, Felix; Luong, Lon; Mastan, Naveed; May, Ryan; Melchor, Jose; Mosqueda, Nerick; Mott, Erika; Ngo, Kiet; Nyhus, Julie; Oldre, Aaron; Olson, Eric; Parente, Jody; Parker, Patrick D.; Parry, Sheana; Pendergraft, Julie; Potekhina, Lydia; Reding, Melissa; Riley, Zackery L.; Roberts, Tyson; Rogers, Brandon; Roll, Kate; Rosen, David; Sandman, David; Sarreal, Melaine; Shapovalova, Nadiya; Shi, Shu; Sjoquist, Nathan; Sodt, Andy J.; Townsend, Robbie; Velasquez, Lissette; Wagley, Udi; Wakeman, Wayne B.; White, Cassandra; Bennett, Crissa; Wu, Jennifer; Young, Rob; Youngstrom, Brian L.; Wohnoutka, Paul; Gibbs, Richard A.; Rogers, Jeffrey; Hohmann, John G.; Hawrylycz, Michael J.; Hevner, Robert F.; Molnár, Zoltán; Phillips, John W.; Dang, Chinh; Jones, Allan R.; Amaral, David G.; Bernard, Amy; Lein, Ed S.

2017-01-01

The transcriptional underpinnings of brain development remain poorly understood, particularly in humans and closely related non-human primates. We describe a high resolution transcriptional atlas of rhesus monkey brain development that combines dense temporal sampling of prenatal and postnatal periods with fine anatomical parcellation of cortical and subcortical regions associated with human neuropsychiatric disease. Gene expression changes more rapidly before birth, both in progenitor cells and maturing neurons, and cortical layers and areas acquire adult-like molecular profiles surprisingly late postnatally. Disparate cell populations exhibit distinct developmental timing but also unexpected synchrony of processes underlying neural circuit construction including cell projection and adhesion. Candidate risk genes for neurodevelopmental disorders including primary microcephaly, autism spectrum disorder, intellectual disability, and schizophrenia show disease-specific spatiotemporal enrichment within developing neocortex. Human developmental expression trajectories are more similar to monkey than rodent, and approximately 9% of genes show human-specific regulation with evidence for prolonged maturation or neoteny. PMID:27409810

Impaired contextual fear extinction and hippocampal synaptic plasticity in adult rats induced by prenatal morphine exposure.

PubMed

Tan, Ji-Wei; Duan, Ting-Ting; Zhou, Qi-Xin; Ding, Ze-Yang; Jing, Liang; Cao, Jun; Wang, Li-Ping; Mao, Rong-Rong; Xu, Lin

2015-07-01

Prenatal opiate exposure causes a series of neurobehavioral disturbances by affecting brain development. However, the question of whether prenatal opiate exposure increases vulnerability to memory-related neuropsychiatric disorders in adult offspring remains largely unknown. Here, we found that rats prenatally exposed to morphine (PM) showed impaired acquisition but enhanced maintenance of contextual fear memory compared with control animals that were prenatally exposed to saline (PS). The impairment of acquisition was rescued by increasing the intensity of footshocks (1.2 mA rather than 0.8 mA). Meanwhile, we also found that PM rats exhibited impaired extinction of contextual fear, which is associated with enhanced maintenance of fear memory. The impaired extinction lasted for 1 week following extinction training. Furthermore, PM rats exhibited reduced anxiety-like behavior in the elevated plus-maze and light/dark box test without differences in locomotor activity. These alterations in PM rats were mirrored by abnormalities in synaptic plasticity in the Schaffer collateral-CA1 synapses of the hippocampus in vivo. PS rats showed blocked long-term potentiation and enabled long-term depression in CA1 synapses following contextual fear conditioning, while prenatal morphine exposure restricted synaptic plasticity in CA1 synapses. The smaller long-term potentiation in PM rats was not further blocked by contextual fear conditioning, and the long-term depression enabled by contextual fear conditioning was abolished. Taken together, our results provide the first evidence suggesting that prenatal morphine exposure may increase vulnerability to fear memory-related neuropsychiatric disorders in adulthood. © 2014 Society for the Study of Addiction.

[Free radical modification of proteins in brain structure of Sprague-Dawley rats and some behaviour indicators after prenatal stress].

PubMed

V'iushina, A V; Pritvorova, A V; Flerov, M A

2012-08-01

We studied the influence of late prenatal stress on free radical oxidation processes in Sprague-Dawley rats cortex, striatum, hippocampus, hypothalamus proteins. It was shown that after prenatal stress most changes were observed in hypothalamus and hippocampus. It was shown that in hypothalamus spontaneous oxidation level increased, but level of induced oxidation decreased, the opposite changes were found in hippocampus. Simultaneously minor changes of protein modification were observed in cortex and striatum. It was shown that prenatal stress changed both correlation of proteins free radical oxidation in studied structures and values of these data regarding to control. In test of "open field" motor activity in rats after prenatal stress decreased and time of freezing and grooming increased; opposite, in T-labyrinth motor activity and time of grooming in rats after prenatal stress increased, but time of freezing decreased.

Maternal salivary testosterone in pregnancy and fetal neuromaturation.

PubMed

Voegtline, Kristin M; Costigan, Kathleen A; DiPietro, Janet A

2017-11-01

Testosterone exposure during pregnancy has been hypothesized as a mechanism for sex differences in brain and behavioral development observed in the postnatal period. The current study documents the natural history of maternal salivary testosterone from 18 weeks gestation of pregnancy to 6 months postpartum, and investigates associations with fetal heart rate, motor activity, and their integration. Findings indicate maternal salivary testosterone increases with advancing gestation though no differences by fetal sex were detected. High intra-individual stability in prenatal testosterone levels extend into the postnatal period, particularly for pregnancies with male fetuses. With respect to fetal development, by 36 weeks gestation higher maternal prenatal salivary testosterone was significantly associated with faster fetal heart rate and less optimal somatic-cardiac integration. Measurement of testosterone in saliva is a useful tool for repeated-measures studies of hormonal concomitants of pregnancy. Moreover, higher maternal testosterone levels are associated with modest interference to fetal neurobehavioral development. © 2017 Wiley Periodicals, Inc.

Behavioral and molecular changes in the mouse in response to prenatal exposure to the anti-epileptic drug valproic acid.

PubMed

Roullet, F I; Wollaston, L; Decatanzaro, D; Foster, J A

2010-10-13

Experiments in rodents have indicated that maternal valproic acid (VPA) exposure has permanent adverse effects upon neurological and behavioral development. In humans, prenatal exposure to VPA can induce fetal valproate syndrome, which has been associated with autism. The present study examined mouse pups exposed in utero to VPA, measuring physical development, olfactory discrimination, and social behavior as well as expression of plasticity-related genes, brain derived neurotrophic factor (BDNF) and NMDA receptor subunits NR2A and NR2B. VPA-exposed mice showed delayed physical development, impaired olfactory discrimination, and dysfunctional pre-weaning social behavior. In situ hybridization experiments revealed lower cortical expression of BDNF mRNA in VPA animals. These results support the validity of the VPA mouse model for human autism and suggest that alterations in plasticity-related genes may contribute to the behavioral phenotype. Copyright 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

Effects of dopaminergic genes, prenatal adversities, and their interaction on attention-deficit/hyperactivity disorder and neural correlates of response inhibition

PubMed Central

van der Meer, Dennis; Hartman, Catharina A.; van Rooij, Daan; Franke, Barbara; Heslenfeld, Dirk J.; Oosterlaan, Jaap; Faraone, Stephen V.; Buitelaar, Jan K.; Hoekstra, Pieter J.

2017-01-01

Background Attention-deficit/hyperactivity disorder (ADHD) is often accompanied by impaired response inhibition; both have been associated with aberrant dopamine signalling. Given that prenatal exposure to alcohol or smoking is known to affect dopamine-rich brain regions, we hypothesized that individuals carrying the ADHD risk alleles of the dopamine receptor D4 (DRD4) and dopamine transporter (DAT1) genes may be especially sensitive to their effects. Methods Functional MRI data, information on prenatal adversities and genetic data were available for 239 adolescents and young adults participating in the multicentre ADHD cohort study NeuroIMAGE (average age 17.3 yr). We analyzed the effects of DRD4 and DAT1, prenatal exposure to alcohol and smoking and their interactions on ADHD severity, response inhibition and neural activity. Results We found no significant gene × environment interaction effects. We did find that the DRD4 7-repeat allele was associated with less superior frontal and parietal brain activity and with greater activity in the frontal pole and occipital cortex. Prenatal exposure to smoking was also associated with lower superior frontal activity, but with greater activity in the parietal lobe. Further, those exposed to alcohol had more activity in the lateral orbitofrontal cortex, and the DAT1 risk variant was associated with lower cerebellar activity. Limitations Retrospective reports of maternal substance use and the cross-sectional study design restrict causal inference. Conclusion While we found no evidence of gene × environment interactions, the risk factors under investigation influenced activity of brain regions associated with response inhibition, suggesting they may add to problems with inhibiting behaviour. PMID:28234207

Diffusion Tensor Imaging of Frontal White Matter and Executive Functioning in Cocaine-Exposed Children

PubMed Central

Warner, Tamara Duckworth; Behnke, Marylou; Eyler, Fonda Davis; Padgett, Kyle; Leonard, Christiana; Hou, Wei; Garvan, Cynthia Wilson; Schmalfuss, Ilona M.; Blackband, Stephen J.

2011-01-01

BACKGROUND Although animal studies have demonstrated frontal white matter and behavioral changes resulting from prenatal cocaine exposure, no human studies have associated neuropsychological deficits in attention and inhibition with brain structure. We used diffusion tensor imaging to investigate frontal white matter integrity and executive functioning in cocaine-exposed children. METHODS Six direction diffusion tensor images were acquired using a Siemens 3T scanner with a spin-echo echo-planar imaging pulse sequence on right-handed cocaine-exposed (n = 28) and sociodemographically similar non-exposed children (n = 25; mean age: 10.6 years) drawn from a prospective, longitudinal study. Average diffusion and fractional anisotropy were measured in the left and right frontal callosal and frontal projection fibers. Executive functioning was assessed using two well-validated neuropsychological tests (Stroop color-word test and Trail Making Test). RESULTS Cocaine-exposed children showed significantly higher average diffusion in the left frontal callosal and right frontal projection fibers. Cocaine-exposed children were also significantly slower on a visual-motor set-shifting task with a trend toward lower scores on a verbal inhibition task. Controlling for gender and intelligence, average diffusion in the left frontal callosal fibers was related to prenatal exposure to alcohol and marijuana and an interaction between cocaine and marijuana exposure. Performance on the visual-motor set-shifting task was related to prenatal cocaine exposure and an interaction between cocaine and tobacco exposure. Significant correlations were found between test performance and fractional anisotropy in areas of the frontal white matter. CONCLUSIONS Prenatal cocaine exposure, alone and in combination with exposure to other drugs, is associated with slightly poorer executive functioning and subtle microstructural changes suggesting less mature development of frontal white matter pathways. The relative contribution of postnatal environmental factors, including characteristics of the caregiving environment and stressors associated with poverty and out-of-home placement, on brain development and behavioral functioning in polydrug-exposed children awaits further research. PMID:17079574

Diffusion tensor imaging of frontal white matter and executive functioning in cocaine-exposed children.

PubMed

Warner, Tamara Duckworth; Behnke, Marylou; Eyler, Fonda Davis; Padgett, Kyle; Leonard, Christiana; Hou, Wei; Garvan, Cynthia Wilson; Schmalfuss, Ilona M; Blackband, Stephen J

2006-11-01

Although animal studies have demonstrated frontal white matter and behavioral changes resulting from prenatal cocaine exposure, no human studies have associated neuropsychological deficits in attention and inhibition with brain structure. We used diffusion tensor imaging to investigate frontal white matter integrity and executive functioning in cocaine-exposed children. Six direction diffusion tensor images were acquired using a Siemens 3T scanner with a spin-echo echo-planar imaging pulse sequence on right-handed cocaine-exposed (n = 28) and sociodemographically similar non-exposed children (n = 25; mean age: 10.6 years) drawn from a prospective, longitudinal study. Average diffusion and fractional anisotropy were measured in the left and right frontal callosal and frontal projection fibers. Executive functioning was assessed using two well-validated neuropsychological tests (Stroop color-word test and Trail Making Test). Cocaine-exposed children showed significantly higher average diffusion in the left frontal callosal and right frontal projection fibers. Cocaine-exposed children were also significantly slower on a visual-motor set-shifting task with a trend toward lower scores on a verbal inhibition task. Controlling for gender and intelligence, average diffusion in the left frontal callosal fibers was related to prenatal exposure to alcohol and marijuana and an interaction between cocaine and marijuana exposure. Performance on the visual-motor set-shifting task was related to prenatal cocaine exposure and an interaction between cocaine and tobacco exposure. Significant correlations were found between test performance and fractional anisotropy in areas of the frontal white matter. Prenatal cocaine exposure, alone and in combination with exposure to other drugs, is associated with slightly poorer executive functioning and subtle microstructural changes suggesting less mature development of frontal white matter pathways. The relative contribution of postnatal environmental factors, including characteristics of the caregiving environment and stressors associated with poverty and out-of-home placement, on brain development and behavioral functioning in polydrug-exposed children awaits further research.

Influences of prenatal and postnatal maternal depression on amygdala volume and microstructure in young children.

PubMed

Wen, D J; Poh, J S; Ni, S N; Chong, Y-S; Chen, H; Kwek, K; Shek, L P; Gluckman, P D; Fortier, M V; Meaney, M J; Qiu, A

2017-04-25

Maternal depressive symptoms influence neurodevelopment in the offspring. Such effects may appear to be gender-dependent. The present study examined contributions of prenatal and postnatal maternal depressive symptoms to the volume and microstructure of the amygdala in 4.5-year-old boys and girls. Prenatal maternal depressive symptoms were measured using the Edinburgh Postnatal Depression Scale (EPDS) at 26 weeks of gestation. Postnatal maternal depression was assessed at 3 months using the EPDS and at 1, 2, 3 and 4.5 years using the Beck's Depression Inventory-II. Structural magnetic resonance imaging and diffusion tensor imaging were performed with 4.5-year-old children to extract the volume and fractional anisotropy (FA) values of the amygdala. Our results showed that greater prenatal maternal depressive symptoms were associated with larger right amygdala volume in girls, but not in boys. Increased postnatal maternal depressive symptoms were associated with higher right amygdala FA in the overall sample and girls, but not in boys. These results support the role of variation in right amygdala structure in transmission of maternal depression to the offspring, particularly to girls. The differential effects of prenatal and postnatal maternal depressive symptoms on the volume and FA of the right amygdala suggest the importance of the timing of exposure to maternal depressive symptoms in brain development of girls. This further underscores the need for intervention targeting both prenatal and postnatal maternal depression to girls in preventing adverse child outcomes.

Influences of prenatal and postnatal maternal depression on amygdala volume and microstructure in young children

PubMed Central

Wen, D J; Poh, J S; Ni, S N; Chong, Y-S; Chen, H; Kwek, K; Shek, L P; Gluckman, P D; Fortier, M V; Meaney, M J; Qiu, A

2017-01-01

Maternal depressive symptoms influence neurodevelopment in the offspring. Such effects may appear to be gender-dependent. The present study examined contributions of prenatal and postnatal maternal depressive symptoms to the volume and microstructure of the amygdala in 4.5-year-old boys and girls. Prenatal maternal depressive symptoms were measured using the Edinburgh Postnatal Depression Scale (EPDS) at 26 weeks of gestation. Postnatal maternal depression was assessed at 3 months using the EPDS and at 1, 2, 3 and 4.5 years using the Beck's Depression Inventory-II. Structural magnetic resonance imaging and diffusion tensor imaging were performed with 4.5-year-old children to extract the volume and fractional anisotropy (FA) values of the amygdala. Our results showed that greater prenatal maternal depressive symptoms were associated with larger right amygdala volume in girls, but not in boys. Increased postnatal maternal depressive symptoms were associated with higher right amygdala FA in the overall sample and girls, but not in boys. These results support the role of variation in right amygdala structure in transmission of maternal depression to the offspring, particularly to girls. The differential effects of prenatal and postnatal maternal depressive symptoms on the volume and FA of the right amygdala suggest the importance of the timing of exposure to maternal depressive symptoms in brain development of girls. This further underscores the need for intervention targeting both prenatal and postnatal maternal depression to girls in preventing adverse child outcomes. PMID:28440816

Prenatal Exposure to Maternal Anxiety is Associated with Less Developed Smooth Pursuit Eye Movements in Six-Month-Old Infants: An Initial Study

PubMed Central

Pellegrino, Laurel; Ross, Randal G.; Hunter, Sharon K.

2014-01-01

Aims There are an increasing number of reports suggesting an association between maternal anxiety experienced during pregnancy and adverse outcomes of the offspring. However, exploration of the biological changes in the brain that mediate that relationship has been hampered by the lack of appropriate biomarkers. This report represents an initial step exploring whether a potential infant biomarker, smooth pursuit eye movements, may be associated with prenatal exposure to maternal anxiety. Study Design Blinded cross-sectional study. Place and Duration of Study Department of Psychiatry, University of Colorado School of Medicine. Data collected from July 2011 to May 2012. Methodology Forty-three infants including 34 whose prenatal maternal anxiety status was identified (12 with a known maternal prenatal anxiety diagnosis and 22 without) had eye movements recorded during a smooth pursuit eye movement task at four and/or six months of age. Results At 6 months of age, infants with prenatal exposure to maternal anxiety, compared to infants without such exposure, spent a higher percentage of time utilizing smooth pursuit (t=2.7, df=24, P=.013), had longer duration of smooth pursuit uninterrupted by saccades (t=2.5, df=24, P=.019), and had decreased frequency of forward saccades (t=3.8, df=24, P=.001). No differences between groups were identified at 4 months of age. Conclusion Smooth pursuit abnormalities may, at six months of age, be a potential biomarker for prenatal maternal anxiety exposure. PMID:25558459

Developmental nicotine exposure affects larval brain size and the adult dopaminergic system of Drosophila melanogaster.

PubMed

Morris, Melanie; Shaw, Ariel; Lambert, Madison; Perry, Haley Halperin; Lowenstein, Eve; Valenzuela, David; Velazquez-Ulloa, Norma Andrea

2018-06-14

Pregnant women may be exposed to nicotine if they smoke or use tobacco products, nicotine replacement therapy, or via e-cigarettes. Prenatal nicotine exposure has been shown to have deleterious effects on the nervous system in mammals including changes in brain size and in the dopaminergic system. The genetic and molecular mechanisms for these changes are not well understood. A Drosophila melanogaster model for these effects of nicotine exposure could contribute to faster identification of genes and molecular pathways underlying these effects. The purpose of this study was to determine if developmental nicotine exposure affects the nervous system of Drosophila melanogaster, focusing on changes to brain size and the dopaminergic system at two developmental stages. We reared flies on control or nicotine food from egg to 3rd instar larvae or from egg to adult and determined effectiveness of the nicotine treatment. We used immunohistochemistry to visualize the whole brain and dopaminergic neurons, using tyrosine hydroxylase as the marker. We measured brain area, tyrosine hydroxylase fluorescence, and counted the number of dopaminergic neurons in brain clusters. We detected an increase in larval brain hemisphere area, a decrease in tyrosine hydroxylase fluorescence in adult central brains, and a decrease in the number of neurons in the PPM3 adult dopaminergic cluster. We tested involvement of Dα7, one of the nicotinic acetylcholine receptor subunits, and found it was involved in eclosion, as previously described, but not involved in brain size. We conclude that developmental nicotine exposure in Drosophila melanogaster affects brain size and the dopaminergic system. Prenatal nicotine exposure in mammals has also been shown to have effects on brain size and in the dopaminergic system. This study further establishes Drosophila melanogaster as model organism to study the effects of developmental nicotine exposure. The genetic and molecular tools available for Drosophila research will allow elucidation of the mechanisms underlying the effects of nicotine exposure during development.

Approaches for Strengthening Causal Inference Regarding Prenatal Risk Factors for Childhood Behavioural and Psychiatric Disorders

ERIC Educational Resources Information Center

Lewis, Sarah J.; Relton, Caroline; Zammit, Stanley; Smith, George Davey

2013-01-01

Background: The risk of childhood behavioural and psychiatric diseases could be substantially reduced if modifiable risk factors for these disorders were identified. The critical period for many of these exposures is likely to be in utero as this is the time when brain development is most rapid. However, due to confounding and other limitations of…

Prenatal exposure to a maternal LP diet decreases BDNF expression in the brains of the neonatal offspring

USDA-ARS?s Scientific Manuscript database

Maternal low protein (LP) diets during gestation cause learning and mernmy impai1ment as well as cognitive deficits in the neonatal and adult offsp1ing. The cellular and molecular mechanism that mediate the deleterious effects of prenatal exposure to a maternal LP diet on cognitive function is egreg...

THE PRENATAL PARENTAL REFLECTIVE FUNCTIONING QUESTIONNAIRE: EXPLORING FACTOR STRUCTURE AND CONSTRUCT VALIDITY OF A NEW MEASURE IN THE FINN BRAIN BIRTH COHORT PILOT STUDY.

PubMed

Pajulo, Marjukka; Tolvanen, Mimmi; Karlsson, Linnea; Halme-Chowdhury, Elina; Öst, Camilla; Luyten, Patrick; Mayes, Linda; Karlsson, Hasse

2015-01-01

Parental reflective functioning (PRF) is the capacity to focus on experience and feelings in oneself and in the child. Individual differences in PRF reportedly affect child attachment and socioemotional development. In this study, we report work on developing a questionnaire to assess PRF during pregnancy (Prenatal Parental Reflective Functioning Questionnaire; P-PRFQ). The factor structure of the 33-item version of the P-PRFQ was explored using pilot study data from the Finn Brain Birth Cohort Study (n = 124 mothers, n = 82 fathers). Construct validity was assessed against the Pregnancy Interview (PI; A. Slade, L. Grunebaum, L. Huganir, & M. Reeves, 1987, 2002, 2011) in a subsample of 29 mothers from the same pilot sample. Exploratory and confirmatory factor analysis resulted in a 14-item P-PRFQ, with three factors which seem to capture relevant aspects of prenatal parental mentalization-F1: "Opacity of mental states," F2: "Reflecting on the fetus-child," and F3: "The dynamic nature of the mental states." Functioning of the factor structure was further tested in the large cohort with 600 mothers and 600 fathers. Correlations with the PI result were high, both regarding total and factor scores of the P-PRFQ. Cost-effective tools to assess key areas of early parenting are needed for both research and clinical purposes. The 14-item P-PRFQ seems to be an applicable and promising new tool for assessing very early parental mentalizing capacity. © 2015 Michigan Association for Infant Mental Health.

Prenatal Drug Exposures Sensitize Noradrenergic Circuits to Subsequent Disruption by Chlorpyrifos

PubMed Central

Slotkin, Theodore A.; Skavicus, Samantha; Seidler, Frederic J.

2015-01-01

We examined whether nicotine or dexamethasone, common prenatal drug exposures, sensitize the developing brain to chlorpyrifos. We gave nicotine to pregnant rats throughout gestation at a dose (3 mg/kg/day) producing plasma levels typical of smokers; offspring were then given chlorpyrifos on postnatal days 1–4, at a dose (1 mg/kg) that produces minimally-detectable inhibition of brain cholinesterase activity. In a parallel study, we administered dexamethasone to pregnant rats on gestational days 17–19 at a standard therapeutic dose (0.2 mg/kg) used in the management of preterm labor, followed by postnatal chlorpyrifos. We evaluated cerebellar noradrenergic projections, a known target for each agent, and contrasted the effects with those in the cerebral cortex. Either drug augmented the effect of chlorpyrifos, evidenced by deficits in cerebellar β-adrenergic receptors; the receptor effects were not due to increased systemic toxicity or cholinesterase inhibition, nor to altered chlorpyrifos pharmacokinetics. Further, the deficits were not secondary adaptations to presynaptic hyperinnervation/hyperactivity, as there were significant deficits in presynaptic norepinephrine levels that would serve to augment the functional consequence of receptor deficits. The pretreatments also altered development of cerebrocortical noradrenergic circuits, but with a different overall pattern, reflecting the dissimilar developmental stages of the regions at the time of exposure. However, in each case the net effects represented a change in the developmental trajectory of noradrenergic circuits, rather than simply a continuation of an initial injury. Our results point to the ability of prenatal drug exposure to create a subpopulation with heightened vulnerability to environmental neurotoxicants. PMID:26419632

Prenatal drug exposures sensitize noradrenergic circuits to subsequent disruption by chlorpyrifos.

PubMed

Slotkin, Theodore A; Skavicus, Samantha; Seidler, Frederic J

2015-12-02

We examined whether nicotine or dexamethasone, common prenatal drug exposures, sensitize the developing brain to chlorpyrifos. We gave nicotine to pregnant rats throughout gestation at a dose (3mg/kg/day) producing plasma levels typical of smokers; offspring were then given chlorpyrifos on postnatal days 1-4, at a dose (1mg/kg) that produces minimally-detectable inhibition of brain cholinesterase activity. In a parallel study, we administered dexamethasone to pregnant rats on gestational days 17-19 at a standard therapeutic dose (0.2mg/kg) used in the management of preterm labor, followed by postnatal chlorpyrifos. We evaluated cerebellar noradrenergic projections, a known target for each agent, and contrasted the effects with those in the cerebral cortex. Either drug augmented the effect of chlorpyrifos, evidenced by deficits in cerebellar β-adrenergic receptors; the receptor effects were not due to increased systemic toxicity or cholinesterase inhibition, nor to altered chlorpyrifos pharmacokinetics. Further, the deficits were not secondary adaptations to presynaptic hyperinnervation/hyperactivity, as there were significant deficits in presynaptic norepinephrine levels that would serve to augment the functional consequence of receptor deficits. The pretreatments also altered development of cerebrocortical noradrenergic circuits, but with a different overall pattern, reflecting the dissimilar developmental stages of the regions at the time of exposure. However, in each case the net effects represented a change in the developmental trajectory of noradrenergic circuits, rather than simply a continuation of an initial injury. Our results point to the ability of prenatal drug exposure to create a subpopulation with heightened vulnerability to environmental neurotoxicants. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Subcortical heterotopia appearing as huge midline mass in the newborn brain.

PubMed

Fukumura, Shinobu; Watanabe, Toshihide; Kimura, Sachiko; Ochi, Satoko; Yoshifuji, Kazuhisa; Tsutsumi, Hiroyuki

2016-02-01

We report the case of a 2-year-old boy who showed a huge midline mass in the brain at prenatal assessment. After birth, magnetic resonance imaging (MRI) revealed a conglomerate mass with an infolded microgyrus at the midline, which was suspected as a midline brain-in-brain malformation. MRI also showed incomplete cleavage of his frontal cortex and thalamus, consistent with lobar holoprosencephaly. The patient underwent an incisional biopsy of the mass on the second day of life. The mass consisted of normal central nervous tissue with gray and white matter, representing a heterotopic brain. The malformation was considered to be a subcortical heterotopia. With maturity, focal signal changes and decreased cerebral perfusion became clear on brain imaging, suggesting secondary glial degeneration. Coincident with these MRI abnormalities, the child developed psychomotor retardation and severe epilepsy focused on the side of the intracranial mass.

How environment and genes shape the adolescent brain.

PubMed

Paus, Tomáš

2013-07-01

This article is part of a Special Issue "Puberty and Adolescence". This review provides a conceptual framework for the study of factors--in our genes and environment--that shape the adolescent brain. I start by pointing out that brain phenotypes obtained with magnetic resonance imaging are complex traits reflecting the interplay of genes and the environment. In some cases, variations in the structural phenotypes observed during adolescence have their origin in the pre-natal or early post-natal periods. I then emphasize the bidirectional nature of brain-behavior relationships observed during this period of human development, where function may be more likely to influence structure rather than vice versa. In the main part of this article, I review our ongoing work on the influence of gonadal hormones on the adolescent brain. I also discuss the importance of social context and brain plasticity on shaping the relevant neural circuits. Copyright © 2013 Elsevier Inc. All rights reserved.

Midline corpus callosum is a neuroanatomical focus of fetal alcohol damage.

PubMed

Bookstein, Fred L; Sampson, Paul D; Connor, Paul D; Streissguth, Ann P

2002-06-15

Prenatal exposure to high levels of alcohol often induces birth defects that combine morphological stigmata with neurological or neuropsychological deficits. But it has proved problematic to diagnose these syndromes in adolescents and adults, in whom the morphological signs are absent or attenuated, the behavioral deficits nonspecific, and the exposure history often difficult to reconstruct. Localizing the associated brain abnormalities might circumvent most of these difficulties. To this end, three-dimensional (3D) locations were recorded for 67 homologous points on or near the corpus callosum in magnetic resonance (MR) brain images from 60 adolescents and adults who were normal, 60 diagnosed with fetal alcohol syndrome, and 60 diagnosed with fetal alcohol effects. We combined the standard statistical approach to this type of geometric data, Procrustes analysis, with a multivariate strategy focusing on differences in variability. In this data set, the shape of the corpus callosum and its vicinity proves systematically much more variable in the alcohol-affected brains than in those of the normal subjects. From this excess variability follows a promising classification rule, having both high sensitivity (100 out of 117) and high specificity (49 out of 60) in this sample. The discrimination uses four landmark points and two summary scores of callosal outline shape. The information from the corpus callosum and vicinity, as viewed in MR brain images of full-grown subjects, may serve as a permanent record of the prenatal effects of alcohol, even in patients who are first suspected of these syndromes relatively late in life or who lack the facial signs of prenatal alcohol damage. The statistical pattern underlying the callosal diagnosis also leads to speculations on mechanisms of the prenatal damage. Copyright 2002 Wiley-Liss, Inc.

DMRTA2 (DMRT5) is mutated in a novel cortical brain malformation.

PubMed

Urquhart, J E; Beaman, G; Byers, H; Roberts, N A; Chervinsky, E; O'Sullivan, J; Pilz, D; Fry, A; Williams, S G; Bhaskar, S S; Khayat, M; Simanovsky, N; Shachar, I B; Shalev, S A; Newman, W G

2016-06-01

Lissencephaly is a phenotypically and genetically heterogeneous group of cortical brain malformations due to abnormal neuronal migration. The identification of many causative genes has increased the understanding of normal brain development. A consanguineous family was ascertained with three siblings affected by a severe prenatal neurodevelopmental disorder characterised by fronto-parietal pachygyria, agenesis of the corpus callosum and progressive severe microcephaly. Autozygosity mapping and exome sequencing identified a homozygous novel single base pair deletion, c.1197delT in DMRTA2, predicted to result in a frameshift variant p.(Pro400Leufs*33). DMRTA2 encodes doublesex and mab-3-related transcription factor a2, a transcription factor key to the development of the dorsal telencephalon. Data from murine and zebrafish knockout models are consistent with the variant of DMTRA2 (DMRT5) as responsible for the cortical brain phenotype. Our study suggests that loss of function of DMRTA2 leads to a novel disorder of cortical development. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Molecular genetics in fetal neurology.

PubMed

Huang, Jin; Wah, Isabella Y M; Pooh, Ritsuko K; Choy, Kwong Wai

2012-12-01

Brain malformations, particularly related to early brain development, are a clinically and genetically heterogeneous group of fetal neurological disorders. Fetal cerebral malformation, predominantly of impaired prosencephalic development namely agenesis of the corpus callosum and septo-optic dysplasia, is the main pathological feature in fetus, and causes prominent neurodevelopmental retardation, and associated with congenital facial anomalies and visual disorders. Differential diagnosis of brain malformations can be extremely difficult even through magnetic resonance imaging. Advances in genomic and molecular genetics technologies have led to the identification of the sonic hedgehog pathways and genes critical to the normal brain development. Molecular cytogenetic and genetic studies have identified numeric and structural chromosomal abnormalities as well as mutations in genes important for the etiology of fetal neurological disorders. In this review, we update the molecular genetics findings of three common fetal neurological abnormalities, holoprosencephaly, lissencephaly and agenesis of the corpus callosum, in an attempt to assist in perinatal and prenatal diagnosis. Copyright © 2012 Elsevier Ltd. All rights reserved.

Prenatal diagnosis of periventricular nodular heterotopia in borderline ventriculomegaly using sonography and magnetic resonance imaging.

PubMed

Sahinoglu, Zeki; Yapicier, Ozlem; Ozcan, Nahit

2016-10-01

Periventricular nodular heterotopia (PNH) is usually missed on prenatal sonographic examinations, even on targeted scans. Irregular ventricular walls on axial view and irregular square-shaped lateral ventricles on coronal view are suggestive of PNH in the early third trimester. To achieve an early prenatal diagnosis, it is important to keep in mind the possible coexistence of PNH with brain malformations such as ventriculomegaly, posterior fossa anomalies, or agenesis of corpus callosum. © 2016 Wiley Periodicals, Inc. J Clin Ultrasound 44:510-513, 2016. © 2016 Wiley Periodicals, Inc.

Acquired alterations of hypothalamic gene expression of insulin and leptin receptors and glucose transporters in prenatally high-glucose exposed three-week old chickens do not coincide with aberrant promoter DNA methylation.

PubMed

Rancourt, Rebecca C; Schellong, Karen; Ott, Raffael; Bogatyrev, Semen; Tzschentke, Barbara; Plagemann, Andreas

2015-01-01

Prenatal exposures may have a distinct impact for long-term health, one example being exposure to maternal 'diabesity' during pregnancy increasing offspring 'diabesity' risk. Malprogramming of the central nervous regulation of body weight, food intake and metabolism has been identified as a critical mechanism. While concrete disrupting factors still remain unclear, growing focus on acquired epigenomic alterations have been proposed. Due to the independent development from the mother, the chicken embryo provides a valuable model to distinctively establish causal factors and mechanisms. The aim of this study was to determine the effects of prenatal hyperglycemia on postnatal hypothalamic gene expression and promoter DNA methylation in the chicken. To temporarily induce high-glucose exposure in chicken embryos, 0.5 ml glucose solution (30 mmol/l) were administered daily via catheter into a vessel of the chorioallantoic egg membrane from days 14 to 17 of incubation. At three weeks of postnatal age, body weight, total body fat, blood glucose, mRNA expression (INSR, LEPR, GLUT1, GLUT3) as well as corresponding promoter DNA methylation were determined in mediobasal hypothalamic brain slices (Nucleus infundibuli hypothalami). Although no significant changes in morphometric and metabolic parameters were detected, strongly decreased mRNA expression occurred in all candidate genes. Surprisingly, however, no relevant alterations were observed in respective promoter methylation. Prenatal hyperglycemia induces strong changes in later hypothalamic expression of INSR, LEPR, GLUT1, and GLUT3 mRNA. While the chicken provides an interesting approach for developmental malprogramming, the classical expression regulation via promoter methylation was not observed here. This may be due to alternative/interacting brain mechanisms or the thus far under-explored bird epigenome.

The effects of sertraline administration from adolescence to adulthood on physiological and emotional development in prenatally stressed rats of both sexes

PubMed Central

Pereira-Figueiredo, Inês; Sancho, Consuelo; Carro, Juan; Castellano, Orlando; López, Dolores E.

2014-01-01

Sertraline (SERT) is a clinically effective Selective Serotonin Reuptake Inhibitor (SSRI) known to increase and stabilize serotonin levels. This neurotransmitter plays an important role in adolescent brain development in both rodents and humans, and its dysregulation has been correlated with deficits in behavior and emotional regulation. Since prenatal stress may disturb serotoninergic homeostasis, the aim of this study was to examine the long-lasting effects of exposure to SERT throughout adolescence on behavioral and physiological developmental parameters in prenatally stressed Wistar rats. SERT was administered (5 mg/kg/day p.o.) from the age of 1–3 months to half of the progeny, of both sexes, of gestating dams stressed by use of a restraint (PS) or not stressed. Our data reveal that long-term SERT treatment slightly reduced weight gain in both sexes, but reversed the developmental disturbed “catch-up” growth found in PS females. Neither prenatal stress nor SERT treatment induced remarkable alterations in behavior and had no effects on mean startle reflex values. However, a sex-dependent effects of PS was found: in males the PS paradigm slightly increased anxiety-like behavior in the open field, while in females, it impaired startle habituation. In both cases, SERT treatment reversed the phenomena. Additionally, the PS animals exhibited a disturbed leukocyte profile in both sexes, which was reversed by SERT. The present findings are evidence that continuous SERT administration from adolescence through adulthood is safe in rodents and lessens the impact of prenatal stress in rats. PMID:25147514

Finger length ratio (2D:4D) in adults with gender identity disorder.

PubMed

Kraemer, Bernd; Noll, Thomas; Delsignore, Aba; Milos, Gabriella; Schnyder, Ulrich; Hepp, Urs

2009-06-01

From early childhood, gender identity and the 2nd to 4th finger length ratio (2D:4D) are discriminative characteristics between sexes. Both the human brain and 2D:4D may be influenced by prenatal testosterone levels. This calls for an examination of 2D:4D in patients with gender identity disorder (GID) to study the possible influence of prenatal testosterone on gender identity. Until now, the only study carried out on this issue suggests lower prenatal testosterone levels in right-handed male-to-female GID patients (MtF). We compared 2D:4D of 56 GID patients (39 MtF; 17 female-to-male GID patients, FtM) with data from a control sample of 176 men and 190 women. Bivariate group comparisons showed that right hand 2D:4D in MtF was significantly higher (feminized) than in male controls, but similar to female controls. The comparison of 2D:4D ratios of biological women revealed significantly higher (feminized) values for right hands of right handed FtM. Analysis of variance confirmed significant effects for sex and for gender identity on 2D:4D ratios but not for sexual orientation or for the interaction among variables. Our results indirectly point to the possibility of a weak influence of reduced prenatal testosterone as an etiological factor in the multifactorially influenced development of MtF GID. The development of FtM GID seems even more unlikely to be notably influenced by prenatal testosterone.

HEAVY PRENATAL ALCOHOL EXPOSURE IS RELATED TO SMALLER CORPUS CALLOSUM IN NEWBORN MRI SCANS

PubMed Central

Jacobson, Sandra W.; Jacobson, Joseph L.; Molteno, Christopher D.; Warton, Christopher M. R.; Wintermark, Pia; Hoyme, H Eugene; De Jong, Greetje; Taylor, Paul; Warton, Fleur; Lindinger, Nadine M.; Carter, R. Colin; Dodge, Neil C.; Grant, Ellen; Warfield, Simon K.; Zöllei, Lilla; van der Kouwe, André J. W.; Meintjes, Ernesta M.

2017-01-01

Background MRI studies have consistently demonstrated disproportionately smaller corpus callosa in individuals with a history of prenatal alcohol exposure but have not previously examined the feasibility of detecting this effect in infants. Tissue segmentation of the newborn brain is challenging because analysis techniques developed for the adult brain are not directly transferable, and segmentation for cerebral morphometry is difficult in neonates, due to the latter’s incomplete myelination. This study is the first to use volumetric structural MRI to investigate prenatal alcohol exposure effects in newborns using manual tracing and to examine the cross-sectional area of the corpus callosum (CC). Methods 43 nonsedated infants born to 32 Cape Coloured heavy drinkers and 11 controls recruited prospectively during pregnancy were scanned using a custom-designed birdcage coil for infants, which increases signal-to-noise ratio almost two-fold compared to the standard head coil. Alcohol use was ascertained prospectively during pregnancy, and FASD diagnosis was conducted by expert dysmorphologists. Data were acquired using a multi-echo FLASH protocol adapted for newborns, and a knowledge-based procedure was used to hand-segment the neonatal brains. Results CC was disproportionately smaller in alcohol-exposed neonates than controls after controlling for intracranial volume. By contrast, CC area was unrelated to infant sex, gestational age, age at scan, or maternal smoking, marijuana, or methamphetamine use during pregnancy. Conclusions Given that midline craniofacial anomalies have been recognized as a hallmark of FAS in humans and animal models since this syndrome was first identified, the CC deficit identified here in newborns may support early identification of a range of midline structural impairments. Smaller CC during the newborn period may provide an early indicator of fetal alcohol-related cognitive deficits that have been linked to this critically important brain structure in childhood and adolescence. PMID:28247416

Are there differences in brain morphometry between twins and unrelated singletons? A pediatric MRI study.

PubMed

Ordaz, S J; Lenroot, R K; Wallace, G L; Clasen, L S; Blumenthal, J D; Schmitt, J E; Giedd, J N

2010-04-01

Twins provide a unique capacity to explore relative genetic and environmental contributions to brain development, but results are applicable to non-twin populations only to the extent that twin and singleton brains are alike. A reason to suspect differences is that as a group twins are more likely than singletons to experience adverse prenatal and perinatal events that may affect brain development. We sought to assess whether this increased risk leads to differences in child or adolescent brain anatomy in twins who do not experience behavioral or neurological sequelae during the perinatal period. Brain MRI scans of 185 healthy pediatric twins (mean age = 11.0, SD = 3.6) were compared to scans of 167 age- and sex-matched unrelated singletons on brain structures measured, which included gray and white matter lobar volumes, ventricular volume, and area of the corpus callosum. There were no significant differences between groups for any structure, despite sufficient power for low type II (i.e. false negative) error. The implications of these results are twofold: (1) within this age range and for these measures, it is appropriate to include healthy twins in studies of typical brain development, and (2) findings regarding heritability of brain structures obtained from twin studies can be generalized to non-twin populations.

Thyroid-disrupting chemicals and brain development: an update

PubMed Central

Mughal, Bilal B; Fini, Jean-Baptiste; Demeneix, Barbara A

2018-01-01

This review covers recent findings on the main categories of thyroid hormone–disrupting chemicals and their effects on brain development. We draw mostly on epidemiological and experimental data published in the last decade. For each chemical class considered, we deal with not only the thyroid hormone–disrupting effects but also briefly mention the main mechanisms by which the same chemicals could modify estrogen and/or androgen signalling, thereby exacerbating adverse effects on endocrine-dependent developmental programmes. Further, we emphasize recent data showing how maternal thyroid hormone signalling during early pregnancy affects not only offspring IQ, but also neurodevelopmental disease risk. These recent findings add to established knowledge on the crucial importance of iodine and thyroid hormone for optimal brain development. We propose that prenatal exposure to mixtures of thyroid hormone–disrupting chemicals provides a plausible biological mechanism contributing to current increases in the incidence of neurodevelopmental disease and IQ loss. PMID:29572405

Puberty and structural brain development in humans.

PubMed

Herting, Megan M; Sowell, Elizabeth R

2017-01-01

Adolescence is a transitional period of physical and behavioral development between childhood and adulthood. Puberty is a distinct period of sexual maturation that occurs during adolescence. Since the advent of magnetic resonance imaging (MRI), human studies have largely examined neurodevelopment in the context of age. A breadth of animal findings suggest that sex hormones continue to influence the brain beyond the prenatal period, with both organizational and activational effects occurring during puberty. Given the animal evidence, human MRI research has also set out to determine how puberty may influence otherwise known patterns of age-related neurodevelopment. Here we review structural-based MRI studies and show that pubertal maturation is a key variable to consider in elucidating sex- and individual- based differences in patterns of human brain development. We also highlight the continuing challenges faced, as well as future considerations, for this vital avenue of research. Copyright © 2016. Published by Elsevier Inc.

Puberty and structural brain development in humans

PubMed Central

Herting, Megan M.; Sowell, Elizabeth R.

2017-01-01

Adolescence is a transitional period of physical and behavioral development between childhood and adulthood. Puberty is a distinct period of sexual maturation that occurs during adolescence. Since the advent of magnetic resonance imaging (MRI), human studies have largely examined neurodevelopment in the context of age. A breadth of animal findings suggest that sex hormones continue to influence the brain beyond the prenatal period, with both organizational and activational effects occurring during puberty. Given the animal evidence, human MRI research has also set out to determine how puberty may influence otherwise known patterns of age-related neurodevelopment. Here we review structural-based MRI studies and show that pubertal maturation is a key variable to consider in elucidating sex- and individual-based differences in patterns of human brain development. We also highlight the continuing challenges faced, as well as future considerations, for this vital avenue of research. PMID:28007528

Prenatal nicotine alters the developmental neurotoxicity of postnatal chlorpyrifos directed toward cholinergic systems: better, worse, or just "different?".

PubMed

Slotkin, Theodore A; Seidler, Frederic J

2015-01-01

This study examines whether prenatal nicotine exposure sensitizes the developing brain to subsequent developmental neurotoxicity evoked by chlorpyrifos, a commonly-used insecticide. We gave nicotine to pregnant rats throughout gestation at a dose (3mg/kg/day) producing plasma levels typical of smokers; offspring were then given chlorpyrifos on postnatal days 1-4, at a dose (1mg/kg) that produces minimally-detectable inhibition of brain cholinesterase activity. We evaluated indices for acetylcholine (ACh) synaptic function throughout adolescence, young adulthood and later adulthood, in brain regions possessing the majority of ACh projections and cell bodies; we measured nicotinic ACh receptor binding, hemicholinium-3 binding to the presynaptic choline transporter and choline acetyltransferase activity, all known targets for the adverse developmental effects of nicotine and chlorpyrifos given individually. By itself nicotine elicited overall upregulation of the ACh markers, albeit with selective differences by sex, region and age. Likewise, chlorpyrifos alone had highly sex-selective effects. Importantly, all the effects showed temporal progression between adolescence and adulthood, pointing to ongoing synaptic changes rather than just persistence after an initial injury. Prenatal nicotine administration altered the responses to chlorpyrifos in a consistent pattern for all three markers, lowering values relative to those of the individual treatments or to those expected from simple additive effects of nicotine and chlorpyrifos. The combination produced global interference with emergence of the ACh phenotype, an effect not seen with nicotine or chlorpyrifos alone. Given that human exposures to nicotine and chlorpyrifos are widespread, our results point to the creation of a subpopulation with heightened vulnerability. Copyright © 2014 Elsevier Inc. All rights reserved.

DNA methylation signature of human fetal alcohol spectrum disorder.

PubMed

Portales-Casamar, Elodie; Lussier, Alexandre A; Jones, Meaghan J; MacIsaac, Julia L; Edgar, Rachel D; Mah, Sarah M; Barhdadi, Amina; Provost, Sylvie; Lemieux-Perreault, Louis-Philippe; Cynader, Max S; Chudley, Albert E; Dubé, Marie-Pierre; Reynolds, James N; Pavlidis, Paul; Kobor, Michael S

2016-01-01

Prenatal alcohol exposure is the leading preventable cause of behavioral and cognitive deficits, which may affect between 2 and 5 % of children in North America. While the underlying mechanisms of alcohol's effects on development remain relatively unknown, emerging evidence implicates epigenetic mechanisms in mediating the range of symptoms observed in children with fetal alcohol spectrum disorder (FASD). Thus, we investigated the effects of prenatal alcohol exposure on genome-wide DNA methylation in the NeuroDevNet FASD cohort, the largest cohort of human FASD samples to date. Genome-wide DNA methylation patterns of buccal epithelial cells (BECs) were analyzed using the Illumina HumanMethylation450 array in a Canadian cohort of 206 children (110 FASD and 96 controls). Genotyping was performed in parallel using the Infinium HumanOmni2.5-Quad v1.0 BeadChip. After correcting for the effects of genetic background, we found 658 significantly differentially methylated sites between FASD cases and controls, with 41 displaying differences in percent methylation change >5 %. Furthermore, 101 differentially methylated regions containing two or more CpGs were also identified, overlapping with 95 different genes. The majority of differentially methylated genes were highly expressed at the level of mRNA in brain samples from the Allen Brain Atlas, and independent DNA methylation data from cortical brain samples showed high correlations with BEC DNA methylation patterns. Finally, overrepresentation analysis of genes with up-methylated CpGs revealed a significant enrichment for neurodevelopmental processes and diseases, such as anxiety, epilepsy, and autism spectrum disorders. These findings suggested that prenatal alcohol exposure is associated with distinct DNA methylation patterns in children and adolescents, raising the possibility of an epigenetic biomarker of FASD.

Prenatal Nicotine Alters the Developmental Neurotoxicity of Postnatal Chlorpyrifos Directed Toward Cholinergic Systems: Better, Worse, or Just “Different?”

PubMed Central

Slotkin, Theodore A.; Seidler, Frederic J.

2014-01-01

This study examines whether prenatal nicotine exposure sensitizes the developing brain to subsequent developmental neurotoxicity evoked by chlorpyrifos, a commonly-used insecticide. We gave nicotine to pregnant rats throughout gestation at a dose (3 mg/kg/day) producing plasma levels typical of smokers; offspring were then given chlorpyrifos on postnatal days 1–4, at a dose (1 mg/kg) that produces minimally-detectable inhibition of brain cholinesterase activity. We evaluated indices for acetylcholine (ACh) synaptic function throughout adolescence, young adulthood and later adulthood, in brain regions possessing the majority of ACh projections and cell bodies; we measured nicotinic ACh receptor binding, hemicholinium-3 binding to the presynaptic choline transporter and choline acetyltransferase activity, all known targets for the adverse developmental effects of nicotine and chlorpyrifos given individually. By itself nicotine elicited overall upregulation of the ACh markers, albeit with selective differences by sex, region and age. Likewise, chlorpyrifos alone had highly sex-selective effects. Importantly, all the effects showed temporal progression between adolescence and adulthood, pointing to ongoing synaptic changes rather than just persistence after an initial injury. Prenatal nicotine administration altered the responses to chlorpyrifos in a consistent pattern for all three markers, lowering values relative to those of the individual treatments or to those expected from simple additive effects of nicotine and chlorpyrifos. The combination produced global interference with emergence of the ACh phenotype, an effect not seen with nicotine or chlorpyrifos alone. Given that human exposures to nicotine and chlorpyrifos are widespread, our results point to the creation of a subpopulation with heightened vulnerability. PMID:25510202

Dietary Choline Levels Modify the Effects of Prenatal Alcohol Exposure in Rats

PubMed Central

Idrus, Nirelia M.; Breit, Kristen R.; Thomas, Jennifer D.

2018-01-01

Prenatal alcohol exposure can cause a range of physical and behavioral alterations; however, the outcome among children exposed to alcohol during pregnancy varies widely. Some of this variation may be due to nutritional factors. Indeed, higher rates of fetal alcohol spectrum disorders (FASD) are observed in countries where malnutrition is prevalent. Epidemiological studies have shown that many pregnant women throughout the world may not be consuming adequate levels of choline, an essential nutrient critical for brain development, and a methyl donor. In this study, we examined the influence of dietary choline deficiency on the severity of fetal alcohol effects. Pregnant Sprague-Dawley rats were randomly assigned to receive diets containing 40, 70, or 100% recommended choline levels. A group from each diet condition was exposed to ethanol (6.0 g/kg/day) from gestational day 5 to 20 via intubation. Pair-fed and ad lib lab chow control groups were also included. Physical and behavioral development was measured in the offspring. Prenatal alcohol exposure delayed motor development, and 40% choline altered performance on the cliff avoidance task, independent of one another. However, the combination of low choline and prenatal alcohol produced the most severe impairments in development. Subjects exposed to ethanol and fed the 40% choline diet exhibited delayed eye openings, significantly fewer successes in hind limb coordination, and were significantly overactive compared to all other groups. These data suggest that suboptimal intake of a single nutrient can exacerbate some of ethanol’s teratogenic effects, a finding with important implications for the prevention of FASD. PMID:27888055

Dietary choline levels modify the effects of prenatal alcohol exposure in rats.

PubMed

Idrus, Nirelia M; Breit, Kristen R; Thomas, Jennifer D

Prenatal alcohol exposure can cause a range of physical and behavioral alterations; however, the outcome among children exposed to alcohol during pregnancy varies widely. Some of this variation may be due to nutritional factors. Indeed, higher rates of fetal alcohol spectrum disorders (FASD) are observed in countries where malnutrition is prevalent. Epidemiological studies have shown that many pregnant women throughout the world may not be consuming adequate levels of choline, an essential nutrient critical for brain development, and a methyl donor. In this study, we examined the influence of dietary choline deficiency on the severity of fetal alcohol effects. Pregnant Sprague-Dawley rats were randomly assigned to receive diets containing 40, 70, or 100% recommended choline levels. A group from each diet condition was exposed to ethanol (6.0g/kg/day) from gestational day 5 to 20 via intubation. Pair-fed and ad lib lab chow control groups were also included. Physical and behavioral development was measured in the offspring. Prenatal alcohol exposure delayed motor development, and 40% choline altered performance on the cliff avoidance task, independent of one another. However, the combination of low choline and prenatal alcohol produced the most severe impairments in development. Subjects exposed to ethanol and fed the 40% choline diet exhibited delayed eye openings, significantly fewer successes in hindlimb coordination, and were significantly overactive compared to all other groups. These data suggest that suboptimal intake of a single nutrient can exacerbate some of ethanol's teratogenic effects, a finding with important implications for the prevention of FASD. Copyright © 2016. Published by Elsevier Inc.

Prenatal exposure to lambda-cyhalothrin alters brain dopaminergic signaling in developing rats.

PubMed

Dhuriya, Yogesh K; Srivastava, Pranay; Shukla, Rajendra K; Gupta, Richa; Singh, Dhirendra; Parmar, Devendra; Pant, Aditya B; Khanna, Vinay K

2017-07-01

The present study is focused to decipher the molecular mechanisms associated with dopaminergic alterations in corpus striatum of developing rats exposed prenatally to lambda-cyhalothrin (LCT), a new generation type II synthetic pyrethroid. There was no significant change in the mRNA and protein expression of DA-D1 receptors at any of the doses of LCT (0.5, 1 and 3mg/kg body weight) in corpus striatum of developing rats exposed prenatally to LCT on PD22 and PD45. Prenatal exposure to LCT (1 and 3mg/kg body weight) resulted to decrease the levels of mRNA and protein of DA-D2 receptors in corpus stratum of developing rats on PD22 as compared to controls. Decrease in the binding of 3H-Spiperone in corpus striatum, known to label DA-D2 receptors was also distinct in developing rats on PD22. These rats also exhibited decrease in the expression of proteins - TH, DAT and VMAT2 involved in pre-dopaminergic signaling. Further, decrease in the expression of DARPP-32 and pCREB associated with increased expression of PP1α was evident in developing rats on PD22 as compared to controls. Interestingly, a trend of recovery in the expression of these proteins was observed in developing rats exposed to LCT at moderate dose (1.0mg/kg body weight) while alteration in the expression of these proteins continued to persist in those exposed at high dose (3.0mg/kg body weight) on PD45 as compared to respective controls. No significant change in the expression of any of these proteins was observed in corpus striatum of developing rats prenatally exposed to LCT at low dose (0.5mg/kg body weight) on PD22 and PD45 as compared to respective controls. The results provide interesting evidence that alterations in dopaminergic signaling on LCT exposure are due to selective changes in DA-D2 receptors in corpus striatum of developing rats. Further, these changes could be attributed to impairment in spontaneous motor activity on LCT exposure in developing rats. Copyright © 2017 Elsevier B.V. All rights reserved.

Exogenous prenatal corticosterone exposure mimics the effects of prenatal stress on adult brain stress response systems and fear extinction behavior.

PubMed

Bingham, Brian C; Sheela Rani, C S; Frazer, Alan; Strong, Randy; Morilak, David A

2013-11-01

Exposure to early-life stress is a risk factor for the development of cognitive and emotional disorders later in life. We previously demonstrated that prenatal stress (PNS) in rats results in long-term, stable changes in central stress-response systems and impairs the ability to extinguish conditioned fear responding, a component of post-traumatic stress disorder (PTSD). Maternal corticosterone (CORT), released during prenatal stress, is a possible mediator of these effects. The purpose of the present study was to investigate whether fetal exposure to CORT at levels induced by PNS is sufficient to alter the development of adult stress neurobiology and fear extinction behavior. Pregnant dams were subject to either PNS (60 min immobilization/day from ED 14-21) or a daily injection of CORT (10mg/kg), which approximated both fetal and maternal plasma CORT levels elicited during PNS. Control dams were given injections of oil vehicle. Male offspring were allowed to grow to adulthood undisturbed, at which point they were sacrificed and the medial prefrontal cortex (mPFC), hippocampus, hypothalamus, and a section of the rostral pons containing the locus coeruleus (LC) were dissected. PNS and prenatal CORT treatment decreased glucocorticoid receptor protein levels in the mPFC, hippocampus, and hypothalamus when compared to control offspring. Both treatments also decreased tyrosine hydroxylase levels in the LC. Finally, the effect of prenatal CORT exposure on fear extinction behavior was examined following chronic stress. Prenatal CORT impaired both acquisition and recall of cue-conditioned fear extinction. This effect was additive to the impairment induced by previous chronic stress. Thus, these data suggest that fetal exposure to high levels of maternal CORT is responsible for many of the lasting neurobiological consequences of PNS as they relate to the processes underlying extinction of learned fear. The data further suggest that adverse prenatal environments constitute a risk factor for PTSD-like symptomatology, especially when combined with chronic stressors later in life. Copyright © 2013 Elsevier Ltd. All rights reserved.

The α-fetoprotein knock-out mouse model suggests that parental behavior is sexually differentiated under the influence of prenatal estradiol

PubMed Central

Keller, Matthieu; Pawluski, Jodi L.; Brock, Olivier; Douhard, Quentin; Bakker, Julie

2010-01-01

In rodent species, sexual differentiation of the brain for many reproductive processes depends largely on estradiol. This was recently confirmed again by using the α-fetoprotein knockout (AFP-KO) mouse model, which lacks the protective actions of α-fetoprotein against maternal estradiol and as a result represents a good model to determine the contribution of prenatal estradiol to the sexual differentiation of the brain and behavior. Female AFP-KO mice were defeminized and masculinized with regard to their neuroendocrine responses as well as sexual behavior. Since parental behavior is also strongly sexually differentiated in mice, we used the AFP-KO mouse model here to ask whether parental responses are differentiated prenatally under the influence of estradiol. It was found that AFP-KO females showed longer latencies to retrieve pups to the nest and also exhibited lower levels of crouching over the pups in the nest in comparison to WT females. In fact, they resembled males (WT and AFP-KO). Other measures of maternal behavior, for example the incidence of infanticide, tended to be higher in AFP-KO females than in WT females but this increase failed to reach statistical significance. The deficits observed in parental behavior of AFP-KO females could not be explained by any changes in olfactory function, novelty recognition or anxiety. Thus our results suggest that prenatal estradiol defeminizes the parental brain in mice. PMID:20109458

Relations among prospective memory, cognitive abilities, and brain structure in adolescents who vary in prenatal drug exposure.

PubMed

Robey, Alison; Buckingham-Howes, Stacy; Salmeron, Betty Jo; Black, Maureen M; Riggins, Tracy

2014-11-01

This investigation examined how prospective memory (PM) relates to cognitive abilities (i.e., executive function, attention, working memory, and retrospective memory) and brain structure in adolescents who vary in prenatal drug exposure (PDE). The sample consisted of 105 (55 female and 50 male) urban, primarily African American adolescents (mean age=15.5 years) from low socioeconomic status (SES) families. Approximately 56% (n=59) were prenatally exposed to drugs (heroin and/or cocaine) and 44% (n=46) were not prenatally exposed, but the adolescents were similar in age, gender, race, and SES. Executive functioning, attentional control, working memory, retrospective memory, and overall cognitive ability were assessed by validated performance measures. Executive functioning was also measured by caregiver report. A subset of 52 adolescents completed MRI (magnetic resonance imaging) scans, which provided measures of subcortical gray matter volumes and thickness of prefrontal, parietal, and temporal cortices. Results revealed no differences in PM performance by PDE status, even after adjusting for age and IQ. Executive function, retrospective memory, cortical thickness in frontal and parietal regions, and volume of subcortical regions (i.e., putamen and hippocampus) were related to PM performance in the sample overall, even after adjusting for age, IQ, and total gray matter volume. Findings suggest that variations in PM ability during adolescence are robustly related to individual differences in cognitive abilities, in particular executive function and retrospective memory, and brain structure, but do not vary by PDE status. Copyright © 2014 Elsevier Inc. All rights reserved.

Prenatal neurologic anomalies: sonographic diagnosis and treatment.

PubMed

De Catte, Luc; De Keersmaeker, Bart; Claus, Filip

2012-06-01

The low prevalence of fetal CNS anomalies results in a restricted level of exposure to, and limited experience for most obstetricians involved in, prenatal ultrasound. Sonographic guidelines for screening the fetal brain in a systematic way may increase the detection rate of fetal CNS anomalies, thus promoting correct referral to tertiary care centers offering patients a multidisciplinary approach to the condition. The aim of this review is to elaborate on the prenatal sonographic diagnosis and outcome of various CNS malformations. Detailed neurosonographic investigation has become available through high-resolution vaginal ultrasound probes and the development of a variety of 3-dimensional (3D) ultrasound modalities, such as ultrasound tomographic imaging. In addition, fetal magnetic resonance imaging is particularly helpful in the detection of gyration and neurulation anomalies, and disorders of the gray and white matter. Isolated mild ventriculomegaly is a rather common finding with good overall outcome. With an increasing diameter of the atria, however, and especially with the presence of associated malformations, long-term neurodevelopmental and behavioral outcome is disturbed in about 15% or more of cases. In view of recent developments in fetal therapy for neural tube defects, there is a clear need for a high level of ultrasound screening, work-up and counseling in tertiary care centers to identify those cases that might benefit from in utero intervention. The failure of prosencephalic midline induction and development results in midline defects ranging from alobar holoprosencephaly to isolated corpus callosum defects. The detection of callosal abnormaties is enhanced by 3D ultrasound, but counseling on neurodevelopmental outcome remains challenging. The Dandy-Walker spectrum includes isolated megacisterna magna, Blake's pouch cyst, hypoplasia of the vermis and Dandy-Walker malformation. Except for complete agenesis of the vermis associated with fourth ventricle cyst formation, data on long-term outcomes for the various conditions is largely lacking. Congenital cytomegalovirus (CMV) results in the highest incidence of children born with, or developing, long-term neurologic conditions. If proof of fetal infection has been delivered, microcephaly, cortical malformations, and intraparenchymal cysts show a strong correlation with poor outcome. Fetuses with CMV-related ultrasound abnormalities might benefit from maternal transplacental treatment. The aneurysm of the vein of Galen, a vascular malformation of the brain, often results in high cardiac output failure. After neonatal arterial embolization, survival is about 50% with normal neurologic development in 36% of cases. Over 50% of intracranial tumors are teratomata, presenting as fast-growing heterogeneous solid-cystic masses with calcifications. Most intracranial hemorrhages are related to the ventricular system, and prognosis is often poor, particularly in cases involving parenchymal and subdural bleeding. Proliferation disorders of the brain are often characterized by microcephaly. Their etiology is heterogeneous and prenatal diagnosis is often made late in gestation.

Preventive effect of α-lipoic acid on prepulse inhibition deficits in a juvenile two-hit model of schizophrenia.

PubMed

Deslauriers, J; Racine, W; Sarret, P; Grignon, S

2014-07-11

Some pathophysiological models of schizophrenia posit that prenatal inflammation sensitizes the developing brain to second insults in early life and enhances brain vulnerability, thereby increasing the risk of developing the disorder during adulthood. We previously developed a two-hit animal model, based on the well-established prenatal immune challenge with poly-inosinic/cytidylic acid (polyI:C), followed by juvenile restraint stress (RS). We observed an additive disruption of prepulse inhibition (PPI) of acoustic startle in juvenile mice submitted to both insults. Previous studies have also reported that oxidative stress is associated with pathophysiological mechanisms of psychiatric disorders, including schizophrenia. We report here that PPI disruption in our two-hit animal model of schizophrenia is associated with an increase in oxidative stress. These findings led us to assess whether α-lipoic acid, an antioxidant, can prevent both increase in oxidative status and PPI deficits in our juvenile in vivo model of schizophrenia. In the offspring submitted to prenatal injection of polyI:C and to RS, treatment with α-lipoic acid prevented the development of PPI deficits 24h after the last period of RS. α-Lipoic acid also improved PPI performance in control mice. The reversal effect of α-lipoic acid pretreatment on these behavioral alterations was further accompanied by a normalization of the associated oxidative status and dopaminergic and GABAergic abnormalities in the prefrontal cortex. Based on our double insult paradigm, these results support the hypothesis that oxidative stress plays an important role in the development of PPI deficits, a well-known behavior associated with schizophrenia. These findings form the basis of future studies aiming to unravel mechanistic insights of the putative role of antioxidants in the treatment of schizophrenia, especially during the prodromal stage. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

Prenatal Exposure to Urban Air Nanoparticles in Mice Causes Altered Neuronal Differentiation and Depression-Like Responses

PubMed Central

Godar, Sean C.; Sander, Thomas K.; Iwata, Nahoko; Pakbin, Payam; Shih, Jean C.; Berhane, Kiros; McConnell, Rob; Sioutas, Constantinos

2013-01-01

Emerging evidence suggests that excessive exposure to traffic-derived air pollution during pregnancy may increase the vulnerability to neurodevelopmental alterations that underlie a broad array of neuropsychiatric disorders. We present a mouse model for prenatal exposure to urban freeway nanoparticulate matter (nPM). In prior studies, we developed a model for adult rodent exposure to re-aerosolized urban nPM which caused inflammatory brain responses with altered neuronal glutamatergic functions. nPMs are collected continuously for one month from a local freeway and stored as an aqueous suspension, prior to re-aerosolization for exposure of mice under controlled dose and duration. This paradigm was used for a pilot study of prenatal nPM impact on neonatal neurons and adult behaviors. Adult C57BL/6J female mice were exposed to re-aerosolized nPM (350 µg/m3) or control filtered ambient air for 10 weeks (3×5 hour exposures per week), encompassing gestation and oocyte maturation prior to mating. Prenatal nPM did not alter litter size, pup weight, or postnatal growth. Neonatal cerebral cortex neurons at 24 hours in vitro showed impaired differentiation, with 50% reduction of stage 3 neurons with long neurites and correspondingly more undifferentiated neurons at Stages 0 and 1. Neuron number after 24 hours of culture was not altered by prenatal nPM exposure. Addition of exogenous nPM (2 µg/ml) to the cultures impaired pyramidal neuron Stage 3 differentiation by 60%. Adult males showed increased depression-like responses in the tail-suspension test, but not anxiety-related behaviors. These pilot data suggest that prenatal exposure to nPM can alter neuronal differentiation with gender-specific behavioral sequelae that may be relevant to human prenatal exposure to urban vehicular aerosols. PMID:23734187

Construct Validity of the Infant Motor Profile: Relation with Prenatal, Perinatal, and Neonatal Risk Factors

ERIC Educational Resources Information Center

Heineman, Kirsten R.; La Bastide-Van Gemert, Sacha; Fidler, Vaclav; Middelburg, Karin J.; Bos, Arend F.; Hadders-Algra, Mijna

2010-01-01

Aim: The Infant Motor Profile (IMP) is a qualitative assessment of motor behaviour of infants aged 3 to 18 months. The aim of this study was to investigate construct validity of the IMP through the relation of IMP scores with prenatal, perinatal, and neonatal variables, including the presence of brain pathology indicated by neonatal ultrasound…

Hypoxic ischemic encephalopathy in a case of intranuclear rod myopathy without any prenatal sentinel event.

PubMed

Kawase, Koya; Nishino, Ichizo; Sugimoto, Mari; Kouwaki, Masanori; Koyama, Norihisa; Yokochi, Kenji

2015-02-01

Intranuclear rod myopathy (IRM), a variant of nemaline myopathy, is characterized by the presence of nemaline bodies in myonuclei. We report a case of IRM presenting with hypoxic ischemic encephalopathy (HIE). There were no prenatal complications caused by fetal brain injury. Although no nemaline bodies were observed in the cytoplasm, intranuclear rods were observed in some fibers under light and electron microscopy. Molecular analysis identified a heterozygous variant, c.449C>T (p.Thr150Ile), in ACTA1. On magnetic resonance imaging at 9days of age, injuries to the basal ganglia, thalamus, and brainstem consistent with perinatal HIE were seen. Respiratory insufficiency at birth was strongly suspected to be the cause of HIE. Our case highlights that a patient with a congenital neuromuscular disorder who presents with severe respiratory dysfunction requiring substantial resuscitative efforts at birth can be complicated by HIE without any prenatal sentinel event. Prenatal detection of neuromuscular disorders, careful management of delivery, and neonatal resuscitation and adequate respiratory management are important in preventing irreversible brain injury in these patients. Copyright © 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Neuroinflammation in Autism: Plausible Role of Maternal Inflammation, Dietary Omega 3, and Microbiota

PubMed Central

Madore, Charlotte; Leyrolle, Quentin; Lacabanne, Chloé; Benmamar-Badel, Anouk; Joffre, Corinne; Nadjar, Agnes

2016-01-01

Several genetic causes of autism spectrum disorder (ASD) have been identified. However, more recent work has highlighted that certain environmental exposures early in life may also account for some cases of autism. Environmental insults during pregnancy, such as infection or malnutrition, seem to dramatically impact brain development. Maternal viral or bacterial infections have been characterized as disruptors of brain shaping, even if their underlying mechanisms are not yet fully understood. Poor nutritional diversity, as well as nutrient deficiency, is strongly associated with neurodevelopmental disorders in children. For instance, imbalanced levels of essential fatty acids, and especially polyunsaturated fatty acids (PUFAs), are observed in patients with ASD and other neurodevelopmental disorders (e.g., attention deficit hyperactivity disorder (ADHD) and schizophrenia). Interestingly, PUFAs, and specifically n-3 PUFAs, are powerful immunomodulators that exert anti-inflammatory properties. These prenatal dietary and immunologic factors not only impact the fetal brain, but also affect the microbiota. Recent work suggests that the microbiota could be the missing link between environmental insults in prenatal life and future neurodevelopmental disorders. As both nutrition and inflammation can massively affect the microbiota, we discuss here how understanding the crosstalk between these three actors could provide a promising framework to better elucidate ASD etiology. PMID:27840741

Even Low Levels of Alcohol during Pregnancy Can Affect Fetal Brain Development. Science Briefs

ERIC Educational Resources Information Center

National Scientific Council on the Developing Child, 2008

2008-01-01

"Science Briefs" summarize the findings and implications of a recent study in basic science or clinical research. This brief reports on the study "Effects of Prenatal Alcohol Exposure on GABAergic Neurons" (V. C. Cuzone; P. W. L. Yeh; Y. Yanagawa; K. Obata; and H. H. Yeh). Study results indicate that even exposure to low levels of alcohol during…

Media representations of early human development: protecting, feeding and loving the developing brain.

PubMed

O'Connor, Cliodhna; Joffe, Helene

2013-11-01

The public profile of neurodevelopmental research has expanded in recent years. This paper applies social representations theory to explore how early brain development was represented in the UK print media in the first decade of the 21st century. A thematic analysis was performed on 505 newspaper articles published between 2000 and 2010 that discussed early brain development. Media coverage centred around concern with 'protecting' the prenatal brain (identifying threats to foetal neurodevelopment), 'feeding' the infant brain (indicating the patterns of nutrition that enhance brain development) and 'loving' the young child's brain (elucidating the developmental significance of emotionally nurturing family environments). The media focused almost exclusively on the role of parental action in promoting optimal neurodevelopment, rarely acknowledging wider structural, cultural or political means of supporting child development. The significance of parental care was intensified by deterministic interpretations of critical periods, which implied that inappropriate parental input would produce profound and enduring neurobiological impairments. Neurodevelopmental research was also used to promulgate normative judgements concerning the acceptability of certain gender roles and family contexts. The paper argues that media representations of neurodevelopment stress parental responsibility for shaping a child's future while relegating the contributions of genetic or wider societal factors, and examines the consequences of these representations for society and family life. Copyright © 2012 Elsevier Ltd. All rights reserved.

Prenatal methyl mercury exposure in relation to neurodevelopment and behavior at 19 years of age in the Seychelles Child Development Study.

PubMed

van Wijngaarden, E; Thurston, S W; Myers, G J; Strain, J J; Weiss, B; Zarcone, T; Watson, G E; Zareba, G; McSorley, E M; Mulhern, M S; Yeates, A J; Henderson, J; Gedeon, J; Shamlaye, C F; Davidson, P W

2013-01-01

Fish are important sources of protein and contain a variety of nutrients, such as n-3 long-chain polyunsaturated fatty acids (PUFA), essential for normal brain development. Nevertheless, all fish also contain methyl mercury (MeHg), a known neurotoxicant in adequate dosage. Our studies of the Seychelles Child Development Study (SCDS) Main Cohort enrolled in 1989-1990 (n=779) have found no consistent pattern of adverse MeHg effects at exposures achieved by daily fish consumption. Rather, we have observed evidence of improved performance on some cognitive endpoints as prenatal MeHg exposure increases in the range studied. These observations cannot be related to MeHg and may reflect the role of unmeasured covariates such as essential nutrients present in fish. To determine if these associations persist into young adulthood, we examined the relationship between prenatal MeHg exposure, recent PUFA exposure and subjects' neurodevelopment and behavior at 19 years of age. We examined 533 participants using the following test battery: the Profile of Mood States-Bipolar (POMS-Bi); Finger Tapping; Kaufman Brief Intelligence Test (K-BIT); measures of Fine Motor Control and Complex Perceptual Motor Control; and Visual Spatial Contrast Sensitivity. We collected the following covariates: maternal IQ, family life course stressors, socioeconomic status, and subjects' recent postnatal MeHg, sex, and computer use. Primary analyses (based on N=392-475) examined covariate-adjusted associations in multiple linear regression models with prenatal MeHg as the primary exposure measure. Secondary analyses additionally adjusted for total n-6 and fish-related n-3 PUFA measured in the subjects' serum at the 19-year examination. Study participants had a mean prenatal MeHg exposure of 6.9 ppm, and a mean recent postnatal exposure of 10.3 ppm. There were no adverse associations between prenatal MeHg and any of the measured endpoints. For recent postnatal MeHg exposure, however, adverse associations were observed for Finger Tapping (non-dominant hand) among women and for the K-BIT Matrices for both sexes, with or without adjustment for PUFA. Our findings continue to provide no evidence for an adverse effect of prenatal MeHg exposure on development in a cohort that consumes fish daily. Observations for postnatal MeHg exposure will need to be confirmed using more comprehensive exposure measures. Copyright © 2013 Elsevier Inc. All rights reserved.

Prenatal methyl mercury exposure in relation to neurodevelopment and behavior at 19 years of age in the Seychelles Child Development Study

PubMed Central

van Wijngaarden, E; Thurston, SW; Myers, GJ; Strain, JJ; Weiss, B; Zarcone, T; Watson, GE; Zareba, G; McSorley, EM; Mulhern, MS; Yeates, AJ; Henderson, J; Gedeon, J; Shamlaye, CF; Davidson, PW

2013-01-01

Background Fish are important sources of protein and contain a variety of nutrients, such as n-3 longchain polyunsaturated fatty acids (PUFA), essential for normal brain development. Nevertheless, all fish also contain methyl mercury (MeHg), a known neurotoxicant in adequate dosage. Our studies of the Seychelles Child Development Study (SCDS) Main Cohort enrolled in 1989–1990 (n=779) have found no consistent pattern of adverse MeHg effects at exposures achieved by daily fish consumption. Rather, we have observed evidence of improved performance on some cognitive endpoints as prenatal MeHg exposure increases in the range studied. These observations cannot be related to MeHg and may reflect the role of unmeasured covariates such as essential nutrients present in fish. To determine if these associations persist into young adulthood, we examined the relationship between prenatal MeHg exposure, recent PUFA exposure and subjects’ neurodevelopment and behavior at 19 years of age. Methods We examined 533 participants using the following test battery: the Profile of Mood States- Bipolar (POMS-Bi); Finger Tapping; Kaufman Brief Intelligence Test (K-BIT); measures of Fine Motor Control and Complex Perceptual Motor Control; and Visual Spatial Contrast Sensitivity. We collected the following covariates: maternal IQ, family life course stressors, socioeconomic status, and subjects’ recent postnatal MeHg, sex, and computer use. Primary analyses (based on N=392–475) examined covariate-adjusted associations in multiple linear regression models with prenatal MeHg as the primary exposure measure. Secondary analyses additionally adjusted for total n-6 and fish-related n-3 PUFA measured in the subjects serum at the 19-year examination. Results Study participants had a mean prenatal MeHg exposure of 6.9 ppm, and a mean recent postnatal exposure of 10.3 ppm. There were no adverse associations between prenatal MeHg and any of the measured endpoints. For recent postnatal MeHg exposure, however, adverse associations were observed for Finger Tapping (non-dominant hand) among women and for the K-BIT matrices for both sexes, with or without adjustment for PUFA. Conclusion Our findings continue to provide no evidence for an adverse effect of prenatal MeHg exposure on development in a cohort that consumes fish daily. Observations for postnatal MeHg exposure will need to be confirmed using more comprehensive exposure measures. PMID:23770126

Fetal Magnetoencephalography--Achievements and Challenges in the Study of Prenatal and Early Postnatal Brain Responses: A Review

ERIC Educational Resources Information Center

Sheridan, Carolin J.; Matuz, Tamara; Draganova, Rossitza; Eswaran, Hari; Preissl, Hubert

2010-01-01

Fetal magnetoencephalography (fMEG) is the only non-invasive method for investigating evoked brain responses and spontaneous brain activity generated by the fetus "in utero". Fetal auditory as well as visual-evoked fields have been successfully recorded in basic stimulus-response studies. Moreover, paradigms investigating precursors for cognitive…

Maternal low protein diet decreases brain-derived neurotrophic factor expression in the brains of the neonatal rat offspring

USDA-ARS?s Scientific Manuscript database

Prenatal exposure to a maternal low protein diet has been known to cause cognitive impairment, learning and memory deficits. However, the underlying mechanisms have not been identified. Herein, we demonstrate that a maternal low protein (LP) diet causes, in the brains of the neonatal rat offspring, ...

Early oestrogens in shaping reproductive networks: evidence for a potential organisational role of oestradiol in female brain development.

PubMed

Bakker, J; Brock, O

2010-07-01

A central tenet of contemporary theories on mammalian brain and behavioural sexual differentiation is that an organisational action of testosterone, secreted by the male's testes, controls male-typical aspects of brain and behavioural development, whereas no active perinatal sex hormone signalling is required for female-typical sexual differentiation. Furthermore, the available evidence suggests that many, although not all, of the perinatal organisational actions of testosterone on the development of the male brain result from the cellular effects of oestradiol formed via neural aromatisation of testosterone. However, a default developmental programme for the female brain has been criticised. Indeed, we review new results obtained in aromatase knockout mice indicating that oestradiol actively contributes to the differentiation of female-typical aspects of brain and behavioural sexual differentiation. Furthermore, we propose that male-typical neural and behavioural differentiation occurs prenatally in genetic males under the influence of oestradiol, which is avoided in foetal genetic females by the neuroprotective actions of alpha-fetoprotein, whereas female-typical neural and behavioural differentiation normally occurs postnatally in genetic females under the influence of oestradiol that is presumably produced by the ovaries.

Gaining Insight of Fetal Brain Development with Diffusion MRI and Histology

PubMed Central

Huang, Hao; Vasung, Lana

2013-01-01

Human brain is extraordinarily complex and yet its origin is a simple tubular structure. Its development during the fetal period is characterized by a series of accurately organized events which underlie the mechanisms of dramatic structural changes during fetal development. Revealing detailed anatomy at different stages of human fetal brain development provides insight on understanding not only this highly ordered process, but also the neurobiological foundations of cognitive brain disorders such as mental retardation, autism, schizophrenia, bipolar and language impairment. Diffusion tensor imaging (DTI) and histology are complementary tools which are capable of delineating the fetal brain structures at both macroscopic and microscopic level. In this review, the structural development of the fetal brains has been characterized with DTI and histology. Major components of the fetal brain, including cortical plate, fetal white matter and cerebral wall layer between the ventricle and subplate, have been delineated with DTI and histology. Anisotropic metrics derived from DTI were used to quantify the microstructural changes during the dynamic process of human fetal cortical development and prenatal development of other animal models. Fetal white matter pathways have been traced with DTI-based tractography to reveal growth patterns of individual white matter tracts and corticocortical connectivity. These detailed anatomical accounts of the structural changes during fetal period may provide the clues of detecting developmental and cognitive brain disorders at their early stages. The anatomical information from DTI and histology may also provide reference standards for diagnostic radiology of premature newborns. PMID:23796901

Prenatal cocaine exposure decreases parvalbumin-immunoreactive neurons and GABA-to-projection neuron ratio in the medial prefrontal cortex.

PubMed

McCarthy, Deirdre M; Bhide, Pradeep G

2012-01-01

Cocaine abuse during pregnancy produces harmful effects not only on the mother but also on the unborn child. The neurotransmitters dopamine and serotonin are known as the principal targets of the action of cocaine in the fetal and postnatal brain. However, recent evidence suggests that cocaine can impair cerebral cortical GABA neuron development and function. We sought to analyze the effects of prenatal cocaine exposure on the number and distribution of GABA and projection neurons (inhibitory interneurons and excitatory output neurons, respectively) in the mouse cerebral cortex. We found that the prenatal cocaine exposure decreased GABA neuron numbers and GABA-to-projection neuron ratio in the medial prefrontal cortex of 60-day-old mice. The neighboring prefrontal cortex did not show significant changes in either of these measures. However, there was a significant increase in projection neuron numbers in the prefrontal cortex but not in the medial prefrontal cortex. Thus, the effects of cocaine on GABA and projection neurons appear to be cortical region specific. The population of parvalbumin-immunoreactive GABA neurons was decreased in the medial prefrontal cortex following the prenatal cocaine exposure. The cocaine exposure also delayed the developmental decline in the volume of the medial prefrontal cortex. Thus, prenatal cocaine exposure produced persisting and region-specific effects on cortical cytoarchitecture and impaired the physiological balance between excitatory and inhibitory neurotransmission. These structural changes may underlie the electrophysiological and behavioral effects of prenatal cocaine exposure observed in animal models and human subjects. Copyright © 2012 S. Karger AG, Basel.

26Al incorporation into the tissues of suckling rats through maternal milk

NASA Astrophysics Data System (ADS)

Yumoto, S.; Nagai, H.; Kobayashi, K.; Tada, W.; Horikawa, T.; Matsuzaki, H.

2004-08-01

Aluminium (Al) is highly neurotoxic and inhibits prenatal and postnatal development of the brain in humans and experimental animals. However, Al incorporation into the brain of sucklings through maternal milk has not yet been well clarified because Al lacks a suitable isotope for radioactive tracer experiments. Using 26Al as a tracer, we measured 26Al incorporation into the brain of suckling rats by accelerator mass spectrometry. Lactating rats were subcutaneously injected with 26AlCl3 from day 1 to day 20 postpartum. Suckling rats were weaned from day 21 postpartum. From day 5 to day 20 postpartum, the 26Al levels measured in the brain, liver, kidneys and bone of suckling rats increased significantly. After weaning, the amounts of 26Al in the liver and kidneys decreased remarkably. However, the 26Al amount in the brain had diminished only slightly up to 140 days after weaning.

Prenatal nutrition, epigenetics and schizophrenia risk: can we test causal effects?

PubMed

Kirkbride, James B; Susser, Ezra; Kundakovic, Marija; Kresovich, Jacob K; Davey Smith, George; Relton, Caroline L

2012-06-01

We posit that maternal prenatal nutrition can influence offspring schizophrenia risk via epigenetic effects. In this article, we consider evidence that prenatal nutrition is linked to epigenetic outcomes in offspring and schizophrenia in offspring, and that schizophrenia is associated with epigenetic changes. We focus upon one-carbon metabolism as a mediator of the pathway between perturbed prenatal nutrition and the subsequent risk of schizophrenia. Although post-mortem human studies demonstrate DNA methylation changes in brains of people with schizophrenia, such studies cannot establish causality. We suggest a testable hypothesis that utilizes a novel two-step Mendelian randomization approach, to test the component parts of the proposed causal pathway leading from prenatal nutritional exposure to schizophrenia. Applied here to a specific example, such an approach is applicable for wider use to strengthen causal inference of the mediating role of epigenetic factors linking exposures to health outcomes in population-based studies.

Prenatal and Early Postnatal Exposure to Cigarette Smoke Decreases BDNF/TrkB Signaling and Increases Abnormal Behaviors Later in Life

PubMed Central

Xiao, Lan; Kish, Vincent L.; Benders, Katherine M.

2016-01-01

Background: Cigarette smoke exposure during prenatal and early postnatal periods increases the incidence of a variety of abnormal behaviors later in life. The purpose of this study was to identify the possible critical period of susceptibility to cigarette smoke exposure and evaluate the possibe effects of cigarette smoke during early life on brain-derived neurotrophic factor/neurotrophic tyrosine kinase receptor B signaling in the brain. Methods: Three different age of imprinting control region mice were exposed to cigarette smoke or filtered air for 10 consecutive days beginning on either gestational day 7 by maternal exposure, or postnatal days 2 or 21 by direct inhalation. A series of behavioral profiles and neurotrophins in brain were measured 24 hours after mice received acute restraint stress for 1 hour on postnatal day 59. Results: Cigarette smoke exposure in gestational day 7 and postnatal day 2 produced depression-like behaviors as evidenced by significantly increased immobility in both tail suspension and forced-swim test. Increased entry latencies, but not ambulation in the open field test, were also observed in the gestational day 7 and postnatal day 2 cigarette smoke exposure groups. Genetic analysis showed that gestational day 7 cigarette smoke exposure significantly altered mRNA level of brain-derived neurotrophic factor/tyrosine kinase receptor B in the hippocampus. However, behavioral profiles and brain-derived neurotrophic factor/tyrosine kinase receptor B signaling were not significantly changed in PND21 cigarette smoke exposure group compared with FA group. Conclusions: These results suggest that a critical period of susceptibility to cigarette smoke exposure exists in the prenatal and early postnatal period, which results a downregulation in brain-derived neurotrophic factor/tyrosine kinase receptor B signaling in the hippocampus and enhances depression-like behaviors later in life. PMID:26503133

Cytokines and the neurodevelopmental basis of mental illness

PubMed Central

Ratnayake, Udani; Quinn, Tracey; Walker, David W.; Dickinson, Hayley

2013-01-01

Epidemiological studies suggest that prenatal exposure to different types of viral or bacterial infections may be associated with similar outcomes; i.e., an increased risk of mental illness disorders in the offspring. Infections arising from various causes have similar debilitating effects in later life, suggesting that the exact pathogen may not be the critical factor in determining the neurological and cognitive outcome in the offspring. Instead, it is thought that response of the innate immune system, specifically the increased production of inflammatory cytokines, may be the critical mediator in altering fetal brain development pre-disposing the offspring to mental illness disorders later in life. Inflammatory cytokines are essential for normal brain development. Factors such as the site of cytokine production, a change in balance between anti- and pro- inflammatory cytokines, placental transfer of cytokines, the effects of cytokines on glial cells, and the effects of glucocorticoids are important when evaluating the impact of maternal infection on fetal brain development. Although it is clear that cytokines are altered in the fetal brain following maternal infection, further evidence is required to determine if cytokines are the critical factor that alters the trajectory of brain development, subsequently leading to postnatal behavioral and neurological abnormalities. PMID:24146637

Sexual behavior, neuroendocrine, and neurochemical aspects in male rats exposed prenatally to stress.

PubMed

Gerardin, Daniela C C; Pereira, Oduvaldo C M; Kempinas, Wilma G; Florio, Jorge C; Moreira, Estefânia G; Bernardi, Maria M

2005-01-31

The present study was designed to examine some short- and long-term effects of maternal restraint stress--during the period of sexual brain differentiation--on reproductive and endocrine systems, sexual behavior, and brain neurotransmitters in male rat descendants. Pregnant rats were exposed to restraint stress for 1 h/day from gestational days (GDs) 18 to 22. Prenatal stress did not influence the wet weight of sexual organs and the quantity of germ cells in adult male pups; however, these animals showed reduced testosterone levels, delayed latency to the first mount and first intromission, and also decreased number of ejaculations. Additionally, there was an increase in the dopamine and serotonin levels in the striatum. Our results indicate that prenatal stress had a long-term effect on neurotransmitter levels and sexual behavior. In this sense, reproductive problems caused by injuries during the fetal period can compromise the later success of mating as well as the capacity to generate descendants.

Perinatal findings of Seckel syndrome: a case report of a fetus showing primordial dwarfism and severe microcephaly.

PubMed

Takikawa, Keiko Miyachi; Kikuchi, Akihiko; Yokoyama, Akiko; Ono, Kyoko; Iwasawa, Yuki; Sunagawa, Sorahiro; Takagi, Kimiyo; Kawame, Hiroshi; Nakamura, Tomohiko

2008-01-01

Seckel syndrome is a rare form of primordial dwarfism and most of the previous reports have been limited to postnatal findings. We report on a fetus showing severe microcephaly, intrauterine growth restriction and a few gyri with shallow sulci on the fetal brain suggesting cortical dysplasia, followed by ultrasound and magnetic resonance imaging in the prenatal period. Cardiotocograph revealed a reassuring fetal status throughout the whole pregnancy period. A male infant weighing 1,556 g was delivered at 39 weeks' gestation, and a diagnosis of Seckel syndrome was made based on postnatal typical findings. Although previous reports on prenatal findings of Seckel syndrome are quite limited, we think that our case presents typical features of a fetus affected by this syndrome. When prenatal ultrasound shows severe microcephaly and intrauterine growth restriction, this rare syndrome should be included in the differential diagnosis. Moreover, magnetic resonance imaging of the affected fetal brain provides further diagnostic clues. Copyright 2008 S. Karger AG, Basel.

Prenatal Exposure to Tributyltin Decreases GluR2 Expression in the Mouse Brain.

PubMed

Ishida, Keishi; Saiki, Takashi; Umeda, Kanae; Miyara, Masatsugu; Sanoh, Seigo; Ohta, Shigeru; Kotake, Yaichiro

2017-01-01

Tributyltin (TBT), a common environmental contaminant, is widely used as an antifouling agent in paint. We previously reported that exposure of primary cortical neurons to TBT in vitro decreased the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit glutamate receptor 2 (GluR2) expression and subsequently increased neuronal vulnerability to glutamate. Therefore, to identify whether GluR2 expression also decreases after TBT exposure in vivo, we evaluated the changes in GluR2 expression in the mouse brain after prenatal or postnatal exposure to 10 and 25 ppm TBT through pellet diets. Although the mean feed intake and body weight did not decrease in TBT-exposed mice compared with that in control mice, GluR2 expression in the cerebral cortex and hippocampus decreased after TBT exposure during the prenatal period. These results indicate that a decrease in neuronal GluR2 may be involved in TBT-induced neurotoxicity, especially during the fetal period.

Mercury: major issues in environmental health.

PubMed Central

Clarkson, T W

1993-01-01

In the past, methylmercury compounds were manufactured as fungicides or appeared as unwanted byproducts of the chemical industry, but today the methylation of inorganic mercury in aquatic sediments and soils is the predominant if not the sole source of methylmercury. This form of mercury is bioaccumulated to a high degree in aquatic food chains to attain its highest concentrations in edible tissues in long-lived predatory fish living in both fresh and ocean waters. It is well absorbed from the diet and distributes within a few days to all tissues in the body. It crosses without hindrance the blood-brain and placental barriers to reach its principal target tissue, the brain. It is eliminated chiefly in the feces after conversion to inorganic mercury. The biological half-time of methylmercury in human tissues is about 50 days, but there is wide individual variation. Adult poisoning is characterized by focal damage to discrete anatomical areas of the brain such as the visual cortex and granule layer of the cerebellum. A latent period of weeks or months may ensue before the appearance of signs and symptoms of poisoning. The latter manifest themselves as paresthesia, ataxia, constriction of the visual fields, and hearing loss. The prenatal period is the most sensitive stage of the life cycle to methylmercury. Prenatally poisoned infants exhibit a range of effects from severe cerebral palsy to subtle developmental delays. Methylmercury is believed to inhibit those processes in the brain specially involved in development and growth such as neuronal cell division and migration. PMID:8354179

From mother to child: orbitofrontal cortex gyrification and changes of drinking behaviour during adolescence.

PubMed

Kühn, Simone; Witt, Charlotte; Banaschewski, Tobias; Barbot, Alexis; Barker, Gareth J; Büchel, Christian; Conrod, Patricia J; Flor, Herta; Garavan, Hugh; Ittermann, Bernd; Mann, Karl; Martinot, Jean-Luc; Paus, Tomas; Rietschel, Marcella; Smolka, Michael N; Ströhle, Andreas; Brühl, Rüdiger; Schumann, Gunter; Heinz, Andreas; Gallinat, Jürgen

2016-05-01

Adolescence is a common time for initiation of alcohol use and alcohol use disorders. Importantly, the neuro-anatomical foundation for later alcohol-related problems may already manifest pre-natally, particularly due to smoking and alcohol consumption during pregnancy. In this context, cortical gyrification is an interesting marker of neuronal development but has not been investigated as a risk factor for adolescent alcohol use. On magnetic resonance imaging scans of 595 14-year-old adolescents from the IMAGEN sample, we computed whole-brain mean curvature indices to predict change in alcohol-related problems over the following 2 years. Change of alcohol use-related problems was significantly predicted from mean curvature in left orbitofrontal cortex (OFC). Less gyrification of OFC was associated with an increase in alcohol use-related problems over the next 2 years. Moreover, lower gyrification in left OFC was related to pre-natal alcohol exposure, whereas maternal smoking during pregnancy had no effect. Current alcohol use-related problems of the biological mother had no effect on offsprings' OFC gyrification or drinking behaviour. The data support the idea that alcohol consumption during pregnancy mediates the development of neuro-anatomical phenotypes, which in turn constitute a risk factor for increasing problems due to alcohol consumption in a vulnerable stage of life. Maternal smoking during pregnancy or current maternal alcohol/nicotine consumption had no significant effect. The OFC mediates behaviours known to be disturbed in addiction, namely impulse control and reward processing. The results stress the importance of pre-natal alcohol exposure for later increases in alcohol use-related problems, mediated by structural brain characteristics. © 2015 Society for the Study of Addiction.

Effects of prenatal exposure to antithyroid drugs on imprinting behavior in chicks.

PubMed

Kagami, Keisuke; Nishigori, Hidekazu; Nishigori, Hideo

2010-09-01

Thyroid hormones play important roles in vertebrate brain development. However, there is little understanding of the direct effects of fetal thyroid dysfunction, i.e., not acquired through the mother, on learning ability. In the present study, we use a chick embryo as a fetal model to investigate the effects of prenatal exposure to antithyroid drugs on imprinting behavior in hatched chicks. Methimazole (MMI) at 20micromol/egg or 5micromol/egg of propylthiouracil (PTU) was administered to eggs on day 14 while the control was given only a vehicle. An imprinting test was conducted after the chicks hatched. Day-old chicks were exposed to a rotating training object for 150min. The next day, the trained chicks were exposed to the training object and a novel object. The imprinting preference was represented as a preference score (PS) calculated as the rate of following the training object to following the training and novel objects. In the MMI-treated chicks, the PS was 0.68+/-0.06 (range, 0.38-0.88), which was significantly lower than that in the control chicks (0.86+/-0.04, p<0.01). In the PTU-treated chicks, the PS was 0.69+/-0.04 (range, 0.52-0.89), which was also significantly lower than that in the control (0.88+/-0.02, p<0.001). The present findings suggested that fetal thyroid dysfunction inhibited brain development, leading to impaired learning and memory. Our chick model can be considered useful for investigating the direct effects of prenatal exposure to antithyroid drugs or substances in the environment on learning ability after birth. Copyright 2010 Elsevier Inc. All rights reserved.

Late emerging effects of prenatal and early postnatal nicotine exposure on the cholinergic system and anxiety-like behavior.

PubMed

Eppolito, Amy K; Bachus, Susan E; McDonald, Craig G; Meador-Woodruff, James H; Smith, Robert F

2010-01-01

Animal models of prenatal nicotine exposure clearly indicate that nicotine is a neuroteratogen. Some of the persisting effects of prenatal nicotine exposure include low birth weight, behavioral changes and deficits in cognitive function, although few studies have looked for neurobehavioral and neurochemical effects that might persist throughout the lifespan. Pregnant rats were given continuous infusions of nicotine (0.96mg/kg/day or 2.0mg/kg/day, freebase) continuing through the third trimester equivalent, a period of rapid brain development. Because the third trimester equivalent occurs postnatally in the rat (roughly the first week of life) nicotine administration to neonate pups continued via maternal milk until postnatal day (P) 10. Exposure to nicotine during pre- and early postnatal development had an anxiogenic effect on adult rats (P75) in the elevated plus maze (EPM), and blocked extinction learning in a fear conditioning paradigm, suggesting that pre- and postnatal nicotine exposure affect anxiety-like behavior and cognitive function well into adulthood. In contrast, nicotine exposure had no effect on anxiety-like behaviors in the EPM in adolescent animals (P30). Analysis of mRNA for the alpha4, alpha7, and beta2 subunits of nicotinic acetylcholine receptors revealed lower expression of these subunits in the adult hippocampus and medial prefrontal cortex following pre- and postnatal nicotine exposure, suggesting that nicotine altered the developmental trajectory of the brain. These long-term behavioral and neurochemical changes strengthen the case for discouraging cigarette smoking during pregnancy and clearly indicate that the use of the patch as a smoking cessation aid during pregnancy is not a safe alternative.

Effects of Prenatal Testosterone Exposure on Sexually Dimorphic Gene Expression in the Neonatal Mouse Cortex and Hippocampus

PubMed Central

Armoskus, Chris; Mota, Thomas; Moreira, Debbie; Tsai, Houng-Wei

2014-01-01

Objective Using gene expression microarrays and reverse transcription with quantitative polymerase chain reaction (RT-qPCR), we have recently identified several novel genes that are differentially expressed in the neonatal male versus female mouse cortex/hippocampus (Armoskus et al.). Since perinatal testosterone (T) secreted by the developing testes masculinizes cortical and hippocampal structures and the behaviors regulated by these brain regions, we hypothesized that sexually dimorphic expression of specific selected genes in these areas might be regulated by T during early development. Methods To test our hypothesis, we treated timed pregnant female mice daily with vehicle or testosterone propionate (TP) starting on embryonic day 16 until the day of birth. The cortex/hippocampus was collected from vehicle- and TP-treated, male and female neonatal pups. Total RNA was extracted from these brain tissues, followed by RT-qPCR to measure relative mRNA levels of seven sex chromosome genes and three autosomal genes that have previously showed sex differences. Results The effect of prenatal TP was confirmed as it stimulated Dhcr24 expression in the neonatal mouse cortex/hippocampus and increased the anogenital distance in females. We found a significant effect of sex, but not TP, on expression of three Y-linked (Ddx3y, Eif2s3y, and Kdm5d), four X-linked (Eif2s3x, Kdm6a, Mid1, and Xist), and one autosomal (Klk8) genes in the neonatal mouse cortex/hippocampus. Conclusion Although most of the selected genes are not directly regulated by prenatal T, their sexually dimorphic expression might play an important role in the control of sexually differentiated cognitive and social behaviors as well as in the etiology of sex-biased neurological disorders and mental illnesses. PMID:25411648

Reversal of prenatal morphine exposure-induced memory deficit in male but not female rats.

PubMed

Nasiraei-Moghadam, Shiva; Sherafat, Mohammad Amin; Safari, Mir-Shahram; Moradi, Fatemeh; Ahmadiani, Abolhassan; Dargahi, Leila

2013-05-01

Impaired memory performance in offspring is one of the long-lasting neurobehavioral consequences of prenatal opiate exposure. Here, we studied the effects of prenatal morphine exposure on inhibitory avoidance memory performance in male and female offspring and also investigated whether these deficits are reversible during the postnatal development. Pregnant Wistar rats received morphine sulfate through drinking water, from the first day of gestation up to the day 13, M₁₋₁₃, or to the time of delivery, M₁₋₂₁. Four- and ten-week-old (adolescent and adult, respectively) male and female offspring were subjected to behavioral assays and then analysis of proteins involved in apoptosis or in synaptic plasticity. Results revealed that adolescent and adult female rats failed in passive avoidance retention task in both M₁₋₁₃ and M₁₋₂₁ groups. Adolescent and adult male offspring were similar to control animals in M₁₋₁₃ group. However M₁₋₂₁ impaired retention task in prepubertal male offspring, and this memory loss was repaired in postpubertal stage. Consistently, Bax/Bcl-2 ratio and cleaved caspase-3 were significantly increased in both M₁₋₁₃ and M₁₋₂₁ adolescent and adult female rats, but only in M₁₋₂₁ adolescent male rats. Furthermore, prenatal morphine exposure reduced the expression of brain-derived neurotrophic factor precursor protein in adolescent and adult female offspring and also decreased p-ca(2+)/calmodulin-dependent kinase II/ca(2+)/calmodulin-dependent kinase II ratio in adolescent male and female rats. Altogether, the results show that prenatal morphine exposure, depending on the time or duration of exposure, has distinct effects on male and female rats, and postnatal development may reverse these deficits more likely in males.

Astaxanthin improves behavioral disorder and oxidative stress in prenatal valproic acid-induced mice model of autism.

PubMed

Al-Amin, Md Mamun; Rahman, Md Mahbubur; Khan, Fazlur Rahman; Zaman, Fahmida; Mahmud Reza, Hasan

2015-06-01

Prenatal exposure to valproic acid on gestational day 12.5 may lead to the impaired behavior in the offspring, which is similar to the human autistic symptoms. To the contrary, astaxanthin shows neuroprotective effect by its antioxidant mechanism. We aimed to (i) develop mice model of autism and (ii) investigate the effect of astaxanthin on such model animals. Valproic acid (600 mg/kg) was administered intraperitoneally to the pregnant mice on gestational day 12.5. Prenatal valproic acid-exposed mice were divided into 2 groups on postnatal day 25 and astaxanthin (2mg/kg) was given to the experimental group (VPA_AST, n=10) while saline was given to the control group (VPA, n=10) for 4 weeks. Behavioral test including social interaction, open field and hot-plate were conducted on postnatal day 25 and oxidative stress markers such as lipid peroxidation, advanced protein oxidation product, nitric oxide, glutathione, and activity of superoxide dismutase and catalase were estimated on postnatal day 26 to confirm mice model of autism and on postnatal day 56 to assess the effect of astaxanthin. On postnatal day 25, prenatal valproic acid-exposed mice exhibited (i) delayed eye opening (ii) longer latency to respond painful stimuli, (iii) poor sociability and social novelty and (iv) high level of anxiety. In addition, an increased level of oxidative stress was found by determining different oxidative stress markers. Treatment with astaxanthin significantly (p<0.05) improved the behavioral disorder and reduced the oxidative stress in brain and liver. In conclusion, prenatal exposure to valproic day in pregnant mice leads to the development of autism-like features. Astaxanthin improves the impaired behavior in animal model of autism presumably by its antioxidant activity. Copyright © 2015 Elsevier B.V. All rights reserved.

Associative DNA methylation changes in children with prenatal alcohol exposure.

PubMed

Laufer, Benjamin I; Kapalanga, Joachim; Castellani, Christina A; Diehl, Eric J; Yan, Liying; Singh, Shiva M

2015-01-01

Prenatal alcohol exposure (PAE) can cause fetal alcohol spectrum disorders (FASD). Previously, we assessed PAE in brain tissue from mouse models, however whether these changes are present in humans remains unknown. In this report, we show some identical changes in DNA methylation in the buccal swabs of six children with FASD using the 450K array. The changes occur in genes related to protocadherins, glutamatergic synapses, and hippo signaling. The results were found to be similar in another heterogeneous replication group of six FASD children. The replicated results suggest that children born with FASD have unique DNA methylation defects that can be influenced by sex and medication exposure. Ultimately, with future clinical development, assessment of DNA methylation from buccal swabs can provide a novel strategy for the diagnosis of FASD.

Prenatal Dexamethasone Augments the Neurobehavioral Teratology of Chlorpyrifos: Significance for Maternal Stress and Preterm Labor

PubMed Central

Levin, Edward D.; Cauley, Marty; Johnson, Joshua E.; Cooper, Ellen M.; Stapleton, Heather M.; Ferguson, P. Lee; Seidler, Frederic J.; Slotkin, Theodore A.

2014-01-01

Glucocorticoids are the consensus treatment given in preterm labor and are also elevated by maternal stress; organophosphate exposures are virtually ubiquitous, so human developmental coexposures to these two agents are common. This study explores how prenatal dexamethasone exposure modifies the neurobehavioral teratology of chlorpyrifos, one of the most widely used organophosphates. We administered dexamethasone to pregnant rats on gestational days 17-19 at a standard therapeutic dose (0.2 mg/kg); offspring were then given chlorpyrifos on postnatal days 1-4, at a dose (1 mg/kg) that produces barely-detectable (<10%) inhibition of brain cholinesterase activity. Dexamethasone did not alter brain chlorpyrifos concentrations, nor did either agent alone or in combination affect brain thyroxine levels. Assessments were carried out from adolescence through adulthood encompassing T-maze alternation, Figure-8 maze (locomotor activity, habituation), novelty-suppressed feeding and novel object recognition tests. For behaviors where chlorpyrifos or dexamethasone individually had small effects, the dual exposure produced larger, significant effects that reflected additivity (locomotor activity, novelty-suppressed feeding, novel object recognition). Where the individual effects were in opposite directions or were restricted to only one agent, we found enhancement of chlorpyrifos’ effects by prenatal dexamethasone (habituation). Finally, for behaviors where controls displayed a normal sex difference in performance, the combined treatment either eliminated or reversed the difference (locomotor activity, novel object recognition). Combined exposure to dexamethasone and chlorpyrifos results in a worsened neurobehavioral outcome, providing a proof-of-principle that prenatal glucocorticoids can create a subpopulation with enhanced vulnerability to environmental toxicants. PMID:24177596

Effects of marijuana on visuospatial working memory: an fMRI study in young adults.

PubMed

Smith, Andra M; Longo, Carmelinda A; Fried, Peter A; Hogan, Matthew J; Cameron, Ian

2010-06-01

The effects of marijuana use on visuospatial working memory were investigated in 19-21-year-olds using functional magnetic resonance imaging (fMRI). Participants were members of the Ottawa Prenatal Prospective Study, a longitudinal study that collected a unique body of information on participants from infancy to young adulthood including: prenatal drug history, detailed cognitive/behavioral performance, and current and past drug usage. This information allowed for the measurement of an unprecedented number of potentially confounding drug exposure variables including: prenatal marijuana, nicotine, alcohol, and caffeine exposure and offspring alcohol, marijuana, and nicotine use. Ten marijuana users and 14 nonusing controls performed a visuospatial 2-back task while fMRI blood oxygen level-dependent response was examined. Despite similar task performance, marijuana users had significantly greater activation in the inferior and middle frontal gyri, regions of the brain normally associated with visuospatial working memory. Marijuana users also had greater activation in the right superior temporal gyrus, a region of the brain not typically associated with visuospatial working memory tasks. These results suggest that marijuana use leads to altered neural functioning during visuospatial working memory after controlling for other prenatal and current drug use. This alteration appears to be compensated for by the recruitment of blood flow in additional brain regions. It is possible that this compensation may not be sufficient in more real-life situations where this type of processing is required and thus deficits may be observed. Awareness of these neural physiological effects of marijuana in youth is critical.

Prenatal treatment of Down syndrome: a reality?

PubMed

Guedj, Fayçal; Bianchi, Diana W; Delabar, Jean-Maurice

2014-04-01

Down syndrome affects more than 5 million people globally. During the last 10 years, there has been a dramatic increase in the research efforts focused on therapeutic interventions to improve learning and memory in Down syndrome. This review summarizes the different functional abnormalities targeted by researchers in mouse models of Down syndrome. Three main strategies have been used: neural stem cell implantation; environmental enrichment and physical exercise; and pharmacotherapy. Pharmacological targets include the choline pathway, GABA and NMDA receptors, DYRK1A protein, oxidative stress and pathways involved in development and neurogenesis. Many strategies have improved learning and memory as well as electrophysiological and molecular alterations in affected animals. To date, eight molecules have been tested in human adult clinical trials. No studies have yet been performed on infants. However, compelling studies reveal that permanent brain alterations originate during fetal life in Down syndrome. Early prenatal diagnosis offers a 28 weeks window to positively impact brain development and improve postnatal cognitive outcome in affected individuals. Only a few approaches (Epigallocatechine gallate, NAP/SAL, fluoxetine, and apigenin) have been used to treat mice in utero; these showed therapeutic effects that persisted to adulthood. In this article, we discuss the challenges, recent progress, and lessons learned that pave the way for new therapeutic approaches in Down syndrome.

Dermatoglyphic anomalies and neurocognitive deficits in sibling pairs discordant for schizophrenia spectrum disorders.

PubMed

Rosa, Araceli; Cuesta, Manuel J; Peralta, Víctor; Zarzuela, Amalia; Serrano, Fermín; Martínez-Larrea, Alfredo; Fañanás, Lourdes

2005-12-15

The neurodevelopmental hypothesis of schizophrenia suggests that adverse genetic loading in conjunction with environmental factors early in fetal life causes a disruption of neural development, decades before the symptomatic manifestation of the disease. Neurocognitive deficits have been observed early on the course of schizophrenia, and their association with an early developmental brain lesion has been postulated. Dermatoglyphics have been analyzed in schizophrenia as markers of prenatal brain injury because of their early fetal ontogenesis and susceptibility to the same environmental factors that can also affect cerebral development. The aim of our study was to conduct a comparative examination of neurocognitive functions and dermatoglyphic variables in 89 sibling pairs discordant for schizophrenia spectrum disorders. Therefore, we investigated the association between these two markers to explore the prenatal origin of cognitive deficits in schizophrenia. The affected siblings were significantly impaired on all the cognitive variables assessed (Wisconsin Card Sorting Test, Trail Making Test and Continuous Performance Test) and had a greater number of dermatoglyphic anomalies. These results suggest the influence of intrauterine environmental factors in the siblings affected with schizophrenia. However, we did not detect a significant association between these two vulnerability markers in the schizophrenic patients, suggesting the role of genetic or late environmental factors in the origin of the neurocognitive deficits found in these patients.

Prenatal choline deficiency does not enhance hippocampal vulnerability after kainic acid-induced seizures in adulthood

PubMed Central

Wong-Goodrich, Sarah J.E.; Tognoni, Christina M.; Mellott, Tiffany J.; Glenn, Melissa J.; Blusztajn, Jan K.; Williams, Christina L.

2011-01-01

Choline is a vital nutrient needed during early development for both humans and rodents. Severe dietary choline deficiency during pregnancy leads to birth defects, while more limited deficiency during mid- to late pregnancy causes deficits in hippocampal plasticity in adult rodent offspring that are accompanied by cognitive deficits only when task demands are high. Because prenatal choline supplementation confers neuroprotection of the adult hippocampus against a variety of neural insults and aids memory, we hypothesized that prenatal choline deficiency may enhance vulnerability to neural injury. To examine this, adult offspring of rat dams either fed a control diet (CON) or one deficient in choline (DEF) during embryonic days 12–17 were given multiple injections (i.p.) of saline (control) or kainic acid to induce seizures and were euthanized 16 days later. Perhaps somewhat surprisingly, DEF rats were not more susceptible to seizure induction and showed similar levels of seizure-induced hippocampal histopathology, GAD expression loss, upregulated hippocampal GFAP and growth factor expression, and increased dentate cell and neuronal proliferation as that seen in CON rats. Although prenatal choline deficiency compromises adult hippocampal plasticity in the intact brain, it does not appear to exacerbate the neuropathological response to seizures in the adult hippocampus at least shortly after excitotoxic injury. PMID:21840511

Prenatal Ethanol Exposure and Neocortical Development: A Transgenerational Model of FASD.

PubMed

Abbott, Charles W; Rohac, David J; Bottom, Riley T; Patadia, Sahil; Huffman, Kelly J

2017-07-06

Fetal Alcohol Spectrum Disorders, or FASD, represent a range of adverse developmental conditions caused by prenatal ethanol exposure (PrEE) from maternal consumption of alcohol. PrEE induces neurobiological damage in the developing brain leading to cognitive-perceptual and behavioral deficits in the offspring. Alcohol-mediated alterations to epigenetic function may underlie PrEE-related brain dysfunction, with these changes potentially carried across generations to unexposed offspring. To determine the transgenerational impact of PrEE on neocortical development, we generated a mouse model of FASD and identified numerous stable phenotypes transmitted via the male germline to the unexposed third generation. These include alterations in ectopic intraneocortical connectivity, upregulation of neocortical Rzrβ and Id2 expression accompanied by both promoter hypomethylation of these genes and decreased global DNA methylation levels. DNMT expression was also suppressed in newborn PrEE cortex, providing further insight into how ethanol perturbs DNA methylation leading to altered regulation of gene transcription. These PrEE-induced, transgenerational phenotypes may be responsible for cognitive, sensorimotor, and behavioral deficits seen in humans with FASD. Thus, understanding the possible epigenetic mechanisms by which these phenotypes are generated may reveal novel targets for therapeutic intervention of FASD and lead to advances in human health. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Sex-related variation in human behavior and the brain

PubMed Central

Hines, Melissa

2010-01-01

Male and female fetuses differ in testosterone concentrations beginning as early as week 8 of gestation. This early hormone difference exerts permanent influences on brain development and behavior. Contemporary research shows that hormones are particularly important for the development of sex-typical childhood behavior, including toy choices, which until recently were thought to result solely from sociocultural influences. Prenatal testosterone exposure also appears to influence sexual orientation and gender identity, as well as some, but not all, sex-related cognitive, motor and personality characteristics. Neural mechanisms responsible for these hormone-induced behavioral outcomes are beginning to be identified, and current evidence suggests involvement of the hypothalamus and amygdala, as well as interhemispheric connectivity, and cortical areas involved in visual processing. PMID:20724210

Minimal Brain Dysfunction: Associations with Perinatal Complications.

ERIC Educational Resources Information Center

Nichols, Paul L.

Examined with over 28,000 7-year-old children whose mothers registered for prenatal care was the relationship between perinatal complications and such characteristics as poor school achievement, hyperactivity, and neurological soft signs associated with the diagnosis of minimal brain dysfunction (MBD). Ten perinatal antecedents were studied:…

PRENATAL EXPOSURE TO CHLORPYRIFOS ALTERS NEUROTROPHIN IMMUNOREACTIVITY AND APOPTOSIS IN RAT BRAIN.

EPA Science Inventory

In the present study, the effects of the organophosphate pesticide chlorpyrifos [CPF; O,O'diethyl O-3,5,6-trichloro-2-pyridyl) phosphorothionate] on the regional distribution of three neurotrophic factors and on levels of apoptosis in gestational rat brain were characterized. P...

Low Dose Prenatal Alcohol Exposure Does Not Impair Spatial Learning and Memory in Two Tests in Adult and Aged Rats

PubMed Central

Cullen, Carlie L.; Burne, Thomas H. J.; Lavidis, Nickolas A.; Moritz, Karen M.

2014-01-01

Consumption of alcohol during pregnancy can have detrimental impacts on the developing hippocampus, which can lead to deficits in learning and memory function. Although high levels of alcohol exposure can lead to severe deficits, there is a lack of research examining the effects of low levels of exposure. This study used a rat model to determine if prenatal exposure to chronic low dose ethanol would result in deficits in learning and memory performance and if this was associated with morphological changes within the hippocampus. Sprague Dawley rats were fed a liquid diet containing 6% (vol/vol) ethanol (EtOH) or an isocaloric control diet throughout gestation. Male and Female offspring underwent behavioural testing at 8 (Adult) or 15 months (Aged) of age. Brains from these animals were collected for stereological analysis of pyramidal neuron number and dendritic morphology within the CA1 and CA3 regions of the dorsal hippocampus. Prenatal ethanol exposed animals did not differ in spatial learning or memory performance in the Morris water maze or Y maze tasks compared to Control offspring. There was no effect of prenatal ethanol exposure on pyramidal cell number or density within the dorsal hippocampus. Overall, this study indicates that chronic low dose prenatal ethanol exposure in this model does not have long term detrimental effects on pyramidal cells within the dorsal hippocampus or impair spatial learning and memory performance. PMID:24978807

A prospective study of fetal head growth, autistic traits and autism spectrum disorder

PubMed Central

Blanken, Laura M. E.; Dass, Alena; Alvares, Gail; van der Ende, Jan; Schoemaker, Nikita K.; El Marroun, Hanan; Hickey, Martha; Pennell, Craig; White, Scott; Maybery, Murray T.; Dissanayake, Cheryl; Jaddoe, Vincent W. V.; Verhulst, Frank C.; Tiemeier, Henning; McIntosh, Will; Whitehouse, Andrew

2018-01-01

Altered trajectories of brain growth are often reported in Autism Spectrum Disorder (ASD), particularly during the first year of life. However, less is known about prenatal head growth trajectories, and no study has examined the relation with postnatal autistic symptom severity. The current study prospectively examined the association between fetal head growth and the spectrum of autistic symptom severity in two large population‐based cohorts, including a sample of individuals with clinically diagnosed ASD. This study included 3,820 children from two longitudinal prenatal cohorts in The Netherlands and Australia, comprising 60 individuals with a confirmed diagnosis of ASD. Latent growth curve models were used to examine the relationship between fetal head circumference measured at three different time points and autistic traits measured in postnatal life using either the Social Responsiveness Scale or the Autism‐Spectrum Quotient. While lower initial prenatal HC was weakly associated with increasing autistic traits in the Dutch cohort, this relationship was not observed in the Australian cohort, nor when the two cohorts were analysed together. No differences in prenatal head growth were found between individuals with ASD and controls. This large population‐based study identified no consistent association across two cohorts between prenatal head growth and postnatal autistic traits. Our mixed findings suggest that further research in this area is needed. Autism Res 2018, 11: 602–612. © 2018 The Authors Autism Research published by International Society for Autism Research and Wiley Periodicals, Inc. Lay Summary It is not known whether different patterns of postnatal brain growth in Autism Spectrum Disorder (ASD) also occurs prenatally. We examined fetal head growth and autistic symptoms in two large groups from The Netherlands and Australia. Lower initial prenatal head circumference was associated with autistic traits in the Dutch, but not the Australian, group. No differences in head growth were found in individuals with ASD and controls when the data was combined. Our mixed findings suggest that more research in this area is needed. PMID:29356450

Hemihydranencephaly: living with half brain dysfunction.

PubMed

Pavone, Piero; Nigro, Francesco; Falsaperla, Raffaele; Greco, Filippo; Ruggieri, Martino; Rizzo, Renata; Praticò, Andrea D; Pavone, Lorenzo

2013-01-16

Hemi-hydranencephaly is a very rare condition characterized by complete or almost near-complete unilateral absence of the cortical cortex, which is filled by a sac of cerebrospinal fluid. Prenatal vascular disruption with occlusion of the carotid artery territories ipsilateral to the damaged brain is the presumed pathogenesis.We have selected nine cases that fit the clinical and pathologic characteristics of hemi-hydranencephaly, demonstrating that destruction of one hemisphere may be not always associated with severe neurologic impairment and may allow an almost normal life. This disorder is an example of a possible prenatal re-organization in which the right and left cerebral hemispheres present functional potentiality to make up the damaged brain.The cases reported in the literature are discussed, including a patient previously reported and followed-up for 10 years. A review of the cases is performed with an evaluation of the most important aspect of this rare and mysterious disorder.

Epileptic encephalopathy in children with risk factors for brain damage.

PubMed

Ricardo-Garcell, Josefina; Harmony, Thalía; Porras-Kattz, Eneida; Colmenero-Batallán, Miguel J; Barrera-Reséndiz, Jesús E; Fernández-Bouzas, Antonio; Cruz-Rivero, Erika

2012-01-01

In the study of 887 new born infants with prenatal and perinatal risk factors for brain damage, 11 children with West syndrome that progressed into Lennox-Gastaut syndrome and another 4 children with Lennox-Gastaut syndrome that had not been preceded by West syndrome were found. In this study we present the main findings of these 15 subjects. In all infants multifactor antecedents were detected. The most frequent risk factors were prematurity and severe asphyxia; however placenta disorders, sepsis, and hyperbilirubinemia were also frequent. In all infants MRI direct or secondary features of periventricular leukomalacia were observed. Followup of all infants showed moderate to severe neurodevelopmental delay as well as cerebral palsy. It is concluded that prenatal and perinatal risk factors for brain damage are very important antecedents that should be taken into account to follow up those infants from an early age in order to detect and treat as early as possible an epileptic encephalopathy.

Early androgen exposure and human gender development.

PubMed

Hines, Melissa; Constantinescu, Mihaela; Spencer, Debra

2015-01-01

During early development, testosterone plays an important role in sexual differentiation of the mammalian brain and has enduring influences on behavior. Testosterone exerts these influences at times when the testes are active, as evidenced by higher concentrations of testosterone in developing male than in developing female animals. This article critically reviews the available evidence regarding influences of testosterone on human gender-related development. In humans, testosterone is elevated in males from about weeks 8 to 24 of gestation and then again during early postnatal development. Individuals exposed to atypical concentrations of testosterone or other androgenic hormones prenatally, for example, because of genetic conditions or because their mothers were prescribed hormones during pregnancy, have been consistently found to show increased male-typical juvenile play behavior, alterations in sexual orientation and gender identity (the sense of self as male or female), and increased tendencies to engage in physically aggressive behavior. Studies of other behavioral outcomes following dramatic androgen abnormality prenatally are either too small in their numbers or too inconsistent in their results, to provide similarly conclusive evidence. Studies relating normal variability in testosterone prenatally to subsequent gender-related behavior have produced largely inconsistent results or have yet to be independently replicated. For studies of prenatal exposures in typically developing individuals, testosterone has been measured in single samples of maternal blood or amniotic fluid. These techniques may not be sufficiently powerful to consistently detect influences of testosterone on behavior, particularly in the relatively small samples that have generally been studied. The postnatal surge in testosterone in male infants, sometimes called mini-puberty, may provide a more accessible opportunity for measuring early androgen exposure during typical development. This approach has recently begun to be used, with some promising results relating testosterone during the first few months of postnatal life to later gender-typical play behavior. In replicating and extending these findings, it may be important to assess testosterone when it is maximal (months 1 to 2 postnatal) and to take advantage of the increased reliability afforded by repeated sampling.

The investigation of the prenatal and postnatal alcohol exposure-induced neurodegeneration in rat brain: protection by betaine and/or omega-3.

PubMed

Kusat Ol, Kevser; Kanbak, Güngör; Oğlakcı Ilhan, Ayşegül; Burukoglu, Dilek; Yücel, Ferruh

2016-03-01

We aim to study the effect of neurodegeneration on the brain of rat pups caused by prenatal and postnatal ethanol exposure with modified liquid diet to elucidate protective effects of betaine and omega-3 supplementation. When ethanol is consumed during prenatal and postnatal periods, it may result in fetal alcohol syndrome (FAS) in the offspring. Rats were divided into control, ethanol, ethanol + betaine, ethanol + omega-3, ethanol + omega-3 + betaine groups. The effect of betaine and omega-3 in response to ethanol-induced changes on the brain, by biochemical analyses cytochrome c, caspase-3, calpain, cathepsin B and L, DNA fragmentation, histological and morfometric methods were evaluated. Caspase-3, calpain, cathepsin B, and cytochrome c levels in ethanol group were significantly higher than control. Caspase-3, calpain levels were decreased in ethanol + betaine, ethanol + omega-3, and ethanol + omega-3 + betaine groups compared to ethanol group. Cathepsin B in ethanol + omega-3 + betaine group was decreased compared to ethanol, ethanol + betaine groups. Cathepsin L and DNA fragmentation were found not statistically significant. We found similar results in histological and morfometric parameters. We found that pre- and postnatal ethanol exposure is capable of triggering necrotic cell death in rat brains, omega-3, and betaine reduce neurodegeneration. Omega-3 and betaine may prove beneficial for neurodegeneration, particularly in preventing FAS.

Cerebral impact of prenatal irradiation by 131I: an experimental model of clinical neuroradioembryological effects.

PubMed

Talko, V V; Loganovsky, K M; Drozd, I P; Tukalenko, Ye V; Loganovska, T K; Nechayev, S Yu; Masiuk, S V; Prokhorova, Ye M

2017-12-01

Human brain in prenatal period is a most vulnerable to ionizing radiation body structure. Unlike atomic bombings or radiological interventions in healthcare leading at most to external irradiation the intensive internal exposure may occur upon nuclear reactor accidents followed by substantial release and fallout of radioactive 131I. The latter can lead to specific neuroradioembryological effects. To create an experimental model of prenatal cerebral radiation effects of 131I in human and to determine the experimental and clinical neuroradioembryological effects.Study object. The neuroradioembryological effects in Vistar rats exposed to 131I in prenatal period. Nervous system status and mental status in 104 persons exposed to ionizing radiation in utero due to the ChNPP accident and the same in 78 not exposed subjects. Experimental i.e. behavioral techniques, including the spontaneous locomotive, exploratory activity and learning ability assessment, clinical i.e. neuropsychiatric, neuro and psychometric, neuropsychological, neurophys iological methods, both with dosimetric and statistical methods were applied. Intrauterine irradiation of Wistar rats by 131I was simulated on a model of one time oral 27.5 kBq radionu clide administration in the mid gestation period (0.72±0.14 Gy fetal thyroid dose), which provides extrapolation of neuroradioembryological effects in rats to that in humans exposed to intrauterine radiation as a result of the Chornobyl catastrophe. Abnormalities in behavioral reactions and decreased output of conditioned reflex reactions identified in the 10 month old rats suggest a deterioration of cerebral cognition in exposed animals. Specific cog nitive deficit featuring a disharmonic intellectual development through the relatively decreased verbal intelligence versus relative increase of nonverbal one is remained in prenatally exposed persons. This can indicate to dysfunc tion of cortical limbic system with especial involvement of a dominant hemisphere hippocampus. Decreased theta band spectral power (4-7 Hz range) of cerebral bioelectrical activity in the left frontotemporal area is suggestive of hippocampal dysfunction mainly in dominant hemisphere of prenatally irradiated persons. Disorders of hippocam pal neurogenesis due to prenatal exposure by radioactive iodine can be a biologic basis here. Innovative approach es in social adaptation, psychoprophylaxis and psychorehabilitation involve the maximum effective application and development of just the most developed psychological and cognitive abilities in survivors. V. V. Talko, K. M. Loganovsky, I. P. Drozd, Ye. V. Tukalenko, T. K. Loganovska, S. Yu. Nechayev, S. V. Masiuk, Ye. M. Prokhorova.

Down-regulation of sup 3 H-imipramine binding sites in rat cerebral cortex prenatal exposure to antidepressants

DOE Office of Scientific and Technical Information (OSTI.GOV)

Montero, D.; de Ceballos, M.L.; Del Rio, J.

1990-01-01

Several antidepressant drugs were given to pregnant rats in the last 15 days of gestation and {sup 3}H-imipramine binding ({sup 3}H-IMI) was subsequently measured in the cerebral cortex of the offspring. The selective serotonin (5-HT) uptake blockers chlorimipramine and fluoxetine as well as the selective monoamine oxidase (MAO) inhibitors clorgyline and deprenyl induced, after prenatal exposure, a down-regulation of {sup 3}H-IMI binding sites at postnatal day 25. The density of these binding sites was still reduced at postnatal day 90 in rats exposed in utero to the MAO inhibitors. The antidepressants desipramine and nomifensine were ineffective in this respect. Aftermore » chronic treatment of adult animals, only chlorimipramine was able to down-regulate the {sup 3}H-IMI binding sites. Consequently, prenatal exposure of rats to different antidepressant drugs affecting predominantly the 5-HT systems induces more marked and long-lasting effects on cortical {sup 3}H-IMI binding sites. The results suggest that the developing brain is more susceptible to the actions of antidepressants.« less

Prenatal stress changes learning strategies in adulthood.

PubMed

Schwabe, Lars; Bohbot, Veronique D; Wolf, Oliver T

2012-11-01

It is well known that stressful experiences may shape hippocampus-dependent learning and memory processes. However, although most studies focused on the impact of stress at the time of learning or memory testing, very little is known about how stress during critical periods of brain development affects learning and memory later in life. In this study, we asked whether prenatal stress exposure may influence the engagement of hippocampus-dependent spatial learning strategies and caudate nucleus-dependent response learning strategies in later life. To this end, we tested healthy participants whose mothers had experienced major negative life events during their pregnancy in a virtual navigation task that can be solved by spatial and response strategies. We found that young adults with prenatal stress used rigid response learning strategies more often than flexible spatial learning strategies compared with participants whose mothers did not experience major negative life events during pregnancy. Individual differences in acute or chronic stress do not account for these findings. Our data suggest that the engagement of hippocampal and nonhippocampal learning strategies may be influenced by stress very early in life. Copyright © 2012 Wiley Periodicals, Inc.

Prenatal metformin exposure in mice programs the metabolic phenotype of the offspring during a high fat diet at adulthood.

PubMed

Salomäki, Henriikka; Vähätalo, Laura H; Laurila, Kirsti; Jäppinen, Norma T; Penttinen, Anna-Maija; Ailanen, Liisa; Ilyasizadeh, Juan; Pesonen, Ullamari; Koulu, Markku

2013-01-01

The antidiabetic drug metformin is currently used prior and during pregnancy for polycystic ovary syndrome, as well as during gestational diabetes mellitus. We investigated the effects of prenatal metformin exposure on the metabolic phenotype of the offspring during adulthood in mice. Metformin (300 mg/kg) or vehicle was administered orally to dams on regular diet from the embryonic day E0.5 to E17.5. Gene expression profiles in liver and brain were analysed from 4-day old offspring by microarray. Body weight development and several metabolic parameters of offspring were monitored both during regular diet (RD-phase) and high fat diet (HFD-phase). At the end of the study, two doses of metformin or vehicle were given acutely to mice at the age of 20 weeks, and Insig-1 and GLUT4 mRNA expressions in liver and fat tissue were analysed using qRT-PCR. Metformin exposed fetuses were lighter at E18.5. There was no effect of metformin on the maternal body weight development or food intake. Metformin exposed offspring gained more body weight and mesenteric fat during the HFD-phase. The male offspring also had impaired glucose tolerance and elevated fasting glucose during the HFD-phase. Moreover, the expression of GLUT4 mRNA was down-regulated in epididymal fat in male offspring prenatally exposed to metformin. Based on the microarray and subsequent qRT-PCR analyses, the expression of Insig-1 was changed in the liver of neonatal mice exposed to metformin prenatally. Furthermore, metformin up-regulated the expression of Insig-1 later in development. Gene set enrichment analysis based on preliminary microarray data identified several differentially enriched pathways both in control and metformin exposed mice. The present study shows that prenatal metformin exposure causes long-term programming effects on the metabolic phenotype during high fat diet in mice. This should be taken into consideration when using metformin as a therapeutic agent during pregnancy.

Gaining insight of fetal brain development with diffusion MRI and histology.

PubMed

Huang, Hao; Vasung, Lana

2014-02-01

Human brain is extraordinarily complex and yet its origin is a simple tubular structure. Its development during the fetal period is characterized by a series of accurately organized events which underlie the mechanisms of dramatic structural changes during fetal development. Revealing detailed anatomy at different stages of human fetal brain development provides insight on understanding not only this highly ordered process, but also the neurobiological foundations of cognitive brain disorders such as mental retardation, autism, schizophrenia, bipolar and language impairment. Diffusion tensor imaging (DTI) and histology are complementary tools which are capable of delineating the fetal brain structures at both macroscopic and microscopic levels. In this review, the structural development of the fetal brains has been characterized with DTI and histology. Major components of the fetal brain, including cortical plate, fetal white matter and cerebral wall layer between the ventricle and subplate, have been delineated with DTI and histology. Anisotropic metrics derived from DTI were used to quantify the microstructural changes during the dynamic process of human fetal cortical development and prenatal development of other animal models. Fetal white matter pathways have been traced with DTI-based tractography to reveal growth patterns of individual white matter tracts and corticocortical connectivity. These detailed anatomical accounts of the structural changes during fetal period may provide the clues of detecting developmental and cognitive brain disorders at their early stages. The anatomical information from DTI and histology may also provide reference standards for diagnostic radiology of premature newborns. Copyright © 2013 ISDN. Published by Elsevier Ltd. All rights reserved.

Effects of perinatal exposure to PCBs and dioxins on play behavior in Dutch children at school age.

PubMed

Vreugdenhil, Hestien J I; Slijper, Froukje M E; Mulder, Paul G H; Weisglas-Kuperus, Nynke

2002-10-01

Polychlorinated biphenyls (PCBs) and dioxins are known as neurotoxic compounds that may modulate sex steroid hormones. Steroid hormones play a mediating role in brain development and may influence behaviors that show sex differences, such as childhood play behavior. In this study we evaluated the effects of perinatal exposure to environmental levels of PCBs and dioxins on childhood play behavior and whether the effects showed sex differences. As part of the follow-up to the Dutch PCB/dioxin study at school age, we used the Pre-School Activity Inventory (PSAI) to assess play behavior in the Rotterdam cohort (n = 207). The PSAI assesses masculine or feminine play behavior scored on three subscales: masculine, feminine, and composite. Prenatal exposure to PCBs was defined as the sum of PCB 118, 138, 153, and 180 in maternal and cord plasma and breast milk. For breast milk we measured additional PCBs as well as 17 dioxins. Respondents returned 160 questionnaires (age 7.5 years +/- 0.4). Effects of prenatal exposure to PCBs, measured in maternal and cord plasma, on the masculine and composite scales were different for boys and girls (p <.05). In boys, higher prenatal PCB levels were related with less masculinized play, assessed by the masculine scale (p(maternal) =.042; p(cord) =.001) and composite scale (p(cord) =.011), whereas in girls higher PCB levels were associated with more masculinized play, assessed by the composite scale (p(PCBmilk) =.028). Higher prenatal dioxin levels were associated with more feminized play in boys as well as girls, assessed by the feminine scale (p =.048). These effects suggest prenatal steroid hormone imbalances caused by prenatal exposure to environmental levels of PCBs, dioxins, and other related organochlorine compounds.

Interactive effects of prenatal exposure to restraint stress and alcohol on pentylenetetrazol-induced seizure behaviors in rat offspring.

PubMed

Hashemi, Paria; Roshan-Milani, Shiva; Saboory, Ehsan; Ebrahimi, Loghman; Soltanineghad, Maryam

2016-11-01

Prenatal exposure to stress or alcohol increases vulnerability of brain regions involved in neurobehavioral development and programs susceptibility to seizure. To examine how prenatal alcohol interferes with stress-sensitive seizures, corticosterone (COS) blood levels and pentylenetetrazol (PTZ)-induced seizure behaviors were investigated in rat pups, prenatally exposed to stress, alcohol, or both. Pregnant rats were exposed to stress and saline/alcohol on 17, 18, and 19 days of pregnancy and divided into four groups of control-saline (CS), control-alcohol (CA), restraint stress-saline (RS), and restraint stress-alcohol (RA). In CS/CA groups, rats received saline/alcohol (20%, 2 g/kg, intraperitoneally [i.p.]). In RS/RA groups, rats were exposed to restraint stress by being held immobile in a Plexiglas ® tube (twice/day, 1 h/session), and received saline/alcohol, simultaneously. After parturition, on postnatal days 6 and 15 (P6 & P15), blood samples were collected from the pups to determine COS level. On P15 and P25, PTZ (45 mg/kg) was injected into the rest of the pups and seizure behaviors were then recorded. COS levels increased in pups of the RS group but not in pups of the RA group. Both focal and tonic-clonic seizures were prevalent and severe in pups of the RS group, whereas only focal seizures were prominent in pups of the CA group. However, pups prenatally exposed to co-administration of alcohol and stress, unexpectedly, did not show additive epileptic effects. The failure of pups prenatally exposed to alcohol to show progressive or facilitatory epileptic responses to stressors, indicates decreased plasticity and adaptability, which may negatively affect HPA-axis performance or hippocampal structure/function. Copyright © 2016 Elsevier Inc. All rights reserved.

Thyroid Hormone Economy in the Perinatal Mouse Brain: Implications for Cerebral Cortex Development.

PubMed

Bárez-López, Soledad; Obregon, Maria Jesus; Bernal, Juan; Guadaño-Ferraz, Ana

2018-05-01

Thyroid hormones (THs, T4 and the transcriptionally active hormone T3) play an essential role in neurodevelopment; however, the mechanisms underlying T3 brain delivery during mice fetal development are not well known. This work has explored the sources of brain T3 during mice fetal development using biochemical, anatomical, and molecular approaches. The findings revealed that during late gestation, a large amount of fetal brain T4 is of maternal origin. Also, in the developing mouse brain, fetal T3 content is regulated through the conversion of T4 into T3 by type-2 deiodinase (D2) activity, which is present from earlier prenatal stages. Additionally, D2 activity was found to be essential to mediate expression of T3-dependent genes in the cerebral cortex, and also necessary to generate the transient cerebral cortex hyperthyroidism present in mice lacking the TH transporter Monocarboxylate transporter 8. Notably, the gene encoding for D2 (Dio2) was mainly expressed at the blood-cerebrospinal fluid barrier (BCSFB). Overall, these data signify that T4 deiodinated by D2 may be the only source of T3 during neocortical development. We therefore propose that D2 activity at the BCSFB converts the T4 transported across the choroid plexus into T3, thus supplying the brain with active hormone to maintain TH homeostasis.

The Manpower Quality Decline: An Ecological Perspective

DTIC Science & Technology

1981-01-01

90 These factors can influence the human brain prenatally as well as during childhood and adolescence. In some cases, the ecological effects appear...decerebrate (as though they had no cerebral cortex) rigidity following application of 6 percent hexachlorophene powder. Examina- tion of brain stems of...correlation between hexachlorophene baths and lesions in white matter of brains .... Phisohex should not be used routinely for bathing infants. The 1976

The effect of prenatal nicotine on mRNA of central cholinergic markers and hematological parameters in rat fetuses

PubMed Central

Mao, Caiping; Yuan, Xin; Zhang, Hong; Lv, Juanxiu; Guan, Junchang; Miao, Liyan; Chen, Linqi; Zhang, Yuying; Zhang, Lubo; Xu, Zhice

2009-01-01

A number of studies have demonstrated the influence of nicotine on fetal development. This study determined the expression of choline acetyltransferase (ChAT), vesicular acetylcholine transporter (VAChT), and high-affinity choline transporter (CHT1) in the forebrain and hindbrain following chronic prenatal nicotine exposure in the rat fetus (maternal rats were subcutaneously injected with nicotine at different gestation periods). We also measured the effect of chronic nicotine exposure on fetal blood pO2, pCO2, pH, Na+ and K+ concentrations, as well as lactic acid levels. Maternal nicotine exposure during pregnancy was associated with a decrease in fetal pO2 coupled with a significant increase in pCO2 and lactic acid as well as restricted fetal growth. Additionally, maternal nicotine administration also reduced ChAT, VAChT, and CHT1 mRNA levels in the fetal brain. Nicotine-induced fetal hypoxic responses and reduced cholinergic marker expression in the brain were more severe when nicotine was started in early gestation. Our results provide new information about the effects of repeated exposure to nicotine in utero on the expression of central ChAT, VAChT, and CHT1 in the rat fetus. These results indicate that repeated hypoxic episodes or/and a direct effect of nicotine on the central cholinergic system during pregnancy may contribute to brain developmental problems in fetal origin. PMID:18407449

Effect of maternal renin-angiotensin-aldosterone system activation on social coping strategies and gene expression of oxytocin and vasopressin in the brain of rat offspring in adulthood.

PubMed

Senko, Tomáš; Svitok, Pavel; Kršková, Lucia

2017-10-01

The intrauterine condition in which the mammalian foetus develops has an important role in prenatal programming. The aim of this study was to determine the extent to which activation of the maternal renin-angiotensin-aldosterone system (RAAS) could influence social behaviour strategies in offspring via changes in social neurotransmitters in the brain. Pregnant female Wistar rats were implanted with osmotic minipumps which continually released angiotensin II for 14 days at concentration of 2 μg/kg/h. The adult offspring (angiotensin and control groups) underwent a social interaction test. The mRNA expression of vasopressin, oxytocin and the oxytocin receptor in selected brain areas was measured by in situ hybridisation. Prenatal exposure to higher levels of angiotensin II resulted in a strong trend toward decreased total social interaction time and significantly decreased time spent in close proximity and frequency of mutual sniffing. The angiotensin group showed no changes in oxytocin mRNA expression in the hypothalamic paraventricular or supraoptic nuclei, but this group had reduced vasopressin mRNA expression in the same areas. We concluded that maternal activation of RAAS (via higher levels of angiotensin II) caused inhibition of some socio-cohesive indicators and decreased vasopressinergic activity of offspring. Taken together, these results suggest a reactive rather than proactive social coping strategy.

SLC9A9 Co-expression modules in autism-associated brain regions.

PubMed

Patak, Jameson; Hess, Jonathan L; Zhang-James, Yanli; Glatt, Stephen J; Faraone, Stephen V

2017-03-01

SLC9A9 is a sodium hydrogen exchanger present in the recycling endosome and highly expressed in the brain. It is implicated in neuropsychiatric disorders, including autism spectrum disorders (ASDs). Little research concerning its gene expression patterns and biological pathways has been conducted. We sought to investigate its possible biological roles in autism-associated brain regions throughout development. We conducted a weighted gene co-expression network analysis on RNA-seq data downloaded from Brainspan. We compared prenatal and postnatal gene expression networks for three ASD-associated brain regions known to have high SLC9A9 gene expression. We also performed an ASD-associated single nucleotide polymorphism enrichment analysis and a cell signature enrichment analysis. The modules showed differences in gene constituents (membership), gene number, and connectivity throughout time. SLC9A9 was highly associated with immune system functions, metabolism, apoptosis, endocytosis, and signaling cascades. Gene list comparison with co-immunoprecipitation data was significant for multiple modules. We found a disproportionately high autism risk signal among genes constituting the prenatal hippocampal module. The modules were enriched with astrocyte and oligodendrocyte markers. SLC9A9 is potentially involved in the pathophysiology of ASDs. Our investigation confirmed proposed functions for SLC9A9, such as endocytosis and immune regulation, while also revealing potential roles in mTOR signaling and cell survival.. By providing a concise molecular map and interactions, evidence of cell type and implicated brain regions we hope this will guide future research on SLC9A9. Autism Res 2017, 10: 414-429. © 2016 International Society for Autism Research, Wiley Periodicals, Inc. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

Combined prenatal and postnatal butyl paraben exposure produces autism-like symptoms in offspring: comparison with valproic acid autistic model.

PubMed

Ali, Elham H A; Elgoly, Amany H Mahmoud

2013-10-01

The aim of this work is to evaluate the impact of butyl paraben (BP) in brain of the pups developed for mothers administered BP from early pregnancy till weaning and its effect on studying the behavior, brain neurotransmitters and brain derived neurotrophic factor BDNF via comparing the results with valproic acid (VA) autistic-rat model preparing by a single oral injection dose of VA (800 mg/kg b.wt) at the 12.5 days of gestation. Butyl paraben was orally and subcutaneously administered (200 mg/kg b.wt) to pregnant rats from gestation day 1 to lactation day 21. The offspring male rats were subjected at the last 3 days of lactation to Morris water maze and three chamber sociability test then decapitated and the brain was excised and dissected to the cortex, hippocampus, cerebellum, midbrain and pons for the determination of norepinephrine, dopamine and serotonin (NE, DA and 5-HT) and cortex amino acids and whole brain BDNF. The results showed similar social and learning and memory behavioral deficits in VA rat model and the butyl paraben offspring in comparison with the controls. Also, some similar alterations were observed in monoamine content, amino acids and BDNF factor in the autistic-like model and butyl paraben offspring in comparison with the controls. The alterations were recorded notably in hippocampus and pons NE, midbrain DA, hippocampus and midbrain 5-HT, and frontal cortex GABA and asparagine. These data suggest that prenatal exposure to butyl paraben induced neuro-developmental disorders similar to some of the neurodevelopmental disorders observed in the VA model of autism. © 2013 Elsevier Inc. All rights reserved.

Ultrasonographic prenatal diagnosis of microcephalic osteodysplastic primordial dwarfism types I/III.

PubMed

Nadjari, M; Fasouliotis, S J; Ariel, I; Raas-Rothschild, A; Bar-Ziv, J; Elchalal, U

2000-08-01

Microcephalic osteodysplastic primordial dwarfism is a rare disease characterized by unique clinical appearance and specific radiographic findings, and distinctive brain abnormalities. We describe the prenatal diagnosis of two siblings with microcephalic osteodysplastic primordial dwarfism types I/III at 23 and 26 weeks of gestation, respectively. Early detection by sequential antenatal sonographic evaluation is important for counselling families known to be at risk of this rare disease. Copyright 2000 John Wiley & Sons, Ltd.

Neurodevelopmental delay with critical congenital heart disease is mainly from prenatal injury not infant cardiac surgery: current evidence based on a meta-analysis of functional magnetic resonance imaging.

PubMed

Li, Y; Yin, S; Fang, J; Hua, Y; Wang, C; Mu, D; Zhou, K

2015-06-01

No consensus has been reached regarding whether brain injury related to congenital heart disease (CHD) is caused by infant cardiac surgery and/or prenatal injury resulting from the CHD. We performed this meta-analysis to identify the likely cause of neurodevelopmental delay in CHD patients. We carried out a literature search without language restriction in December 2013, retrieving records from PubMed, EMBASE, the Cochrane Library and the World Health Organization trials center, to identify studies applying functional magnetic resonance imaging (fMRI) evaluation of brain function before surgery and, in some cases, after surgery (both immediate term and short term postoperatively). The preoperative and postoperative fMRI results were extracted, and meta-analysis was performed using Revman 5.1.1 and STATA 11.0, according to the guidelines from the Cochrane review and MOOSE groups. The electronic search yielded 937 citations. Full text was retrieved for 15 articles and eight articles (nine studies) were eligible for inclusion: six studies (n = 312 cases) with fMRI analysis before surgery and three (n = 36 cases) with complete perioperative fMRI analysis. The overall average diffusivity of CHD cases was significantly higher than that of controls, with a summarized standard (std) mean difference of 1.39 (95% CI, 0.70-2.08), and the fractional anisotropy was lower in CHD cases, with a summarized mean difference of -1.43 (95% CI, -1.95 to -0.91). N-acetylaspartate (NAA)/choline (Cho) for the whole brain was significantly lower in CHD cases compared with healthy ones, while lactate/Cho was significantly higher in CHD cases. Immediate term postoperatively, significant changes in NAA/creatine and NAA/Cho, relative to preoperative values, were found. However, the difference did not persist at the short-term follow-up. This meta-analysis suggests that the delay in neurological development in newborns with CHD is due mainly to prenatal injury, and cardiac surgery might lead to mild brain injuries postoperatively, but fMRI shows recovery within a short period. Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.

Electromagnetic field and brain development.

PubMed

Kaplan, Suleyman; Deniz, Omur Gulsum; Önger, Mehmet Emin; Türkmen, Aysın Pınar; Yurt, Kıymet Kübra; Aydın, Işınsu; Altunkaynak, Berrin Zuhal; Davis, Devra

2016-09-01

Rapid advances in technology involve increased exposures to radio-frequency/microwave radiation from mobile phones and other wireless transmitting devices. As cell phones are held close to the head during talking and often stored next to the reproductive organs, studies are mostly focused on the brain. In fact, more research is especially needed to investigate electromagnetic field (EMF)'s effects on the central nervous system (CNS). Several studies clearly demonstrate that EMF emitted by cell phones could affect a range of body systems and functions. Recent work has demonstrated that EMF inhibit the formation and differentiation of neural stem cells during embryonic development and also affect reproductive and neurological health of adults that have undergone prenatal exposure. The aim of this review is to discuss the developing CNS and explain potential impacts of EMF on this system. Copyright © 2015 Elsevier B.V. All rights reserved.

Prenatal maternal immune activation causes epigenetic differences in adolescent mouse brain

PubMed Central

Basil, P; Li, Q; Dempster, E L; Mill, J; Sham, P-C; Wong, C C Y; McAlonan, G M

2014-01-01

Epigenetic processes such as DNA methylation have been implicated in the pathophysiology of neurodevelopmental disorders including schizophrenia and autism. Epigenetic changes can be induced by environmental exposures such as inflammation. Here we tested the hypothesis that prenatal inflammation, a recognized risk factor for schizophrenia and related neurodevelopmental conditions, alters DNA methylation in key brain regions linked to schizophrenia, namely the dopamine rich striatum and endocrine regulatory centre, the hypothalamus. DNA methylation across highly repetitive elements (long interspersed element 1 (LINE1) and intracisternal A-particles (IAPs)) were used to proxy global DNA methylation. We also investigated the Mecp2 gene because it regulates transcription of LINE1 and has a known association with neurodevelopmental disorders. Brain tissue was harvested from 6 week old offspring of mice exposed to the viral analog PolyI:C or saline on gestation day 9. We used Sequenom EpiTYPER assay to quantitatively analyze differences in DNA methylation at IAPs, LINE1 elements and the promoter region of Mecp2. In the hypothalamus, prenatal exposure to PolyI:C caused significant global DNA hypomethylation (t=2.44, P=0.019, PolyI:C mean 69.67%, saline mean 70.19%), especially in females, and significant hypomethylation of the promoter region of Mecp2, (t=3.32, P=0.002; PolyI:C mean 26.57%, saline mean 34.63%). IAP methylation was unaltered. DNA methylation in the striatum was not significantly altered. This study provides the first experimental evidence that exposure to inflammation during prenatal life is associated with epigenetic changes, including Mecp2 promoter hypomethylation. This suggests that environmental and genetic risk factors associated with neurodevelopmental disorders may act upon similar pathways. This is important because epigenetic changes are potentially modifiable and their investigation may open new avenues for treatment. PMID:25180573

Moderate Perinatal Choline Deficiency Elicits Altered Physiology and Metabolomic Profiles in the Piglet.

PubMed

Getty, Caitlyn M; Dilger, Ryan N

2015-01-01

Few studies have evaluated the impact of dietary choline on the health and well-being of swine, and those pivotal papers were aimed at determining dietary requirements for sows and growing pigs. This is of importance as the piglet is becoming a widely accepted model for human infant nutrition, but little is known about the impacts of perinatal choline status on overall health and metabolism of the growing piglet. In the present study, sows were provided either a choline deficient (CD, 625 mg choline/kg dry matter) or choline sufficient (CS, 1306 mg choline/kg dry matter) diet for the last 65 d of gestation (prenatal intervention). Piglets were weaned from the sow 48 h after farrowing and provided either a CD (477 mg choline/kg dry matter) or CS (1528 mg choline/kg dry matter) milk replacer (postnatal intervention) for 29 ± 2 d, resulting in a factorial arrangement of 4 treatment (prenatal/postnatal) groups: CS/CS, CS/CD, CD/CS, and CD/CD. Piglet growth was normal for artificially-reared piglets, and was not impacted by perinatal choline status. Piglets receiving the postnatal CD treatment had lower (P < 0.01) plasma choline and choline-containing phospholipid concentrations and higher (P < 0.05) liver enzyme (alkaline phosphatase and gamma-glutamyl transferase) values compared with piglets receiving the postnatal CS treatment. Hepatic lipid content of piglets receiving the postnatal CD treatment was higher (P < 0.01) compared with piglets receiving the postnatal CS treatment. Additionally, postnatally CD piglets had lower (P = 0.01) plasma cholesterol than postnatally CS piglets. Brain development was also impacted by perinatal choline status, with brains of piglets exposed to prenatal CD being smaller (P = 0.01) than those of prenatally CS piglets. These findings support the hypothesis that the piglet is a sensitive model for choline deficiency during the perinatal period. In the present study, piglets exhibited similarities in health markers and metabolomic profiles to rodents and humans when exposed to moderate choline deficiency.

Effects of In utero environment and maternal behavior on neuroendocrine and behavioral alterations in a mouse model of prenatal trauma.

PubMed

Golub, Y; Canneva, F; Funke, R; Frey, S; Distler, J; von Hörsten, S; Freitag, C M; Kratz, O; Moll, G H; Solati, J

2016-11-01

Maternal posttraumatic stress disorder (PTSD) following trauma exposure during pregnancy is associated with an increased risk of affective disorders in children. To investigate the mechanisms by which prenatal trauma and/or maternal PTSD affect brain development and behavior we established a mouse model of prenatal traumatic (PT) experience based on the application of an electric foot shock to C57Bl/6N female mice on the gestational day 12 during their pregnancy. The model is based on a previously validated animal model of PTSD. We found high anxiety levels and poor maternal care along with reduced serum prolactin and increased corticosterone levels in dams following maternal trauma (MT). PT-pups were born smaller and stayed smaller throughout their life. We show increased time and frequency of ultrasonic calls in PT-pups when separated from the mothers on the postnatal day (PND) 9. Cross-fostering experiments reveal lower anxiety levels in PT pups raised by healthy mothers as compared to trauma-naive pups raised by MT-dams. Importantly, the combination of prenatal trauma and being raised by a traumatized mother leads to: (1) the highest corticosterone levels in pups, (2) longest USV-call time and (3) highest anxiety levels in comparison to other experimental groups. Our data indicates a distinct change in maternal care following MT which is possibly associated with trauma-induced decrease in prolactin levels. Furthermore, we show that maternal behavior is crucial for the development of the offspring anxiety and specific aspects in maternal care overwrite to a significant extend the effects of in utero and postnatal environment. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 76: 1254-1265, 2016. © 2016 Wiley Periodicals, Inc.

Schizophrenia Risk Variation in the NRG1 gene Exerts Effects on NRG1-IV Splicing During Fetal and Early Postnatal Human Neocortical Development

PubMed Central

Paterson, Clare; Wang, Yanhong; Kleinman, Joel E.; Law, Amanda J.

2015-01-01

OBJECTIVE Neuregulin 1 (NRG1) is a multifunctional neurotrophin and a critical mediator of neurodevelopment and risk for schizophrenia. NRG1 undergoes extensive alternative splicing, and association of brain NRG1-IV isoform expression with the schizophrenia-risk polymorphism, rs6994992, is a potential molecular mechanism of risk. Novel splice variants of NRG1-IV (NRG1-IVNV), with predicted unique signaling capabilities, have been cloned in fetal brain. Because the developmental expression and genetic regulation of NRG1-IVNV in human brain and relationship to schizophrenia is unknown, the authors investigated the temporal dynamics of NRG1-IVNV transcription, compared to the major NRG1 isoforms (types I-IV), across human prenatal and postnatal prefrontal cortical development and examined the association of rs6994992 with NRG1-IVNV expression. METHOD NRG1, types I-IV and NRG1-IVNV isoform expression was evaluated using quantitative real-time PCR in prefrontal cortex during human fetal brain development (14-39 weeks gestation: N=41) and postnatally through aging (age range 0-83 years: N=195). The association of rs6994992 genotype with NRG1-IVNV expression was determined. In-vitro assays were performed to determine the subcellular distribution and proteolytic processing of NRG1-IVNV isoforms. RESULTS Expression of NRG1, types I, II, III was temporally regulated during human prenatal and postnatal neocortical development and the trajectory of NRG1-IVNV was unique, being expressed from 16 weeks gestation until 3 years of age, after which it was undetectable. NRG1-IVNVs expression was associated with rs6994992 genotype, whereby homozygosity for the schizophrenia-risk allele (T) conferred lower cortical NRG1-IVNV levels. Finally, in-vitro cellular assays demonstrate that NRG1-IVNV is a novel nuclear enriched, truncated NRG1 protein that is resistant to proteolytic processing. CONCLUSION This study provides the first quantitative map of NRG1 isoform expression during human neocortical development and aging and identifies a potential mechanism of early developmental risk for schizophrenia at the NRG1 locus, involving a novel class of NRG1 proteins. PMID:24935406

Imaging the fetal central nervous system

PubMed Central

De Keersmaecker, B.; Claus, F.; De Catte, L.

2011-01-01

The low prevalence of fetal central nervous system anomalies results in a restricted level of exposure and limited experience for most of the obstetricians involved in prenatal ultrasound. Sonographic guidelines for screening the fetal brain in a systematic way will probably increase the detection rate and enhance a correct referral to a tertiary care center, offering the patient a multidisciplinary approach of the condition. This paper aims to elaborate on prenatal sonographic and magnetic resonance imaging (MRI) diagnosis and outcome of various central nervous system malformations. Detailed neurosonographic investigation has become available through high resolution vaginal ultrasound probes and the development of a variety of 3D ultrasound modalities e.g. ultrasound tomographic imaging. In addition, fetal MRI is particularly helpful in the detection of gyration and neurulation anomalies and disorders of the gray and white matter. PMID:24753859

Effects of prenatal stress on anxiety- and depressive-like behaviors are sex-specific in prepubertal rats.

PubMed

Iturra-Mena, Ann Mary; Arriagada-Solimano, Marcia; Luttecke-Anders, Ariane; Dagnino-Subiabre, Alexies

2018-05-17

The fetal brain is highly susceptible to stress in late pregnancy, with lifelong effects of stress on physiology and behavior. The aim of this study was to determine the physiological and behavioral effects of prenatal stress during the prepubertal period of female and male rats. We subjected pregnant Sprague-Dawley rats to a restraint stress protocol from gestational day 14 until 21, a critical period for fetal brain susceptibility to stress effects. Male and female offspring were subsequently assessed at postnatal day 24 for anxiety- and depressive-like behaviors, and spontaneous social interaction. We also assessed maternal behaviors and two stress markers: basal vs. acute-evoked stress levels of serum corticosterone and body weight gain. Prenatal stress did not affect the maternal behavior, while both female and male offspring had higher body weight gain. On the other hand, lower levels of corticosterone after acute stress stimulation as well as anxiety- and depressive-like behaviors were only evident in stressed males compared to control males. These results suggest that prenatal stress induced sex-specific effects on the hypothalamus-pituitary-adrenal (HPA) axis activity and on behavior during prepuberty. The HPA axis of prenatally stressed male rats was less active compared to control males, as well as they were more anxious and experienced depressive-like behaviors. Our results can be useful to study the neurobiological basis of childhood depression at a pre-clinical level. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Unusual association of SCN2A epileptic encephalopathy with severe cortical dysplasia detected by prenatal MRI.

PubMed

Bernardo, Silvia; Marchionni, Enrica; Prudente, Sabrina; De Liso, Paola; Spalice, Alberto; Giancotti, Antonella; Manganaro, Lucia; Pizzuti, Antonio

2017-05-01

We present an atypical association of SCN2A epileptic encephalopathy with severe cortical dysplasia. SCN2A mutations are associated with epileptic syndromes from benign to extremely severe in absence of such macroscopic brain findings. Prenatal MRI (Magnetic Resonance Imaging) in a 32 weeks fetus, with US (Ultrasonography) diagnosis of isolated ventriculomegaly showed CNS (Central Nervous System) dysplasia characterized by lack of differentiation between cortical and subcortical layers, pachygyria and corpus callosum dysgenesis. Postnatal MRI confirmed the prenatal findings. On day 6 the baby presented a focal status epilepticus, partially controlled by phenobarbital, phenytoin, and levetiracetam. After three weeks a moderate improvement in seizure control has been achieved with carbamazepine. Exome sequencing detected a de novo heterozygous mutation in the SCN2A gene, encoding the α II -subunit of a sodium channel. The patient findings expand the phenotype spectrum of SCN2A mutations to epileptic encephalopathies with macroscopic brain developmental features. Copyright © 2017 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Reduced expression of brain cannabinoid receptor 1 (Cnr1) is coupled with an increased complementary micro-RNA (miR-26b) in a mouse model of fetal alcohol spectrum disorders.

PubMed

Stringer, Randa L; Laufer, Benjamin I; Kleiber, Morgan L; Singh, Shiva M

2013-08-02

Prenatal alcohol exposure is known to result in fetal alcohol spectrum disorders, a continuum of physiological, behavioural, and cognitive phenotypes that include increased risk for anxiety and learning-associated disorders. Prenatal alcohol exposure results in life-long disorders that may manifest in part through the induction of long-term gene expression changes, potentially maintained through epigenetic mechanisms. Here we report a decrease in the expression of Canabinoid receptor 1 (Cnr1) and an increase in the expression of the regulatory microRNA miR-26b in the brains of adult mice exposed to ethanol during neurodevelopment. Furthermore, we show that miR-26b has significant complementarity to the 3'-UTR of the Cnr1 transcript, giving it the potential to bind and reduce the level of Cnr1 expression. These findings elucidate a mechanism through which some genes show long-term altered expression following prenatal alcohol exposure, leading to persistent alterations to cognitive function and behavioural phenotypes observed in fetal alcohol spectrum disorders.

Chronic Allopurinol Treatment during the Last Trimester of Pregnancy in Sows: Effects on Low and Normal Birth Weight Offspring

PubMed Central

Gieling, Elise T.; Antonides, Alexandra; Fink-Gremmels, Johanna; ter Haar, Kim; Kuller, Wikke I.; Meijer, Ellen; Nordquist, Rebecca E.; Stouten, Jacomijn M.; Zeinstra, Elly; van der Staay, Franz Josef

2014-01-01

Low-birth-weight (LBW) children are born with several risk factors for disease, morbidity and neonatal mortality, even if carried to term. Placental insufficiency leading to hypoxemia and reduced nutritional supply is the main cause for LBW. Brain damage and poor neurological outcome can be the consequence. LBW after being carried to term gives better chances for survival, but these children are still at risk for poor health and the development of cognitive impairments. Preventive therapies are not yet available. We studied the risk/efficacy of chronic prenatal treatment with the anti-oxidative drug allopurinol, as putative preventive treatment in piglets. LBW piglets served as a natural model for LBW. A cognitive holeboard test was applied to study the learning and memory abilities of these allopurinol treated piglets after weaning. Preliminary analysis of the plasma concentrations in sows and their piglets suggested that a daily dose of 15 mg.kg−1 resulted in effective plasma concentration of allopurinol in piglets. No adverse effects of chronic allopurinol treatment were found on farrowing, birth weight, open field behavior, learning abilities, relative brain, hippocampus and spleen weights. LBW piglets showed increased anxiety levels in an open field test, but cognitive performance was not affected by allopurinol treatment. LBW animals treated with allopurinol showed the largest postnatal compensatory body weight gain. In contrast to a previous study, no differences in learning abilities were found between LBW and normal-birth-weight piglets. This discrepancy might be attributable to experimental differences. Our results indicate that chronic prenatal allopurinol treatment during the third trimester of pregnancy is safe, as no adverse side effects were observed. Compensatory weight gain of treated piglets is a positive indication for the chronic prenatal use of allopurinol in these animals. Further studies are needed to assess the possible preventive effects of allopurinol on brain functions in LBW piglets. PMID:24466072

Prenatal exposure to paracetamol/acetaminophen and precursor aniline impairs masculinisation of male brain and behaviour.

PubMed

Hay-Schmidt, Anders; Finkielman, Olivia T Ejlstrup; Jensen, Benjamin A H; Høgsbro, Christine F; Bak Holm, Jacob; Johansen, Kristoffer Haurum; Jensen, Tina Kold; Andrade, Anderson Martino; Swan, Shanna H; Bornehag, Carl-Gustaf; Brunak, Søren; Jegou, Bernard; Kristiansen, Karsten; Kristensen, David Møbjerg

2017-08-01

Paracetamol/acetaminophen (N-Acetyl-p-Aminophenol; APAP) is the preferred analgesic for pain relief and fever during pregnancy. It has therefore caused concern that several studies have reported that prenatal exposure to APAP results in developmental alterations in both the reproductive tract and the brain. Genitals and nervous system of male mammals are actively masculinised during foetal development and early postnatal life by the combined actions of prostaglandins and androgens, resulting in the male-typical reproductive behaviour seen in adulthood. Both androgens and prostaglandins are known to be inhibited by APAP. Through intrauterine exposure experiments in C57BL/6 mice, we found that exposure to APAP decreased neuronal number in the sexually dimorphic nucleus (SDN) of the preoptic area (POA) in the anterior hypothalamus of male adult offspring. Likewise, exposure to the environmental pollutant and precursor of APAP, aniline, resulted in a similar reduction. Decrease in neuronal number in the SDN-POA is associated with reductions in male sexual behaviour. Consistent with the changes, male mice exposed in uteri to APAP exhibited changes in urinary marking behaviour as adults and had a less aggressive territorial display towards intruders of the same gender. Additionally, exposed males had reduced intromissions and ejaculations during mating with females in oestrus. Together, these data suggest that prenatal exposure to APAP may impair male sexual behaviour in adulthood by disrupting the sexual neurobehavioral programming. These findings add to the growing body of evidence suggesting the need to limit the widespread exposure and use of APAP by pregnant women. © 2017 Society for Reproduction and Fertility.

Prenatal Dexamethasone, as Used in Preterm Labor, Worsens the Impact of Postnatal Chlorpyrifos Exposure on Serotonergic Pathways

PubMed Central

Slotkin, Theodore A.; Card, Jennifer; Seidler, Frederic J.

2014-01-01

This study explores how glucocorticoids sensitize the developing brain to the organophosphate pesticide, chlorpyrifos. Pregnant rats received a standard therapeutic dose (0.2 mg/kg) of dexamethasone on gestational days 17–19; pups were given subtoxic doses of chlorpyrifos on postnatal days 1–4, (1 mg/kg, <10% cholinesterase inhibition). We evaluated serotonin (5HT) synaptic function from postnatal day 30 to day 150, assessing the expression of 5HT receptors and the 5HT transporter, along with 5HT turnover (index of presynaptic impulse activity) in brain regions encompassing all the 5HT projections and cell bodies. These parameters are known targets for neurodevelopmental effects of dexamethasone and chlorpyrifos individually. In males, chlorpyrifos evoked overall elevations in the expression of 5HT synaptic proteins, with a progressive increase from adolescence to adulthood; this effect was attenuated by prenatal dexamethasone treatment. The chlorpyrifos-induced upregulation was preceded by deficits in 5HT turnover, indicating that the receptor upregulation was an adaptive response to deficient presynaptic activity. Turnover deficiencies were magnified by dexamethasone pretreatment, worsening the functional impairment caused by chlorpyrifos. In females, chlorpyrifos-induced receptor changes reflected relative sparing of adverse effects compared to males. Nevertheless, prenatal dexamethasone still worsened the 5HT turnover deficits and reduced 5HT receptor expression in females, demonstrating the same adverse interaction. Glucocorticoids are used in 10% of U.S. pregnancies, and are also elevated in maternal stress; accordingly, our results indicate that this group represents a large subpopulation that may have heightened vulnerability to developmental neurotoxicants such as the organophosphates. PMID:24280657

Prenatal marijuana exposure impacts executive functioning into young adulthood: An fMRI study.

PubMed

Smith, Andra M; Mioduszewski, Ola; Hatchard, Taylor; Byron-Alhassan, Aziza; Fall, Carley; Fried, Peter A

Understanding the potentially harmful long term consequences of prenatal marijuana exposure is important given the increase in number of pregnant women smoking marijuana to relieve morning sickness. Altered executive functioning is one area of research that has suggested negative consequences of prenatal marijuana exposure into adolescence. Investigating if these findings continue into young adulthood and exploring the neural basis of these effects was the purpose of this research. Thirty one young adults (ages 18-22years) from the longitudinal Ottawa Prenatal Prospective Study (OPPS) underwent functional magnetic resonance imaging (fMRI) during four tasks; 1) Visuospatial 2-Back, 2) Go/NoGo, 3) Letter 2-Back and 4) Counting Stroop task. Sixteen participants were prenatally exposed to marijuana while 15 had no prenatal marijuana exposure. Task performance was similar for both groups but blood flow was significantly different between the groups. This paper presents the results for all 4 tasks, highlighting the consistently increased left posterior brain activity in the prenatally exposed group compared with the control group. These alterations in neurophysiological functioning of young adults prenatally exposed to marijuana emphasizes the importance of education for women in child bearing years, as well as for policy makers and physicians interested in the welfare of both the pregnant women and their offspring's future success. Copyright © 2016 Elsevier Inc. All rights reserved.

Disruption of Fetal Hormonal Programming (Prenatal Stress) Implicates Shared Risk for Sex Differences in Depression and Cardiovascular Disease

PubMed Central

Goldstein, JM; Handa, RJ; Tobet, SA

2014-01-01

Comorbidity of major depressive disorder (MDD) and cardiovascular disease (CVD) represents the fourth leading cause of morbidity and mortality worldwide, and women have a two times greater risk than men. Thus understanding the pathophysiology has widespread implications for attenuation and prevention of disease burden. We suggest that sex-dependent MDD-CVD comorbidity may result from alterations in fetal programming consequent to the prenatal maternal environments that produce excess glucocorticoids, which then drive sex-dependent developmental alterations of the fetal hypothalamic-pituitary-adrenal (HPA) axis circuitry impacting mood, stress regulation, autonomic nervous system (ANS), and the vasculature in adulthood. Evidence is consistent with the hypothesis that disruptions of pathways associated with gamma aminobutyric acid (GABA) in neuronal and vascular development and growth factors have critical roles in key developmental periods and adult responses to injury in heart and brain. Understanding the potential fetal origins of these sex differences will contribute to development of novel sex-dependent therapeutics. PMID:24355523

Cerebellar level of neurotransmitters in rats exposed to paracetamol during development.

PubMed

Blecharz-Klin, Kamilla; Joniec-Maciejak, Ilona; Jawna-Zboińska, Katarzyna; Pyrzanowska, Justyna; Piechal, Agnieszka; Wawer, Adriana; Widy-Tyszkiewicz, Ewa

2016-12-01

The present study was designed to clarify the effect of prenatal and postnatal paracetamol administration on the neurotransmitter level and balance of amino acids in the cerebellum. Biochemical analysis to determine the concentration of neurotransmitters in this brain structure was performed on two-month-old Wistar male rats previously exposed to paracetamol in doses of 5 (P5, n=10) or 15mg/kg (P15, n=10) throughout the entire prenatal period, lactation and until the completion of the second month of life, when the experiment was terminated. Control animals were given tapped water (Con, n=10). The cerebellar concentration of monoamines, their metabolites and amino acids were assayed using High Performance Liquid Chromatography (HPLC). The present experiment demonstrates that prenatal and postnatal paracetamol exposure results in modulation of cerebellar neurotransmission with changes concerning mainly 5-HIAA and MHPG levels. The effect of paracetamol on monoaminergic neurotransmission in the cerebellum is reflected by changes in the level of catabolic end-products of serotonin (5-HIAA) and noradrenaline (MHPG) degradation. Further work is required to define the mechanism of action and impact of prenatal and postnatal exposure to paracetamol in the cerebellum and other structures of the central nervous system (CNS). Copyright © 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Prenatal choline deficiency does not enhance hippocampal vulnerability after kainic acid-induced seizures in adulthood.

PubMed

Wong-Goodrich, Sarah J E; Tognoni, Christina M; Mellott, Tiffany J; Glenn, Melissa J; Blusztajn, Jan K; Williams, Christina L

2011-09-21

Choline is a vital nutrient needed during early development for both humans and rodents. Severe dietary choline deficiency during pregnancy leads to birth defects, while more limited deficiency during mid- to late pregnancy causes deficits in hippocampal plasticity in adult rodent offspring that are accompanied by cognitive deficits only when task demands are high. Because prenatal choline supplementation confers neuroprotection of the adult hippocampus against a variety of neural insults and aids memory, we hypothesized that prenatal choline deficiency may enhance vulnerability to neural injury. To examine this, adult offspring of rat dams either fed a control diet (CON) or one deficient in choline (DEF) during embryonic days 12-17 were given multiple injections (i.p.) of saline (control) or kainic acid to induce seizures and were euthanized 16 days later. Perhaps somewhat surprisingly, DEF rats were not more susceptible to seizure induction and showed similar levels of seizure-induced hippocampal histopathology, GAD expression loss, upregulated hippocampal GFAP and growth factor expression, and increased dentate cell and neuronal proliferation as that seen in CON rats. Although prenatal choline deficiency compromises adult hippocampal plasticity in the intact brain, it does not appear to exacerbate the neuropathological response to seizures in the adult hippocampus at least shortly after excitotoxic injury. Copyright © 2011 Elsevier B.V. All rights reserved.

Effects of environmental enrichment on behavioral deficits and alterations in hippocampal BDNF induced by prenatal exposure to morphine in juvenile rats.

PubMed

Ahmadalipour, A; Sadeghzadeh, J; Vafaei, A A; Bandegi, A R; Mohammadkhani, R; Rashidy-Pour, A

2015-10-01

Prenatal morphine exposure throughout pregnancy can induce a series of neurobehavioral and neurochemical disturbances by affecting central nervous system development. This study was designed to investigate the effects of an enriched environment on behavioral deficits and changes in hippocampal brain-derived neurotrophic factor (BDNF) levels induced by prenatal morphine in rats. On pregnancy days 11-18, female Wistar rats were randomly injected twice daily with saline or morphine. Offspring were weaned on postnatal day (PND) 21. They were subjected to a standard rearing environment or an enriched environment on PNDs 22-50. On PNDs 51-57, the behavioral responses including anxiety and depression-like behaviors, and passive avoidance memory as well as hippocampal BDNF levels were investigated. The light/dark (L/D) box and elevated plus maze (EPM) were used for the study of anxiety, forced swimming test (FST) was used to assess depression-like behavior and passive avoidance task was used to evaluate learning and memory. Prenatal morphine exposure caused a reduction in time spent in the EPM open arms and a reduction in time spent in the lit side of the L/D box. It also decreased step-through latency and increased time spent in the dark side of passive avoidance task. Prenatal morphine exposure also reduced immobility time and increased swimming time in FST. Postnatal rearing in an enriched environment counteracted with behavioral deficits in the EPM and passive avoidance task, but not in the L/D box. This suggests that exposure to an enriched environment during adolescence period alters anxiety profile in a task-specific manner. Prenatal morphine exposure reduced hippocampal BDNF levels, but enriched environment significantly increased BDNF levels in both saline- and morphine-exposed groups. Our results demonstrate that exposure to an enriched environment alleviates behavioral deficits induced by prenatal morphine exposure and up-regulates the decreased levels of BDNF. BDNF may contribute to the beneficial effects of an enriched environment on prenatal morphine-exposed to rats. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Mild prenatal protein malnutrition increases alpha 2C-adrenoceptor expression in the rat cerebral cortex during postnatal life.

PubMed

Sierralta, Walter; Hernández, Alejandro; Valladares, Luis; Pérez, Hernán; Mondaca, Mauricio; Soto-Moyano, Rubén

2006-05-15

Mild reduction in the protein content in the diet of pregnant rats from 25 to 8% casein, calorically compensated by carbohydrates, does not alter body and brain weights of rat pups at birth, but results in significant changes of the concentration and release of cortical noradrenaline during postnatal life, together with impaired long-term potentiation and memory formation. Since some central noradrenergic receptors are critically involved in neuroplasticity, the present study evaluated, by utilizing immunohistochemical methods, the effect of mild prenatal protein malnutrition on the alpha 2C-adrenoceptor expression in the frontal and occipital cortices of 8- and 60-day-old rats. At day 8 of postnatal age, prenatally malnourished rats exhibited a three-fold increase of alpha 2C-adrenoceptor expression in both the frontal and the occipital cortices, as compared to well-nourished controls. At 60 days of age, prenatally malnourished rats showed normal expression levels scores of alpha 2C-adrenoceptor in the neocortex. Results suggest that overexpression of neocortical alpha 2C-adrenoceptors during early postnatal life, subsequent to mild prenatal protein malnutrition, could in part be responsible for neural and behavioral disturbances showing prenatally malnourished animals during the postnatal life.

Prenatal arsenic exposure alters the programming of the glucocorticoid signaling system during embryonic development

PubMed Central

Caldwell, Katharine E.; Labrecque, Matthew T.; Solomon, Benjamin R.; Ali, Abdulmehdi; Allan, Andrea M.

2015-01-01

The glucocorticoid system, which plays a critical role in a host of cellular functions including mood disorders and learning and memory, has been reported to be disrupted by arsenic. In previous work we have developed and characterized a prenatal moderate arsenic exposure (50 ppb) model and identified several deficits in learning and memory and mood disorders, as well as alterations within the glucocorticoid receptor signaling system in the adolescent mouse. In these present studies we assessed the effects of arsenic on the glucocorticoid receptor (GR) pathway in both the placenta and the fetal brain in response at two critical periods, embryonic days 14 and 18. The focus of these studies was on the 11β-hydroxysteroid dehydrogenase enzymes (11β-HSD1 and 11β-HSD2) which play a key role in glucorticoid synthesis, as well as the expression and set point of the GR negative feedback regulation. Negative feedback regulation is established early in development. At E14 we found arsenic exposure significantly decreased expression of both protein and message in brain of GR and the 11β-HSD1, while 11β-HSD2 enzyme protein levels were increased but mRNA levels were decreased in the brain. These changes in brain protein continued into the E18 time point, but mRNA levels were no longer significantly altered. Placental HSD11B2 mRNA was not altered by arsenic treatment but protein levels were elevated at E14. GR placental protein levels were decreased at E18 in the arsenic exposed condition. This suggests that arsenic exposure may alter GR expression levels as a consequence of a prolonged developmental imbalance between 11β-HSD1 and 11β-HSD2 protein expression despite decreased 11HSDB2 mRNA. The suppression of GR and the failure to turn down 11β-HSD2 protein expression during fetal development may lead to an altered set point for GR signaling throughout adulthood. To our knowledge, these studies are the first to demonstrate that gestational exposure to moderate levels of arsenic results in altered fetal programming of the glucocorticoid system. PMID:25459689

Effect of growth hormone deficiency on brain MRI findings among children with growth restrictions.

PubMed

Naderi, Fariba; Eslami, Samira Rajabi; Mirak, Sohrab Afshari; Khak, Mohammad; Amiri, Jalaladin; Beyrami, Bahram; Shekarchi, Babak; Poureisa, Masoud

2015-01-01

Growth hormone deficiency (GHD) is a major problem among children with short stature. In this study, the role of brain magnetic resonance imaging (MRI) in defining the underlying defects among short children with GHD is evaluated. In a cross-sectional study, data of 158 children were evaluated. Growth hormone (GH) levels were measured using stimulating tests and brain MRI with gadolinium contrast was applied, as well. Some 25.3% of patients had GHD with a mean age of 8.01±3.40 years. MRI results showed 35 as normal, four with pituitary hypoplasia, and one with microadenoma. The MRI results were significantly associated with GH levels and presence of other endocrine disorders. There was a significant association between prenatal disorders and patients' bone age delay. In patients with severe GHD and patients with multiple pituitary hormone deficiencies, MRI is more likely to be abnormal, and bone age is much delayed in patients with history of prenatal disorders.

Is fetal brain monoamine oxidase inhibition the missing link between maternal smoking and conduct disorders?

PubMed Central

Baler, Ruben D.; Volkow, Nora D.; Fowler, Joanna S.; Benveniste, Helene

2008-01-01

Smoking is the leading cause of preventable illness in the world today. Prenatal cigarette smoke exposure (PCSE) is a particularly insidious form because so many of its associated health effects befall the unborn child and produce behavioural outcomes that manifest themselves only years later. Among these are the associations between PCSE and conduct disorders, which have been mostly ascribed to the deleterious effects of nicotine on the fetal brain. Here we hypothesize that inhibition of brain monoamine oxidase (MAO) during fetal brain development, secondary to maternal cigarette smoking and in addition to nicotine, is a likely contributor to this association. MAOs play a central role in monoaminergic balance in the brain, and their inhibition during fetal development — but not during adult life — is known to result in an aggressive phenotype in laboratory animals. This paper provides theoretical and experimental support for the notion that cigarette smoke–induced inhibition of MAO in the fetal brain, particularly when it occurs in combination with polymorphisms in the MAOA gene that lead to lower enzyme concentration in the brain, may result in brain morphologic and functional changes that enhance the risk of irritability, poor self-control and aggression in the offspring. It also encourages research to evaluate whether the interaction of smoking exposure during fetal development and MAOA genotype increases the risk for conduct disorder over that incurred by mere fetal exposure to tobacco smoke. PMID:18592036

Testing the Language of German Cerebral Palsy Patients with Right Hemispheric Language Organization after Early Left Hemispheric Damage

ERIC Educational Resources Information Center

Schwilling, Eleonore; Krageloh-Mann, Ingeborg; Konietzko, Andreas; Winkler, Susanne; Lidzba, Karen

2012-01-01

Language functions are generally represented in the left cerebral hemisphere. After early (prenatally acquired or perinatally acquired) left hemispheric brain damage language functions may be salvaged by reorganization into the right hemisphere. This is different from brain lesions acquired in adulthood which normally lead to aphasia. Right…

Prenatal Exposure to DEHP Induces Neuronal Degeneration and Neurobehavioral Abnormalities in Adult Male Mice.

PubMed

Barakat, Radwa; Lin, Po-Ching; Park, Chan Jin; Best-Popescu, Catherine; Bakery, Hatem H; Abosalum, Mohamed E; Abdelaleem, Nabila M; Flaws, Jodi A; Ko, CheMyong

2018-04-23

Phthalates are a family of synthetic chemicals that are used in producing a variety of consumer products. Di-(2-ethylhexyl) phthalate (DEHP) is an widely used phthalate and poses a public health concern. Prenatal exposure to DEHP has been shown to induce premature reproductive senescence in animal studies. In this study, we tested the hypothesis that prenatal exposure to DEHP impairs neurobehavior and recognition memory in her male offspring and we investigated one possible mechanism-oxidative damage in the hippocampus. Pregnant CD-1 female mice were orally administered 200μg, 500mg, or 750mg/kg/day DEHP or vehicle from gestational day 11 until birth. The neurobehavioral impact of the prenatal DEHP exposure was assessed at the ages of 16 to 22 months. Elevated plus maze and open field tests were used to measure anxiety levels. Y-maze and novel object recognition tests were employed to measure memory function. The oxidative damage in the hippocampus was measured by the levels of oxidative DNA damage and by SLIM microscopic counting of hippocampal neurons. Adult male mice that were prenatally exposed to DEHP exhibited anxious behaviors and impaired spatial and short-term recognition memory. The number of hippocampal pyramidal neurons was significantly decreased in the DEHP mice. Furthermore, DEHP mice expressed remarkably high levels of cyclooxygenase-2, 8-hydroxyguanine, and thymidine glycol in their hippocampal neurons. DEHP mice also had lower circulating testosterone concentrations and displayed a weaker immunoreactivity than the control mice to androgen receptor expression in the brain. This study found that prenatal exposure to DEHP caused elevated anxiety behavior and impaired recognition memory. These behavioral changes may originate from neurodegeneration caused by oxidative damage and inflammation in the hippocampus. Decreased circulating testosterone concentrations and decreased expression of androgen receptor in the brain also may be factors contributing to the impaired neurobehavior in the DEHP mice.

A prospective study of fetal head growth, autistic traits and autism spectrum disorder.

PubMed

Blanken, Laura M E; Dass, Alena; Alvares, Gail; van der Ende, Jan; Schoemaker, Nikita K; El Marroun, Hanan; Hickey, Martha; Pennell, Craig; White, Scott; Maybery, Murray T; Dissanayake, Cheryl; Jaddoe, Vincent W V; Verhulst, Frank C; Tiemeier, Henning; McIntosh, Will; White, Tonya; Whitehouse, Andrew

2018-04-01

Altered trajectories of brain growth are often reported in Autism Spectrum Disorder (ASD), particularly during the first year of life. However, less is known about prenatal head growth trajectories, and no study has examined the relation with postnatal autistic symptom severity. The current study prospectively examined the association between fetal head growth and the spectrum of autistic symptom severity in two large population-based cohorts, including a sample of individuals with clinically diagnosed ASD. This study included 3,820 children from two longitudinal prenatal cohorts in The Netherlands and Australia, comprising 60 individuals with a confirmed diagnosis of ASD. Latent growth curve models were used to examine the relationship between fetal head circumference measured at three different time points and autistic traits measured in postnatal life using either the Social Responsiveness Scale or the Autism-Spectrum Quotient. While lower initial prenatal HC was weakly associated with increasing autistic traits in the Dutch cohort, this relationship was not observed in the Australian cohort, nor when the two cohorts were analysed together. No differences in prenatal head growth were found between individuals with ASD and controls. This large population-based study identified no consistent association across two cohorts between prenatal head growth and postnatal autistic traits. Our mixed findings suggest that further research in this area is needed. Autism Res 2018, 11: 602-612. © 2018 The Authors Autism Research published by International Society for Autism Research and Wiley Periodicals, Inc. It is not known whether different patterns of postnatal brain growth in Autism Spectrum Disorder (ASD) also occurs prenatally. We examined fetal head growth and autistic symptoms in two large groups from The Netherlands and Australia. Lower initial prenatal head circumference was associated with autistic traits in the Dutch, but not the Australian, group. No differences in head growth were found in individuals with ASD and controls when the data was combined. Our mixed findings suggest that more research in this area is needed. © 2018 The Authors Autism Research published by International Society for Autism Research and Wiley Periodicals, Inc.

Ethanol-Induced Neurodegeneration and Glial Activation in the Developing Brain.

PubMed

Saito, Mariko; Chakraborty, Goutam; Hui, Maria; Masiello, Kurt; Saito, Mitsuo

2016-08-16

Ethanol induces neurodegeneration in the developing brain, which may partially explain the long-lasting adverse effects of prenatal ethanol exposure in fetal alcohol spectrum disorders (FASD). While animal models of FASD show that ethanol-induced neurodegeneration is associated with glial activation, the relationship between glial activation and neurodegeneration has not been clarified. This review focuses on the roles of activated microglia and astrocytes in neurodegeneration triggered by ethanol in rodents during the early postnatal period (equivalent to the third trimester of human pregnancy). Previous literature indicates that acute binge-like ethanol exposure in postnatal day 7 (P7) mice induces apoptotic neurodegeneration, transient activation of microglia resulting in phagocytosis of degenerating neurons, and a prolonged increase in glial fibrillary acidic protein-positive astrocytes. In our present study, systemic administration of a moderate dose of lipopolysaccharides, which causes glial activation, attenuates ethanol-induced neurodegeneration. These studies suggest that activation of microglia and astrocytes by acute ethanol in the neonatal brain may provide neuroprotection. However, repeated or chronic ethanol can induce significant proinflammatory glial reaction and neurotoxicity. Further studies are necessary to elucidate whether acute or sustained glial activation caused by ethanol exposure in the developing brain can affect long-lasting cellular and behavioral abnormalities observed in the adult brain.

Exposure to prenatal psychobiological stress exerts programming influences on the mother and her fetus.

PubMed

Sandman, Curt A; Davis, Elysia P; Buss, Claudia; Glynn, Laura M

2012-01-01

Accumulating evidence from a relatively small number of prospective studies indicates that exposure to prenatal stress profoundly influences the developing human fetus with consequences that persist into childhood and very likely forever. Maternal/fetal dyads are assessed at ∼20, ∼25, ∼31 and ∼36 weeks of gestation. Infant assessments begin 24 h after delivery with the collection of cortisol and behavioral responses to the painful stress of the heel-stick procedure and measures of neonatal neuromuscular maturity. Infant cognitive, neuromotor development, stress and emotional regulation are evaluated at 3, 6 12 and 24 months of age. Maternal psychosocial stress and demographic information is collected in parallel with infant assessments. Child neurodevelopment is assessed with cognitive tests, measures of adjustment and brain imaging between 5 and 8 years of age. Psychobiological markers of stress during pregnancy, especially early in gestation, result in delayed fetal maturation, disrupted emotional regulation and impaired cognitive performance during infancy and decreased brain volume in areas associated with learning and memory in 6- to 8-year-old children. We review findings from our projects that maternal endocrine alterations that accompany pregnancy and influence fetal/infant/child development are associated with decreased affective responses to stress, altered memory function and increased risk for postpartum depression. Our findings indicate that the mother and her fetus both are influenced by exposure to psychosocial and biological stress. The findings that fetal and maternal programming occur in parallel may have important implications for long-term child development and mother/child interactions. Copyright © 2011 S. Karger AG, Basel.

Can cognitive deterioration associated with Down syndrome be reduced?

PubMed

Thiel, R; Fowkes, S W

2005-01-01

Individuals with Down syndrome have signs of possible brain damage prior to birth. In addition to slowed and reduced mental development, they are much more likely to have cognitive deterioration and develop dementia at an earlier age than individuals without Down syndrome. Some of the cognitive impairments are likely due to post-natal hydrogen peroxide-mediated oxidative stress caused by overexpression of the superoxide dismutase (SOD-1) gene, which is located on the triplicated 21st chromosome and known to be 50% overexpressed. However, some of this disability may also be due to early accumulation of advanced protein glycation end-products, which may play an adverse role in prenatal and postnatal brain development. This paper suggests that essential nutrients such as folate, vitamin B6, vitamin C, vitamin E, selenium, and zinc, as well as alpha-lipoic acid and carnosine may possibly be partially preventive. Acetyl-L-carnitine, aminoguanidine, cysteine, and N-acetylcysteine are also discussed, but have possible safety concerns for this population. This paper hypothesizes that nutritional factors begun prenatally, in early infancy, or later may prevent or delay the onset of dementia in the Down syndrome population. Further examination of these data may provide insights into nutritional, metabolic and pharmacological treatments for dementias of many kinds. As the Down syndrome population may be the largest identifiable group at increased risk for developing dementia, clinical research to verify the possible validity of the prophylactic use of anti-glycation nutrients should be performed. Such research might also help those with glycation complications associated with diabetes or Alzheimer's.

Exposure to Low Levels of Lead in Utero and Umbilical Cord Blood DNA Methylation in Project Viva: An Epigenome-Wide Association Study

PubMed Central

Hivert, Marie-France; Cardenas, Andres; Zhong, Jia; Rifas-Shiman, Sheryl L.; Agha, Golareh; Colicino, Elena; Just, Allan C.; Amarasiriwardena, Chitra; Lin, Xihong; Litonjua, Augusto A.; DeMeo, Dawn L.; Gillman, Matthew W.; Wright, Robert O.; Oken, Emily

2017-01-01

Background: Early-life exposure to lead is associated with deficits in neurodevelopment and with hematopoietic system toxicity. DNA methylation may be one of the underlying mechanisms for the adverse effects of prenatal lead on the offspring, but epigenome-wide methylation data for low levels of prenatal lead exposure are lacking. Objectives: We investigated the association between prenatal maternal lead exposure and epigenome-wide DNA methylation in umbilical cord blood nucleated cells in Project Viva, a prospective U.S.-based prebirth cohort with relatively low levels of lead exposure. Methods: Among 268 mother–infant pairs, we measured lead concentrations in red blood cells (RBC) from prenatal maternal blood samples, and using HumanMethylation450 Bead Chips, we measured genome-wide methylation levels at 482,397 CpG loci in umbilical cord blood and retained 394,460 loci after quality control. After adjustment for batch effects, cell types, and covariates, we used robust linear regression models to examine associations of prenatal lead exposure with DNA methylation in cord blood at epigenome-wide significance level [false discovery rate (FDR)<0.05]. Results: The mean [standard deviation (SD)] maternal RBC lead level was 1.22 (0.63) μg/dL. CpG cg10773601 showed an epigenome-wide significant negative association with prenatal lead exposure (−1.4% per doubling increase in lead exposure; p=2.3×10−7) and was annotated to C-Type Lectin Domain Family 11, Member A (CLEC11A), which functions as a growth factor for primitive hematopoietic progenitor cells. In sex-specific analyses, we identified more CpGs with FDR<0.05 among female infants (n=38) than among male infants (n=2). One CpG (cg24637308), which showed a strong negative association with prenatal lead exposure among female infants (−4.3% per doubling increase in lead exposure; p=1.1×10−06), was annotated to Dynein Heavy Chain Domain 1 gene (DNHD1) which is highly expressed in human brain. Interestingly, there were strong correlations between blood and brain methylation for CpG (cg24637308) based on another independent set of samples with a high proportion of female participants. Conclusion: Prenatal low-level lead exposure was associated with newborn DNA methylation, particularly in female infants. https://doi.org/10.1289/EHP1246 PMID:28858830

Exposure to Low Levels of Lead in Utero and Umbilical Cord Blood DNA Methylation in Project Viva: An Epigenome-Wide Association Study.

PubMed

Wu, Shaowei; Hivert, Marie-France; Cardenas, Andres; Zhong, Jia; Rifas-Shiman, Sheryl L; Agha, Golareh; Colicino, Elena; Just, Allan C; Amarasiriwardena, Chitra; Lin, Xihong; Litonjua, Augusto A; DeMeo, Dawn L; Gillman, Matthew W; Wright, Robert O; Oken, Emily; Baccarelli, Andrea A

2017-08-25

Early-life exposure to lead is associated with deficits in neurodevelopment and with hematopoietic system toxicity. DNA methylation may be one of the underlying mechanisms for the adverse effects of prenatal lead on the offspring, but epigenome-wide methylation data for low levels of prenatal lead exposure are lacking. We investigated the association between prenatal maternal lead exposure and epigenome-wide DNA methylation in umbilical cord blood nucleated cells in Project Viva, a prospective U.S.-based prebirth cohort with relatively low levels of lead exposure. Among 268 mother-infant pairs, we measured lead concentrations in red blood cells (RBC) from prenatal maternal blood samples, and using HumanMethylation450 Bead Chips, we measured genome-wide methylation levels at 482,397 CpG loci in umbilical cord blood and retained 394,460 loci after quality control. After adjustment for batch effects, cell types, and covariates, we used robust linear regression models to examine associations of prenatal lead exposure with DNA methylation in cord blood at epigenome-wide significance level [false discovery rate (FDR)<0.05]. The mean [standard deviation (SD)] maternal RBC lead level was 1.22 (0.63) μg/dL. CpG cg10773601 showed an epigenome-wide significant negative association with prenatal lead exposure (-1.4% per doubling increase in lead exposure; p=2.3×10-7) and was annotated to C-Type Lectin Domain Family 11, Member A ( CLEC11A ), which functions as a growth factor for primitive hematopoietic progenitor cells. In sex-specific analyses, we identified more CpGs with FDR<0.05 among female infants (n=38) than among male infants (n=2). One CpG (cg24637308), which showed a strong negative association with prenatal lead exposure among female infants (-4.3% per doubling increase in lead exposure; p=1.1×10-06), was annotated to Dynein Heavy Chain Domain 1 gene ( DNHD1 ) which is highly expressed in human brain. Interestingly, there were strong correlations between blood and brain methylation for CpG (cg24637308) based on another independent set of samples with a high proportion of female participants. Prenatal low-level lead exposure was associated with newborn DNA methylation, particularly in female infants. https://doi.org/10.1289/EHP1246.

Proceedings of the 2017 annual meeting of the Fetal Alcohol Spectrum Disorders study group.

PubMed

Wozniak, Jeffrey R; Klintsova, Anna Y; Hamilton, Derek A; Mooney, Sandra M

2018-06-01

The 2017 Fetal Alcohol Spectrum Disorders Study Group (FASDSG) meeting was titled "Prenatal alcohol exposure in the context of multiple factors affecting brain development." The theme was reflected in the interactions between members of the Teratology Society and the FASDSG this year. The first keynote speaker, Elaine Faustman, Ph.D., was a liaison between the societies and spoke about systems biology and the multiple genetic and environmental influences on development. The second keynote speaker, Rebecca Knickmeyer, Ph.D., discussed population neuroscience and multiple influences on brain development. The conference presented updates from three government agencies and short presentations by junior and senior investigators showcasing late-breaking FASD research. The conference was capped by Dr. John Hannigan, Ph.D., the recipient of the 2017 Henry Rosett award for career-long contributions to the field. Copyright © 2017 Elsevier Inc. All rights reserved.

Developmental Programming: Postnatal Steroids Complete Prenatal Steroid Actions to Differentially Organize the GnRH Surge Mechanism and Reproductive Behavior in Female Sheep

PubMed Central

Jackson, Leslie M.; Mytinger, Andrea; Roberts, Eila K.; Lee, Theresa M.; Foster, Douglas L.; Padmanabhan, Vasantha

2013-01-01

In female sheep, estradiol (E2) stimulates the preovulatory GnRH/LH surge and receptive behavior, whereas progesterone blocks these effects. Prenatal exposure to testosterone disrupts both the positive feedback action of E2 and sexual behavior although the mechanisms remain unknown. The current study tested the hypothesis that both prenatal and postnatal steroids are required to organize the surge and sex differences in reproductive behavior. Our approach was to characterize the LH surge and mating behavior in prenatally untreated (Control) and testosterone-treated (T) female sheep subsequently exposed to one of three postnatal steroid manipulations: endogenous E2, excess E2 from a chronic implant, or no E2 due to neonatal ovariectomy (OVX). All females were then perfused at the time of the expected surge and brains processed for estrogen receptor and Fos immunoreactivity. None of the T females exposed postnatally to E2 exhibited an E2-induced LH surge, but a surge was produced in five of six T/OVX and all Control females. No surges were produced when progesterone was administered concomitantly with E2. All Control females were mounted by males, but significantly fewer T females were mounted by a male, including the T/OVX females that exhibited LH surges. The percentage of estrogen receptor neurons containing Fos was significantly influenced in a brain region-, developmental stage-, and steroid-specific fashion by testosterone and E2 treatments. These findings support the hypothesis that the feedback controls of the GnRH surge are sensitive to programming by prenatal and postnatal steroids in a precocial species. PMID:23417422

Sexual orientation and gender identity after prenatal exposure to the Dutch famine.

PubMed

de Rooij, Susanne R; Painter, Rebecca C; Swaab, Dick F; Roseboom, Tessa J

2009-06-01

Sexual differentiation of the human brain has been suggested to take place through exposure to sex steroids during intrauterine development. Animal experiments have shown that interference in this process by underfeeding of the mother can result in feminization of the male offspring. We explored the possible effects of prenatal exposure to famine on sexual orientation and gender identity in humans. We used the Klein Sexual Orientation Grid to assess sexual orientation and also assessed gender identity in a group of 380 men and 472 women who were born as term singletons around the time of the 1944-1945 Dutch famine. Prenatal exposure to famine did not affect sexual orientation in men or in women. Three people indicated having some gender identity problems: one woman born before the famine and one man and woman exposed to famine in late gestation. In men, a later birth order was associated with a non-exclusively heterosexual identification. In conclusion, we found no evidence for a significant association between exposure to famine in utero and altered sexual orientation and gender identity. The small sample size of participants with non-exclusively heterosexual identification (possibly due to underreporting of homosexuality) may have reduced our power to detect any differences.

Effects of Tianeptine on Adult Rats Following Prenatal Stress

PubMed Central

Lee, Hwayoung; Kim, Hyung-Ki; Kwon, Jun-Tack; Kim, Young Ock; Seo, Jonghoon; Lee, Sanghyun; Cho, Ik-Hyun

2018-01-01

Objective Exposing a pregnant female to stress during the critical period of embryonic fetal brain development increases the risk of psychiatric disorders in the offspring. The objective of this study was to investigate the effect of antidepressant tianeptine on prenatally stressed (PNS) rats. Methods In this study, a repeated variable stress paradigm was applied to pregnant rats during the last week of gestation. To investigate the effects of antidepressant tianeptine on PNS rats, behavioral and protein expression analyses were performed. Forced swim test, open field test, and social interaction test were performed to determine changes in PNS rats compared to non-stressed offspring. Haloperidol was used as a positive control as an antipsychotic drug based on previous studies. Results Behavioral changes were restored after treatment with tianeptine or haloperidol. Western blot and immunohistochemical analyses of the prefrontal cortex revealed downregulation of several neurodevelopmental proteins in PNS rats. After treatment with tianeptine or haloperidol, their expression levels were increased. Conclusion Downregulation of several proteins in PNS rats might have caused subsequent behavioral changes in PNS rats. After tianeptine or haloperidol treatment, behavioral changes in PNS rats were restored. Therefore, tianeptine might decrease incidence of prenatal stress related-psychiatric disorders such as depression and schizophrenia. PMID:29739134

Prevention and schizophrenia--the role of dietary factors.

PubMed

McGrath, John; Brown, Alan; St Clair, David

2011-03-01

Adequate prenatal nutrition is essential for optimal brain development. There is a growing body of evidence from epidemiology linking exposure to nutritional deprivation and increased risk of schizophrenia. Based on studies from the Netherlands and China, those exposed to macronutrient deficiencies during famine have an increased risk of schizophrenia. With respect to micronutrients, we focus on 3 candidates where there is biological plausibility for a role in this disorder and at least 1 study of an association with schizophrenia. These nutrients include vitamin D, folic acid, and iron. While the current evidence is incomplete, we discuss the potential implications of these findings for the prevention of schizophrenia. We argue that schizophrenia can draw inspiration from public health interventions related to prenatal nutrition and other outcomes and speculate on relevant factors that bear on the nature, risks, impact, and logistics of various nutritional strategies that may be employed to prevent this disorder.

A self-medication hypothesis for increased vulnerability to drug abuse in prenatally restraint stressed rats.

PubMed

Reynaert, Marie-Line; Marrocco, Jordan; Gatta, Eleonora; Mairesse, Jérôme; Van Camp, Gilles; Fagioli, Francesca; Maccari, Stefania; Nicoletti, Ferdinando; Morley-Fletcher, Sara

Stress-related events that occur in the perinatal period can permanently change brain and behavior of the developing individual and there is increasing evidence that early-life adversity is a contributing factor in the etiology of drug abuse and mood disorders. Neural adaptations resulting from early-life stress may mediate individual differences in novelty responsiveness and in turn contribute to drug abuse vulnerability. Prenatal restraint stress (PRS) in rats is a well-documented model of early stress known to induce long-lasting neurobiological and behavioral alterations including impaired feedback mechanisms of the HPA axis, enhanced novelty seeking, and increased sensitiveness to psychostimulants as well as anxiety/depression-like behavior. Together with the HPA axis, functional alterations of the mesolimbic dopamine system and of the metabotropic glutamate receptors system appear to be involved in the addiction-like profile of PRS rats.

Moderate prenatal alcohol exposure and quantification of social behavior in adult rats.

PubMed

Hamilton, Derek A; Magcalas, Christy M; Barto, Daniel; Bird, Clark W; Rodriguez, Carlos I; Fink, Brandi C; Pellis, Sergio M; Davies, Suzy; Savage, Daniel D

2014-12-14

Alterations in social behavior are among the major negative consequences observed in children with Fetal Alcohol Spectrum Disorders (FASDs). Several independent laboratories have demonstrated robust alterations in the social behavior of rodents exposed to alcohol during brain development across a wide range of exposure durations, timing, doses, and ages at the time of behavioral quantification. Prior work from this laboratory has identified reliable alterations in specific forms of social interaction following moderate prenatal alcohol exposure (PAE) in the rat that persist well into adulthood, including increased wrestling and decreased investigation. These behavioral alterations have been useful in identifying neural circuits altered by moderate PAE(1), and may hold importance for progressing toward a more complete understanding of the neural bases of PAE-related alterations in social behavior. This paper describes procedures for performing moderate PAE in which rat dams voluntarily consume ethanol or saccharin (control) throughout gestation, and measurement of social behaviors in adult offspring.

Neuronal ceroid lipofuscinoses (NCL)

MedlinePlus

... problems with the brain's ability to remove and recycle proteins. Lipofuscinoses are inherited as autosomal recessive traits. ... is recommended if your family has a known history of NCL. Prenatal tests, or a test called ...

Recalled and current gender role behavior, gender identity and sexual orientation in adults with Disorders/Differences of Sex Development.

PubMed

Callens, Nina; Van Kuyk, Maaike; van Kuppenveld, Jet H; Drop, Stenvert L S; Cohen-Kettenis, Peggy T; Dessens, Arianne B

2016-11-01

The magnitude of sex differences in human brain and behavior and the respective contributions of biology versus socialization remain a topic of ongoing study in science. The preponderance of evidence attests to the notion that sexual differentiation processes are at least partially hormonally mediated, with high levels of prenatal androgens facilitating male-typed and inhibiting female-typed behaviors. In individuals with Disorders/Differences of Sex Development (DSD), hormonal profiles or sensitivities have been altered due to genetic influences, presumably affecting gender(ed) activity interests as well as gender identity development in a minority of the affected population. While continued postnatal androgen exposure in a number of DSD syndromes has been associated with higher rates of gender dysphoria and gender change, the role of a number of mediating and moderating factors, such as initial gender assignment, syndrome severity and clinical management remains largely unclear. Limited investigations of the associations between these identified influences and gendered development outcomes impede optimization of clinical care. Participants with DSD (n=123), recruited in the context of a Dutch multi-center follow-up audit, were divided in subgroups reflecting prenatal androgen exposure, genital appearance at birth and gender of rearing. Recalled childhood play and playmate preferences, gender identity and sexual orientation were measured with questionnaires and semi-structured interviews. Data were compared to those of control male (n=46) and female participants (n=79). The findings support that (a) prenatal androgen exposure has large effects on (gendered) activity interests, but to a much lesser extent on sexual orientation and that (b) initial gender of rearing remains a better predictor of gender identity contentedness than prenatal androgen exposure, beyond syndrome severity and medical treatment influences. Nonetheless, 3.3% of individuals with DSD in our sample self-reported gender dysphoria from an early age and changed gender, which further underlines the need for thorough long- term follow-up and specific clinical support. Copyright © 2016 Elsevier Inc. All rights reserved.

Prenatal exposure to angiotensin II increases blood pressure and decreases salt sensitivity in rats.

PubMed

Svitok, Pavel; Senko, Tomas; Panakova, Zuzana; Olexova, Lucia; Krskova, Lucia; Okuliarova, Monika; Zeman, Michal

2017-01-01

Renin angiotensin aldosterone system (RAAS) plays an essential role in the homeostatic control of arterial blood pressure, perfusion of tissues, and control of extracellular fluid. Its components are highly expressed in the developing kidney, general vasculature, brain, and heart. A modified intrauterine environment alters mechanisms controlling blood pressure (BP) and can lead to hypertension in the adult offspring and developmentally programmed RAAS can be involved in this process. There are very little data about the effects of increased angiotensin II (Ang II) concentrations during pregnancy on in utero development of the fetus. In our study, we administered Ang II to pregnant female rats via osmotic mini-pumps and evaluated the postnatal development and BP control in the offspring. To estimate possible developmental changes in sensitivity to salt, we exposed the offspring to a diet with increased salt content and measured plasma aldosterone levels and plasma renin activity. Increased Ang II during pregnancy raised BP in the offspring; however, salt sensitivity was decreased in comparison to controls. Relative weight of the left ventricle was decreased in the offspring prenatally exposed to Ang II, while relative kidney weight was reduced only in female offspring. Prenatal treatment led to increased aldosterone levels and decreased plasma renin activity, suggesting a complex physiological response. Our results suggest that conditions leading to upregulation of RAAS during pregnancy can influence the cardiovascular system of the fetus and have a long-term impact on the offspring's health.

Expression of the ADHD candidate gene Diras2 in the brain.

PubMed

Grünewald, Lena; Becker, Nils; Camphausen, Annika; O'Leary, Aet; Lesch, Klaus-Peter; Freudenberg, Florian; Reif, Andreas

2018-06-01

The distinct subgroup of the Ras family member 2 (DIRAS2) gene has been found to be associated with attention-deficit/hyperactivity disorder (ADHD) in one of our previous studies. This gene is coding for a small Ras GTPase with unknown function. DIRAS2 is highly expressed in the brain. However, the exact neural expression pattern of this gene was unknown so far. Therefore, we investigated the expressional profile of DIRAS2 in the human and murine brain. In the present study, qPCR analyses in the human and in the developing mouse brain, immunocytological double staining on murine hippocampal primary cells and RNA in situ hybridization (ISH) on brain sections of C57BL/6J wild-type mice, have been used to reveal the expression pattern of DIRAS2 in the brain. We could show that DIRAS2 expression in the human brain is the highest in the hippocampus and the cerebral cortex, which is in line with the ISH results in the mouse brain. During mouse brain development, Diras2 levels strongly increase from prenatal to late postnatal stages. Co-expression studies indicate Diras2 expression in glutamatergic and catecholaminergic neurons. Our findings support the idea of DIRAS2 as a candidate gene for ADHD as the timeline of its expression as well as the brain regions and cell types that show Diras2 expression correspond to those assumed to underlie the pathomechanisms of the disease.

The long-term effects of prenatal nicotine exposure on verbal working memory: an fMRI study of young adults.

PubMed

A Longo, Carmelinda; A Fried, Peter; Cameron, Ian; M Smith, Andra

2014-11-01

Using functional magnetic resonance imaging (fMRI), the long-term effects of prenatal nicotine exposure on verbal working memory were investigated in young adults. Participants were members of the Ottawa Prenatal Prospective Study, a longitudinal study that collected a unique body of information on participants from infancy to young adulthood. This allowed for the measurement of an unprecedented number of potentially confounding drug exposure variables including: prenatal marijuana and alcohol exposure and current marijuana, nicotine and alcohol use. Twelve young adults with prenatal nicotine exposure and 13 non-exposed controls performed a 2-Back working memory task while fMRI blood oxygen level-dependent responses were examined. Despite similar task performance, participants with more prenatal nicotine exposure demonstrated significantly greater activity in several regions of the brain that typically subserve verbal working memory including the middle frontal gyrus, precentral gyrus, the inferior parietal lobe and the cingulate gyrus. These results suggest that prenatal nicotine exposure contributes to altered neural functioning during verbal working memory that continues into adulthood. Working memory is critical for a wide range of cognitive skills such as language comprehension, learning and reasoning. Thus, these findings highlight the need for continued educational programs and public awareness campaigns to reduce tobacco use among pregnant women. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Neonatal handling and environmental enrichment increase the expression of GAP-43 in the hippocampus and promote cognitive abilities in prenatally stressed rat offspring.

PubMed

Zhang, Zhengyu; Zhang, Hua; Du, Baoling; Chen, Zhiqiang

2012-07-26

Neonatal handling and environmental enrichment have been used to aid the treatment and recovery of a diverse variety of brain dysfunctions. However, the underlying mechanism and the effects on cognitive function following neonatal handling and environmental enrichment are still unclear. In this study, we investigated GAP-43 protein levels in the hippocampus of prenatally stressed rat pups by Western blot on postnatal day (P) 10, P20 and P45. The cognitive ability of prenatally stressed rat pups was tested by using the Morris water maze on P45. GAP-43 protein levels were upregulated on P10 in the prenatal restraint stress (RS) group and the prenatal restraint stress plus neonatal handling and environmental enrichment (RE) group compared to the negative control (NC) group. However, the expression of GAP-43 in RS pups was lower on P20 and P45 than that in NC and RE pups. Exposure to prenatal stress prolonged average latency and total swim distance, but neonatal handling and environmental enrichment could reverse the change. Differences were also observed in the selection of search strategies. These results indicate that neonatal handling and environmental enrichment can improve the spatial learning and memory ability of prenatally stressed offspring, and the possible mechanism is the upregulation of GAP-43. Copyright © 2012. Published by Elsevier Ireland Ltd.

Zika Virus: Transmission, Detection, Control, and Prevention

PubMed Central

Sharma, Anshika; Lal, Sunil K.

2017-01-01

Zika virus (ZIKV) is a mosquito-borne Flavivirus discovered in Uganda in the 1940s. To date, three major ZIKV outbreaks have been reported. ZIKV infections have known to be primarily asymptomatic while causing mild illness in a few cases. However, the recent emergence and spread of ZIKV in the Americas has resulted in the declaration of “Public Health Emergency of International Concern” due to the potential association between the infection and prenatal microcephaly or other brain anomalies. In Brazil, a 20-fold increase in prenatal microcephaly cases and 19% increase in Guillain-Barré Syndrome (GBS) cases were reported in 2015, as compared to the preceding year. The probable deleterious effects of ZIKV infection prompt the urgent development of diagnostics and therapeutics. To this end, the existing evidences supporting the increasingly common prenatal microcephaly and GBS association and the current known ZIKV transmission dynamics, modes of detection (molecular and serology-based), and current control strategies are summarized in this review. This review also emphasizes the importance of understanding ZIKV transmission in order to design a sensitive yet cost and time-efficient detection technique. Development of an efficient detection technique would subsequently allow for better surveillance and control of ZIKV infection. Currently, limited literature is available on the pathogenesis of ZIKV, hence, focusing on the modes of ZIKV transmission could potentially contribute to the understanding of the disease spectrum and formulation of targeted treatment and control. PMID:28217114

Perinatal treatment of rats with opiates affects the development of the blood-brain barrier transport system PTS-1.

PubMed

Banks, W A; Kastin, A J; Harrison, L M; Zadina, J E

1996-01-01

Previous results have shown that treatment of rats with morphine during the neonatal period can influence development of peptide transport system-1 (PTS-1), the blood-brain barrier transport system for Tyr-MIF-1 and methionine enkephalin. Previous work has suggested that the activity level of PTS-1 correlates with the concentration of methionine enkephalin in the brain. We show here that rats treated peripherally with morphine sulfate (MS) in both the prenatal and neonatal periods have enhanced activity of PTS-1. The degree of enhancement increases with age to reach a 66% increase in comparison with controls at age 9 weeks. The mu agonist MS was more powerful than the kappa agonist ethylketocyclazocine (EKC) or the delta agonist [D-Pen2.5,pCl-Phe4]enkephalin (pCl-DPDPE) in producing this effect. Opiate antagonists had complex effects with methylnaltrexone blocking the action of MS on PTS-1. These results show that the level of PTS-1 activity in adult rats can be modified by perinatal events that affect opiate tone during development.

Informing Rodent Behavior in Space: Gene Expression and Hyper-Emotionality Following Prenatal Stress

NASA Technical Reports Server (NTRS)

Moyer, E. L.; Talyansky, Y.; Baer, L. A.; Ronca, A. E.

2017-01-01

As space exploration pushes our boundaries further away from Earth and for longer durations, we will inevitably require the use of multi-generational studies to continue our expansion. Space is a stressful environment not only due to the deleterious effect of spaceflight on physiology, but also due to confinement, limited social interactions, inherently dangerous circumstances, and many other stresses of an unknown environment. Stress can alter the brain chemistry, and these alterations can affect behavior at all stages of development, but it is especially pronounced during the perinatal period and can have longstanding effects, even into adulthood, which manifest through augmented brain function and psychopathology. This study investigated the nexus of brain chemistry and brain function by observing behavior of adult rats whose mothers were exposed to unpredictable variable prenatal stress (UVPS) while they were in the womb. The UVPS consisted of strobe light, tube restraint, and white noise, and was administered at unpredictable times of the day and also varied in length, both of which were measures taken to prevent habituation to the stressor. The offspring rats were then allowed to reach adulthood and at 90 days were subjected to a series of behavioral tests including novel object, startle response, and an unknown intruder to quantify the adult rats stress response and anxiety. Here we report these results of the behavioral analysis and correlate adult behavioral measures with the expression of genes involved in the hypothalamic-pituitary-adrenal axis, which modulates the animals stress response. We hypothesized that hyper-expression of genes involved in the HPA axis would correlate with the observed anxiety-like behaviors associated with early stress.

Transplacental cocaine exposure. 2: Effects of cocaine dose and gestational timing.

PubMed

Wilkins, A S; Jones, K; Kosofsky, B E

1998-01-01

We have utilized a mouse model of transplacental cocaine exposure to investigate the effects of cocaine dose and gestational timing in altering brain and body growth and postnatal behavior in exposed offspring. Pregnant dams were injected with cocaine HCl at 40 mg/kg/day (COC 40) or 20 mg/kg/day (COC 20), or 10 mg/kg/day (COC 10) SC from embryonic day (E) 8 to E17, or cocaine HCl at 40 mg/kg/day SC from E8 to E13 (COC Early) or from E13 to E17 (COC Late) divided in two daily doses. COC 40 and COC Late dams, as well as dams in nutritionally paired control groups (injected with saline vehicle and pair-fed with the COC dams: SPF 40, SPF 20, SPF 10), demonstrated less weight gain than SAL controls (injected with saline vehicle and allowed access to food ad lib). The surrogate fostered offspring of COC 40 and SPF 40 dams demonstrated brain and body growth retardation [on postnatal day (P) 1 and P9] when compared to pups born to SAL dams. Offspring of COC Late, SPF 20, and SPF 10 dams demonstrated brain and body growth retardation on P1 when compared to pups born to SAL dams. Pups from all groups were tested for first-order Pavlovian conditioning on P9, or for the ability to ignore redundant information in a blocking paradigm on P50. Only COC 40 mice (i.e., offspring born to COC 40 dams) were unable to acquire an aversion to an odor previously paired with shock on P9. When compared with SAL controls, COC 40 mice (and to a less significant extent SPF 40 mice) demonstrated a persistent behavioral deficit in the blocking paradigm on P50, which may reflect alterations in selective attention. Correlation analyses indicated that the dose and gestational timing of transplacental cocaine exposure, and varying degrees of malnutrition, had effects on blocking performance, with greater prenatal cocaine exposure and increased prenatal malnutrition resulting in more significant behavioral impairments. A path regression analysis demonstrated independent and significant effects of prenatal cocaine as well as prenatal malnutrition in contributing to impaired performance in the blocking paradigm. As suggested by the clinical literature, our preclinical data support a model whereby the dose and duration of prenatal cocaine exposure have direct effects on offspring brain and body growth and on behavioral performance.

Beneficial effect of feeding a ketogenic diet to mothers on brain development in their progeny with a murine model of pyruvate dehydrogenase complex deficiency.

PubMed

Pliss, Lioudmila; Jatania, Urvi; Patel, Mulchand S

2016-06-01

Pyruvate dehydrogenase complex (PDC) deficiency is a major inborn error of oxidative metabolism of pyruvate in the mitochondria causing congenital lactic acidosis and primarily structural and functional abnormalities of the central nervous system. To provide an alternate source of acetyl-CoA derived from ketone bodies to the developing brain, a formula high in fat content is widely employed as a treatment. In the present study we investigated efficacy of a high-fat diet given to mothers during pregnancy and lactation on lessening of the impact of PDC deficiency on brain development in PDC-deficient female progeny. A murine model of systemic PDC deficiency by interrupting the X-linked Pdha1 gene was employed in this study. Maternal consumption of a high-fat diet during pregnancy and lactation had no effect on number of live-birth, body growth, tissue PDC activity levels, as well as the in vitro rates of glucose oxidation and fatty acid biosynthesis by the developing brain of PDC-deficient female offspring during the postnatal age 35 days, as compared to the PDC-deficient progeny born to dams on a chow diet. Interestingly, brain weight was normalized in PDC-deficient progeny of high fat-fed mothers with improvement in impairment in brain structure deficit whereas brain weight was significantly decreased and was associated with greater cerebral structural defects in progeny of chow-fed mothers as compared to control progeny of mothers fed either a chow or high fat diet. The findings provide for the first time experimental support for beneficial effects of a ketogenic diet during the prenatal and early postnatal periods on the brain development of PDC-deficient mammalian progeny.

Prenatal exposure to common environmental factors affects brain lipids and increases risk of developing autism spectrum disorders.

PubMed

Wong, Christine T; Wais, Joshua; Crawford, Dorota A

2015-11-01

The prevalence of autism spectrum disorders (ASDs) has been on the rise over recent years. The presence of diverse subsets of candidate genes in each individual with an ASD and the vast variability of phenotypical differences suggest that the interference of an exogenous environmental component may greatly contribute to the development of ASDs. The lipid mediator prostaglandin E2 (PGE2 ) is released from phospholipids of cell membranes, and is important in brain development and function; PGE2 is involved in differentiation, synaptic plasticity and calcium regulation. The previous review already described extrinsic factors, including deficient dietary supplementation, and exposure to oxidative stress, infections and inflammation that can disrupt signaling of the PGE2 pathway and contribute to ASDs. In this review, the structure and establishment of two key protective barriers for the brain during early development are described: the blood-brain barrier; and the placental barrier. Then, the first comprehensive summary of other environmental factors, such as exposure to chemicals in air pollution, pesticides and consumer products, which can also disturb PGE2 signaling and increase the risk for developing ASDs is provided. Also, how these exogenous agents are capable of crossing the protective barriers of the brain during critical developmental periods when barrier components are still being formed is described. This review underlines the importance of avoiding or limiting exposure to these factors during vulnerable periods in development. © 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Assessment of neurotoxic effects and brain region distribution in rat offspring prenatally co-exposed to low doses of BDE-99 and methylmercury.

PubMed

Zhao, Wenchang; Cheng, Jinping; Gu, Jinmin; Liu, Yuanyuan; Fujimura, Masatake; Wang, Wenhua

2014-10-01

Exposure to polybrominated diphenyl ether (PDBE) and methylmercury (MeHg) can occur simultaneously as both contaminants are found in the same food sources, especially fish, seafood, marine mammals and milk. The aim of this study was to assess the effects of exposure to low levels of MeHg (2.0 μg mL(-1) in drinking water) and BDE-99 (0.2 mg kg(-1) d(-1)) from gestational day 6 to postnatal day (PND) 21, alone and in combination, on neurobehavioral development and redox responses in offspring. The present study demonstrated an interaction due to co-exposure with low doses of MeHg and BDE-99 enhanced developmental neurotoxic effects. These effects were manifested as the delayed appearance of negative geotaxis reflexes, impaired motor coordination, and induction of oxidative stress in the cerebellum. In particular, the cerebellum may be a sensitive target for combined MeHg and BDE-99 toxicity. The neurotoxicity of low dose MeHg was exacerbated by the presence of low dose of BDE-99. It is concluded that prenatal co-exposure to MeHg and BDE-99 causes oxidative stress in the cerebellum of offspring by altering the activity of different antioxidant enzymes and producing free radicals. Hg retention was not affected by co-exposure to BDE-99. However, MeHg co-exposure seemed to increase BDE-99 concentrations in selected brain regions in pups compared to pups exposed to BDE-99 only. These results showed that the adverse effects following prenatal co-exposure to MeHg and BDE-99 were associated with tissue concentrations very close to the current human body burden of this persistent bioaccumulative compound. Copyright © 2014 Elsevier Ltd. All rights reserved.

Reduced expression of brain cannabinoid receptor 1 (Cnr1) is coupled with an increased complementary micro-RNA (miR-26b) in a mouse model of fetal alcohol spectrum disorders

PubMed Central

2013-01-01

Background Prenatal alcohol exposure is known to result in fetal alcohol spectrum disorders, a continuum of physiological, behavioural, and cognitive phenotypes that include increased risk for anxiety and learning-associated disorders. Prenatal alcohol exposure results in life-long disorders that may manifest in part through the induction of long-term gene expression changes, potentially maintained through epigenetic mechanisms. Findings Here we report a decrease in the expression of Canabinoid receptor 1 (Cnr1) and an increase in the expression of the regulatory microRNA miR-26b in the brains of adult mice exposed to ethanol during neurodevelopment. Furthermore, we show that miR-26b has significant complementarity to the 3’-UTR of the Cnr1 transcript, giving it the potential to bind and reduce the level of Cnr1 expression. Conclusions These findings elucidate a mechanism through which some genes show long-term altered expression following prenatal alcohol exposure, leading to persistent alterations to cognitive function and behavioural phenotypes observed in fetal alcohol spectrum disorders. PMID:23915435

Prenatal bisphenol A (BPA) exposure alters the transcriptome of the neonate rat amygdala in a sex-specific manner: a CLARITY-BPA consortium study.

PubMed

Arambula, Sheryl E; Jima, Dereje; Patisaul, Heather B

2018-03-01

Bisphenol A (BPA) is a widely recognized endocrine disruptor prevalent in many household items. Because experimental and epidemiological data suggest links between prenatal BPA exposure and altered affective behaviors in children, even at levels below the current US FDA No Observed Adverse Effect Level (NOAEL) of 5mg/kg body weight (bw)/day, there is concern that early life exposure may alter neurodevelopment. The current study was conducted as part of the CLARITY-BPA (Consortium Linking Academic and Regulatory Insights on BPA Toxicity) program and examined the full amygdalar transcriptome on postnatal day (PND) 1, with the hypothesis that prenatal BPA exposure would alter the expression of genes and pathways fundamental to sex-specific affective behaviors. NCTR Sprague-Dawley dams were gavaged from gestational day 6 until parturition with BPA (2.5, 25, 250, 2500, or 25000μg/kg bw/day), a reference estrogen (0.05 or 0.5μg ethinyl estradiol (EE 2 )/kg bw/day), or vehicle. PND 1 amygdalae were microdissected and gene expression was assessed with qRT-PCR (all exposure groups) and RNAseq (vehicle, 25 and 250μg BPA, and 0.5μg EE 2 groups only). Our results demonstrate that that prenatal BPA exposure can disrupt the transcriptome of the neonate amygdala, at doses below the FDA NOAEL, in a sex-specific manner and indicate that the female amygdala may be more sensitive to BPA exposure during fetal development. We also provide additional evidence that developmental BPA exposure can interfere with estrogen, oxytocin, and vasopressin signaling pathways in the developing brain and alter signaling pathways critical for synaptic organization and transmission. Copyright © 2017 Elsevier B.V. All rights reserved.

Prenatal androgenization affects gender-related behavior but not gender identity in 5-12-year-old girls with congenital adrenal hyperplasia.

PubMed

Meyer-Bahlburg, Heino F L; Dolezal, Curtis; Baker, Susan W; Carlson, Ann D; Obeid, Jihad S; New, Maria I

2004-04-01

Gender assignment of children with intersexuality and related conditions has recently become highly controversial. On the basis of extensive animal research and a few human case reports, some authors have proposed the putative masculinization of the brain by prenatal hormones-indicated by the degree of genital masculinization-as the decisive criterion of gender assignment and have derived the recommendation that 46,XX newborns with congenital adrenal hyperplasia (CAH) and full genital masculinization should be assigned to the male gender. The purpose of this study was to test in CAH girls of middle childhood the assumption that prenatal androgens determine the development of gender identity. Fifteen girls with CAH (range of genital Prader stage, 2-4/5), 30 control girls, and 16 control boys (age range, 5-12 years) underwent 2 gender-play observation sessions, and a gender identity interview yielding scales of gender confusion/dysphoria. About half a year earlier, mothers had completed 2 questionnaires concerning their children's gender-related behavior. The results showed that, as expected, CAH girls scored more masculine than control girls on all scales measuring gender-related behavior, with robust effect sizes. By contrast, neither conventionally significant differences nor trends were found on the 3 scales of the gender identity interview. We conclude that prenatal androgenization of 46,XX fetuses leads to marked masculinization of later gender-related behavior, but the absence of any increased gender-identity confusion/dysphoria does not indicate a direct determination of gender identity by prenatal androgens and does not, therefore, support a male gender assignment at birth of the most markedly masculinized girls.

Prenatal air pollution exposure induces sexually dimorphic fetal programming of metabolic and neuroinflammatory outcomes in adult offspring.

PubMed

Bolton, Jessica L; Auten, Richard L; Bilbo, Staci D

2014-03-01

Environmental chemical exposures during critical windows of development may contribute to the escalating prevalence of obesity. We tested the hypothesis that prenatal exposure to diesel exhaust particles (DEP), a primary component of air pollution, would prime microglia long-term, resulting in exacerbated metabolic and affective outcomes following exposure to a high-fat diet in adulthood. Time-mated mouse dams were intermittently exposed to respiratory instillations of either vehicle (VEH) or DEP throughout gestation. Adult male and female offspring were then fed either a low-fat diet (LFD) or high-fat diet (HFD) for 9 weeks. The male offspring of DEP-exposed dams exhibited exaggerated weight gain, insulin resistance, and anxiety-like behavior on HFD compared to the male offspring of VEH-exposed dams, whereas female offspring did not differ according to prenatal treatment. Furthermore, HFD induced evidence of macrophage infiltration of both adipose tissue and the brain in both sexes, but these cells were more activated specifically in DEP/HFD males. DEP/HFD males also expressed markedly higher levels of microglial/macrophage, but not astrocyte, activation markers in the hippocampus, whereas females exhibited only a suppression of astrocyte activation markers due to HFD. In a second experiment, DEP male offspring mounted an exaggerated peripheral IL-1β response to an LPS challenge at postnatal day (P)30, whereas their central IL-1β response did not differ from VEH male offspring, which is suggestive of macrophage priming due to prenatal DEP exposure. In sum, prenatal air pollution exposure "programs" offspring for increased susceptibility to diet-induced metabolic, behavioral, and neuroinflammatory changes in adulthood in a sexually dimorphic manner. Copyright © 2013 Elsevier Inc. All rights reserved.

A Complex Interaction Between Reduced Reelin Expression and Prenatal Organophosphate Exposure Alters Neuronal Cell Morphology.

PubMed

Mullen, Brian R; Ross, Brennan; Chou, Joan Wang; Khankan, Rana; Khialeeva, Elvira; Bui, Kimberly; Carpenter, Ellen M

2016-06-01

Genetic and environmental factors are both likely to contribute to neurodevelopmental disorders including schizophrenia, autism spectrum disorders, and major depressive disorders. Prior studies from our laboratory and others have demonstrated that the combinatorial effect of two factors-reduced expression of reelin protein and prenatal exposure to the organophosphate pesticide chlorpyrifos oxon-gives rise to acute biochemical effects and to morphological and behavioral phenotypes in adolescent and young adult mice. In the current study, we examine the consequences of these factors on reelin protein expression and neuronal cell morphology in adult mice. While the cell populations that express reelin in the adult brain appear unchanged in location and distribution, the levels of full length and cleaved reelin protein show persistent reductions following prenatal exposure to chlorpyrifos oxon. Cell positioning and organization in the hippocampus and cerebellum are largely normal in animals with either reduced reelin expression or prenatal exposure to chlorpyrifos oxon, but cellular complexity and dendritic spine organization is altered, with a skewed distribution of immature dendritic spines in adult animals. Paradoxically, combinatorial exposure to both factors appears to generate a rescue of the dendritic spine phenotypes, similar to the mitigation of behavioral and morphological changes observed in our prior study. Together, our observations support an interaction between reelin expression and chlorpyrifos oxon exposure that is not simply additive, suggesting a complex interplay between genetic and environmental factors in regulating brain morphology. © The Author(s) 2016.

4D Ultrasound - Medical Devices for Recent Advances on the Etiology of Cerebral Palsy

PubMed Central

Tomasovic, Sanja; Predojevic, Maja

2011-01-01

Children cerebral palsy (CCP) encompasses a group of nonprogessive and noninfectious conditions, which cause light, moderate, and severe deviations in neurological development. Diagnosis of CCP is set mostly by the age of 3 years. The fact that a large number of cerebral damage occurs prenatally and the fact that early intervention in cases of neurological damage is successful, prompted some researchers to explore the possibility of detecting neurologically damaged fetus in the uterus. This research was made possible thanks to the development of two-dimensional ultrasound technology in a real time, which enabled the display of the mobility of the fetus. Advancement of the ultrasound technology has enabled the development of 4D ultrasound where a spontaneous fetal movement can be observed almost in a real time. Estimate of the number and quality of spontaneous fetal movements and stitches on the head, the neurology thumb and a high palate were included in the prenatal neurological screening of the fetus. This raises the question, as to does the fetal behavior reflect, (which was revealed in 2D or 4D ultrasound), fetal neurological development in a manner that will allow the detection of the brain damage. PMID:23407920

Neurobehavioral Deficits and Increased Blood Pressure in School-Age Children Prenatally Exposed to Pesticides

PubMed Central

Harari, Raul; Julvez, Jordi; Murata, Katsuyuki; Barr, Dana; Bellinger, David C.; Debes, Frodi; Grandjean, Philippe

2010-01-01

Background The long-term neurotoxicity risks caused by prenatal exposures to pesticides are unclear, but a previous pilot study of Ecuadorian school children suggested that blood pressure and visuospatial processing may be vulnerable. Objectives In northern Ecuador, where floriculture is intensive and relies on female employment, we carried out an intensive cross-sectional study to assess children’s neurobehavioral functions at 6–8 years of age. Methods We examined all 87 children attending two grades in the local public school with an expanded battery of neurobehavioral tests. Information on pesticide exposure during the index pregnancy was obtained from maternal interview. The children’s current pesticide exposure was assessed from the urinary excretion of organophosphate metabolites and erythrocyte acetylcholine esterase activity. Results Of 84 eligible participants, 35 were exposed to pesticides during pregnancy via maternal occupational exposure, and 23 had indirect exposure from paternal work. Twenty-two children had detectable current exposure irrespective of their prenatal exposure status. Only children with prenatal exposure from maternal greenhouse work showed consistent deficits after covariate adjustment, which included stunting and socioeconomic variables. Exposure-related deficits were the strongest for motor speed (Finger Tapping Task), motor coordination (Santa Ana Form Board), visuospatial performance (Stanford-Binet Copying Test), and visual memory (Stanford-Binet Copying Recall Test). These associations corresponded to a developmental delay of 1.5–2 years. Prenatal pesticide exposure was also significantly associated with an average increase of 3.6 mmHg in systolic blood pressure and a slight decrease in body mass index of 1.1 kg/m2. Inclusion of the pilot data strengthened these results. Conclusions These findings support the notion that prenatal exposure to pesticides—at levels not producing adverse health outcomes in the mother—can cause lasting adverse effects on brain development in children. Pesticide exposure therefore may contribute to a “silent pandemic” of developmental neurotoxicity. PMID:20185383

Neurobehavioral deficits and increased blood pressure in school-age children prenatally exposed to pesticides.

PubMed

Harari, Raul; Julvez, Jordi; Murata, Katsuyuki; Barr, Dana; Bellinger, David C; Debes, Frodi; Grandjean, Philippe

2010-06-01

The long-term neurotoxicity risks caused by prenatal exposures to pesticides are unclear, but a previous pilot study of Ecuadorian school children suggested that blood pressure and visuospatial processing may be vulnerable. In northern Ecuador, where floriculture is intensive and relies on female employment, we carried out an intensive cross-sectional study to assess children's neurobehavioral functions at 6-8 years of age. We examined all 87 children attending two grades in the local public school with an expanded battery of neurobehavioral tests. Information on pesticide exposure during the index pregnancy was obtained from maternal interview. The children's current pesticide exposure was assessed from the urinary excretion of organophosphate metabolites and erythrocyte acetylcholine esterase activity. Of 84 eligible participants, 35 were exposed to pesticides during pregnancy via maternal occupational exposure, and 23 had indirect exposure from paternal work. Twenty-two children had detectable current exposure irrespective of their prenatal exposure status. Only children with pre-natal exposure from maternal greenhouse work showed consistent deficits after covariate adjustment, which included stunting and socioeconomic variables. Exposure-related deficits were the strongest for motor speed (Finger Tapping Task), motor coordination (Santa Ana Form Board), visuospatial performance (Stanford-Binet Copying Test), and visual memory (Stanford-Binet Copying Recall Test). These associations corresponded to a developmental delay of 1.5-2 years. Prenatal pesticide exposure was also significantly associated with an average increase of 3.6 mmHg in systolic blood pressure and a slight decrease in body mass index of 1.1 kg/m2. Inclusion of the pilot data strengthened these results. These findings support the notion that prenatal exposure to pesticides-at levels not producing adverse health outcomes in the mother-can cause lasting adverse effects on brain development in children. Pesticide exposure therefore may contribute to a "silent pandemic" of developmental neurotoxicity.

Prenatal exposure to polychlorinated biphenyls and their hydroxylated metabolites is associated with motor development of three-month-old infants.

PubMed

Berghuis, Sietske A; Soechitram, Shalini D; Hitzert, Marrit M; Sauer, Pieter J J; Bos, Arend F

2013-09-01

Polychlorinated biphenyls (PCBs) are ubiquitous environmental pollutants that are potentially toxic to the developing brain. Hydroxylated metabolites of PCBs (OH-PCBs) are suggested to be even more toxic. Little is known about their short-term effects on human health. To determine whether prenatal background exposure to PCBs and OH-PCBs was associated with the motor development of three-month-old infants. Ninety-seven mother-infant pairs participated in this Dutch, observational cohort study. We determined the concentrations of PCBs and OH-PCBs in cord blood samples. When the infants were three months old we evaluated their motor development by assessing the presence and performance of spontaneous movement patterns from video recordings. We calculated a Motor Optimality Score (MOS). The score could range from low (5) to high (28) optimality. We explored the correlations between PCB and OH-PCB levels and MOS. Subsequently, we tested whether the levels differed between infants with a low (<26) or high (≥26) MOS and whether the levels associated with detailed aspects of their motor repertoires. We found several associations between PCB and OH-PCB levels and MOS, including detailed aspects of the early motor development. High 4-OH-PCB-107 levels were associated with a low MOS (P=.013). High PCB-187 levels were associated with reduced midline arm and leg movements (P=.047 and P=.043, respectively). High 4'-OH-PCB-172 levels were associated with more manipulation (P=.033). Prenatal exposure to high background levels of most PCBs and 4-OH-PCB-107 seems to impair early motor development, whereas only 4'-OH-PCB-172 showed the opposite. Copyright © 2013 Elsevier Inc. All rights reserved.

Effects of morphine on brain plasticity.

PubMed

Beltrán-Campos, V; Silva-Vera, M; García-Campos, M L; Díaz-Cintra, S

2015-04-01

Morphine shares with other opiates and drugs of abuse the ability to modify the plasticity of brain areas that regulate the morphology of dendrites and spines, which are the primary sites of excitatory synapses in regions of the brain involved in incentive motivation, rewards, and learning. In this review we discuss the impact of morphine use during the prenatal period of brain development and its long-term consequences in murines, and then link those consequences to similar effects occurring in human neonates and adults. Repeated exposure to morphine as treatment for pain in terminally ill patients produces long-term changes in the density of postsynaptic sites (dendrites and spines) in sensitive areas of the brain, such as the prefrontal cortex, the limbic system (hippocampus, amygdala), and caudate nuclei and nucleus accumbens. This article reviews the cellular mechanisms and receptors involved, primarily dopaminergic and glutamatergic receptors, as well as synaptic plasticity brought about by changes in dendritic spines in these areas. The actions of morphine on both developing and adult brains produce alterations in the plasticity of excitatory postsynaptic sites of the brain areas involved in limbic system functions (reward and learning). Doctors need further studies on plasticity in dendrites and spines and on signaling molecules, such as calcium, in order to improve treatments for addiction. Copyright © 2014 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

Effects of prenatal chronic mild stress exposure on hippocampal cell proliferation, expression of GSK-3α, β and NR2B in adult offspring during fear extinction in rats.

PubMed

Li, Min; Li, Xiaobai; Zhang, Xinxin; Ren, Jintao; Jiang, Han; Wang, Yan; Ma, Yuchao; Cheng, Wenwen

2014-06-01

Stress during pregnancy has been implicated as a risk factor for the development of many mental disorders; however, the influence of prenatal stress on the fear or anxiety-related behaviors, especially the fear extinction in adult offspring has been little investigated. In order to investigate how prenatal stress affects fear extinction, which is regarded as a form of new learning that counteracts the expression of Pavlovian's conditioned fear, a rat model of prenatal chronic mild stress (PNS) was used to evaluate the effects of PNS on fear extinction in adult offspring. The expression of hippocampal glycogen synthase kinase-3s (GSK-3α, β), N-methyl-d-aspartic acid receptors (NMDARs)-2B and the hippocampal cell proliferation in dentate gyrus in the adult offspring during fear extinction were studied. Our results showed that PNS significantly reduced body weight of pups, indicating PNS might induce growth retardation in offspring. Moreover, PNS significantly enhanced the freezing behavior of offspring at the phase of extinction, suggesting PNS impaired the abilities of fear extinction learning. In addition, PNS significantly increased the levels of GSK-3α, β and NR2B, but reduced hippocampal cell proliferation during fear extinction. Taken together, our findings suggest that maternal stress during pregnancy can impair the fear extinction of adult offspring, probably by affecting the neural plasticity of brain. Copyright © 2014 ISDN. Published by Elsevier Ltd. All rights reserved.

Maternal exposure to silver nanoparticles are associated with behavioral abnormalities in adulthood: Role of mitochondria and innate immunity in developmental toxicity.

PubMed

Amiri, Shayan; Yousefi-Ahmadipour, Aliakbar; Hosseini, Mir-Jamal; Haj-Mirzaian, Arya; Momeny, Majid; Hosseini-Chegeni, Heshmat; Mokhtari, Tahmineh; Kharrazi, Sharmin; Hassanzadeh, Gholamreza; Amini, Seyed Mohammad; Jafarinejad, Somayeh; Ghazi-Khansari, Mahmoud

2018-05-01

Silver nanoparticles (Ag-NPs) are currently used in a wide range of consumer products. Considering the small size of Ag-NPs, they are able to pass through variety of biological barriers and exert their effects. In this regard, the unique physicochemical properties of Ag-NPs along with its high application in the industry have raised concerns about their negative effects on human health. Therefore, it investigated whether prenatal exposure to low doses of Ag-NPs is able to induce any abnormality in the cognitive and behavioral performance of adult offspring. We gavaged pregnant NMRI mice with, 1) Deionized water as vehicle, 2) Ag-NPs 10 nm (0.26 mg/kg/day), 3) Ag-NPs 30 nm (0.26 mg/kg/day), and 4) AgNO 3 (0.26 mg/kg/day) from gestational day (GD) 0 until delivery day. At the postnatal day (PD) 1, our results showed that high concentration of silver is present in the brain of pups. Further, we observed mitochondrial dysfunction and upregulation of the genes relevant to innate immune system in the brain. At PD 60, results revealed that prenatal exposure to Ag-NPs provoked severe cognitive and behavioral abnormalities in male offspring. In addition, we found that prenatal exposure to Ag-NPs was associated with abnormal mitochondrial function and significant up-regulation of the genes relevant to innate immunity in the brain. Although the Ag-NPs have been considered as safe compounds at low doses, our results indicate that prenatal exposure to low doses of Ag-NPs is able to induce behavioral and cognitive abnormalities in adulthood. Also, we found that these effects are at least partly associated with hippocampal mitochondrial dysfunction and the activation of sterile inflammation during early stages of life. Copyright © 2018 Elsevier B.V. All rights reserved.

The effects of prenatal and early postnatal tocotrienol-rich fraction supplementation on cognitive function development in male offspring rats

PubMed Central

2013-01-01

Background Recent findings suggest that the intake of specific nutrients during the critical period in early life influence cognitive and behavioural development profoundly. Antioxidants such as vitamin E have been postulated to be pivotal in this process, as vitamin E is able to protect the growing brain from oxidative stress. Currently tocotrienols are gaining much attention due to their potent antioxidant and neuroprotective properties. It is thus compelling to look at the effects of prenatal and early postnatal tocotrienols supplementation, on cognition and behavioural development among offsprings of individual supplemented with tocotrienols. Therefore, this study is aimed to investigate potential prenatal and early postnatal influence of Tocotrienol-Rich Fraction (TRF) supplementation on cognitive function development in male offspring rats. Eight-week-old adult female Sprague Dawley (SD) rats were randomly assigned into five groups of two animals each. The animals were fed either with the base diet as control (CTRL), base diet plus vehicle (VHCL), base diet plus docosahexanoic acid (DHA), base diet plus Tocotrienol-Rich fraction (TRF), and base diet plus both docosahexaenoic acid, and tocotrienol rich fraction (DTRF) diets for 2 weeks prior to mating. The females (F0 generation) were maintained on their respective treatment diets throughout the gestation and lactation periods. Pups (F1 generation) derived from these dams were raised with their dams from birth till four weeks post natal. The male pups were weaned at 8 weeks postnatal, after which they were grouped into five groups of 10 animals each, and fed with the same diets as their dams for another eight weeks. Learning and behavioural experiments were conducted only in male off-spring rats using the Morris water maze.Eight-week-old adult female Sprague Dawley (SD) rats were randomly assigned into five groups of two animals each. The animals were fed either with the base diet as control (CTRL), base diet plus vehicle (VHCL), base diet plus docosahexanoic acid (DHA), base diet plus Tocotrienol-Rich fraction (TRF), and base diet plus both docosahexaenoic acid, and tocotrienol rich fraction (DTRF) diets for 2 weeks prior to mating. The females (F0 generation) were maintained on their respective treatment diets throughout the gestation and lactation periods. Pups (F1 generation) derived from these dams were raised with their dams from birth till four weeks post natal. The male pups were weaned at 8 weeks postnatal, after which they were grouped into five groups of 10 animals each, and fed with the same diets as their dams for another eight weeks. Learning and behavioural experiments were conducted only in male off-spring rats using the Morris water maze. Results Results showed that prenatal and postnatal TRF supplementation increased the brain (4–6 fold increase) and plasma α-tocotrienol (0.8 fold increase) levels in male off-springs. There is also notably better cognitive performance based on the Morris water maze test among these male off-springs. Conclusion Based on these results, it is concluded that prenatal and postnatal TRF supplementation improved cognitive function development in male progeny rats. PMID:23902378

The effects of prenatal and early postnatal tocotrienol-rich fraction supplementation on cognitive function development in male offspring rats.

PubMed

Nagapan, Gowri; Meng Goh, Yong; Shameha Abdul Razak, Intan; Nesaretnam, Kalanithi; Ebrahimi, Mahdi

2013-07-31

Recent findings suggest that the intake of specific nutrients during the critical period in early life influence cognitive and behavioural development profoundly. Antioxidants such as vitamin E have been postulated to be pivotal in this process, as vitamin E is able to protect the growing brain from oxidative stress. Currently tocotrienols are gaining much attention due to their potent antioxidant and neuroprotective properties. It is thus compelling to look at the effects of prenatal and early postnatal tocotrienols supplementation, on cognition and behavioural development among offsprings of individual supplemented with tocotrienols. Therefore, this study is aimed to investigate potential prenatal and early postnatal influence of Tocotrienol-Rich Fraction (TRF) supplementation on cognitive function development in male offspring rats. Eight-week-old adult female Sprague Dawley (SD) rats were randomly assigned into five groups of two animals each. The animals were fed either with the base diet as control (CTRL), base diet plus vehicle (VHCL), base diet plus docosahexanoic acid (DHA), base diet plus Tocotrienol-Rich fraction (TRF), and base diet plus both docosahexaenoic acid, and tocotrienol rich fraction (DTRF) diets for 2 weeks prior to mating. The females (F0 generation) were maintained on their respective treatment diets throughout the gestation and lactation periods. Pups (F1 generation) derived from these dams were raised with their dams from birth till four weeks post natal. The male pups were weaned at 8 weeks postnatal, after which they were grouped into five groups of 10 animals each, and fed with the same diets as their dams for another eight weeks. Learning and behavioural experiments were conducted only in male off-spring rats using the Morris water maze. Eight-week-old adult female Sprague Dawley (SD) rats were randomly assigned into five groups of two animals each. The animals were fed either with the base diet as control (CTRL), base diet plus vehicle (VHCL), base diet plus docosahexanoic acid (DHA), base diet plus Tocotrienol-Rich fraction (TRF), and base diet plus both docosahexaenoic acid, and tocotrienol rich fraction (DTRF) diets for 2 weeks prior to mating. The females (F0 generation) were maintained on their respective treatment diets throughout the gestation and lactation periods. Pups (F1 generation) derived from these dams were raised with their dams from birth till four weeks post natal. The male pups were weaned at 8 weeks postnatal, after which they were grouped into five groups of 10 animals each, and fed with the same diets as their dams for another eight weeks. Learning and behavioural experiments were conducted only in male off-spring rats using the Morris water maze. Results showed that prenatal and postnatal TRF supplementation increased the brain (4-6 fold increase) and plasma α-tocotrienol (0.8 fold increase) levels in male off-springs. There is also notably better cognitive performance based on the Morris water maze test among these male off-springs. Based on these results, it is concluded that prenatal and postnatal TRF supplementation improved cognitive function development in male progeny rats.

Normal variation in early parental sensitivity predicts child structural brain development.

PubMed

Kok, Rianne; Thijssen, Sandra; Bakermans-Kranenburg, Marian J; Jaddoe, Vincent W V; Verhulst, Frank C; White, Tonya; van IJzendoorn, Marinus H; Tiemeier, Henning

2015-10-01

Early caregiving can have an impact on brain structure and function in children. The influence of extreme caregiving experiences has been demonstrated, but studies on the influence of normal variation in parenting quality are scarce. Moreover, no studies to date have included the role of both maternal and paternal sensitivity in child brain maturation. This study examined the prospective relation between mothers' and fathers' sensitive caregiving in early childhood and brain structure later in childhood. Participants were enrolled in a population-based prenatal cohort. For 191 families, maternal and paternal sensitivity was repeatedly observed when the child was between 1 year and 4 years of age. Head circumference was assessed at 6 weeks, and brain structure was assessed using magnetic resonance imaging (MRI) measurements at 8 years of age. Higher levels of parental sensitivity in early childhood were associated with larger total brain volume (adjusted β = 0.15, p = .01) and gray matter volume (adjusted β = 0.16, p = .01) at 8 years, controlling for infant head size. Higher levels of maternal sensitivity in early childhood were associated with a larger gray matter volume (adjusted β = 0.13, p = .04) at 8 years, independent of infant head circumference. Associations with maternal versus paternal sensitivity were not significantly different. Normal variation in caregiving quality is related to markers of more optimal brain development in children. The results illustrate the important role of both mothers and fathers in child brain development. Copyright © 2015 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.

Exploring the complexity of intellectual disability in fetal alcohol spectrum disorders.

PubMed

Chokroborty-Hoque, Aniruddho; Alberry, Bonnie; Singh, Shiva M

2014-01-01

Brain development in mammals is long lasting. It begins early during embryonic growth and is finalized in early adulthood. This progression represents a delicate choreography of molecular, cellular, and physiological processes initiated and directed by the fetal genotype in close interaction with environment. Not surprisingly, most aberrations in brain functioning including intellectual disability (ID) are attributed to either gene(s), or environment or the interaction of the two. The ensuing complexity has made the assessment of this choreography, ever challenging. A model to assess this complexity has used a mouse model (C57BL/6J or B6) that is subjected to prenatal alcohol exposure. The resulting pups show learning and memory deficits similar to patients with fetal alcohol spectrum disorder (FASD), which is associated with life-long changes in gene expression. Interestingly, this change in gene expression underlies epigenetic processes including DNA methylation and miRNAs. This paradigm is applicable to ethanol exposure at different developmental times (binge at trimesters 1, 2, and 3 as well as continuous preference drinking (70%) of 10% alcohol by B6 females during pregnancy). The exposure leads to life-long changes in neural epigenetic marks, gene expression, and a variety of defects in neurodevelopment and CNS function. We argue that this cascade may be reversed postnatally via drugs, chemicals, and environment including maternal care. Such conclusions are supported by two sets of results. First, antipsychotic drugs that are used to treat ID including psychosis function via changes in DNA methylation, a major epigenetic mark. Second, post-natal environment may improve (with enriched environments) or worsen (with negative and maternal separation stress) the cognitive ability of pups that were prenatally exposed to ethanol as well as their matched controls. In this review, we will discuss operational epigenetic mechanisms involved in the development of intellectual ability/disability in response to alcohol during prenatal or post-natal development. In doing so, we will explore the potential of epigenetic manipulation in the treatment of FASD and related disorders implicated in ID.

Exploring the Complexity of Intellectual Disability in Fetal Alcohol Spectrum Disorders

PubMed Central

Chokroborty-Hoque, Aniruddho; Alberry, Bonnie; Singh, Shiva M.

2014-01-01

Brain development in mammals is long lasting. It begins early during embryonic growth and is finalized in early adulthood. This progression represents a delicate choreography of molecular, cellular, and physiological processes initiated and directed by the fetal genotype in close interaction with environment. Not surprisingly, most aberrations in brain functioning including intellectual disability (ID) are attributed to either gene(s), or environment or the interaction of the two. The ensuing complexity has made the assessment of this choreography, ever challenging. A model to assess this complexity has used a mouse model (C57BL/6J or B6) that is subjected to prenatal alcohol exposure. The resulting pups show learning and memory deficits similar to patients with fetal alcohol spectrum disorder (FASD), which is associated with life-long changes in gene expression. Interestingly, this change in gene expression underlies epigenetic processes including DNA methylation and miRNAs. This paradigm is applicable to ethanol exposure at different developmental times (binge at trimesters 1, 2, and 3 as well as continuous preference drinking (70%) of 10% alcohol by B6 females during pregnancy). The exposure leads to life-long changes in neural epigenetic marks, gene expression, and a variety of defects in neurodevelopment and CNS function. We argue that this cascade may be reversed postnatally via drugs, chemicals, and environment including maternal care. Such conclusions are supported by two sets of results. First, antipsychotic drugs that are used to treat ID including psychosis function via changes in DNA methylation, a major epigenetic mark. Second, post-natal environment may improve (with enriched environments) or worsen (with negative and maternal separation stress) the cognitive ability of pups that were prenatally exposed to ethanol as well as their matched controls. In this review, we will discuss operational epigenetic mechanisms involved in the development of intellectual ability/disability in response to alcohol during prenatal or post-natal development. In doing so, we will explore the potential of epigenetic manipulation in the treatment of FASD and related disorders implicated in ID. PMID:25207264

Developmental neurotoxicity elicited by prenatal or postnatal chlorpyrifos exposure: effects on neurospecific proteins indicate changing vulnerabilities.

PubMed

Garcia, Stephanie J; Seidler, Frederic J; Slotkin, Theodore A

2003-03-01

The developmental neurotoxicity of the organophosphate pesticide chlorpyrifos (CPF) is thought to involve both neurons and glia, thus producing a prolonged window of vulnerability. To characterize the cell types and brain regions involved in these effects, we administered CPF to developing rats and examined neuroprotein markers for oligodendrocytes (myelin basic protein, MBP), for neuronal cell bodies (neurofilament 68 kDa, NF68), and for developing axons (neurofilament 200 kDa, NF200). Prenatal CPF administration on gestational days (GDs) 17-20 elicited an immediate (GD21) enhancement of MBP and NF68; by postnatal day (PN) 30, however, there were deficits in all three biomarkers, with the effect restricted to females. Exposure in the early postnatal period, PN1-4, did not evoke significant short-term or long-term changes in the neuroproteins. However, with treatment on PN11-14, we found reductions in MBP in the immediate posttreatment period (PN15, PN20) throughout the brain, and deficiencies across all three proteins emerged by PN30. With this regimen, males were targeted preferentially. The sex-selective effects seen here for the GD17-20 and PN11-14 regimens match those reported earlier for subsequent behavioral performance. These results indicate a shift in the populations of neural cells targeted by CPF, dependent upon the period of exposure. Similarly, developmental differences in the sex selectivity of the biochemical mechanisms underlying neurotoxicant actions are likely to contribute to discrete behavioral outcomes.

Appraisal of neurobehavioral methods in environmental health research: the developing brain as a target for neurotoxic chemicals.

PubMed

Winneke, Gerhard

2007-10-01

Psychological tests as developed and validated in the field of differential psychology have a longstanding tradition as tools to study individual differences. In clinical neuropsychology, global or more specific tests are used as neuropsychological tools in the differential diagnosis of various forms of brain damage or neurobehavioral dysfunction following chemical insults, such as mental sequelae of prenatal alcohol consumption by pregnant mothers (fetal alcohol syndrome) or of maternal thyroid deficiency during pregnancy. Psychometric tests are constructed to fulfill basic quality criteria, namely objectivity, reliability and validity. For strictly diagnostic purposes in individual cases they must also possess normative values based on representative reference groups. Intelligence tests or their developmental variants are often used as endpoints in environmental health research for studying neurodevelopmental adversity due to early exposure to neurotoxic chemicals in the environment. Intelligence as treated in psychology is a complex construct made up of specific cognitive functions which usually cover verbal, numerical and spatial skills, as well as perceptual speed, memory and reasoning. In this paper, case studies covering neurodevelopmental adversity of inorganic lead, of methylmercury and of polychlorinated biphenyls (PCBs) are reviewed, and the issue of postnatal behavioral sequelae of prenatal exposure is covered. In such observational studies precautions must be taken in order to avoid pitfalls of causative interpretation of associations between exposure and neurobehavioral outcome. This requires consideration of co-exposure and confounding. Important confounders considered in most modern developmental cohort studies are maternal intelligence and quality of the home environment.

Genetic and epigenetic transgenerational implications related to omega-3 fatty acids. Part II: maternal FADS2 rs174575 genotype and DNA methylation predict toddler cognitive performance.

PubMed

Cheatham, Carol L; Lupu, Daniel S; Niculescu, Mihai D

2015-11-01

Maternal transfer of fatty acids is important to fetal brain development. The prenatal environment may differentially affect the substrates supporting declarative memory abilities, as the level of fatty acids transferred across the placenta may be affected by the maternal fatty acid desaturase 2 (FADS2) rs174575 single nucleotide polymorphism. In this study, we hypothesized that toddler and maternal rs174575 genotype and FADS2 promoter methylation would be related to the toddlers' declarative memory performance. Seventy-one 16-month-old toddlers participated in an imitation paradigm designed to test immediate and long-term declarative memory abilities. FADS2 rs174575 genotype was determined and FADS2 promoter methylation was quantified from blood by bisulfite pyrosequencing for the toddlers and their natural mothers. Toddlers of GG mothers at the FADS2 rs174575 single nucleotide polymorphism did not perform as well on memory assessments as toddlers of CC or CG mothers when controlling for plasma α-linolenic acid and child genotype. Toddler methylation status was related to immediate memory performance, whereas maternal methylation status was related to delayed memory performance. Thus, prenatal experience and maternal FADS2 status have a pervasive, long-lasting influence on the brain development of the offspring, but as the postnatal environment becomes more primary, the offsprings' own biology begins to have an effect. Copyright © 2015 Elsevier Inc. All rights reserved.

Prenatal inhibition of the kynurenine pathway leads to structural changes in the hippocampus of adult rat offspring

PubMed Central

Khalil, Omari S; Pisar, Mazura; Forrest, Caroline M; Vincenten, Maria C J; Darlington, L Gail; Stone, Trevor W

2014-01-01

Glutamate receptors for N-methyl-d-aspartate (NMDA) are involved in early brain development. The kynurenine pathway of tryptophan metabolism includes the NMDA receptor agonist quinolinic acid and the antagonist kynurenic acid. We now report that prenatal inhibition of the pathway in rats with 3,4-dimethoxy-N-[4-(3-nitrophenyl)thiazol-2-yl]benzenesulphonamide (Ro61-8048) produces marked changes in hippocampal neuron morphology, spine density and the immunocytochemical localisation of developmental proteins in the offspring at postnatal day 60. Golgi–Cox silver staining revealed decreased overall numbers and lengths of CA1 basal dendrites and secondary basal dendrites, together with fewer basal dendritic spines and less overall dendritic complexity in the basal arbour. Fewer dendrites and less complexity were also noted in the dentate gyrus granule cells. More neurons containing the nuclear marker NeuN and the developmental protein sonic hedgehog were detected in the CA1 region and dentate gyrus. Staining for doublecortin revealed fewer newly generated granule cells bearing extended dendritic processes. The number of neuron terminals staining for vesicular glutamate transporter (VGLUT)-1 and VGLUT-2 was increased by Ro61-8048, with no change in expression of vesicular GABA transporter or its co-localisation with vesicle-associated membrane protein-1. These data support the view that constitutive kynurenine metabolism normally plays a role in early embryonic brain development, and that interfering with it has profound consequences for neuronal structure and morphology, lasting into adulthood. PMID:24646396

Prenatal care in your first trimester

MedlinePlus

... for birth defects and genetic problems, such as Down syndrome or brain and spinal column defects. If your ... if the baby is at risk for having Down syndrome. If a test called a quadruple screen is ...

Prenatal Alcohol Exposure Alters Fetal Iron Distribution and Elevates Hepatic Hepcidin in a Rat Model of Fetal Alcohol Spectrum Disorders123

PubMed Central

Huebner, Shane M; Blohowiak, Sharon E; Kling, Pamela J; Smith, Susan M

2016-01-01

Background: Prenatal alcohol exposure (PAE) causes neurodevelopmental disabilities, and gestational iron deficiency (ID) selectively worsens learning and neuroanatomical and growth impairments in PAE. It is unknown why ID worsens outcomes in alcohol-exposed offspring. Objective: We hypothesized that PAE alters maternal-fetal iron distribution or its regulation. Methods: Nulliparous, 10-wk-old, Long-Evans rats were mated and then fed iron-sufficient (100 mg Fe/kg) or iron-deficient (≤4 mg Fe/kg) diets. On gestational days 13.5–19.5, dams received either 5.0 g ethanol/kg body weight (PAE) or isocaloric maltodextrin by oral gavage. On gestational day 20.5, maternal and fetal clinical blood counts, tissue mineral and iron transport protein concentrations, and hepatic hepcidin mRNA expression were determined. Results: In fetal brain and liver (P < 0.001) and in maternal liver (P < 0.005), ID decreased iron (total and nonheme) and ferritin content by nearly 200%. PAE reduced fetal bodyweight (P < 0.001) and interacted with ID (P < 0.001) to reduce it by an additional 20%. Independent of maternal iron status, PAE increased fetal liver iron (30–60%, P < 0.001) and decreased brain iron content (total and nonheme, 15–20%, P ≤ 0.050). ID-PAE brains had lower ferritin, transferrin, and transferrin receptor content (P ≤ 0.002) than ID-maltodextrin brains. PAE reduced fetal hematocrit, hemoglobin, and red blood cell numbers (P < 0.003) independently of iron status. Unexpectedly, and also independent of iron status, PAE increased maternal and fetal hepatic hepcidin mRNA expression >300% (P < 0.001). Conclusions: PAE altered fetal iron distribution independent of maternal iron status in rats. The elevated iron content of fetal liver suggests that PAE may have limited iron availability for fetal erythropoiesis and brain development. Altered fetal iron distribution may partly explain why maternal ID substantially worsens growth and behavioral outcomes in PAE. PMID:27146918

How Early Hormones Shape Gender Development

PubMed Central

Berenbaum, Sheri A.; Beltz, Adriene M.

2015-01-01

Many important psychological characteristics show sex differences, and are influenced by sex hormones at different developmental periods. We focus on the role of sex hormones in early development, particularly the differential effects of prenatal androgens on aspects of gender development. Increasing evidence confirms that prenatal androgens have facilitative effects on male-typed activity interests and engagement (including child toy preferences and adult careers), and spatial abilities, but relatively minimal effects on gender identity. Recent emphasis has been directed to the psychological mechanisms underlying these effects (including sex differences in propulsive movement, and androgen effects on interest in people versus things), and neural substrates of androgen effects (including regional brain volumes, and neural responses to mental rotation, sexually arousing stimuli, emotion, and reward). Ongoing and planned work is focused on understanding the ways in which hormones act jointly with the social environment across time to produce varying trajectories of gender development, and clarifying mechanisms by which androgens affect behaviors. Such work will be facilitated by applying lessons from other species, and by expanding methodology. Understanding hormonal influences on gender development enhances knowledge of psychological development generally, and has important implications for basic and applied questions, including sex differences in psychopathology, women’s underrepresentation in science and math, and clinical care of individuals with variations in gender expression. PMID:26688827

Epigenetic Influence of Stress and the Social Environment

PubMed Central

Gudsnuk, Kathryn; Champagne, Frances A.

2012-01-01

Animal models of early-life stress and variation in social experience across the lifespan have contributed significantly to our understanding of the environmental regulation of the developing brain. Plasticity in neurobiological pathways regulating stress responsivity, cognition, and reproductive behavior is apparent during the prenatal period and continues into adulthood, suggesting a lifelong sensitivity to environmental cues. Recent evidence suggests that dynamic epigenetic changes—molecular modifications that alter gene expression without altering the underlying DNA sequence—account for this plasticity. In this review, we highlight studies of laboratory rodents that illustrate the association between the experience of prenatal stress, maternal separation, maternal care, abusive caregiving in infancy, juvenile social housing, and adult social stress and variation in DNA methylation and histone modification. Moreover, we discuss emerging evidence for the transgenerational impact of these experiences. These experimental paradigms have yielded insights into the potential role of epigenetic mechanisms in mediating the effects of the environment on human development and also indicate that consideration of the sensitivity of laboratory animals to environmental cues may be an important factor in predicting long-term health and welfare. PMID:23744967

Psychological Aspects of the Treatment of Patients with Disorders of Sex Development

PubMed Central

Sandberg, David E.; Gardner, Melissa; Cohen-Kettenis, Peggy T.

2013-01-01

Research on the psychological development of persons with Disorders of Sex Development (DSD) has focused on understanding the influence of atypical sex hormone exposure during steroid-sensitive periods of prenatal brain development on the process of psychosexual differentiation (i.e., gender identity, gender role, and sexual orientation). In contrast, analysis of clinical management strategies has focused on gender assignment and the desirability and timing of genital surgery. This review focuses on the psychological issues that confront clinicians managing the care of persons born with DSD and their families. Particular attention is paid to processes and factors that potentially mediate or moderate psychosocial and psychosexual outcomes within and across developmental stages. PMID:23044882

Effects of prenatal exposure to WIFI signal (2.45GHz) on postnatal development and behavior in rat: Influence of maternal restraint.

PubMed

Othman, Haifa; Ammari, Mohamed; Sakly, Mohsen; Abdelmelek, Hafedh

2017-05-30

The present study was carried out to investigate the potential combined influence of maternal restraint stress and 2.45GHz WiFi signal exposure on postnatal development and behavior in the offspring of exposed rats. 24 pregnant albino Wistar rats were randomly assigned to four groups: Control, WiFi-exposed, restrained and both WiFi-exposed and restrained groups. Each of WiFi exposure and restraint occurred 2h/day along gestation till parturition. The pups were evaluated for physical development and neuromotor maturation. Moreover, elevated plus maze test, open field activity and stationary beam test were also determined on postnatal days 28, 30 and 31, respectively. After behavioral tests, the rats were anesthetized and their brains were removed for biochemical analysis. Our main findings showed no detrimental effects on gestation progress and outcomes at delivery in all groups. Subsequently, WiFi and restraint, per se and mainly in concert altered physical development of pups with slight differences between genders. Behaviorally, the gestational WiFi irradiation, restraint and especially the associated treatment affected the neuromotor maturation mainly in male progeny. At adult age, we noticed anxiety, motor deficit and exploratory behavior impairment in male offspring co-exposed to WiFi radiation and restraint, and in female progeny subjected to three treatments. The biochemical investigation showed that, all three treatments produced global oxidative stress in brain of both sexes. As for serum biochemistry, phosphorus, magnesium, glucose, triglycerides and calcium levels were disrupted. Taken together, prenatal WiFi radiation and restraint, alone and combined, provoked several behavioral and biochemical impairments at both juvenile and adult age of the offspring. Copyright © 2017 Elsevier B.V. All rights reserved.

Reduced prefrontal dopaminergic activity in valproic acid-treated mouse autism model.

PubMed

Hara, Yuta; Takuma, Kazuhiro; Takano, Erika; Katashiba, Keisuke; Taruta, Atsuki; Higashino, Kosuke; Hashimoto, Hitoshi; Ago, Yukio; Matsuda, Toshio

2015-08-01

Previous studies suggest that dysfunction of neurotransmitter systems is associated with the pathology of autism in humans and the disease model rodents, but the precise mechanism is not known. Rodent offspring exposed prenatally to VPA shows autism-related behavioral abnormalities. The present study examined the effect of prenatal VPA exposure on brain monoamine neurotransmitter systems in male and female mice. The prenatal VPA exposure did not affect the levels of dopamine (DA), noradrenaline (NA), serotonin (5-HT) and their metabolites in the prefrontal cortex and striatum, while it significantly reduced methamphetamine (METH) (1.0 mg/kg)-induced hyperlocomotion in male offspring. In vivo microdialysis study demonstrated that prenatal VPA exposure attenuated METH-induced increases in extracellular DA levels in the prefrontal cortex, while it did not affect those in extracellular NA and 5-HT levels. Prenatal VPA exposure also decreased METH-induced c-Fos expression in the prefrontal cortex and the mRNA levels of DA D1 and D2 receptors in the prefrontal cortex. These effects of VPA were not observed in the striatum. In contrast to male offspring, prenatal VPA exposure did not affect METH-induced increases in locomotor activity and prefrontal DA levels and the D1 and D2 receptor mRNA levels in the prefrontal cortex in female offspring. These findings suggest that prenatal VPA exposure causes hypofunction of prefrontal DA system in a sex-dependent way. Copyright © 2015 Elsevier B.V. All rights reserved.

Mid-gestation brain Doppler and head biometry in fetuses with congenital heart disease predict abnormal brain development at birth.

PubMed

Masoller, N; Sanz-CortéS, M; Crispi, F; Gómez, O; Bennasar, M; Egaña-Ugrinovic, G; Bargalló, N; Martínez, J M; Gratacós, E

2016-01-01

Fetuses with congenital heart disease (CHD) show evidence of abnormal brain development before birth, which is thought to contribute to adverse neurodevelopment during childhood. Our aim was to evaluate whether brain development in late pregnancy can be predicted by fetal brain Doppler, head biometry and the clinical form of CHD at the time of diagnosis. This was a prospective cohort study including 58 fetuses with CHD, diagnosed at 20-24 weeks' gestation, and 58 normal control fetuses. At the time of diagnosis, we recorded fetal head circumference (HC), biparietal diameter, middle cerebral artery pulsatility index (MCA-PI), cerebroplacental ratio (CPR) and brain perfusion by fractional moving blood volume. We classified cases into one of two clinical types defined by the expected levels (high or low) of placental (well-oxygenated) blood perfusion, according to the anatomical defect. All fetuses underwent subsequent 3T-magnetic resonance imaging (MRI) at 36-38 weeks' gestation. Abnormal prenatal brain development was defined by a composite score including any of the following findings on MRI: total brain volume <  10(th) centile, parietoccipital or cingulate fissure depth <  10(th) centile or abnormal metabolic profile in the frontal lobe. Logistic regression analysis demonstrated that MCA-PI (odds ratio (OR), 12.7; P = 0.01), CPR (OR, 8.7; P = 0.02) and HC (OR, 6.2; P = 0.02) were independent predictors of abnormal neurodevelopment; however, the clinical type of CHD was not. Fetal brain Doppler and head biometry at the time of CHD diagnosis are independent predictors of abnormal brain development at birth, and could be used in future algorithms to improve counseling and targeted interventions. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Diverse types of genetic variation converge on functional gene networks involved in schizophrenia.

PubMed

Gilman, Sarah R; Chang, Jonathan; Xu, Bin; Bawa, Tejdeep S; Gogos, Joseph A; Karayiorgou, Maria; Vitkup, Dennis

2012-12-01

Despite the successful identification of several relevant genomic loci, the underlying molecular mechanisms of schizophrenia remain largely unclear. We developed a computational approach (NETBAG+) that allows an integrated analysis of diverse disease-related genetic data using a unified statistical framework. The application of this approach to schizophrenia-associated genetic variations, obtained using unbiased whole-genome methods, allowed us to identify several cohesive gene networks related to axon guidance, neuronal cell mobility, synaptic function and chromosomal remodeling. The genes forming the networks are highly expressed in the brain, with higher brain expression during prenatal development. The identified networks are functionally related to genes previously implicated in schizophrenia, autism and intellectual disability. A comparative analysis of copy number variants associated with autism and schizophrenia suggests that although the molecular networks implicated in these distinct disorders may be related, the mutations associated with each disease are likely to lead, at least on average, to different functional consequences.

Autism as a neurodevelopmental disorder affecting communication and learning in early childhood: prenatal origins, post-natal course and effective educational support.

PubMed

Trevarthen, C

2000-01-01

Colwyn Trevarthen, working on autism, discussed the importance of time, rhythm and temporal processing in brain function. The brains of new born infants show highly coherent and coordinated patterns of activity over time, and their rhythms are remarkably similar to those of adults. Since the cortex has not yet developed, this coordination must be subcortical in origin. The likely source is the emotional motor system. He noted that the cerebellum might regulate the intricate timing of the development and expression of emotional communication. He also pointed out that emotional and motivational factors have often been seriously neglected in psychology (largely owing to a misplaced focus on 'cognition' as some isolated entity) and emphasized the potential importance of empathetic support and music therapy in helping autistic children. Copyright 2000 Harcourt Publishers Ltd.

Effects of exogenous agents on brain development: stress, abuse and therapeutic compounds.

PubMed

Archer, Trevor

2011-10-01

The range of exogenous agents likely to affect, generally detrimentally, the normal development of the brain and central nervous system defies estimation although the amount of accumulated evidence is enormous. The present review is limited to certain types of chemotherapeutic and "use-and-abuse" compounds and environmental agents, exemplified by anesthetic, antiepileptic, sleep-inducing and anxiolytic compounds, nicotine and alcohol, and stress as well as agents of infection; each of these agents have been investigated quite extensively and have been shown to contribute to the etiopathogenesis of serious neuropsychiatric disorders. To greater or lesser extent, all of the exogenous agents discussed in the present treatise have been investigated for their influence upon neurodevelopmental processes during the period of the brain growth spurt and during other phases uptill adulthood, thereby maintaining the notion of critical phases for the outcome of treatment whether prenatal, postnatal, or adolescent. Several of these agents have contributed to the developmental disruptions underlying structural and functional brain abnormalities that are observed in the symptom and biomarker profiles of the schizophrenia spectrum disorders and the fetal alcohol spectrum disorders. In each case, the effects of the exogenous agents upon the status of the affected brain, within defined parameters and conditions, is generally permanent and irreversible. © 2010 Blackwell Publishing Ltd.

Neuronal nuclei isolation from human postmortem brain tissue.

PubMed

Matevossian, Anouch; Akbarian, Schahram

2008-10-01

Neurons in the human brain become postmitotic largely during prenatal development, and thus maintain their nuclei throughout the full lifespan. However, little is known about changes in neuronal chromatin and nuclear organization during the course of development and aging, or in chronic neuropsychiatric disease. However, to date most chromatin and DNA based assays (other than FISH) lack single cell resolution. To this end, the considerable cellular heterogeneity of brain tissue poses a significant limitation, because typically various subpopulations of neurons are intermingled with different types of glia and other non-neuronal cells. One possible solution would be to grow cell-type specific cultures, but most CNS cells, including neurons, are ex vivo sustainable, at best, for only a few weeks and thus would provide an incomplete model for epigenetic mechanisms potentially operating across the full lifespan. Here, we provide a protocol to extract and purify nuclei from frozen (never fixed) human postmortem brain. The method involves extraction of nuclei in hypotonic lysis buffer, followed by ultracentrifugation and immunotagging with anti-NeuN antibody. Labeled neuronal nuclei are then collected separately using fluorescence-activated sorting. This method should be applicable to any brain region in a wide range of species and suitable for chromatin immunoprecipitation studies with site- and modification-specific anti-histone antibodies, and for DNA methylation and other assays.

Beyond classical inheritance: the influence of maternal genotype upon child's brain morphology and behavior.

PubMed

van der Knaap, Noortje J F; El Marroun, Hanan; Klumpers, Floris; Mous, Sabine E; Jaddoe, Vincent W V; Hofman, Albert; Homberg, Judith R; White, Tonya; Tiemeier, Henning; Fernández, Guillén

2014-07-16

Genetic variance has been associated with variations in brain morphology, cognition, behavior, and disease risk. One well studied example of how common genetic variance is associated with brain morphology is the serotonin transporter gene polymorphism within the promoter region (5-HTTLPR). Because serotonin is a key neurotrophic factor during brain development, genetically determined variations in serotonin activity during maturation, in particular during early prenatal development, may underlie the observed association. However, the intrauterine microenvironment is not only determined by the child's, but also the mother's genotype. Therefore, we hypothesized that maternal 5-HTTLPR genotype influences the child's brain development beyond direct inheritance. To test this hypothesis, we investigated 76 children who were all heterozygous for the 5-HTTLPR (sl) and who had mothers who were either homozygous for the long (ll) or the short allele (ss). Using MRI, we assessed brain morphology as a function of maternal genotype. Gray matter density of the somatosensory cortex was found to be greater in children of ss mothers compared with children of ll mothers. Behavioral assessment showed that fine motor task performance was altered in children of ll mothers and the degree of this behavioral effect correlated with somatosensory cortex density across individuals. Our findings provide initial evidence that maternal genotype can affect the child's phenotype beyond effects of classical inheritance. Our observation appears to be explained by intrauterine environmental differences or by differences in maternal behavior. Copyright © 2014 the authors 0270-6474/14/349516-06$15.00/0.

Prenatal ketamine exposure causes abnormal development of prefrontal cortex in rat

PubMed Central

Zhao, Tianyun; Li, Chuanxiang; Wei, Wei; Zhang, Haixing; Ma, Daqing; Song, Xingrong; Zhou, Libing

2016-01-01

Ketamine is commonly used for anesthesia and as a recreational drug. In pregnant users, a potential neurotoxicity in offspring has been noted. Our previous work demonstrated that ketamine exposure of pregnant rats induces affective disorders and cognitive impairments in offspring. As the prefrontal cortex (PFC) is critically involved in emotional and cognitive processes, here we studied whether maternal ketamine exposure influences the development of the PFC in offspring. Pregnant rats on gestational day 14 were treated with ketamine at a sedative dose for 2 hrs, and pups were studied at postnatal day 0 (P0) or P30. We found that maternal ketamine exposure resulted in cell apoptosis and neuronal loss in fetal brain. Upon ketamine exposure in utero, PFC neurons at P30 showed more dendritic branching, while cultured neurons from P0 PFC extended shorter neurites than controls. In addition, maternal ketamine exposure postponed the switch of NR2B/2A expression, and perturbed pre- and postsynaptic protein expression in the PFC. These data suggest that prenatal ketamine exposure impairs neuronal development of the PFC, which may be associated with abnormal behavior in offsprings. PMID:27226073

Prenatal Cell-Free DNA Screening

MedlinePlus

Prenatal cell-free DNA screening Overview Prenatal cell-free DNA (cfDNA) screening, also known as noninvasive prenatal screening, is a method to screen ... in a developing baby. During prenatal cell-free DNA screening, DNA from the mother and fetus is ...

Benefits of agomelatine in behavioral, neurochemical and blood brain barrier alterations in prenatal valproic acid induced autism spectrum disorder.

PubMed

Kumar, Hariom; Sharma, B M; Sharma, Bhupesh

2015-12-01

Valproic acid administration during gestational period causes behavior and biochemical deficits similar to those observed in humans with autism spectrum disorder. Although worldwide prevalence of autism spectrum disorder has been increased continuously, therapeutic agents to ameliorate the social impairment are very limited. The present study has been structured to investigate the therapeutic potential of melatonin receptor agonist, agomelatine in prenatal valproic acid (Pre-VPA) induced autism spectrum disorder in animals. Pre-VPA has produced reduction in social interaction (three chamber social behavior apparatus), spontaneous alteration (Y-Maze), exploratory activity (Hole board test), intestinal motility, serotonin levels (prefrontal cortex and ileum) and prefrontal cortex mitochondrial complex activity (complex I, II, IV). Furthermore, Pre-VPA has increased locomotor activity (actophotometer), anxiety, brain oxidative stress (thiobarbituric acid reactive species, glutathione, and catalase), nitrosative stress (nitrite/nitrate), inflammation (brain and ileum myeloperoxidase activity), calcium levels and blood brain barrier leakage in animals. Treatment with agomelatine has significantly attenuated Pre-VPA induced reduction in social interaction, spontaneous alteration, exploratory activity intestinal motility, serotonin levels and prefrontal cortex mitochondrial complex activity. Furthermore, agomelatine also attenuated Pre-VPA induced increase in locomotion, anxiety, brain oxidative stress, nitrosative stress, inflammation, calcium levels and blood brain barrier leakage. It is concluded that, Pre-VPA has induced autism spectrum disorder, which was attenuated by agomelatine. Agomelatine has shown ameliorative effect on behavioral, neurochemical and blood brain barrier alteration in Pre-VPA exposed animals. Thus melatonin receptor agonists may provide beneficial therapeutic strategy for managing autism spectrum disorder. Copyright © 2015 Elsevier Ltd. All rights reserved.

Effect of iron deficiency anemia in pregnancy on child mental development in rural China.

PubMed

Chang, Suying; Zeng, Lingxia; Brouwer, Inge D; Kok, Frans J; Yan, Hong

2013-03-01

To determine the impact of iron deficiency anemia (IDA) in pregnancy on young child development. A 2-year follow-up of 850 children born to women who participated in a double-blind cluster randomized controlled trial of prenatal micronutrient supplementation in western rural China. These women were randomly assigned to receive either daily folic acid, iron/folic acid (60 mg iron), or multiple micronutrients (with 30 mg iron) during pregnancy. Children were categorized into the prenatal-IDA and prenatal-non-IDA groups based on the mother's hemoglobin in the third trimester. Each group contained 3 subgroups based on mother's treatment: folic acid, iron/folic acid, and multiple micronutrients. Bayley scales of infant development were administered to the children to assess their development at 3, 6, 12, 18, and 24 months of age. Compared with the prenatal-non-IDA group, the prenatal-IDA group showed a significantly lower mental development index at 12, 18, and 24 months of age. The adjusted mean difference was 5.8 (95% confidence interval [CI], 1.1-10.5), 5.1 (95% CI, 1.2-9.0), and 5.3 (95% CI, 0.9-9.7), respectively. Further analysis showed that the mental development indexes in the prenatal-IDA group and prenatal-non-IDA group were similar with supplementation of iron/folic acid but were significantly lower in the prenatal-IDA group with supplementation of folic acid or multiple micronutrients. Prenatal IDA in the third trimester is associated with mental development of the child. However, prenatal supplementation with sufficient iron protects child development even when the woman's IDA was not properly corrected in pregnancy.

White matter integrity of the cerebellar peduncles as a mediator of effects of prenatal alcohol exposure on eyeblink conditioning

PubMed Central

Fan, Jia; Meintjes, Ernesta M.; Molteno, Christopher D.; Spottiswoode, Bruce S.; Dodge, Neil C.; Alhamud, Alkathafi A.; Stanton, Mark E.; Peterson, Bradley S.; Jacobson, Joseph L.; Jacobson, Sandra W.

2015-01-01

Fetal alcohol spectrum disorders (FASD) are characterized by a range of neurodevelopmental deficits that result from prenatal exposure to alcohol. These can include cognitive, behavioural, and neurological impairment, as well as structural and functional brain damage. Eyeblink conditioning (EBC) is among the most sensitive endpoints affected in FASD. The cerebellar peduncles, large bundles of myelinated nerve fibers that connect the cerebellum to the brainstem, constitute the principal white matter element of the EBC circuit. Diffusion tensor imaging (DTI) is used to assess white matter integrity in fibre pathways linking brain regions. DTI scans of 54 children with FASD and 23 healthy controls, mean age 10.1±1.0 yrs, from the Cape Town Longitudinal Cohort were processed using voxelwise group comparisons. Prenatal alcohol exposure was related to lower fractional anisotropy (FA) bilaterally in the superior cerebellar peduncles and higher mean diffusivity (MD) in the left middle peduncle, effects that remained significant after controlling for potential confounding variables. Lower FA and higher MD in these regions were associated with poorer EBC performance. Moreover, effects of alcohol exposure on EBC decreased significantly after inclusion of these DTI measures in regression models, suggesting that these white matter deficits partially mediate the relation of prenatal alcohol exposure to EBC. The associations of greater alcohol consumption with these DTI measures are largely attributable to greater radial diffusivity, possibly indicating poorer myelination. Thus, these data suggest that fetal alcohol-related deficits in EBC are attributable, in part, to poorer myelination in key regions of the cerebellar peduncles. PMID:25783559

Functional connectivity in prenatally stressed rats with and without maternal treatment with ladostigil, a brain-selective monoamine oxidase inhibitor.

PubMed

Goelman, G; Ilinca, R; Zohar, I; Weinstock, M

2014-09-01

Stress during pregnancy in humans is known to be a risk factor for neuropsychiatric disorders in the offspring. Prenatal stress in rats caused depressive-like behavior that was restored to that of controls by maternal treatment with ladostigil (8.5 mg/kg per day), a brain-selective monoamine oxidase (MAO) inhibitor that prevented increased anxiety-like behavior in stressed mothers. Ladostigil inhibited maternal striatal MAO-A and -B by 45-50% at the time the pups were weaned. Using resting state-functional connectivity magnetic resonance imaging on rat male offspring of control mothers, and mothers stressed during gestation with and without ladostigil treatment, we identified neuronal connections that differed between these groups. The percentage of significant connections within a predefined predominantly limbic network in control rats was 23.3 within the right and 22.0 within the left hemisphere. Prenatal stress disturbed hemispheric symmetry, resulting in 30.2 and 21.6%, significant connections in the right and left hemispheres, respectively, but this was fully restored in the maternal ladostigil group to 24.6% in both hemispheres. All connections that were modified in prenatally stressed rats and restored by maternal drug treatment were associated with the dopaminergic system. Specifically, we observed that restoration of the connections of the right nucleus accumbens shell with frontal areas, the cingulate, septum and motor and sensory cortices, and those of the right globus pallidus with the infra-limbic and the dentate gyrus, were most important for prevention of depressive-like behavior. © 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

The pharmacokinetic profile of synthetic cathinones in a pregnancy model.

PubMed

Strange, Lauren G; Kochelek, Kerri; Keasling, Robert; Brown, Stacy D; Pond, Brooks B

2017-09-01

In recent years, the abuse of synthetic cathinones or 'bath salts' has become a major public health concern. Although these compounds were initially sold legally and labeled "not for human consumption", the 'bath salts' are psychostimulants, with similar structures and pharmacologic mechanisms to cocaine, the amphetamines, and 3,4 methylendioxymethamphetamine (MDMA, Molly, or Ecstasy). The reported use of these substances by women of child-bearing age highlights the necessity of studies seeking to delineate risks of prenatal exposure. Three popular drugs of this type are methylone, mephedrone, and 3, 4-methylenedioxypyrovalerone (MDPV). Unfortunately, there is currently no information available on the teratogenicity of these compounds, or of the extent to which they cross the placenta. As such, the purpose of this study was to examine the pharmacokinetic profile of the 'bath salts' in a pregnancy model. Pregnant mice (E17.5 gestation) were injected intraperitoneally with a cocktail of 5mg/kg methylone, 10mg/kg mephedrone, and 3mg/kg (MDPV) dissolved in sterile saline. Maternal brain, maternal plasma, placenta, and fetal brain were collected at 30s, 1min, 5min, 10min, 15min, 30min, 1h, 2h, 4h, and 8h following injection. Methylone, mephedrone, and MDPV were extracted from tissue by solid phase extraction, and concentrations were determined using a previously validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Interestingly, all 3 cathinones reached measurable concentrations in the placenta, as well as the fetal brain; in fact, for MDPV, the maximal concentration (Cmax) was highest in fetal brain, while mephedrone's highest Cmax value was achieved in placenta. Additionally, the total drug exposure for all 3 compounds (as represented by area under the curve, AUC) was higher in fetal matrices (placenta and fetal brain) than in maternal matrices (maternal brain and plasma), and the half-lives for the drugs were longer. Given the extensive presence of methylone, mephedrone, and MDPV in the fetal brain following prenatal exposure, fetal risk is definitely a concern. As there are currently no prenatal studies available on the teratogenicity of these agents, pregnant patients should be informed about the potential risks that these substances may have. Copyright © 2017 Elsevier Inc. All rights reserved.

Effects of Radioprotective Agents on Foot Deformities and Gait Defects in the Prenatally X-Irradiated Rat.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ershoff, B. H.; Steers, C. W.; Kruger, L.

1962-11-01

The radioprotective agents AET, cysteamine, and MEG largely prevented the occurrence of foot deformities and a defect in gait in the young of rats exposed to a single dose of 150 r total-body x irradiation on the 14th day og pregnancy'. These substances also prevented in part the occurrence of an abnormality in development of the cerebral hemispheres of such young but were without significant effect in altering an attendant reduction in the ratio of brain to body weight.

Postnatal treatment using curcumin supplements to amend the damage in VPA-induced rodent models of autism.

PubMed

Al-Askar, Maha; Bhat, Ramesa Shafi; Selim, Manar; Al-Ayadhi, Laila; El-Ansary, Afaf

2017-05-10

Valproic acid (VPA) is used as a first-line antiepileptic agent and is undergoing clinical trials for use as a treatment for many disorders. Mothers undergoing VPA treatment during early pregnancy reportedly show increased rates of autism among their offspring. The benefits of curcumin supplementation were investigated using an animal model of VPA-induced autism. The study was performed using a rodent model of autism by exposing rat fetuses to valproic acid (VPA) on the 12.5th day of gestation. At 7 days from their birth, the animals were supplemented with a specific dose of curcumin. Forty neonatal male Western Albino rats were divided into four groups. Rats in group I received only phosphate-buffered saline, rats in group II were the prenatal VPA exposure newborns, rats in group III underwent prenatal VPA exposure supplemented with postnatal curcumin, and rats in group IV were given only postnatal curcumin supplements. VPA rats exhibited delayed maturation and lower body and brain weights with numerous signs of brain toxicity, such as depletion of IFN-γ, serotonin, glutamine, reduced glutathione, glutathione S-transferase, lipid peroxidase with an increase in CYP450, IL-6, glutamate, and oxidized glutathione. A curcumin supplement moderately corrected these dysfunctions and was especially noticeable in improving delayed maturation and abnormal weight. Curcumin plays a significant therapeutic role in attenuating brain damage that has been induced by prenatal VPA exposure in rats; however, its therapeutic role as a dietary supplement still must be certified for use in humans.

Flow cytometric examination of apoptotic effect on brain tissue in postnatal period created by intrauterine oxcarbazepine and gabapentin exposure.

PubMed

Erisgin, Z; Tekelioglu, Y

For epileptics, pregnancy contains the balance between no seizure period and antiepileptic use having the least teratogenicity risk. The purpose is to analyse with flow cytometry the apoptotic effects on postnatal brain tissue caused by prenatal use of second generation antiepileptics oxcarbazepine (OXC) and gabapentin (GBP) having different effect mechanisms. 30 (n = 5 each group) Wistar albino male rats (45-days-old) are used. First 3 groups are exposed to OXC (100 mg/kg/day), GBP (50 mg/kg/day), and saline, respectively on the 1st-5th prenatal days (preimplantation-implantation period) while the second 3 groups are exposed to the same substances on the 6th-15th prenatal days (organogenesis), respectively. After sacrifice, brain tissue samples were made into suspension with mechanic and enzymatic digestion and examined with flow cytometry. While apoptosis rate appeared high in rats exposed to OXC on the 1st-5th (p < 0.001) and 6th-15th days (p < 0.001), no significant difference occurred for GBP (p = 0.004; p = 0.012) and saline (p = 0.012). Considering time effect in three treatment groups, while difference was not significant for PSS and GBP groups (p = 0.847 and p = 0.934), apoptosis rate was significantly high for OXC on the 6th-15th days compared to the 1st-5th days (p < 0.001). It is observed that the use of OXC causes neurotoxicity during preimplantation, implantation and, especially, organogenesis period (neurogenesis) whereas GBP does not (Fig. 3, Ref. 32).

Prenatal and lactational exposure to low-doses of bisphenol A alters adult mice behavior.

PubMed

Nakamura, Keiko; Itoh, Kyoko; Dai, Hongmei; Han, Longzhe; Wang, Xiaohang; Kato, Shingo; Sugimoto, Tohru; Fushiki, Shinji

2012-01-01

Bisphenol A (BPA) is an endocrine-disrupting chemical, widely used in dentistry and various industries. We previously reported that BPA affected murine neocortical development by accelerating neuronal differentiation/migration, resulting in abnormal neocortical architecture as well as aberrant thalamocortical connections in the brains of adult mice. The aim of this study was to investigate whether prenatal and lactational BPA exposure affected behavior in adult mice. Pregnant mice were injected subcutaneously with 20μg/kg of BPA daily from embryonic day 0 (E0) until postnatal day 21 (P21). Control animals received a vehicle alone. Behavioral tests (n=15-20) were conducted at postnatal 3weeks (P3W) and P10-15W. After an open-field test, an elevated plus maze and Morris water maze tests were performed. The total distance in the elevated plus maze test at P3W and in the open-field test at P10W was significantly decreased in the BPA-exposed group, compared with the control group. Significant sex differences were observed in the time spent in the central area in the open-field test at P3W and in the total distance in the elevated plus maze test at P11W. These results indicated that prenatal and lactational BPA exposure disturbed the murine behavior in the postnatal development period and the adult mice. Copyright © 2011 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Conceptions of Prenatal Development: Behavioral Embryology

ERIC Educational Resources Information Center

Gottlieb, Gilbert

1976-01-01

Describes recent progress in research on prenatal behavioral development and in a systematic fashion the various ways in which prenatal experience can affect the development of behavior in the neonate as well as in the embryo and fetus. (Author/RK)

Assessment of sex specific endocrine disrupting effects in the prenatal and pre-pubertal rodent brain.

PubMed

Rebuli, Meghan E; Patisaul, Heather B

2016-06-01

Brain sex differences are found in nearly every region of the brain and fundamental to sexually dimorphic behaviors as well as disorders of the brain and behavior. These differences are organized during gestation and early adolescence and detectable prior to puberty. Endocrine disrupting compounds (EDCs) interfere with hormone action and are thus prenatal exposure is hypothesized to disrupt the formation of sex differences, and contribute to the increased prevalence of pediatric neuropsychiatric disorders that present with a sex bias. Available evidence for the ability of EDCs to impact the emergence of brain sex differences in the rodent brain was reviewed here, with a focus on effects detected at or before puberty. The peer-reviewed literature was searched using PubMed, and all relevant papers published by January 31, 2015 were incorporated. Endpoints of interest included molecular cellular and neuroanatomical effects. Studies on behavioral endpoints were not included because numerous reviews of that literature are available. The hypothalamus was found to be particularly affected by estrogenic EDCs in a sex, time, and exposure dependent manner. The hippocampus also appears vulnerable to endocrine disruption by BPA and PCBs although there is little evidence from the pre-pubertal literature to make any conclusions about sex-specific effects. Gestational EDC exposure can alter fetal neurogenesis and gene expression throughout the brain including the cortex and cerebellum. The available literature primarily focuses on a few, well characterized EDCs, but little data is available for emerging contaminants. The developmental EDC exposure literature demonstrates evidence of altered neurodevelopment as early as fetal life, with sex specific effects observed throughout the brain even before puberty. Copyright © 2015 Elsevier Ltd. All rights reserved.

Corticosterone mediates some but not other behavioural changes induced by prenatal stress in rats.

PubMed

Salomon, S; Bejar, C; Schorer-Apelbaum, D; Weinstock, M

2011-02-01

The effect of daily varied stress from days 13-21 of gestation in Wistar rats was investigated by tests of learning and memory and anxiogenic behaviour in the 60-day-old offspring of both sexes. Prenatal stress decreased the anogenital distance in males at 1 day of age. Anxiogenic behaviour in the elevated plus maze was seen in prenatally-stressed rats of both genders. There was no significant gender difference in the rate of spatial learning in the Morris water maze but prenatal stress only slowed that of males. In the object recognition test with an inter-trial interval of 40 min, females but not males, discriminated between a familiar and novel object. Prenatal stress did not affect object discrimination in females but feminised that in males. Maternal adrenalectomy with replacement of basal corticosterone levels in the drinking fluid prevented all of the above effects of prenatal stress in the offspring. To mimic the peak corticosterone levels and time course of elevation in response to stress, corticosterone (3 mg/kg) was injected twice (0 and 30 min) on days 13-16 and once on days 17-20 of gestation to adrenalectomised mothers. This treatment re-instated anxiogenic behaviour similar to that induced by prenatal stress, indicating that it is mediated by exposure of the foetal brain to raised levels of corticosterone. However, steroid administration to adrenalectomised dams did not decrease anogenital distance, feminise object recognition memory or slow spatial learning in their male offspring. The findings indicate that other adrenal hormones are necessary to induce these effects of prenatal stress. © 2011 The Authors. Journal of Neuroendocrinology © 2011 Blackwell Publishing Ltd.

Developmental expression of VGF mRNA in the prenatal and postnatal rat.

PubMed

Snyder, S E; Pintar, J E; Salton, S R

1998-04-27

VGF is a developmentally regulated, secretory peptide precursor that is expressed by neurons and neuroendocrine cells and that has its transcription and secretion induced rapidly by neurotrophins and by depolarization. To gain insight into the possible functions and regulation of VGF in vivo, we have characterized the distribution of VGF mRNA in the developing rat nervous system. VGF expression was first detectable at embryonic day 11.5 in the primordia of cranial, sympathetic, and dorsal root ganglia, and its distribution expanded throughout development to include significant expression throughout the brain, spinal cord, and retina of the adult rat. The earliest expression of VGF, therefore, appeared in the peripheral nervous system as developing neurons settled in their designated ganglia. In many regions of the brain, VGF mRNA levels were found to be highest during periods when axonal outgrowth and synaptogenesis predominate. Areas of the central nervous system that contain predominantly dividing cells never displayed any VGF mRNA expression, nor did the vast majority of nonneural tissues.

The intersection of stress, drug abuse and development.

PubMed

Thadani, Pushpa V

2002-01-01

Use or abuse of licit and illicit substances is often associated with environmental stress. Current clinical evidence clearly demonstrates neurobehavioral, somatic growth and developmental deficits in children born to drug-using mothers. However, the effects of environmental stress and its interaction with prenatal drug exposure on a child's development is unknown. Studies in pregnant animals under controlled conditions show drug-induced long-term alterations in brain structures and functions of the offspring. These cytoarchitecture alterations in the brain are often associated with perturbations in neurotransmitter systems that are intimately involved in the regulation of the stress responses. Similar abnormalities have been observed in the brains of animals exposed to other adverse exogenous (e.g., environmental stress) and/or endogenous (e.g., glucocorticoids) experiences during early life. The goal of this article is to: (1) provide evidence and a perspective that common neural systems are influenced during development both by perinatal drug exposure and early stress exposure; and (2) identify gaps and encourage new research examining the effects of early stress and perinatal drug exposure, in animal models, that would elucidate how stress- and drug-induced perturbations in neural systems influence later vulnerability to abused drugs in adult offspring.

Testosterone-related cortical maturation across childhood and adolescence.

PubMed

Nguyen, Tuong-Vi; McCracken, James; Ducharme, Simon; Botteron, Kelly N; Mahabir, Megan; Johnson, Wendy; Israel, Mimi; Evans, Alan C; Karama, Sherif

2013-06-01

Neuroendocrine theories of brain development hold testosterone as the predominant factor mediating sex-specific cortical growth and the ensuing lateralization of hemispheric function. However, studies to date have focussed on prenatal testosterone rather than pubertal changes in testosterone. Yet, animal studies have shown a high density of androgen-sensitive receptors in multiple key cortical areas, and puberty is known to coincide with both a significant rise in testosterone and the emergence of behavioral sex differences, suggesting peripubertal influences of testosterone on brain development. Here, we used linear mixed models to examine sex-specific cortical maturation associated with changes in testosterone levels in a longitudinal sample of developmentally healthy children and adolescents. A significant "sex by age by testosterone" interaction on cortical thickness (CTh) involving widespread areas of the developing brain was found. Testosterone levels were associated with CTh changes in regions of the left hemisphere in males and of the right hemisphere in females. In both sexes, the relationship between testosterone and CTh varied across the age span. These findings show the association between testosterone and CTh to be complex, highly dynamic, and to vary, depending on sex and age; they also suggest sex-related hemispheric lateralization effects of testosterone in humans.

Moderate prenatal alcohol exposure alters behavior and neuroglial parameters in adolescent rats.

PubMed

Brolese, Giovana; Lunardi, Paula; Broetto, Núbia; Engelke, Douglas S; Lírio, Franciane; Batassini, Cristiane; Tramontina, Ana Carolina; Gonçalves, Carlos-Alberto

2014-08-01

Alcohol consumption by women during gestation has become increasingly common. Although it is widely accepted that exposure to high doses of ethanol has long-lasting detrimental effects on brain development, the case for moderate doses is underappreciated, and benchmark studies have demonstrated structural and behavioral defects associated with moderate prenatal alcohol exposure in humans and animal models. This study aimed to investigate the influence of in utero exposure to moderate levels of ethanol throughout pregnancy on learning/memory, anxiety parameters and neuroglial parameters in adolescent offspring. Female rats were exposed to an experimental protocol throughout gestation up to weaning. After mating, the dams were divided into three groups and treated with only water (control), non-alcoholic beer (vehicle) or 10% (vv) beer solution (moderate prenatal alcohol exposure - MPAE). Adolescent male offspring were subjected to the plus-maze discriminative avoidance task to evaluate learning/memory and anxiety-like behavior. Hippocampi were dissected and slices were obtained for immunoquantification of GFAP, NeuN, S100B and the NMDA receptor. The MPAE group clearly presented anxiolytic-like behavior, even though they had learned how to avoid the aversive arm. S100B protein was increased in the cerebrospinal fluid (CSF) in the group treated with alcohol, and alterations in GFAP expression were also shown. This study indicates that moderate ethanol doses administered during pregnancy could induce anxiolytic-like effects, suggesting an increase in risk-taking behavior in adolescent male offspring. Furthermore, the data show the possibility that glial cells are involved in the altered behavior present after prenatal ethanol treatment. Copyright © 2014 Elsevier B.V. All rights reserved.

Genetic and non-genetic animal models for autism spectrum disorders (ASD).

PubMed

Ergaz, Zivanit; Weinstein-Fudim, Liza; Ornoy, Asher

2016-09-01

Autism spectrum disorder (ASD) is associated, in addition to complex genetic factors, with a variety of prenatal, perinatal and postnatal etiologies. We discuss the known animal models, mostly in mice and rats, of ASD that helps us to understand the etiology, pathogenesis and treatment of human ASD. We describe only models where behavioral testing has shown autistic like behaviors. Some genetic models mimic known human syndromes like fragile X where ASD is part of the clinical picture, and others are without defined human syndromes. Among the environmentally induced ASD models in rodents, the most common model is the one induced by valproic acid (VPA) either prenatally or early postnatally. VPA induces autism-like behaviors following single exposure during different phases of brain development, implying that the mechanism of action is via a general biological mechanism like epigenetic changes. Maternal infection and inflammation are also associated with ASD in man and animal models. Copyright © 2016 Elsevier Inc. All rights reserved.

Prenatal stress challenge impairs fetal lung development and asthma severity sex-specifically in mice.

PubMed

Zazara, Dimitra E; Perani, Clara V; Solano, María E; Arck, Petra C

2018-02-01

Allergic asthma is an increasing health problem worldwide. Interestingly, prenatal challenges such as stress have been associated with an increased risk for asthma during childhood. The underlying pathogenesis of how prenatal stress increases the risk for asthma still remains unclear. Potential targets could be that the fetal immune ontogeny or fetal lung development are compromised by prenatal challenges. Here, we aimed to identify whether prenatal stress challenge affects fetal lung development in mice. C57BL/6 pregnant mice were challenged with sound stress and fetal lung development was assessed histologically. Whilst prenatal stress challenge did not profoundly affect lung development in male fetuses, it resulted in less extensive terminal sacs, surrounded by thicker mesenchymal tissue in female fetuses. Thus, prenatal stress disrupted fetal lung development sex-specifically. Interestingly, upon prenatal stress challenge, the airway hyperresponsiveness and eosinophilic inflammation- two hallmarks of asthma - were significantly increased in adult female offspring, whilst regulatory CD4+ T cells were reduced. These findings strongly underpin the sex-specific association between s challenged fetal development and a sex-specific altered severity of asthma in adult offspring. Our model now allows to identify maternal markers through which the risk for asthma and possible other diseases is vertically transferred before birth in response to challenges. Such identification then opens avenues for primary disease prevention. Copyright © 2017 Elsevier B.V. All rights reserved.

Epigenetic Mechanisms in Developmental Alcohol-Induced Neurobehavioral Deficits

PubMed Central

Basavarajappa, Balapal S.; Subbanna, Shivakumar

2016-01-01

Alcohol consumption during pregnancy and its damaging consequences on the developing infant brain are significant public health, social, and economic issues. The major distinctive features of prenatal alcohol exposure in humans are cognitive and behavioral dysfunction due to damage to the central nervous system (CNS), which results in a continuum of disarray that is collectively called fetal alcohol spectrum disorder (FASD). Many rodent models have been developed to understand the mechanisms of and to reproduce the human FASD phenotypes. These animal FASD studies have provided several molecular pathways that are likely responsible for the neurobehavioral abnormalities that are associated with prenatal alcohol exposure of the developing CNS. Recently, many laboratories have identified several immediate, as well as long-lasting, epigenetic modifications of DNA methylation, DNA-associated histone proteins and microRNA (miRNA) biogenesis by using a variety of epigenetic approaches in rodent FASD models. Because DNA methylation patterns, DNA-associated histone protein modifications and miRNA-regulated gene expression are crucial for synaptic plasticity and learning and memory, they can therefore offer an answer to many of the neurobehavioral abnormalities that are found in FASD. In this review, we briefly discuss the current literature of DNA methylation, DNA-associated histone proteins modification and miRNA and review recent developments concerning epigenetic changes in FASD. PMID:27070644

Behavior and Brain Gene Expression Changes in Mice Exposed to Preimplantation and Prenatal Stress

PubMed Central

Strata, Fabrizio; Giritharan, Gnanaratnam; Sebastiano, Francesca Di; Piane, Luisa Delle; Kao, Chia-Ning; Donjacour, Annemarie

2015-01-01

Preimplantation culture of mouse embryos has been suggested to result in reduced anxiety-like behavior in adulthood. Here, we investigated the effects of in vitro fertilization (IVF), embryo culture, and different diets on anxiety-like behavior using the elevated plus maze (EPM). We hypothesized that exposure to suboptimal conditions during the preimplantation stage would interact with the suboptimal diet to alter behavior. The expression of genes related to anxiety was then assessed by quantitative real-time polymerase chain reaction in various brain regions. When fed a normal diet during gestation and a moderately high-fat Western diet (WD) postnatally, naturally conceived (NC) and IVF mice showed similar anxiety-like behavior on the EPM. However, when fed a low-protein diet prenatally and a high-fat diet postnatally (LP/HF), NC mice showed a modest increase in anxiety-like behavior, whereas IVF mice showed the opposite: a strongly reduced anxiety-like behavior on the EPM. The robust reduction in anxiety-like behavior in IVF males fed the LP/HF diets was, intriguingly, associated with reduced expression of MAO-A, CRFR2, and GABA markers in the hypothalamus and cortex. These findings are discussed in relation to the developmental origin of health and disease hypothesis and the 2-hit model, which suggests that 2 events, occurring at different times in development, can act synergistically with long-term consequences observed during adulthood. PMID:25398605

Influence of prenatal iron deficiency and MAOA genotype on response to social challenge in rhesus monkey infants.

PubMed

Golub, M S; Hogrefe, C E; Unger, E L

2012-04-01

Social and emotional behaviors are known to be sensitive to both developmental iron deficiency (ID) and monoamine oxidase A (MAOA) gene polymorphisms. In this study, male rhesus monkey infants deprived of dietary iron in utero were compared with iron sufficient (IS) controls (n = 10/group). Half of each group had low MAOA activity genotypes and half had high MAOA activity genotypes. A series of social response tests were conducted at 3-14 months of age. MAOA genotype influenced attention to a video of aggressive behavior, emotional expression (fear, grimace and sniff) in the social intruder test, social actions (displacement, grooming) in the social dyad test, and aggressive responses to a threatening picture. Interactions between MAOA and prenatal ID were seen in response to the aggressive video, in temperament ratings, in affiliative behavior in the social dyad test, in cortisol response in the social buffering test and in response to a social intruder and to pictures with social and nonsocial themes. In general, the effects of ID were dependent on MAOA genotype in terms of both direction and size of the effect. Nutrition/genotype interactions may shed new light on behavioral consequences of nutritional deprivation during brain development. © 2012 The Authors. Genes, Brain and Behavior © 2012 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.

Prenatal Nicotine Exposure Disrupts Infant Neural Markers of Orienting.

PubMed

King, Erin; Campbell, Alana; Belger, Aysenil; Grewen, Karen

2018-06-07

Prenatal nicotine exposure (PNE) from maternal cigarette smoking is linked to developmental deficits, including impaired auditory processing, language, generalized intelligence, attention, and sleep. Fetal brain undergoes massive growth, organization, and connectivity during gestation, making it particularly vulnerable to neurotoxic insult. Nicotine binds to nicotinic acetylcholine receptors, which are extensively involved in growth, connectivity, and function of developing neural circuitry and neurotransmitter systems. Thus, PNE may have long-term impact on neurobehavioral development. The purpose of this study was to compare the auditory K-complex, an event-related potential reflective of auditory gating, sleep preservation and memory consolidation during sleep, in infants with and without PNE and to relate these neural correlates to neurobehavioral development. We compared brain responses to an auditory paired-click paradigm in 3- to 5-month-old infants during Stage 2 sleep, when the K-complex is best observed. We measured component amplitude and delta activity during the K-complex. Infants with PNE demonstrated significantly smaller amplitude of the N550 component and reduced delta-band power within elicited K-complexes compared to nonexposed infants and also were less likely to orient with a head turn to a novel auditory stimulus (bell ring) when awake. PNE may impair auditory sensory gating, which may contribute to disrupted sleep and to reduced auditory discrimination and learning, attention re-orienting, and/or arousal during wakefulness reported in other studies. Links between PNE and reduced K-complex amplitude and delta power may represent altered cholinergic and GABAergic synaptic programming and possibly reflect early neural bases for PNE-linked disruptions in sleep quality and auditory processing. These may pose significant disadvantage for language acquisition, attention, and social interaction necessary for academic and social success.

Long-term alterations to DNA methylation as a biomarker of prenatal alcohol exposure: From mouse models to human children with fetal alcohol spectrum disorders.

PubMed

Laufer, Benjamin I; Chater-Diehl, Eric J; Kapalanga, Joachim; Singh, Shiva M

2017-05-01

Rodent models of Fetal Alcohol Spectrum Disorders (FASD) have revealed that prenatal alcohol exposure (PAE) results in differential DNA cytosine methylation in the developing brain. The resulting genome-wide methylation changes are enriched in genes with neurodevelopmental functions. The profile of differential methylation is dynamic and present in some form for life. The methylation changes are transmitted across subsequent mitotic divisions, where they are maintained and further modified over time. More recent follow up has identified a profile of the differential methylation in the buccal swabs of young children born with FASD. While distinct from the profile observed in brain tissue from rodent models, there are similarities. These include changes in genes belonging to a number of neurodevelopmental and behavioral pathways. Specifically, there is increased methylation at the clustered protocadherin genes and deregulation of genomically imprinted genes, even though no single gene is affected in all patients studied to date. These novel results suggest further development of a methylation based strategy could enable early and accurate diagnostics and therapeutics, which have remained a challenge in FASD research. There are two aspects of this challenge that must be addressed in the immediate future: First, the long-term differential methylomics observed in rodent models must be functionally confirmed. Second, the similarities in differential methylation must be further established in humans at a methylomic level and overcome a number of technical limitations. While a cure for FASD is challenging, there is an opportunity for the development of early diagnostics and attenuations towards a higher quality of life. Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.

Effects of prenatal X-irradiation on postnatal testicular development and function in the Wistar rat: development/teratology/behavior/radiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jensh, R.P.; Brent, R.L.

1988-11-01

It is evident that significant permanent tissue hypoplasia can be produced following radiation exposure late in fetal development. Because two organs, brain and testes, are developmentally and functionally interrelated, it was of interest to determine whether fetal testicular hypoplasia was a primary or a secondary effect of fetal brain irradiation. Twenty-four pregnant Wistar strain rats were randomly assigned to one of four groups, and a laparotomy was performed on day 18 of gestation. The fetuses received sham irradiation, whole body irradiation, or only head/thorax or pelvic body irradiation at a dosage level of 1.5 Gy. Mothers were allowed to delivermore » and raise their offspring until postnatal day 30, when the offspring were weaned. At 60 days of age, 74 male offspring were allowed to mate with colony control females of similar age until successful insemination or until the males reached 90 days of age, when they were killed. Testes were weighed and processed for histologic examination. Direct radiation of testes, due to whole body or pelvic exposure, resulted in testicular growth retardation and significantly reduced spermatogenesis. Breeding activity of the males and the percent of positive inseminations were also slightly reduced. However, a significant percentage of male offspring receiving direct testicular radiation did produce offspring. Head/thorax-only irradiation did not adversely affect testicular growth or spermatogenesis. Therefore, the use of histologic analysis as the sole determinant of infertility may be misleading. This study indicates that testicular growth retardation and an increased infertility rate result from direct prenatal exposure of rat testes to X-radiation and are not necessarily mediated via X-irradiation effects on the central nervous system.« less

[Birth weight and later nutritional status, cognitive development and job status: a critical revision].

PubMed

Villegas, S; Ivanovic, R; Pérez, H; Almagià, A; Urrutia, M S; Rodríguez, M del P; Larrain, C; Ivanovic, D

2009-12-01

The impact of prenatal nutritional status, assessed through birth weight (BW) and their effects in the short, medium and long-term on nutritional status, cognitive development and job status in the adult life, has been a problem of interest for several researchers; as regards, some of these report a positive and significant association between these variables and others do not find any relation. Children with insufficient, low or very low BW despite the early more deteriorate nutritional status should present higher risk for brain maturation, failure cognitive development and lowered head circumference which implies both lowered brain volume and intellectual development. In the short and medium-term, this situation damages the learning process at school-age, while in the long-term this might condition the quality of jobs. At present, the body of knowledge pinpoints that findings related to these associations is not conclusive verifying a great controversy in these matters. This review article has the purpose of analyzing the current evidence, in order to stimulate research about to these aspects which are relevant for child development and their future life.

Prenatal low-dose methylmercury exposure impairs neurite outgrowth and synaptic protein expression and suppresses TrkA pathway activity and eEF1A1 expression in the rat cerebellum

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fujimura, Masatake, E-mail: fujimura@nimd.go.jp; Usuki, Fusako; Cheng, Jinping

Methylmercury (MeHg) is a highly neurotoxic environmental chemical that can cause developmental impairments. Human fetuses and neonates are particularly susceptible to MeHg toxicity; however, the mechanisms governing its effects in the developing brain are unclear. In the present study, we investigated the effects of prenatal and lactational MeHg exposure on the developing cerebellum in rats. We demonstrated that exposure to 5 ppm MeHg decreased postnatal expression of pre- and postsynaptic proteins, suggesting an impairment in synaptic development. MeHg exposure also reduced neurite outgrowth, as shown by a decrease in the expression of the neurite marker neurofilament H. These changes weremore » not observed in rats exposed to 1 ppm MeHg. In order to define the underlying mechanism, we investigated the effects of MeHg exposure on the tropomyosin receptor kinase (Trk) A pathway, which plays important roles in neuronal differentiation and synapse formation. We demonstrated suppression of the TrkA pathway on gestation day 20 in rats exposed to 5 ppm MeHg. In addition, down-regulation of eukaryotic elongation factor 1A1 (eEF1A1) was observed on postnatal day 1. eEF1A1 knockdown in differentiating PC12 cells impaired neurite outgrowth and synaptic protein expression, similar to the results of MeHg exposure in the cerebellum. These results suggest that suppression of the TrkA pathway and subsequent decreases in eEF1A1 expression induced by prenatal exposure to MeHg may lead to reduced neurite outgrowth and synaptic protein expression in the developing cerebellum. - Highlights: • Prenatal exposure to MeHg decreased postnatal expression of synaptic proteins. • MeHg exposure also reduced neurite outgrowth postnatally. • Suppression of the TrkA pathway and eEF1A1 expression was induced by MeHg exposure. • eEF1A1 knockdown impaired neurite outgrowth and synaptic protein expression.« less

Prenatal β-catenin/Brn2/Tbr2 transcriptional cascade regulates adult social and stereotypic behaviors

PubMed Central

Belinson, H; Nakatani, J; Babineau, BA; Birnbaum, RY; Ellegood, J; Bershteyn, M; McEvilly, RJ; Long, JM; Willert, K; Klein, OD; Ahituv, N; Lerch, JP; Rosenfeld, GM; Wynshaw-Boris, A

2015-01-01

Social interaction is a fundamental behavior in all animal species, but the developmental timing of the social neural circuit formation and the cellular and molecular mechanisms governing its formation are poorly understood. We generated a mouse model with mutations in two Dishevelled genes, Dvl1 and Dvl3, that displays adult social and repetitive behavioral abnormalities associated with transient embryonic brain enlargement during deep layer cortical neuron formation. These phenotypes were mediated by the embryonic expansion of basal neural progenitor cells (NPCs) via deregulation of a β-catenin/Brn2/Tbr2 transcriptional cascade. Transient pharmacological activation of the canonical Wnt pathway during this period of early corticogenesis rescued the β-catenin/Brn2/Tbr2 transcriptional cascade and the embryonic brain phenotypes. Remarkably, this embryonic treatment prevented adult behavioral deficits and partially rescued abnormal brain structure in Dvl mutant mice. Our findings define a mechanism that links fetal brain development and adult behavior, demonstrating a fetal origin for social and repetitive behavior deficits seen in disorders such as autism. PMID:26830142

Prenatal β-catenin/Brn2/Tbr2 transcriptional cascade regulates adult social and stereotypic behaviors.

PubMed

Belinson, H; Nakatani, J; Babineau, B A; Birnbaum, R Y; Ellegood, J; Bershteyn, M; McEvilly, R J; Long, J M; Willert, K; Klein, O D; Ahituv, N; Lerch, J P; Rosenfeld, M G; Wynshaw-Boris, A

2016-10-01

Social interaction is a fundamental behavior in all animal species, but the developmental timing of the social neural circuit formation and the cellular and molecular mechanisms governing its formation are poorly understood. We generated a mouse model with mutations in two Disheveled genes, Dvl1 and Dvl3, that displays adult social and repetitive behavioral abnormalities associated with transient embryonic brain enlargement during deep layer cortical neuron formation. These phenotypes were mediated by the embryonic expansion of basal neural progenitor cells (NPCs) via deregulation of a β-catenin/Brn2/Tbr2 transcriptional cascade. Transient pharmacological activation of the canonical Wnt pathway during this period of early corticogenesis rescued the β-catenin/Brn2/Tbr2 transcriptional cascade and the embryonic brain phenotypes. Remarkably, this embryonic treatment prevented adult behavioral deficits and partially rescued abnormal brain structure in Dvl mutant mice. Our findings define a mechanism that links fetal brain development and adult behavior, demonstrating a fetal origin for social and repetitive behavior deficits seen in disorders such as autism.

Psychological aspects of the treatment of patients with disorders of sex development.

PubMed

Sandberg, David E; Gardner, Melissa; Cohen-Kettenis, Peggy T

2012-10-01

Research on the psychological development of persons with Disorders of Sex Development (DSD) has focused on understanding the influence of atypical sex hormone exposure during steroid-sensitive periods of prenatal brain development on the process of psychosexual differentiation (i.e., gender identity, gender role, and sexual orientation). In contrast, analysis of clinical management strategies has focused on gender assignment and the desirability and timing of genital surgery. This review focuses on the psychological issues that confront clinicians managing the care of persons born with DSD and their families. Particular attention is paid to processes and factors that potentially mediate or moderate psychosocial and psychosexual outcomes within and across developmental stages. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Effects of Acute Prenatal Exposure to Ethanol on microRNA Expression are Ameliorated by Social Enrichment

PubMed Central

Ignacio, Cherry; Mooney, Sandra M.; Middleton, Frank A.

2014-01-01

Fetal alcohol spectrum disorders (FASDs) are associated with abnormal social behavior. These behavioral changes may resemble those seen in autism. Rats acutely exposed to ethanol on gestational day 12 show decreased social motivation at postnatal day 42. We previously showed that housing these ethanol-exposed rats with non-exposed controls normalized this deficit. The amygdala is critical for social behavior and regulates it, in part, through connections with the basal ganglia, particularly the ventral striatum. MicroRNAs (miRNAs) are short, hairpin-derived RNAs that repress mRNA expression. Many brain disorders, including FASD, show dysregulation of miRNAs. In this study, we tested if miRNA and mRNA networks are altered in the amygdala and ventral striatum as a consequence of prenatal ethanol exposure and show any evidence of reversal as a result of social enrichment. RNA samples from two different brain regions in 72 male and female adolescent rats were analyzed by RNA-Seq and microarray analysis. Several miRNAs showed significant changes due to prenatal ethanol exposure and/or social enrichment in one or both brain regions. The top predicted gene targets of these miRNAs were mapped and subjected to pathway enrichment analysis. Several miRNA changes caused by ethanol were reversed by social enrichment, including mir-204, mir-299a, miR-384-5p, miR-222-3p, miR-301b-3p, and mir-6239. Moreover, enriched gene networks incorporating the targets of these miRNAs also showed reversal. We also extended our previously published mRNA expression analysis by directly examining all annotated brain-related canonical pathways. The additional pathways that were most strongly affected at the mRNA level included p53, CREB, glutamate, and GABA signaling. Together, our data suggest a number of novel epigenetic mechanisms for social enrichment to reverse the effects of ethanol exposure through widespread influences on gene expression. PMID:25309888

Prenatal inhibition of the kynurenine pathway leads to structural changes in the hippocampus of adult rat offspring.

PubMed

Khalil, Omari S; Pisar, Mazura; Forrest, Caroline M; Vincenten, Maria C J; Darlington, L Gail; Stone, Trevor W

2014-05-01

Glutamate receptors for N-methyl-d-aspartate (NMDA) are involved in early brain development. The kynurenine pathway of tryptophan metabolism includes the NMDA receptor agonist quinolinic acid and the antagonist kynurenic acid. We now report that prenatal inhibition of the pathway in rats with 3,4-dimethoxy-N-[4-(3-nitrophenyl)thiazol-2-yl]benzenesulphonamide (Ro61-8048) produces marked changes in hippocampal neuron morphology, spine density and the immunocytochemical localisation of developmental proteins in the offspring at postnatal day 60. Golgi-Cox silver staining revealed decreased overall numbers and lengths of CA1 basal dendrites and secondary basal dendrites, together with fewer basal dendritic spines and less overall dendritic complexity in the basal arbour. Fewer dendrites and less complexity were also noted in the dentate gyrus granule cells. More neurons containing the nuclear marker NeuN and the developmental protein sonic hedgehog were detected in the CA1 region and dentate gyrus. Staining for doublecortin revealed fewer newly generated granule cells bearing extended dendritic processes. The number of neuron terminals staining for vesicular glutamate transporter (VGLUT)-1 and VGLUT-2 was increased by Ro61-8048, with no change in expression of vesicular GABA transporter or its co-localisation with vesicle-associated membrane protein-1. These data support the view that constitutive kynurenine metabolism normally plays a role in early embryonic brain development, and that interfering with it has profound consequences for neuronal structure and morphology, lasting into adulthood. © 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Maternal treatment with picrotoxin in late pregnancy improved female sexual behavior but did not alter male sexual behavior of offspring.

PubMed

Bernardi, Maria M; Scanzerla, Kayne K; Chamlian, Mayra; Teodorov, Elizabeth; Felicio, Luciano F

2013-08-01

Previous studies from our laboratory investigated the effects of picrotoxin (PT), a γ-aminobutyric acid receptor antagonist administered during several perinatal periods, on the sexual behavior of male and female rats. We observed that the time of perinatal exposure to PT is critical to determine either facilitation or impairment of sexual behavior. The present study evaluated the effects of prenatal administration of a single dose of PT on gestation day 18 of dams (the first critical period of male brain sexual differentiation) on sexual behavior of male and female offspring. Thus, female Wistar rats were mated with males and, on gestation day 18, received 0.6 mg/kg of PT or 0.9% saline solution subcutaneously. On postnatal day 1, the offspring were weighed and several measures of sexual development were assessed. The sexual behaviors and the general activity in the open field of adult male and ovariectomized, hormone-treated female rats were observed. On comparison with the control group, maternal PT treatment: (i) did not alter the maternal weight, pup weight, anogenital distance, or male and female general activity; (ii) increased female sexual behavior, that is, decreased the latencies to first mount, first lordosis, and tenth lordosis, and the percentage of females presenting lordosis; and (iii) did not alter male sexual behavior. It is suggested that prenatal PT exposure interfered with epigenetic mechanisms related to the development of sex differences in the brain, leading to the observed sexually dimorphic effects on sexual behavior.

Differential diagnosis of ventriculomegaly and brainstem kinking on fetal MRI.

PubMed

Amir, Tali; Poretti, Andrea; Boltshauser, Eugen; Huisman, Thierry A G M

2016-01-01

Fetal ventriculomegaly is a common and frequently leading neuroimaging finding in complex brain malformations. Here we report on pre- and postnatal neuroimaging findings in three fetuses with prenatal ventriculomegaly and brainstem kinking. We aim to identify key neuroimaging features that may allow the prenatal differentiation between diseases associated with fetal ventriculomegaly and brainstem kinking. All pre- and postnatal magnetic resonance imaging (MRI) data were qualitatively evaluated for infra- and supratentorial abnormalities. Data about clinical features and genetic findings were collected from clinical histories. In all three patients, fetal MRI showed ventriculomegaly and brainstem kinking. In two patients, postnatal MRI also showed supratentorial migration abnormalities and eye abnormalities were found. In these children, the diagnosis of α-dystroglycanopathy was genetically confirmed. In the third patient, basal ganglia had an abnormal shape on MRI suggesting a tubulinopathy. The differential diagnosis of prenatal ventriculomegaly and brainstem kinking includes α-dystroglycanopathies, X-linked hydrocephalus due to mutations in L1CAM, and tubulinopathies. The prenatal differentiation between these diseases may be difficult. The presence of ocular abnormalities on prenatal neuroimaging may favor α-dystroglycanopathies, while dysplastic basal ganglia may suggest a tubulinopathy. However, in some patients the final differentiation between these diseases is possible only postnatally. Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.