Effects of prenatal ethanol exposure on choline-induced long-term depression in the hippocampus.

Choline is an essential nutrient under evaluation as a cognitive enhancing treatment for fetal alcohol spectrum disorders (FASD) in clinical trials. As a result, there is increased pressure to identify therapeutic mechanism(s) of action. Choline is not only a precursor for several essential cell membrane components and signaling molecules but also has the potential to directly affect synaptic mechanisms that are believed important for cognitive processes. In the current work, we study how the direct application of choline can affect synaptic transmission in the dentate gyrus (DG) of hippocampal slices obtained from adolescent (postnatal days 21-28) Sprague-Dawley rats (Rattus norvegicus). The acute administration of choline chloride (2 mM) reliably induced a long-term depression (LTD) of field excitatory postsynaptic potentials (fEPSPs) in the DG in vitro. The depression required the involvement of M1 receptors, and the magnitude of the effect was similar in slices obtained from male and female animals. To further study the impact of choline in an animal model of FASD, we examined offspring from dams fed an ethanol-containing diet (35.5% ethanol-derived calories) throughout gestation. In slices from the adolescent animals that experienced prenatal ethanol exposure (PNEE), we found that the choline induced an LTD that uniquely involved the activation of N-methyl-d-aspartate (NMDA) and M1 receptors. This study provides a novel insight into how choline can modulate hippocampal transmission at the level of the synapse and that it can have unique effects following PNEE.NEW & NOTEWORTHY Choline supplementation is a nutraceutical therapy with significant potential for a variety of developmental disorders; however, the mechanisms involved in its therapeutic effects remain poorly understood. Our research shows that choline directly impacts synaptic communication in the brain, inducing a long-term depression of synaptic efficacy in brain slices. The depression is equivalent in male and female animals, involves M1 receptors in control animals, but uniquely involves NMDA receptors in a model of FASD.

Neuroinflammation and Brain Development: Possible Risk Factors in COVID-19-Infected Children.

COVID-19, a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) betacoronavirus, affects children in a different way than it does in adults, with milder symptoms. However, several cases of neurological symptoms with neuroinflammatory syndromes, such as the multisystem inflammatory syndrome (MIS-C), following mild cases, have been reported. As with other viral infections, such as rubella, influenza, and cytomegalovirus, SARS-CoV-2 induces a surge of proinflammatory cytokines that affect microglial function, which can be harmful to brain development. Along with the viral induction of neuroinflammation, other noninfectious conditions may interact to produce additional inflammation, such as the nutritional imbalance of fatty acids and polyunsaturated fatty acids and alcohol consumption during pregnancy. Additionally, transient thyrotoxicosis induced by SARS-CoV-2 with secondary autoimmune hypothyroidism has been reported, which could go undetected during pregnancy. Together, those factors may pose additional risk factors for SARS-CoV-2 infection impacting mechanisms of neural development such as synaptic pruning and neural circuitry formation. The present review discusses those conditions in the perspective of the understanding of risk factors that should be considered and the possible emergence of neurodevelopmental disorders in COVID-19-infected children.

Executive functioning-specific behavioral impairments in a rat model of human third trimester binge drinking implicate prefrontal-thalamo-hippocampal circuitry in Fetal Alcohol Spectrum Disorders.

Individuals diagnosed with Fetal Alcohol Spectrum Disorders (FASD) often display behavioral impairments in executive functioning (EF). Specifically, the domains of working memory, inhibition, and set shifting are frequently impacted by prenatal alcohol exposure. Coordination between prefrontal cortex and hippocampus appear to be essential for these domains of executive functioning. The current study uses a rodent model of human third-trimester binge drinking to identify the extent of persistent executive functioning deficits following developmental alcohol by using a behavioral battery of hippocampus- and prefrontal cortex-dependent behavioral assays in adulthood. Alcohol added to milk formula was administered to Long Evans rat pups on postnatal days 4-9 (5.25 g/kg/day of ethanol; intragastric intubation), a period when rodent brain development undergoes comparable processes to human third-trimester neurodevelopment. Procedural control animals underwent sham intubation, without administration of any liquids (i.e., alcohol, milk solution). In adulthood, male rats were run on a battery of behavioral assays: novel object recognition, object-in-place associative memory, spontaneous alternation, and behavioral flexibility tasks. Alcohol-exposed rats demonstrated behavioral impairment in object-in-place preference and performed worse when the rule was switched on a plus maze task. All rats showed similar levels of novel object recognition, spontaneous alternation, discrimination learning, and reversal learning, suggesting alcohol-induced behavioral alterations are selective to executive functioning domains of spatial working memory and set-shifting in this widely-utilized rodent model. These specific behavioral alterations support the hypothesis that behavioral impairments in EF following prenatal alcohol exposure are caused by distributed damage to the prefrontal-thalamo-hippocampal circuit consisting of the medial prefrontal cortex, thalamic nucleus reuniens, and CA1 of hippocampus.

Experiences of Children with Fetal Alcohol Spectrum Disorder and Their Families: A Critical Review.

Evidence suggests that children with fetal alcohol spectrum disorder (FASD) experience challenges across many areas of their daily lives and often require interprofessional supports. Recent studies have emphasized the need for an integrated system of care for children with FASD, incorporating medical, allied health, and education services, to facilitate open communication and support for the complex needs that many children experience. To develop such a system of care, it is important to first understand the impact of FASD on children's functioning during daily activities in different environmental contexts. A critical review of existing research was conducted using a critical interpretive synthesis approach. Results revealed that while many studies discussed impacts at the body functions and structures level of children with FASD, they often did not consider the activity, participation, and environmental factors also contributing to the daily functioning of this population. Several studies discussed caregiver experiences and challenges raising a child with FASD; however, no studies investigated the lived experiences relating to impacts across activities and environments from children's perspectives. In addition, the focus on deficits overshadowed investigation into the strengths of children with FASD, leaving a gap in the picture of their daily lives. Further research is required to determine the strengths that children with FASD demonstrate and the challenges impacting their daily functioning within different environmental contexts. Insights gleaned from such research would support intervention practices to become more holistic and interprofessional.

Role of zinc insufficiency in fetal alveolar macrophage dysfunction and RSV exacerbation associated with fetal ethanol exposure.

BACKGROUND: We previously reported that maternal alcohol use significantly increases the risk of sepsis in premature and term newborns. In the mouse, fetal ethanol exposure results in an immunosuppressed phenotype for the alveolar macrophage (AM) and decreases bacterial phagocytosis. In pregnant mice, ethanol decreased AM zinc homeostasis, which contributed to immunosuppression and impaired AM phagocytosis. In this study, we explored whether ethanol-induced zinc insufficiency extended to the pup AMs and contributed to immunosuppression and exacerbated viral lung infections. METHODS: C57BL/6 female mice were fed a liquid diet with 25% ethanol-derived calories or pair-fed a control diet with 25% of calories as maltose-dextrin. Some pup AMs were treated in vitro with zinc acetate before measuring zinc pools or transporter expression and bacteria phagocytosis. Some dams were fed additional zinc supplements in the ethanol or control diets, and then we assessed pup AM zinc pools, zinc transporters, and the immunosuppressant TGFß1. On postnatal day 10, some pups were given intranasal saline or respiratory syncytial virus (RSV), and then AM RSV phagocytosis and the RSV burden in the airway lining fluid were assessed. RESULTS: Fetal ethanol exposure decreased pup AM zinc pools, zinc transporter expression, and bacterial clearance, but in vitro zinc treatments reversed these alterations. In addition, the expected ethanol-induced increase in TGFß1 and immunosuppression were associated with decreased RSV phagocytosis and exacerbated RSV infections. However, additional maternal zinc supplements blocked the ethanol-induced perturbations in the pup AM zinc homeostasis and TGFß1 immunosuppression, thereby improving RSV phagocytosis and attenuating the RSV burden in the lung. CONCLUSION: These studies suggest that, despite normal maternal dietary zinc intake, in utero alcohol exposure results in zinc insufficiency, which contributes to compromised neonatal AM immune functions, thereby increasing the risk of bacterial and viral infections.

Physiological self-regulation and mindfulness in children with a diagnosis of fetal alcohol spectrum disorder.

OBJECTIVE: To explore the differences in baseline respiratory sinus arrhythmia (RSA) between children with fetal alcohol spectrum disorder (FASD) and typically developing children (TDC) and to investigate whether children with FASD have the capacity to engage in a brief mindfulness exercise. METHODS: Participants were 14 children with FASD and 20 TDC. RSA was measured at baseline, during, and following a mindfulness exercise. A mindfulness compliance checklist was completed to ascertain if children could follow the task instructions. RESULTS: Both groups obtained high scores on the mindfulness compliance checklist. There was a trend for children with FASD to have lower baseline RSA compared to TDC. Children in both groups demonstrated an increase in RSA during the mindfulness task. CONCLUSIONS: Children with FASD could engage in a mindfulness task, and both groups showed an increase in RSA. Further research is needed to establish whether prolonged mindfulness practice could be beneficial.

A review of interventions against fetal alcohol spectrum disorder targeting oxidative stress.

INTRODUCTION: Fetal alcohol spectrum disorder is caused by maternal ethanol exposure; it causes physical, behavioral, cognitive, and neural impairments (Murawski et al., 2015). Mechanisms of FASD causing damage are not yet fully elucidated. Oxidative stress might be one of its mechanisms (Henderson et al., 1995). Yet no effective treatment against FASD has been found other than ethanol abstention (Long et al., 2010). METHODS: This review summarizes relevant literatures regarding interventions targeting oxidative stress that may relieve fetal alcohol spectrum disorder. RESULTS: Astaxanthin was found to mitigate embryonic growth retardation induced by prenatal ethanol treatment through ameliorating the down regulation of hydrogen peroxide (H2O2) and malondialdehyde (MDA) caused by alcohol in a mice model (Zheng et al., 2014; Vabulas et al., 2002). Vitamin E protected against fatal alchol spectrum disorders by ameliorating oxidative stress in rat models (Mitchell et al., 1999a), and yielded a better outcome when it was combined with Vitamin C (Packer et al., 1979; Peng et al., 2005). Vitamin C mitigated embryonic retardation caused by alcohol and reversed ethanol induced NF-κB activation and ROS (reactive oxygen species) formation in a Xenopus laevis model (Peng et al., 2005). Beta carotene supplement was proved to protect against neurotoxicity in hippocampal cultures of embryos induced by alcohol in a rats model (Mitchell et al., 1999a). Prenatal folic acid supplement reversed the decrease of body weight caused by maternal ethanol treatment and ameliorated the increment of glutathione reductase specific activities as well as the increase of thiobarbituric acid reactive substances (TBARS) induced by alcohol in a rats model (Cano et al., 2001). Omega-3 fatty acids reversed the decrease of reduced glutathione (GSH) levels in brain caused by prenatal ethanol treatment in a rats model (Patten et al., 2013). EUK-134 treatment reduced the incidence of forelimb defects caused by ethanol treatment in a mice model (Chen et al., 2004). Pretreatment of activity-dependent neurotrophic factor-9 (ADNF-9) and NAPVSIPQ (NAP) protected against prenatal ethanol induced fetal death as well as fetal growth abnormalities in a mice model, and such treatment reversed the decrease of the rate of reduced glutathione (GSH)/ oxidative glutathione (GSSG) caused by alcohol (Spong et al., 2001). CONCLUSION: By now interventions against fetal alcohol spectrum disorder targeting oxidative stress includes astaxanthin, Ascorbic acid (Vitamin C), Vitamin E, beta-carotene, (-)-Epigallocatechin-3-gallate (EGCG), Omega-3 fatty acids, etc (see Fig. 1). However, most interventions are only assayed in animal models, more clinical trials are needed to show whether antioxidants make an effort against FASD damage.

Altered Neural Oscillations During Multisensory Integration in Adolescents with Fetal Alcohol Spectrum Disorder.

BACKGROUND: Children with fetal alcohol spectrum disorder (FASD), who were exposed to alcohol in utero, display a broad range of sensory, cognitive, and behavioral deficits, which are broadly theorized to be rooted in altered brain function and structure. Based on the role of neural oscillations in multisensory integration from past studies, we hypothesized that adolescents with FASD would show a decrease in oscillatory power during event-related gamma oscillatory activity (30 to 100 Hz), when compared to typically developing healthy controls (HC), and that such decrease in oscillatory power would predict behavioral performance. METHODS: We measured sensory neurophysiology using magnetoencephalography (MEG) during passive auditory, somatosensory, and multisensory (synchronous) stimulation in 19 adolescents (12 to 21 years) with FASD and 23 age- and gender-matched HC. We employed a cross-hemisphere multisensory paradigm to assess interhemispheric connectivity deficits in children with FASD. RESULTS: Time-frequency analysis of MEG data revealed a significant decrease in gamma oscillatory power for both unisensory and multisensory conditions in the FASD group relative to HC, based on permutation testing of significant group differences. Greater beta oscillatory power (15 to 30 Hz) was also noted in the FASD group compared to HC in both unisensory and multisensory conditions. Regression analysis revealed greater predictive power of multisensory oscillations from unisensory oscillations in the FASD group compared to the HC group. Furthermore, multisensory oscillatory power, for both groups, predicted performance on the Intra-Extradimensional Set Shift Task and the Cambridge Gambling Task. CONCLUSIONS: Altered oscillatory power in the FASD group may reflect a restricted ability to process somatosensory and multisensory stimuli during day-to-day interactions. These alterations in neural oscillations may be associated with the neurobehavioral deficits experienced by adolescents with FASD and may carry over to adulthood.

Turmeric Extract Rescues Ethanol-Induced Developmental Defect in the Zebrafish Model for Fetal Alcohol Spectrum Disorder (FASD).

Prenatal ethanol exposure causes the most frequent preventable birth disorder, fetal alcohol spectrum disorder (FASD). The effect of turmeric extracts in rescuing an ethanol-induced developmental defect using zebrafish as a model was determined. Ethanol-induced oxidative stress is one of the major mechanisms underlying FASD. We hypothesize that antioxidant inducing properties of turmeric may alleviate ethanol-induced defects. Curcuminoid content of the turmeric powder extract (5 mg/mL turmeric in ethanol) was determined by UPLC and found to contain Curcumin (124.1 ± 0.2 µg/mL), Desmethoxycurcumin (43.4 ± 0.1 µg/mL), and Bisdemethoxycurcumin (36.6 ± 0.1 µg/mL). Zebrafish embryos were treated with 100 mM (0.6% v/v) ethanol during gastrulation through organogenesis (2 to 48 h postfertilization (hpf)) and supplemented with turmeric extract to obtain total curcuminoid concentrations of 0, 1.16, 1.72, or 2.32 µM. Turmeric supplementation showed significant rescue of the body length at 72 hpf compared to ethanol-treated embryos. The mechanism underlying the rescue remains to be determined.

Fetal alcohol exposure reduces responsiveness of taste nerves and trigeminal chemosensory neurons to ethanol and its flavor components.

Fetal alcohol exposure (FAE) leads to increased intake of ethanol in adolescent rats and humans. We asked whether these behavioral changes may be mediated in part by changes in responsiveness of the peripheral taste and oral trigeminal systems. We exposed the experimental rats to ethanol in utero by administering ethanol to dams through a liquid diet; we exposed the control rats to an isocaloric and isonutritive liquid diet. To assess taste responsiveness, we recorded responses of the chorda tympani (CT) and glossopharyngeal (GL) nerves to lingual stimulation with ethanol, quinine, sucrose, and NaCl. To assess trigeminal responsiveness, we measured changes in calcium levels of isolated trigeminal ganglion (TG) neurons during stimulation with ethanol, capsaicin, mustard oil, and KCl. Compared with adolescent control rats, the adolescent experimental rats exhibited diminished CT nerve responses to ethanol, quinine, and sucrose and GL nerve responses to quinine and sucrose. The reductions in taste responsiveness persisted into adulthood for quinine but not for any of the other stimuli. Adolescent experimental rats also exhibited reduced TG neuron responses to ethanol, capsaicin, and mustard oil. The lack of change in responsiveness of the taste nerves to NaCl and the TG neurons to KCl indicates that FAE altered only a subset of the response pathways within each chemosensory system. We propose that FAE reprograms development of the peripheral taste and trigeminal systems in ways that reduce their responsiveness to ethanol and surrogates for its pleasant (i.e., sweet) and unpleasant (i.e., bitterness, oral burning) flavor attributes.NEW & NOTEWORTHY Pregnant mothers are advised to avoid alcohol. This is because even small amounts of alcohol can alter fetal brain development and increase the risk of adolescent alcohol abuse. We asked how fetal alcohol exposure (FAE) produces the latter effect in adolescent rats by measuring responsiveness of taste nerves and trigeminal chemosensory neurons. We found that FAE substantially reduced taste and trigeminal responsiveness to ethanol and its flavor components.

Dietary Nutrient Intake in School-Aged Children With Heavy Prenatal Alcohol Exposure.

BACKGROUND: Nutrition is an important factor that affects brain development. Nutritional deficiencies can exacerbate alcohol's damaging effects. Conversely, nutritional supplementation can serve a protective role against alcohol damage and may prove to be a worthwhile intervention strategy. This study investigated dietary intake in school-aged children with heavy prenatal alcohol exposure to understand their nutritional status, compared to a national sample of typically developing children and Dietary Reference Intakes. METHODS: Dietary intake data were collected from children with confirmed histories of heavy prenatal alcohol exposure (5 to 10 years, n = 55) using the Automated Self-Administered 24-Hour Dietary Recall (ASA24). Observed nutrient levels were compared to the Dietary Reference Intakes to evaluate adequacy of nutrient intake as well as to national averages for same-aged children (What We Eat in America, NHANES 2007-2008). RESULTS: Alcohol-exposed children exhibited poorer nutritional status compared to the typically developing NHANES sample, consuming lower levels of protein, omega-3 fatty acids, magnesium, potassium, zinc, vitamins C and K, niacin, and choline. Moreover, their diets did not meet Recommended Dietary Allowance or Adequate Intake for dietary fiber, potassium, vitamins E and K, omega-3 fatty acids, and choline. CONCLUSIONS: The present findings are consistent with prior studies investigating nutritional intake in preschoolers with FASD, indicating that these children are vulnerable to nutritional inadequacies. Moreover, data suggest a specific profile of dietary intake in this population. As several nutrients are important for cognitive development, targeted interventions in clinical populations might be effective in boosting outcomes. Thus, further clinical investigation into the role of nutrition in improving cognitive outcomes is warranted.

Choline supplementation in children with fetal alcohol spectrum disorders: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Fetal alcohol spectrum disorders (FASDs) are conditions characterized by physical anomalies, neurodevelopmental abnormalities, and neurocognitive deficits, including intellectual, executive, and memory deficits. There are no specific biological treatments for FASDs, but rodent models have shown that prenatal or postnatal choline supplementation reduces cognitive and behavioral deficits. Potential mechanisms include phospholipid production for axonal growth and myelination, acetylcholine enhancement, and epigenetic effects. OBJECTIVE: Our primary goal was to determine whether postnatal choline supplementation has the potential to improve neurocognitive functioning, particularly hippocampal-dependent memory, in children with FASDs. DESIGN: The study was a double-blind, randomized, placebo-controlled pilot trial in children (aged 2.5-5 y at enrollment) with FASDs (n = 60) who received 500 mg choline or a placebo daily for 9 mo. Outcome measures were Mullen Scales of Early Learning (primary) and the elicited imitation (EI) memory paradigm (secondary). RESULTS: The administration proved feasible, and choline was well tolerated. Participants received a dose on 88% of enrolled days. The only adverse event linked to choline was a fishy body odor. Choline supplementation improved the secondary outcome (EI) only after immediate recall performance was controlled for, and the outcome was moderated by age. The treatment effect on EI items recalled was significant in the younger participants (2.5- to ≤4.0-y-olds); the young choline group showed an increase of 12-14 percentage points greater than that of the young placebo group on delayed recall measures during treatment. However, there was a marginal baseline difference in delayed item recall between the young choline and placebo groups as well as a potential ceiling effect for item recall, both of which likely contributed to the observed treatment effect. We also observed a trend toward a negative effect of choline supplementation on the immediate EI recall of ordered pairs; the young placebo group showed an increase of 8-17 percentage points greater than that of the choline group during treatment. There was an inverse relation between choline dose (in mg/kg) and memory improvement (P = 0.041); the data suggest that weight-adjusted doses may be a better alternative to a fixed dose in future studies. Limitations included trend-level baseline differences in performance, the post-hoc determination of age moderation, and potential ceiling effects for the memory measure. CONCLUSIONS: This pilot study suggests that an additional evaluation of choline supplementation as an intervention for memory functioning in children with FASDs is warranted. The observed interaction between age and choline's effect on EI suggests that potential sensitive periods should be considered in future work. This trial was registered at clinicaltrials.gov as NCT01149538.

An animal model of fetal alcohol spectrum disorder: Trace conditioning as a window to inform memory deficits and intervention tactics.

Animal models of Fetal Alcohol Spectrum Disorders (FASD) afford the unique capacity to precisely control timing of alcohol exposure and alcohol exposure amounts in the developing animal. These models have powerfully informed neurophysiological alterations associated with fetal and perinatal alcohol. In two experiments presented here we expand use of the Pavlovian Trace Conditioning procedure to examine cognitive deficits and intervention strategies in a rat model of FASD. Rat pups were exposed to 5g/kg/day ethanol on postnatal days (PD) 4-9, simulating alcohol exposure in the third trimester in humans. During early adolescence, approximately PD 30, the rats were trained in the trace conditioning task in which a light conditioned stimulus (CS) and shock unconditioned stimulus (US) were paired but separated by a 10-s stimulus free trace interval. Learning was assessed in freezing behavior during shock-free tests. Experiment 1 revealed that neonatal ethanol exposure significantly impaired hippocampus-dependent trace conditioning relative to controls. In Experiment 2 a serial compound conditioning procedure known as 'gap filling' completely reversed the ethanol-induced deficit in trace conditioning. We also discuss prior data regarding the beneficial effects of supplemental choline and novel preliminary data regarding the pharmacological cognitive enhancer physostigmine, both of which mitigate the alcohol-induced cognitive deficit otherwise seen in trace conditioning controls. We suggest trace conditioning as a useful tool for characterizing some of the core cognitive deficits seen in FASD, and as a model for developing effective environmental as well as nutritional and pharmacological interventions.

Inadequate intake of nutrients essential for neurodevelopment in children with fetal alcohol spectrum disorders (FASD).

This study evaluated dietary intake in children with fetal alcohol spectrum disorders (FASD). Pre-clinical research suggests that nutrient supplementation may attenuate cognitive and behavioral deficits in FASD. Currently, the dietary adequacy of essential nutrients in children with FASD is unknown. Dietary data were collected as part of a randomized, double-blind controlled trial of choline supplementation in FASD. Participants included 31 children with FASD, ages 2.5-4.9 years at enrollment. Dietary intake data was collected three times during the nine-month study via interview-administered 24-hour recalls with the Automated Self-Administered 24-hour Recall. Dietary intake of macronutrients and 17 vitamins/minerals from food was averaged across three data collection points. Observed nutrient intakes were compared to national dietary intake data of children ages 2-5 years (What we Eat in America, NHANES 2007-2008) and to the Dietary Reference Intakes. Compared to the dietary intakes of children in the NHANES sample, children with FASD had lower intakes of saturated fat, vitamin D, and calcium. The majority (>50%) of children with FASD did not meet the Recommended Dietary Allowance (RDA) or Adequate Intake (AI) for fiber, n-3 fatty acids, vitamin D, vitamin E, vitamin K, choline, and calcium. This pattern of dietary intake in children with FASD suggests that there may be opportunities to benefit from nutritional intervention. Supplementation with several nutrients, including choline, vitamin D, and n-3 fatty acids, has been shown in animal models to attenuate the cognitive deficits of FASD. These results highlight the potential of nutritional clinical trials in FASD.

Delays in auditory processing identified in preschool children with FASD.

BACKGROUND: Both sensory and cognitive deficits have been associated with prenatal exposure to alcohol; however, very few studies have focused on sensory deficits in preschool-aged children. As sensory skills develop early, characterization of sensory deficits using novel imaging methods may reveal important neural markers of prenatal alcohol exposure. METHODS: Participants in this study were 10 children with a fetal alcohol spectrum disorder (FASD) and 15 healthy control (HC) children aged 3 to 6 years. All participants had normal hearing as determined by clinical screens. We measured their neurophysiological responses to auditory stimuli (1,000 Hz, 72 dB tone) using magnetoencephalography (MEG). We used a multidipole spatio-temporal modeling technique to identify the location and timecourse of cortical activity in response to the auditory tones. The timing and amplitude of the left and right superior temporal gyrus sources associated with activation of left and right primary/secondary auditory cortices were compared across groups. RESULTS: There was a significant delay in M100 and M200 latencies for the FASD children relative to the HC children (p = 0.01), when including age as a covariate. The within-subjects effect of hemisphere was not significant. A comparable delay in M100 and M200 latencies was observed in children across the FASD subtypes. CONCLUSIONS: Auditory delay revealed by MEG in children with FASDs may prove to be a useful neural marker of information processing difficulties in young children with prenatal alcohol exposure. The fact that delayed auditory responses were observed across the FASD spectrum suggests that it may be a sensitive measure of alcohol-induced brain damage. Therefore, this measure in conjunction with other clinical tools may prove useful for early identification of alcohol affected children, particularly those without dysmorphia.

Zebrafish embryos and larvae: a new generation of disease models and drug screens.

Technological innovation has helped the zebrafish embryo gain ground as a disease model and an assay system for drug screening. Here, we review the use of zebrafish embryos and early larvae in applied biomedical research, using selected cases. We look at the use of zebrafish embryos as disease models, taking fetal alcohol syndrome and tuberculosis as examples. We discuss advances in imaging, in culture techniques (including microfluidics), and in drug delivery (including new techniques for the robotic injection of compounds into the egg). The use of zebrafish embryos in early stages of drug safety-screening is discussed. So too are the new behavioral assays that are being adapted from rodent research for use in zebrafish embryos, and which may become relevant in validating the effects of neuroactive compounds such as anxiolytics and antidepressants. Readouts, such as morphological screening and cardiac function, are examined. There are several drawbacks in the zebrafish model. One is its very rapid development, which means that screening with zebrafish is analogous to "screening on a run-away train." Therefore, we argue that zebrafish embryos need to be precisely staged when used in acute assays, so as to ensure a consistent window of developmental exposure. We believe that zebrafish embryo screens can be used in the pre-regulatory phases of drug development, although more validation studies are needed to overcome industry scepticism. Finally, the zebrafish poses no challenge to the position of rodent models: it is complementary to them, especially in early stages of drug research.

From research to practice: an integrative framework for the development of interventions for children with fetal alcohol spectrum disorders.

Since fetal alcohol syndrome was first described over 35 years ago, considerable progress has been made in the delineation of the neurocognitive profile in children with prenatal alcohol exposure. Preclinical investigators have made impressive strides in elucidating the mechanisms of alcohol teratogenesis and in testing the effectiveness of pharmacological agents and dietary supplementation in the amelioration of alcohol-induced deficits. Despite these advances, only limited progress has been made in the development of evidence-based comprehensive interventions for functional impairment in alcohol-exposed children. Having performed a search in PubMed and PsycINFO using key words, interventions, treatment, fetal alcohol syndrome, prenatal alcohol exposure, and fetal alcohol spectrum disorders, we found only 12 papers on empirically-based interventions. Only two of these interventions had been replicated and none met the criteria of "well-established," as defined by Chambless and Hollon (Journal of Consulting and Clinical Psychology 66(1):7-18, 1998). There has been only limited cross-fertilization of ideas between preclinical and clinical research with regard to the development of interventions. Therefore, we propose a framework that allows integrating data from preclinical and clinical investigations to develop comprehensive intervention programs for children with fetal alcohol spectrum disorders. This framework underscores the importance of multi-level evaluations and interventions.

Fetal alcohol syndrome: cardiac birth defects in mice and prevention with folate.

OBJECTIVE: Alcohol (ethanol) consumption during pregnancy is linked to congenital heart defects that are associated with fetal alcohol syndrome. Recent reports have associated ethanol exposure with the Wnt/beta-catenin pathway. Therefore, we defined whether ethanol affects Wnt/beta-catenin signaling during cardiac cell specification. STUDY DESIGN: Pregnant mice on embryonic day 6.75 during gastrulation were exposed by an intraperitoneal injection to a binge-drinking dose of ethanol. Folic acid supplementation of mouse diet was tested for the prevention of ethanol-induced cardiac birth defects. RESULTS: Acute ethanol exposure induced myocardial wall changes and atrioventricular and semilunar valve defects, which was determined by echocardiography on embryonic day 15.5. A high folate diet prevented the ethanol-induced cardiac defects. Ethanol exposure in avian embryos suppressed 2 key Wnt-modulated genes that are involved in cardiac induction; folic acid rescued normal gene expression. CONCLUSION: Folic acid supplementation alone or with myoinositol prevented alcohol potentiation of Wnt/beta-catenin signaling that allowed normal gene activation and cardiogenesis.

Effects of prenatal or postnatal ethanol consumption on zinc intestinal absorption and excretion in rats.

AIMS: The effect of ethanol consumption, either during the pregnancy or lactation period, on the altered metabolism of zinc is not well-defined; consequently, this study was performed to analyze the effect of chronic ethanol exposure on milk consumption, serum, milk, duodenal absorption, fecal and urinary excretion of zinc in dams and offspring during either gestation or lactation in the rat. A complementary study was performed regarding pregnancy outcome. We evaluated testosterone values, the offspring born/litter and several indices such as fertility, viable gestations and the survival index. METHODS: To study the effect of chronic alcoholism during gestation or lactation separately, at birth control newborns were cross-fostered to ethanol dams (ED), and the offspring issued from the ethanol treated mothers were cross-fostered to control dams (CD). Thus, three experimental groups of offspring were formed: (i) control offspring receiving no treatment (CO); (ii) offspring exposed to ethanol only during gestation (GO); and (iii) offspring exposed to ethanol only during lactation (LO). All the results were compared with offspring pair-fed groups (PFO) born of the pair-fed dams (PFD). RESULTS: Duodenal absorption of zinc increased significantly in LO offspring when the substrate concentrations in the perfusion medium were 25, 75, and 150 microM. A higher faecal excretion in GO pups compared with those with LO exposure and control groups (CO and PFO). The urine excretion of zinc was higher for LO offspring with respect to the other three experimental groups (CO, GO, and PFO). CONCLUSIONS: Maternal adaptation resulted in zinc retention, adequate to meet the demands of pup's growth in the face of a lower diet intake. The zinc status in pups is regulated by a higher absorption of zinc and intestinal conservation of endogenous fecal zinc after postnatal ethanol consumption. The increase in urinary zinc excretion could be responsible for decreased serum zinc. However, we found an increase in serum zinc probably due to an increase in the zinc absorption values.

Prenatal exposure to ethanol causes partial diabetes insipidus in adult rats.

Chronic consumption of ethanol in adult rats and humans leads to reduced AVP-producing neurons, and prenatal ethanol (PE) exposure has been reported to cause changes in the morphology of AVP-producing cells in the suprachiasmatic nucleus of young rats. The present studies further characterize the effects of PE exposure on AVP in the young adult rat, its hypothalamic synthesis, pituitary storage, and osmotically stimulated release. Pregnant rats were fed a liquid diet with 35% of the calories from ethanol or a control liquid diet for days 7-22 of pregnancy. Water consumption and urine excretion rate were measured in the offspring at 60-68 days of age. Subsequently, the offspring were infused with 5% NaCl at 0.05 ml.kg(-1).min(-1) with plasma samples taken before and at three 40-min intervals during infusion for measurement of AVP and osmolality. Urine output and water intake were approximately 20% greater in PE-exposed rats than in rats with no PE exposure, and female rats had a greater water intake than males. The relationship between plasma osmolality and AVP in PE-exposed rats was parallel to, but shifted to the right of, the control rats, indicating an increase in osmotic threshold for AVP release. Pituitary AVP was reduced by 13% and hypothalamic AVP mRNA content was reduced by 35% in PE-exposed rats. Our data suggest that PE exposure can cause a permanent condition of a mild partial central diabetes insipidus.