Alcohol-exposed Research Articles

Prenatal Alcohol Exposure Disrupts Performance in a Differential Reinforcement of Low Rates Task Specifically in Adolescent Male Rats.

Prenatal alcohol exposure (PAE) can lead to a wide range of adverse effects in humans, including impaired self-control and increased impulsive behavior. Deficits in self-control can interfere with academic performance and have lasting impacts. In the present study, a rodent model of PAE was used to assess impulsivity through operant conditioning. Pregnant rats were assigned to one of three groups: ad-lib control (CON), pair-fed (PF), and alcohol-exposed (ALC). ALC rats were given a liquid diet containing 6% alcohol, PF rats were yoked to an ALC rat and given a CON liquid diet, and CON rats received ad libitum food. Operant conditioning was used to evaluate extinction in adolescents (Experiment 1) and differential reinforcement of low rates (DRL) in adolescents and adults (Experiment 2). PAE resulted in an increase in responses and resets during DRL testing, indicative of impaired self-control, an effect that was only observed in adolescent males. Females, regardless of age, did not show increased impulsivity following PAE. This indicates that children with PAE may exhibit attentional deficits similar to those with attention deficit hyperactivity disorder, with males at a higher risk.

Altered circadian expression of clock genes and clock-regulatory epigenetic modifiers in saliva of children with fetal alcohol spectrum disorders

Prenatal alcohol-exposed (AE) infants and children often demonstrate disrupted sleep patterns, including more frequent awakenings, reduced total sleep time, and more night-to-night sleep variability. Despite the strong connection between sleep patterns and circadian rhythmicity, relatively little is known about circadian rhythm disruptions in individuals with AE. Recently, several reports demonstrated that evaluating the expression patterns of human clock genes in biological fluids could reveal an individual’s circadian phenotype. Human saliva offers an emerging and easily available physiological sample that can be collected non-invasively for core-clock gene transcript analyses. We compared the expression patterns of core-clock genes and their regulatory genes in salivary samples of children aged 6–10 years-old with and without AE during the light cycle between ZT0-ZT11. We isolated the RNA from the samples and measured the expression patterns of core clock genes and clock regulating genes using the human specific primers with quantitative real-time PCR. Analysis of core clock genes expression levels in saliva samples from AE children indicates significantly altered levels in expression of core-clock BMAL1, CLOCK, PER1-3 and CRY1,2, as compared to those in age-matched control children. We did not find any sex difference in levels of clock genes in AE and control groups. Cosinor analysis was used to evaluate the rhythmic pattern of these clock genes, which identified circadian patterns in the levels of core clock genes in the control group but absent in the AE group. The gene expression profile of a salivary circadian biomarker ARRB1 was rhythmic in saliva of control children but was arhythmic in AE children. Altered expression patterns were also observed in clock regulatory genes: NPAS2, NFL3, NR1D1, DEC1, DEC2, and DBP, as well as chromatin modifiers: MLL1, P300, SIRT1, EZH2, HDAC3, and ZR1D1, known to maintain rhythmic expression of core-clock genes. Overall, these findings provide the first evidence that AE disturbs the circadian patten expression of core clock genes and clock-regulatory chromatin modifiers in saliva.

Magnetic resonance elastography captures a transient benefit of exercise intervention on forebrain stiffness in a rat model of fetal alcohol spectrum disorders.

Fetal alcohol spectrum disorders (FASD), a group of prevalent conditions resulting from prenatal alcohol exposure, affect the maturation of cerebral white matter as first identified with neuroimaging. However, traditional methods are unable to track subtle microstructural alterations to white matter. This preliminary study uses a highly sensitive and clinically translatable magnetic resonance elastography (MRE) protocol to assess brain tissue microstructure through its mechanical properties following an exercise intervention in a rat model of FASD. Female rat pups were either alcohol-exposed (AE) via intragastric intubation of alcohol in milk substitute (5.25 g/kg/day) or sham-intubated (SI) on postnatal days (PD) four through nine to model alcohol exposure during the brain growth spurt. On PD 30, half of AE and SI rats were randomly assigned to either a wheel-running or standard cage for 12 days. Magnetic resonance elastography was used to measure whole brain and callosal mechanical properties at the end of the intervention (around PD 42) and at 1 month post-intervention, and findings were validated with histological quantification of oligoglia. Alcohol exposure reduced forebrain stiffness (p = 0.02) in standard-housed rats. The adolescent exercise intervention mitigated this effect, confirming that increased aerobic activity supports proper neurodevelopmental trajectories. Forebrain damping ratio was lowest in standard-housed AE rats (p < 0.01), but this effect was not mitigated by intervention exposure. At 1 month post-intervention, all rats exhibited comparable forebrain stiffness and damping ratio (p > 0.05). Callosal stiffness and damping ratio increased with age. With cessation of exercise, there was a negative rebound effect on the quantity of callosal oligodendrocytes, irrespective of treatment group, which diverged fromour MRE results. This is the first application of MRE to measure the brain's mechanical properties in a rodent model of FASD. MRE successfully captured alcohol-related changes in forebrain stiffness and damping ratio. Additionally, MRE identified an exercise-related increase to forebrain stiffness in AE rats.

Prenatal alcohol exposure causes persistent microglial activation and age- and sex- specific effects on cognition and metabolic outcomes in an Alzheimer’s Disease mouse model

ABSTRACT Background: Prenatal alcohol exposure (PAE) causes behavioral deficits and increases risk of metabolic diseases. Alzheimer’s Disease (AD) is a neurodegenerative disease that has a higher risk in adults with metabolic diseases. Both present with persistent neuroinflammation. Objectives: We tested whether PAE exacerbates AD-related cognitive decline in a mouse model (3xTg-AD; presenilin/amyloid precursor protein/tau), and assessed associations among cognition, metabolic impairment, and microglial reactivity. Methods: Alcohol-exposed (ALC) pregnant 3xTg-AD mice received 3 g/kg alcohol from embryonic day 8.5–17.5. We evaluated recognition memory and associative memory (fear conditioning) in 8–10 males and females per group at 3 months of age (3mo), 7mo, and 11mo, then assessed glucose tolerance, body composition, and hippocampal microglial activation at 12mo. Results: ALC females had higher body weights than controls from 5mo (p < .0001). Controls showed improved recognition memory at 11mo compared with 3mo (p = .007); this was not seen in ALC mice. Older animals froze more during fear conditioning than younger, and ALC mice were hyper-responsive to the fear-related cue (p = .017). Fasting blood glucose was lower in ALC males and higher in ALC females than controls. Positive associations occurred between glucose and fear-related context (p = .04) and adiposity and fear-related cue (p = .0002) in ALC animals. Hippocampal microglial activation was higher in ALC than controls (p < .0001); this trended to correlate with recognition memory. Conclusions: ALC animals showed age-related cognitive impairments that did not interact with AD risk but did correlate with metabolic dysfunction and somewhat with microglial activation. Thus, metabolic disorders may be a therapeutic target for people with FASDs.

Community Perceptions of Alcohol Exposed Pregnancy Prevention Program for American Indian and Alaska Native Teens.

A community needs assessment during a tribally-led Changing High-Risk Alcohol Use and Increasing Contraception Effectiveness Study (CHOICES) intervention highlighted the need to reduce the risk for alcohol exposed pregnancy (AEP) among American Indian and Alaska Native (AIAN) adolescent girls. The CHOICES for American Indian Teens (CHAT) Program aims to reduce the risk of AEP among AIAN teens in one Northern Plains tribal community. The CHAT team adopted an iterative process to modify the tribally-led CHOICES curriculum for AIAN teens. This paper describes the iterative process as well as the community perception towards AEP prevention among AIAN teens. The CHAT team conducted several levels of formative and qualitative research, including one-on-one interviews (n = 15) with community members, AIAN elders and school counsellors; and three focus groups with AIAN adolescent girls (n = 15). A qualitative data analysis identified several recommendations that centered on making the information regarding alcohol and birth control appealing to teens; ensuring the confidentiality of the participants; making the program culturally relevant; and including boys in the program. This study outlines various components prioritized by community members in creating a culturally-relevant and age-appropriate AEP prevention program and provides community perceptions of AEP prevention for the teens in this community

Sex Differences in Early Postnatal Microglial Colonization of the Developing Rat Hippocampus Following a Single-Day Alcohol Exposure.

Microglia are involved in various homeostatic processes in the brain, including phagocytosis, apoptosis, and synaptic pruning. Sex differences in microglia colonization of the developing brain have been reported, but have not been established following alcohol insult. Developmental alcohol exposure represents a neuroimmune challenge that may contribute to cognitive dysfunction prevalent in humans with Fetal Alcohol Spectrum Disorders (FASD) and in rodent models of FASD. Most studies have investigated neuroimmune activation following adult alcohol exposure or following multiple exposures. The current study uses a single day binge alcohol exposure model (postnatal day [PD] 4) to examine sex differences in the neuroimmune response in the developing rat hippocampus on PD5 and 8. The neuroimmune response was evaluated through measurement of microglial number and cytokine gene expression at both time points. Male pups had higher microglial number compared to females in many hippocampal subregions on PD5, but this difference disappeared by PD8, unless exposed to alcohol. Expression of pro-inflammatory marker CD11b was higher on PD5 in alcohol-exposed (AE) females compared to AE males. After alcohol exposure, C-C motif chemokine ligand 4 (CCL4) was significantly increased in female AE pups on PD5 and PD8. Tumor necrosis factor-α (TNF-α) levels were also upregulated by AE in males on PD8. The results demonstrate a clear difference between the male and female neuroimmune response to an AE challenge, which also occurs in a time-dependent manner. These findings are significant as they add to our knowledge of specific sex-dependent effects of alcohol exposure on microglia within the developing brain.

Implications of altered maternal cytokine concentrations on infant outcomes in children with prenatal alcohol exposure.

Excessive alcohol consumption has been shown to increase serum plasma levels of numerous immune cytokines. Maternal immune activation and elevated cytokines have been implicated in certain neurological disorders (e.g., autism and schizophrenia) in the offspring. We investigated the hypothesis that elevated cytokines during pregnancy are a risk factor in women who gave birth to a child with Fetal Alcohol Spectrum Disorder (FASD) or a child with neurobehavioral impairment, regardless of prenatal alcohol exposure. Moderate to heavy alcohol-exposed (AE) (N=149) and low or no alcohol-exposed (LNA) (N=92) women were recruited into the study during mid pregnancy (mean of 19.8±5.8 weeks' gestation) in two regions of Ukraine: Khmelnytsky and Rivne. Maternal blood samples were obtained at enrollment into the study at early to mid-pregnancy and during a third-trimester follow-up visit and analyzed for plasma cytokines. Children were examined at 6 and/or 12 months of age and were classified as having FASD if their mothers reported alcohol use and if they had at least one standardized score (Bayley Scales of Infant Development II Mental Development Index [MDI], or Psychomotor Development Index [PDI]) below 85 with the presence or absence of physical features of FASD. In multivariate analyses of maternal cytokine levels in relation to infant MDI and PDI scores in the entire sample, increases in the ratio of TNF-α/IL-10 and IL-6/IL-10 were negatively associated with PDI scores at 6 months (p=0.020 and p=0.036, respectively) and 12 months (p=0.043 and p=0.029, respectively), and with MDI scores at 12 months (p=0.013 and p=0.050, respectively). A reduction in the odds ratio of having an FASD child was observed with increasing levels of IL-1β, IL-2, IL-4, IL-6, and IL-10 in early to mid-pregnancy and IL-1β and IL-10 during late pregnancy. However, women that failed to increase IL-10 levels in the third trimester in order to maintain the balance of pro- and anti-inflammatory cytokines had an elevated risk of having an FASD child, specifically a significant increase in the odds ratio of FASD with every one-unit log increase in late pregnancy TNF-α/IL-10 levels (aOR: 1.654, CI: 1.096-2.495, p=0.017). These data support the concept that disruptions in the balance between pro- and anti-inflammatory cytokines may contribute to neurobehavioral impairment and alter the risk of FASD.

Exercise and environment as an intervention for neonatal alcohol effects on hippocampal adult neurogenesis and learning

Neonatal alcohol exposure impairs cognition and learning in adulthood and permanently damages the hippocampus. Wheel running (WR) improves hippocampus-associated learning and memory and increases the genesis and survival of newly generated neurons in the hippocampal dentate gyrus. WR significantly increases proliferation of newly generated dentate granule cells in alcohol-exposed (AE) and control rats on Postnatal Day (PD) 42 but only control rats show an increased number of surviving cells thirty days after WR (Helfer et al., 2009b). The present studies examined whether proliferation-promoting WR followed by survival-enhancing environmental complexity (EC) during adolescence could increase survival of new neurons in AE rats. On PD 4–9, pups were intubated with alcohol in a binge-like manner (5.25g/kg/day, AE), were sham-intubated (SI), or were reared normally (suckle control, SC). On PD 30 animals were assigned to WR (PD 30–42) followed by EC (PD 42–72; WR/EC) or were socially housed (SH/SH) for the duration of the experiment. All animals were injected with 200mg/kg bromodeoxyuridine (BrdU) on PD 41. In Experiment 1, survival of newly generated cells was significantly enhanced in the AE-WR/EC group in comparison with AE-SH/SH group. Experiment 2A examined trace eyeblink conditioning. In the SH/SH condition, AE impaired trace eyeblink conditioning relative to SI and SC controls. In the WR/EC condition, AE rats performed as well as controls. In Experiment 2B, the same intervention was examined using the context preexposure facilitation effect (CPFE); a hippocampus-dependent variant of contextual fear conditioning. Again, the WR/EC intervention reversed the deficit in conditioned fear to the context that was evident in the SH/SH condition. Post-weaning environmental manipulations promote cell survival and reverse learning deficits in rats that were exposed to alcohol during development. These manipulations may provide a basis for developing interventions that ameliorate learning impairments associated with human fetal alcohol spectrum disorders.

Housing in Environmental Complexity Following Wheel Running Augments Survival of Newly Generated Hippocampal Neurons in a Rat Model of Binge Alcohol Exposure During the Third Trimester Equivalent

Binge-like alcohol exposure in neonatal rats during the brain growth spurt causes deficits in adult neurogenesis in the hippocampal dentate gyrus (DG). Previous data from our laboratory demonstrated that 12 days of voluntary wheel running (WR) beginning on postnatal day (PD) 30 significantly increased the number of newly generated cells evident in the DG on PD42 in both alcohol-exposed (AE) and control rats, but 30 days later a sustained beneficial effect of WR was evident only in control rats. This study tested the hypothesis that housing rats in environmental complexity (EC) following WR would promote the survival of the newly generated cells stimulated by WR, particularly in AE rats. On PD4 to 9, pups were intubated with alcohol in a binge-like manner (5.25 g/kg/d), sham-intubated (SI), or reared normally. In Experiment 1, animals were either assigned to WR during PD30 to 42 or socially housed (SH). On PD42, animals were injected with bromodeoxyuridine (BrdU; 200 mg/kg) and perfused 2 hours later to confirm the WR-induced stimulation of proliferation. In Experiment 2, all animals received WR on PD30 to 42 and were injected with BrdU on the last full day of WR. On PD42, animals were randomly assigned either to EC (WR/EC) or to SH (WR/SH) for 30 days and subsequently perfused and brains were processed for immunohistochemical staining to identify BrdU+-, Ki67+-, and BrdU+/NeuN+-labeled cells in DG. In Experiment 1, WR exposure significantly increased the number of proliferating cells in all 3 postnatal conditions. In Experiment 2, the AE rats given WR/SH had significantly fewer BrdU+ cells compared with control rats given WR/SH. However, WR/EC experience significantly increased the number of surviving BrdU+ cells in both the AE and SI groups compared with WR/SH rats of the same neonatal treatment. Approximately 80% of the surviving BrdU+ cells in the DG across the conditions were colabeled with NeuN. WR followed by EC could provide a behavioral model for developing interventions in humans to ameliorate hippocampal-dependent impairments associated with fetal alcohol spectrum disorders.

Neuropsychological comparison of children with heavy prenatal alcohol exposure and an IQ-matched comparison group.

An objective in current research on children with fetal alcohol spectrum disorders (FASD) is to determine neurobehavioral profiles to identify affected individuals. Deficits observed when children with FASD are compared to typically developing controls may be confounded by lower IQ scores in the subjects with FASD. To determine if prenatal alcohol exposure is associated with neurobehavioral deficits after controlling for IQ differences, multivariate analyses were conducted to compare alcohol-exposed (ALC) subjects to a comparison group closely matched on IQ (IQC). The initial analysis included a broad neuropsychological battery with measures of language, executive function, visual-motor integration, motor ability, and academic achievement. Additional, in depth comparisons focused on visual sustained attention, verbal learning and memory and parent/guardian-reported behavior problems. Group differences (ALC < IQC) were found on verbal learning and parent-rated behavior problems. Group differences were marginally significant (measures within the broad neuropsychological comparison) or not significant (visual attention, retention of verbal material) on the remaining comparisons. Therefore, some deficits (e.g., verbal learning and behavior problems) in children with heavy prenatal alcohol exposure cannot be explained by the lower FSIQ observed in the population. These areas of relative weakness could be useful in distinguishing children with FASD from other children with lowered IQ.

The effects of maternal binge drinking during pregnancy on neural correlates of response inhibition and memory in childhood.

Although an extensive literature has documented a broad range of cognitive performance deficits in children with prenatal alcohol exposure, little is known about how the neurophysiological processes underlying these deficits may be affected. Event-related potentials (ERPs), which reflect task-specific changes in brain electrical activity, provide a method for examining multiple constituents of cognitive processing at the neural level. We recorded ERPs in 217 children from Inuit communities in Arctic Quebec (M age = 11.3 years) during 2 different tasks-Go/No-go response inhibition and continuous recognition memory. Children were classified as either alcohol-exposed (ALC) or controls (CON) depending on whether the mother reported binge drinking during pregnancy. Both groups performed comparably in terms of accuracy and reaction time on the tasks, and both tasks elicited the expected effects on ERPs when responses were compared across conditions. However, the ALC group showed slower P2 latencies on Go/No-go, suggesting an altered neurophysiological response associated with initial visual processing of the stimuli. On the memory task, the ALC group showed reduced FN400 amplitude to New items, known as the familiarity effect, and reduced amplitude for the late positive component, possibly reflecting impairment in memory retrieval. These findings show that, even in tasks in which alcohol-exposed children exhibit behavioral performance that is comparable to controls, fetal alcohol exposure is associated with altered neurophysiological processing of response inhibition and recognition memory. The data suggest that fetal alcohol exposure is associated with reduced efficiency in the initial extracting of the meaning of a stimulus, reduced allocation of attention to the task, and poorer conscious, explicit recognition memory processing.

Postnatal binge-like alcohol exposure reduces spine density without affecting dendritic morphology in rat mPFC.

Among the deficits associated with fetal alcohol syndrome (FAS), cognitive impairments are the most debilitating and permanent. These impairments, including deficits in goal-directed behavior, attention, temporal planning, and other executive functions, could result from damage to the prefrontal cortex (PFC), an area that has not been studied sufficiently in the context of FAS. Neuronal connectivity in this area, as measured by distribution of dendritic spines and the complexity of dendritic tree structure, can be influenced by exogenous variables other than alcohol, and the neuronal connectivity in other brain regions can be affected by alcohol exposure. The goal of this study was to determine whether binge-like alcohol exposure on postnatal days (PD) 4-9 affects dendritic spine density and other dendritic tree parameters in mPFC that could possibly underlie functional damage. Rats were intubated with alcohol [5.25 g/kg/day; alcohol exposed (AE)], sham intubated (SI), or remained with the mother (SC, suckle control) on PD 4-9. Animals were sacrificed between PD 26 and PD 30 and brains were processed for Golgi-Cox staining. Apical dendrite complexity and spine density were evaluated for layer III neurons in the mPFC using NeuroLucida software (MicroBrightField, Inc.). Spine density was significantly decreased in AE animals relative to SI and SC controls, but no differences in dendritic complexity were found across experimental groups. Our findings demonstrate that neonatal alcohol exposure has a persistent effect on the spine density in mPFC that can explain functional deficits in this cortical area.

Persistent Impairment of Hippocampal Neurogenesis in Young Adult Rats Following Early Postnatal Alcohol Exposure

Prenatal alcohol exposure can cause damage to the developing fetus with outcomes including growth deficiency, facial dysmorphology, brain damage, and cognitive and behavioral deficits. Smaller brains in children with FASD have been linked both with reduced cell proliferation in the developing CNS and with apoptotic cell loss of postmitotic neurons. Prenatal alcohol exposure in rodents during the period of brain development comparable to that of the first and second trimesters of human pregnancy persistently alters adult neurogenesis. Long-term effects of alcohol exposure during the third trimester equivalent, which occurs postnatally in the rat, on adult neurogenesis have not been previously reported. The goal of this study was to examine the effect of postnatal binge-like alcohol exposure on cell proliferation and neurogenesis in hippocampal dentate gyrus during adolescence and young adulthood. Male Long-Evans rat pups were assigned to 3 groups: alcohol-exposed (AE), sham-intubated (SI) or suckle control (SC). AE pups received ethanol in a milk formula in a binge manner (2 feedings, 2 hours apart, total dose 5.25 g/kg/day) on postnatal days (PD) 4-9. BrdU was injected every other day on PD30-50. Animals were perfused either on PD50 to examine cytogenesis and neurogenesis in hippocampal dentate gyrus at the end of BrdU injections or on PD80 to evaluate new cell survival. Dorsal hippocampal sections were immunostained for BrdU, a marker for proliferating cells, Ki67, endogenous marker of proliferation, and NeuN, a marker for mature neurons. Binge-like alcohol exposure on PD4-9 significantly reduced the number of mature neurons in adult hippocampal dentate gyrus (DG) both on PD50 and PD80, without altering cumulative cytogenesis on PD50. In addition, the number of new neurons, that were generated between PD30 and 50, was further reduced after 30 days of survival in all 3 groups (SC, SI, and AE). These observations suggest that early postnatal binge alcohol exposure results in long-term deficits of adult hippocampal neurogenesis, providing a potential basis for the deficits of hippocampus-dependent behaviors reported for this model.

Effects of acute alcohol intoxication in the second trimester of pregnancy on development of the murine fetal lung

We hypothesized that administration of alcohol during the second trimester of gestation at the pseudoglandular phase of lung development might lead to aberrant differentiation and growth, similar to that seen in congenital cystic adenomatoid malformation in human. We further hypothesized that these effects would be apparent morphologically and by altered Hoxb5 expression. C57BL/6J mice, exposed to ethanol at embryonic day (E) 11.5 to E13.5, which corresponds to the pseudoglandular stage of lung development, were examined at E18.5. The lungs were analyzed histologically by immunostaining. The average body and lung weight of alcohol-exposed (AE) fetuses were lower than those of control fetuses, the reduction in lung mass being more than the body weight. Histology showed that AE lungs were less developed and exhibited higher expression of Hoxb5 in AE lungs than controls. Alcohol exposure at E13.5 affected fetal lung development, with delayed differentiation and increased Hoxb5.

813 Preoperative concurrent chemoradiotherapy in non-small-cell lung cancer. Feasibility, toxicity and long-term results of a phase II study

Neonatal alcohol exposure impairs cognition and learning in adulthood and permanently damages the hippocampus. Wheel running (WR) improves hippocampus-associated learning and memory and increases the genesis and survival of newly generated neurons in the hippocampal dentate gyrus. WR significantly increases proliferation of newly generated dentate granule cells in alcohol-exposed (AE) and control rats on Postnatal Day (PD) 42 but only control rats show an increased number of surviving cells thirty days after WR (Helfer et al., 2009b). The present studies examined whether proliferation-promoting WR followed by survival-enhancing environmental complexity (EC) during adolescence could increase survival of new neurons in AE rats. On PD 4–9, pups were intubated with alcohol in a binge-like manner (5.25 g/kg/day, AE), were sham-intubated (SI), or were reared normally (suckle control, SC). On PD 30 animals were assigned to WR (PD 30–42) followed by EC (PD 42–72; WR/EC) or were socially housed (SH/SH) for the duration of the experiment. All animals were injected with 200 mg/kg bromodeoxyuridine (BrdU) on PD 41. In Experiment 1, survival of newly generated cells was significantly enhanced in the AE-WR/EC group in comparison with AE-SH/SH group. Experiment 2A examined trace eyeblink conditioning. In the SH/SH condition, AE impaired trace eyeblink conditioning relative to SI and SC controls. In the WR/EC condition, AE rats performed as well as controls. In Experiment 2B, the same intervention was examined using the context preexposure facilitation effect (CPFE); a hippocampus-dependent variant of contextual fear conditioning. Again, the WR/EC intervention reversed the deficit in conditioned fear to the context that was evident in the SH/SH condition. Post-weaning environmental manipulations promote cell survival and reverse learning deficits in rats that were exposed to alcohol during development. These manipulations may provide a basis for developing interventions that ameliorate learning impairments associated with human fetal alcohol spectrum disorders.

Alcohol Deters the Outgrowth of Serotonergic Neurons at Midgestation

We have previously demonstrated that treatment of pregnant C57BL mice from gestation days 8 to 14 with alcohol with 20% ethanol-derived calories (EDC) reduced the number of serotonin (5-HT) neurons and retarded their migration in the fetal brains. In the present study, we obtained similar results with the use of 25% EDC and extended our previous findings by demonstrating that besides the alteration of the number of 5-HT neurons, prenatal alcohol exposure also affects their projecting fibers in their early development. Pregnant C57BL mice were divided into an alcohol-exposed (ALC) group given 25% EDC (4.49%, v/v), a pair-fed group to the ethanol-fed group (PF) and a chow-fed group (Chow). The PF and Chow groups served as controls. Our results showed that in the ALC group, when compared with the control groups, prenatal alcohol exposure with 25% EDC reduced the number of 5-HT-immunoreactive neurons in both the median and dorsal raphe, and the amount of 5-HT-immunoreactive fibers in the medial forebrain bundle (MFB). The diameter of the 5-HT-immunoreactive MFB was also reduced as a result of treatment. No significant differences of the above parameters were found between the PF and Chow groups. The previous and present work confirmed that alcohol reduces the normal formation and growth of 5-HT neurons in the midbrain. Furthermore, the projection of 5-HT fibers, in density as well as in distribution, is reduced in the major trajectory bundle. This may affect the amount of 5-HT fibers available to the forebrain. In light of the importance of the 5-HT system in brain development, alcohol may affect the growth of the forebrain through its effect on 5-HT signaling.

Alcohol deters the outgrowth of serotonergic neurons at midgestation.

We have previously demonstrated that treatment of pregnant C57BL mice from gestation days 8 to 14 with alcohol with 20% ethanol-derived calories (EDC) reduced the number of serotonin (5-HT) neurons and retarded their migration in the fetal brains. In the present study, we obtained similar results with the use of 25% EDC and extended our previous findings by demonstrating that besides the alteration of the number of 5-HT neurons, prenatal alcohol exposure also affects their projecting fibers in their early development. Pregnant C57BL mice were divided into an alcohol-exposed (ALC) group given 25% EDC (4.49%, v/v), a pair-fed group to the ethanol-fed group (PF) and a chow-fed group (Chow). The PF and Chow groups served as controls. Our results showed that in the ALC group, when compared with the control groups, prenatal alcohol exposure with 25% EDC reduced the number of 5-HT-immunoreactive neurons in both the median and dorsal raphe, and the amount of 5-HT-immunoreactive fibers in the medial forebrain bundle (MFB). The diameter of the 5-HT-immunoreactive MFB was also reduced as a result of treatment. No significant differences of the above parameters were found between the PF and Chow groups. The previous and present work confirmed that alcohol reduces the normal formation and growth of 5-HT neurons in the midbrain. Furthermore, the projection of 5-HT fibers, in density as well as in distribution, is reduced in the major trajectory bundle. This may affect the amount of 5-HT fibers available to the forebrain. In light of the importance of the 5-HT system in brain development, alcohol may affect the growth of the forebrain through its effect on 5-HT signaling.

Therapeutic motor training ameliorates cerebellar effects of postnatal binge alcohol.

We have used training on complex motor tasks to ameliorate effect of neonatal alcohol exposure. On postnatal days 4-9, alcohol-exposed (AE) rats were given 4.5 g/kg/day of alcohol by artificial rearing; gastrostomy control (GC) rats were given an isocaloric mixture of maltose/dextrin; suckling control (SC) rats were suckled normally. At 6 months of age, animals from the three groups underwent either rehabilitation training on a series of complex motor tasks, motor conditioning on a flat runway, or an inactive home cage condition. Subsequently, animals were either tested on three tests of balance and coordination, or were used for cerebellar morphology. After rehabilitation, but not after motor conditioning, male and female AE rats exhibited significant improvement in independent tests of motor skills. Using unbiased stereological morphological techniques, rehabilitated SC and AE animals were found to exhibit significantly more parallel fiber synapses per Purkinje cell in the paramedian lobule.

Neuromuscular Responses to Disturbance of Balance in Children with Prenatal Exposure to Alcohol

Alcohol-exposed children display delayed motor development and impaired fine- and gross-motor skills, including deficits in the maintenance of balance. In a recent study, we assessed the contribution of visual, somatosensory, and vestibular information to the ability to maintain balance. Our findings suggested that alcohol-exposed children were overly reliant on somatosensory information and were unable to compensate by using the visual and/or vestibular systems. To understand the nature of these observed balance deficits, corrective postural reactions were examined by exposing standing subjects to rapid toe-up movements of the support surface. Subjects for this study were alcohol-exposed (ALC) and normal control (NC) children matched for age and sex. Postural reactions were quantified by measuring electromyographic activity of the triceps surae and anterior tibialis muscles. Analyses revealed no differences between the ALC and NC groups on short- and medium-latency electromyographic responses, which are thought to be involuntary mono- and polysynaptic spinal reflexes, respectively. However, when compared with the NC group, the ALC group displayed increased long-latency responses, which are thought to involve a transcortical pathway. Although we are not able to rule out the possibility of additional peripheral (e.g., vestibular) disturbance as a contributing factor to postural instability, our findings suggest that the balance deficits seen in alcohol-exposed children are, at least in part, central in nature.

Neuromuscular Responses to Disturbance of Balance in Children with Prenatal Exposure to Alcohol

Alcohol-exposed children display delayed motor development and impaired fine- and gross-motor skills, including deficits in the maintenance of balance. In a recent study, we assessed the contribution of visual, somatosensory, and vestibular information to the ability to maintain balance. Our findings suggested that alcohol-exposed children were overly reliant on somatosensory information and were unable to compensate by using the visual and/or vestibular systems. To understand the nature of these observed balance deficits, corrective postural reactions were examined by exposing standing subjects to rapid toe-up movements of the support surface. Subjects for this study were alcohol-exposed (ALC) and normal control (NC) children matched for age and sex. Postural reactions were quantified by measuring electromyographic activity of the triceps surae and anterior tibialis muscles. Analyses revealed no differences between the ALC and NC groups on short- and medium-latency electromyographic responses, which are thought to be involuntary mono- and polysynaptic spinal reflexes, respectively. However, when compared with the NC group, the ALC group displayed increased long-latency responses, which are thought to involve a transcortical pathway. Although we are not able to rule out the possibility of additional peripheral (e.g., vestibular) disturbance as a contributing factor to postural instability, our findings suggest that the balance deficits seen in alcohol-exposed children are, at least in part, central in nature.