Article

Timing of Moderate Level Prenatal Alcohol Exposure Influences Gene Expression of Sensory Processing Behavior in Rhesus Monkeys

Department of Kinesiology, University of Wisconsin-Madison Madison, WI, USA.
Frontiers in Integrative Neuroscience 11/2009; 3:30. DOI: 10.3389/neuro.07.030.2009
Source: PubMed

ABSTRACT Sensory processing disorder, characterized by over- or under-responsivity to non-noxious environmental stimuli, is a common but poorly understood disorder. We examined the role of prenatal alcohol exposure, serotonin transporter gene polymorphic region variation (rh5-HTTLPR), and striatal dopamine (DA) function on behavioral measures of sensory responsivity to repeated non-noxious sensory stimuli in macaque monkeys. Results indicated that early gestation alcohol exposure induced behavioral under-responsivity to environmental stimuli in monkeys carrying the short (s) rh5-HTTLPR allele compared to both early-exposed monkeys homozygous for the long (l) allele and monkeys from middle-to-late exposed pregnancies and controls, regardless of genotype. Moreover, prenatal timing of alcohol exposure altered the relationship between sensory scores and DA D(2)R availability. In early-exposed monkeys, a positive relationship was shown between sensory scores and DA D(2)R availability, with low or blunted DA function associated with under-responsive sensory function. The opposite pattern was found for the middle-to-late gestation alcohol-exposed group. These findings raise questions about how the timing of prenatal perturbation and genotype contributes to effects on neural processing and possibly alters neural connections.

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    • "It has been shown using both non-human primates [111] [112] [113] and rodent models as well as in humans [50] that prenatal exposure to alcohol impairs habituation to external stimuli, requiring more trials to habituate to olfactory, visual, tactile or auditory stimuli, which suggest impairment in the regulatory brain mechanisms. Schneider and colleagues [111] [112], in a study using non-human primates, reported that animals submitted to alcohol exposure presented an exacerbated response to sensory (tactile) stimuli in adulthood. Similar results were observed in children who had FAS [114]. "
    Advances in Medicine and Biology, V. 74 edited by Leon V. Berhardt, 01/2014: chapter Alcohol in pregnancy and its repercussion on Central Nervous System: pages 25-42; Nova Science Publishers., ISBN: 978-1-62948-379-5
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    • "It has been shown that the timing of heavy episodes of alcohol consumption during pregnancy may determine which functional system may be affected depending on the cytoarchitectonic areas that are at the peak of neuronal migration at that period (Sidman and Rakic 1973). Furthermore , the timing of the prenatal alcohol exposure may alter gene expression (Schneider et al. 2009; Hashimoto-Torii et al. 2011) and differentially affect both neural migration and differentiation. Future studies with detailed information on the amount, frequency, and timing of prenatal alcohol use can advance our understanding on the teratogenic effect of alcohol on the brain, though this information is rarely available in human populations. "
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    ABSTRACT: Accumulating evidence from structural brain imaging studies on individuals with fetal alcohol spectrum disorder (FASD) has supported links between prenatal alcohol exposure and brain morphological deficits. Although global and regional volumetric reductions appear relatively robust, the effects of alcohol exposure on cortical thickness and relationships with facial dysmorphology are not yet known. The structural magnetic resonance imaging data from 69 children and adolescents with FASD and 58 nonexposed controls collected from 3 sites were examined using FreeSurfer to detect cortical thickness changes across the entire brain in FASD and their associations with facial dysmorphology. Controlling for brain size, subjects with FASD showed significantly thicker cortices than controls in several frontal, temporal, and parietal regions. Analyses conducted within site further revealed prominent group differences in left inferior frontal cortex within all 3 sites. In addition, increased inferior frontal thickness was significantly correlated with reduced palpebral fissure length. Consistent with previous reports, findings of this study are supportive of regional increases in cortical thickness serving as a biomarker for disrupted brain development in FASD. Furthermore, the significant associations between thickness and dysmorphic measures suggest that the severity of brain anomalies may be reflected by that of the face.
    Cerebral Cortex 07/2011; 22(5):1170-9. DOI:10.1093/cercor/bhr193 · 8.67 Impact Factor
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    • "Our previous work showed that prenatal alcohol-exposed monkeys carrying the serotonin transporter gene polymorphic region (rh5-HTTLPR) short (s) allele exhibited increased neonatal irritability and higher levels of ACTH during weaning at 6 months of age compared with prenatal alcohol exposed monkeys homozygous for the long allele and monkeys not prenatal alcohol exposed, regardless of genotype (Kraemer et al., 2008). Moreover, we found that early gestation alcohol exposure induced behavioral under-responsivity or blunting of responses to non-noxious tactile stimuli in monkeys carrying the short rh5- HTTLPR allele compared to early alcohol-exposed monkeys homozygous for the long allele and monkeys from middle-to-late alcohol-exposed pregnancies and controls, regardless of genotype (Schneider et al., 2009). Others have reported that monkeys carrying a copy of the rh5-HTTLPR short allele differed in concentrations of 5-HT metabolites in cerebral spinal fluid (Bennett et al., 2002), neonatal visual orienting to stimuli (Champoux et al., 2002) and ACTH levels during social separation when compared to monkeys with the l/l genotype (Barr et al., 2004). "
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    ABSTRACT: Moderate prenatal alcohol exposure can contribute to neurodevelopmental impairments and disrupt several neurotransmitter systems. We examined the timing of moderate level alcohol exposure, serotonin transporter gene polymorphic region variation (rh5-HTTLPR), and levels of primary serotonin and dopamine (DA) metabolites in cerebrospinal fluid (CSF) in rhesus monkeys. Thirty-two 30-month old rhesus monkeys (Macaca mulatta) from 4 groups of females were assessed: (i) early alcohol-exposed group (n = 9), in which mothers voluntarily consumed 0.6 g/kg/d alcohol solution on gestational days 0 to 50; (ii) middle-to-late gestation alcohol-exposed group (n = 6), mothers consumed 0.6 g/kg/d alcohol solution on gestational days 50 to 135; (iii) a continuous-exposure group (n = 8), mothers consumed 0.6 g/kg/d alcohol solution on gestational days 0 to 135; and (iv) controls (n = 9), mothers consumed an isocaloric control solution on gestational days 0 to 50, 50 to 135, or 0 to 135. Serotonin transporter promoter region allelic variants (homozygous s/s or heterozygous s/l vs. homozygous l/l) were determined. We examined CSF concentrations of the 5-HT and DA metabolites, 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA), respectively, at baseline and 50 hours after separation from cage-mates, when the monkeys were 30 months old. Early- and middle-to-late gestation-alcohol exposed monkeys carrying the short allele had lower concentrations of 5-HIAA in CSF relative to other groups. Concentrations of 5-HIAA in CSF were lower for s allele carriers and increased from baseline relative to pre-separation values, whereas 5-HIAA levels in l/l allele carriers were not affected by separation. Monkeys carrying the short allele had lower basal concentrations of HVA in CSF compared with monkeys homozygous for the long allele. Carrying the s allele of the 5-HT transporter increased the probability of reduced 5-HIAA in early- and middle-to-late gestation alcohol-exposed monkeys and reduced HVA at baseline. These findings that prenatal alcohol exposure altered central 5-HT activity in genetically sensitive monkeys raise questions about whether abnormal serotonin biological pathways could underlie some of the psychiatric disorders reported in fetal alcohol spectrum disorder.
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