Dataset Information

The effects of chronic alcohol self-administration in nonhuman primate brain networks.

ABSTRACT: BACKGROUND:Long-term alcohol abuse is associated with change in behavior, brain structure, and brain function. However, the nature of these changes is not well understood. In this study, we used network science to analyze a nonhuman primate model of ethanol self-administration to evaluate functional differences between animals with chronic alcohol use and animals with no exposure to alcohol. Of particular interest was how chronic alcohol exposure may affect the resting state network. METHODS:Baseline resting state functional magnetic resonance imaging was acquired in a cohort of vervet monkeys. Animals underwent an induction period where they were exposed to an isocaloric maltose dextrin solution (control) or ethanol in escalating doses over three 30-day epochs. Following induction, animals were given ad libitum access to water and a maltose dextrin solution (control) or water and ethanol for 22 h/d over 12 months. Cross-sectional analyses examined region of interests in hubs and community structure across animals to determine differences between drinking and nondrinking animals after the 12-month free access period. RESULTS:Animals were classified as lighter (<2.0 g/kg/d) or heavier drinkers (?2.0 g/kg/d) based on a median split of their intake pattern during the 12-month ethanol free access period. Statistical analysis of hub connectivity showed significant differences in heavier drinkers for hubs in the precuneus, posterior parietal cortices, superior temporal gyrus, subgenual cingulate, and sensorimotor cortex. Heavier drinkers were also shown to have less consistent communities across the brain compared to lighter drinkers. The different level of consumption between the lighter and heavier drinking monkeys suggests that differences in connectivity may be intake dependent. CONCLUSIONS:Animals that consume alcohol show topological differences in brain network organization, particularly in animals that drink heavily. Differences in the resting state network were linked to areas that are associated with spatial association, working memory, and visuomotor processing.

SUBMITTER: Telesford QK

PROVIDER: S-EPMC6724209 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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The effects of chronic alcohol self-administration in nonhuman primate brain networks.

Telesford Qawi K QK Laurienti Paul J PJ Davenport April T AT Friedman David P DP Kraft Robert A RA Daunais James B JB

Alcoholism, clinical and experimental research 20150401 4

<h4>Background</h4>Long-term alcohol abuse is associated with change in behavior, brain structure, and brain function. However, the nature of these changes is not well understood. In this study, we used network science to analyze a nonhuman primate model of ethanol self-administration to evaluate functional differences between animals with chronic alcohol use and animals with no exposure to alcohol. Of particular interest was how chronic alcohol exposure may affect the resting state network.<h4> ...[more]

PMID: 25833027

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Project description:BackgroundRodent models of chronic alcohol exposure are typically constrained to relatively short periods of forced ethanol due to the lifespan of these animals. Nonhuman primate models, particularly those employing long-term self-administration, are conceptually more similar to human alcoholic individuals.MethodsWe performed whole-cell patch clamp recordings on acutely dissociated amygdala neurons isolated from cynomolgus macaque coronal temporal lobe slices. Slices were prepared from control monkeys or monkeys allowed to self-administer oral ethanol for 18 months. Flunitrazepam and acute ethanol modulation of currents gated by exogenous gamma-aminobutyric acid (GABA) application was assessed in these isolated neurons. Complementary experiments were performed on amygdala total RNA using quantitative real-time reverse transcription/polymerase chain reaction to understand potential ethanol-dependent adaptations to subunit composition.ResultsGamma-aminobutyric acid-gated currents from ethanol-exposed macaque amygdala neurons exhibited reduced modulation by flunitrazepam compared with control neurons. However, this was specific for benzodiazepines as the modest inhibition of GABA-gated currents by acute ethanol was not affected by the chronic ethanol consumption. We also measured mRNA expression levels for the beta, gamma, and delta subunits in total amygdala RNA isolated from control and ethanol-drinking animals. beta1 and gamma2 expression was significantly reduced in samples from ethanol-exposed amygdala.ConclusionsOur findings demonstrate that chronic ethanol self-administration reduces the benzodiazepine sensitivity of amygdala GABA(A) receptors. This reduced sensitivity may be the result of decreased expression of an amygdala gamma subunit. These findings suggest that, while rodent and nonhuman primate models of chronic ethanol exposure share many characteristics, the specific molecular adaptations associated with the amygdala GABAergic system may not be identical.

Project description:BackgroundBased upon experimental animal studies, the neurodevelopmental abnormalities associated with prenatal alcohol exposure (PNAE)/fetal alcohol spectrum disorder (FASD) have been attributed, at least in part, to epigenetic modifications. However, there are no direct analyses of human brain tissue.MethodsImmunohistochemical detection of global epigenetic markers was performed on temporal lobe samples of autopsied fetuses and infants with documented PNAE. They were compared to age-, sex-, and postmortem delay-matched control cases (18 pairs; 20 to 70.5 weeks postconception). Temporal lobe tissue from a macaque monkey model of PNAE was also studied (5.7 to 6 months of age). We used antibodies targeting 4 DNA cytosine, 4 histone methylation, and 6 histone acetylation modifications and assigned scores based upon the semiquantitatively graded intensity and proportion of positively labeled nuclei in the ventricular and subventricular zones, ependyma, temporal cortex, temporal white matter, dentate gyrus (DG), and CA1 pyramidal layer.ResultsTemporal changes were identified for almost all marks according to the state of maturation in the human brain. In the DG (and 3 other brain regions), a statistically significant increase in H3K9ac was associated with PNAE. Statistically significant decreases were seen among 5mC, H3K4me3, H3K9ac, H3K27ac, H4K12ac, and H4K16ac in select regions. In the macaques, H3K36me3 decreased in the DG, and the ependyma showed decreases in 5fC and H3K36me3.ConclusionsIn human brain, global intranuclear epigenetic modifications are brain region and maturation state-specific. These exploratory results support the general hypothesis that PNAE is associated with a global decrease in DNA methylation, a global decrease in histone methylation, and a global increase in histone acetylation. Although the human and monkey subjects are not directly comparable in terms of brain maturation, considering the rapid temporal changes in global epigenetic modifications during brain development, interspecies comparisons may be extremely difficult.

Dataset Information

The effects of chronic alcohol self-administration in nonhuman primate brain networks.

Publications

The effects of chronic alcohol self-administration in nonhuman primate brain networks.

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