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Regionally-specific alterations in myelin proteins in nonhuman primate white matter following prolonged cocaine self-administration.

ABSTRACT: Neuroimaging studies of cocaine users have demonstrated white matter abnormalities associated with behavioral measures of impulsivity and decision-making deficits. The underlying bases for this dysregulation in white matter structure and function have yet to be determined. The aim of the present studies was to investigate the influence of prolonged cocaine self-administration on the levels of myelin-associated proteins and mRNAs in nonhuman primate white matter.Rhesus monkeys (N=4) self-administered cocaine (0.3mg/kg/inj, 30 reinforcers per session) for 300 sessions. Control animals (N=4) responded for food. Following the final session monkeys were euthanized and white matter tissue at three brain levels was processed for immunoblotting analysis of proteolipid protein (PLP) and myelin basic protein (MBP), as well as for in situ hybridization histochemical analysis of PLP and MBP mRNAs.Both MBP and PLP immunoreactivities in white matter at the level of the precommissural striatum were significantly lower in tissue from monkeys self-administering cocaine as compared to controls. No significant differences were seen for either protein at the levels of the prefrontal cortex or postcommissural striatum. In addition, no differences were observed in expression of mRNA for either protein.These preliminary findings, in a nonhuman model of prolonged cocaine self-administration, provide further evidence that compromised myelin may underlie the deficits in white matter integrity described in studies of human cocaine users.

SUBMITTER: Smith HR

PROVIDER: S-EPMC4000724 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Regionally-specific alterations in myelin proteins in nonhuman primate white matter following prolonged cocaine self-administration.

Smith Hilary R HR Beveridge Thomas J R TJ Nader Michael A MA Porrino Linda J LJ

Drug and alcohol dependence 20140130

<h4>Background</h4>Neuroimaging studies of cocaine users have demonstrated white matter abnormalities associated with behavioral measures of impulsivity and decision-making deficits. The underlying bases for this dysregulation in white matter structure and function have yet to be determined. The aim of the present studies was to investigate the influence of prolonged cocaine self-administration on the levels of myelin-associated proteins and mRNAs in nonhuman primate white matter.<h4>Methods</h4 ...[more]

PMID: 24529965

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Project description:White matter hyperintensities negatively impact white matter structure and relate to cognitive decline in aging. Diffusion tensor imaging detects changes to white matter microstructure, both within the white matter hyperintensity and extending into surrounding (perilesional) normal-appearing white matter. However, diffusion tensor imaging markers are not specific to tissue components, complicating the interpretation of previous microstructural findings. Myelin water imaging is a novel imaging technique that provides specific markers of myelin content (myelin water fraction) and interstitial fluid (geometric mean T2). Here we combined diffusion tensor imaging and myelin water imaging to examine tissue characteristics in white matter hyperintensities and perilesional white matter in 80 individuals (47 older adults and 33 individuals with chronic stroke). To measure perilesional normal-appearing white matter, white matter hyperintensity masks were dilated in 2 mm segments up to 10 mm in distance from the white matter hyperintensity. Fractional anisotropy, mean diffusivity, myelin water fraction, and geometric mean T2 were extracted from white matter hyperintensities and perilesional white matter. We observed a spatial gradient of higher mean diffusivity and geometric mean T2, and lower fractional anisotropy, in the white matter hyperintensity and perilesional white matter. In the chronic stroke group, myelin water fraction was reduced in the white matter hyperintensity but did not show a spatial gradient in perilesional white matter. Across the entire sample, white matter metrics within the white matter hyperintensity related to whole-brain white matter hyperintensity volume; with increasing white matter hyperintensity volume there was increased mean diffusivity and geometric mean T2, and decreased myelin water fraction in the white matter hyperintensity. Normal-appearing white matter adjacent to white matter hyperintensities exhibits characteristics of a transitional stage between healthy white matter and white matter hyperintensities. This effect was observed in markers sensitive to interstitial fluid, but not in myelin water fraction, the specific marker of myelin concentration. Within the white matter hyperintensity, interstitial fluid was higher and myelin concentration was lower in individuals with more severe cerebrovascular disease. Our data suggests white matter hyperintensities have penumbra-like effects in perilesional white matter that specifically reflect increased interstitial fluid, with no changes to myelin concentration. In contrast, within the white matter hyperintensity there are varying levels of demyelination, which vary based on the severity of cerebrovascular disease. Diffusion tensor imaging and myelin imaging may be useful clinical markers to predict white matter hyperintensity formation, and to stage neuronal damage within white matter hyperintensities.

Project description: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.

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Regionally-specific alterations in myelin proteins in nonhuman primate white matter following prolonged cocaine self-administration.

Publications

Regionally-specific alterations in myelin proteins in nonhuman primate white matter following prolonged cocaine self-administration.

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