Grey matter dysmyelination during abstinence in ethanol dependence

다국어 초록 (Multilingual Abstract)

White matter atrophy/demyelination observed in heavy alcohol users is often reported as reduced fractional anisotropy (FA) and increased mean and radial diffusivity (MD and RD, respectively) quantified using diffusion tensor imaging (DTI). Several lines of research suggest that neurobehavioral impairments in grey matter areas like the medial prefrontal cortex (mPFC) are critical components of alcohol dependence and relapse vulnerability. Previous research revealed that homeostatic imbalance in myelinating cells in mPFC of a rat model of alcoholism was associated with increased risk of relapse‐like behavior during protracted abstinence. Therefore, we investigated the demyelination in the mPFC at several time points during protracted abstinence from heavy alcohol exposure. Adult male rats underwent chronic intermittent ethanol exposure (CIE), where rats breathed air containing ethanol vapor for 14 hours/day to elicit blood alcohol levels (125–250 mg/dl), and neurobehavioral deficits mirroring moderate‐severe alcohol use disorder. Myelination was investigated first using DTI in vivo, followed by post‐mortem immunoblotting analyses of myelin‐associated proteins in mPFC after various durations of ethanol abstinence (1 day; 1d, 7d, 21d, and 42d) in CIE rats and in age‐matched ethanol‐naive controls (n = 6–10/group). In the corpus callosum (white matter), we observed a transient decrease in FA (to ~ 90% of controls) and increase in RD (~ 180%) at 7d that normalized later (21–42d; ps < 0.05). These white‐matter microstructural data indicate demyelination followed by recovery in the CIE model, which mirrors the results obtained from neuroimaging in human alcoholics. In the mPFC (grey matter), increased MD and RD (both ~160%), and surprisingly, increased FA (~105%) was observed at 7d (ps < 0.05). Concurrently, increased expression of myelin basic protein and myelin oligodendrocyte glycoprotein in the mPFC were observed at 7d (ps < 0.05). All changes in DTI measures and protein expression were normalized by 21–42d (ps < 0.05). These results suggest microstructural damage that is inconsistent qualitatively, with both demyelination and hypermyelination. Electron microscopic analysis was conducted in 7d abstinent and control rats (n = 4–5/group) to determine ultrastructural characteristics of mPFC neurons at this critical interval. Results revealed damaged myelinated axons in the mPFC, such that more fibers were flayed (~160%), and these flays occupied a greater portion of the axonal perimeter (~160%) in rats with a history of CIE compared to naïve controls (ps < 0.05). The flayed damage is consistent with demyelination suggested by the increased MD and RD. The increased FA may reflect the accumulation of myelin‐associated proteins due to reduced turnover and compensatory de novo protein synthesis. Taken together, these results suggest transient dysmyelination in the mPFC of rats with a history of CIE; future studies should investigate its functional implications. DTI measures observed in white matter area (corpus callosum) of the rat model was translationally valid, therefore providing credence to the translational relevance of the observed grey matter (mPFC) DTI changes. Thus, the current model may provide valuable insights into the causal link between heavy alcohol intake, mPFC myelin neuropathology, and relapse and thereby may be developed into a diagnostic indicator for future risk for relapse during abstinence.
Support or Funding Information
Funding: AA020098, AA06420 and DA034140All research reported has been conducted in conformance with the FASEB Statement of Principles for the use of Animals in Research and Education.




Damaged (flayed) myelin in mPFC of alcohol abstinent subject

Damaged (flayed) myelin in mPFC of alcohol abstinent subject
This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.