Function and Mechanism of Myelin Regulation in Alcohol Abuse and Alcoholism

Abstract

Excessive alcohol use has adverse effects on the central nervous system (CNS) and can lead to alcohol use disorders (AUDs). Recent studies have suggested that myelin reductions may directly contribute to CNS dysfunctions associated with AUDs. Myelin consists of compact lipid membranes wrapped around axons to provide electrical insulation and trophic support. Regulation of myelin is considered as a new form of neural plasticity due to its profound impacts on the computation of neural networks. In this review, the authors first discuss experimental evidence showing how alcohol exposure causes demyelination in different brain regions, often accompanied by deficits in cognition and emotion. Next, they discuss postulated molecular and cellular mechanisms underlying alcohol's impact on myelin. It is clear that more extensive investigations are needed in this important but underexplored research field in order to gain a better understanding of the myelin-behavior relationship and to develop new treatment strategies for AUDs.

Keywords: activity-dependent neural plasticity; alcohol addiction and dependence; alcohol use disorder (AUD); central nervous system (CNS); myelin; oligodendrocyte (OL); oligodendrocyte progenitor cell (OPC).

Figure 1.. EtOH-induced alterations in myelin ultrastructure.

A, Transmission electron microscopy (TEM) image of myelinated axons in the normal CNS (modified from Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Siegel GJ, Agranoff BW, Albers RW, et al., editors. Philadelphia: Lippincott-Raven; 1999). B, TEM image of altered ultrastructure of myelin in substantia nigra of a human alcoholic brain (modified from ^[20]). Black arrowheads, vacuoles between the myelin lamellae. C, The representative TEM images from the PFC of adult (3 weeks after the last treatment administration) WT mice received intermittent ethanol or saline treatment in adolescence. Arrows indicate inter-laminar splitting of myelin sheaths (modified from ^[33]). Scale bars, 500 nm.

Figure 2.. EtOH can affect OLs at different developmental stages through different potential pathways.

Perinatal OPC and Late OPC were from purified OPC culture from rats (modified from ^[103]). Mature non-myelinating OL (shown by a black arrowhead) and Mature myelinating OL were from hippocampal myelin coculture (modified from ^[104]). In Mature myelinating OL, myelin coculture was infected with AAV9-GFP at 16 days in vitro (DIV), 2 d after OPCs were seeded. The coculture was fixed and stained after 28 DIV. Some mature OLs expressed GFP. One example of GFP-positive and mature OL (green) that developed multiple myelin basic protein (MBP)-positive (red) myelin segments ^[104]. White arrowheads, GFP- and MBP-positive myelin segments. Red arrows, potential impacts of EtOH on myelin have been implicated at different developmental stages. Scale bar, 100 μm. PDGFRα, platelet-derived growth factor receptor alpha. Wnt, Wingless/Integrated. Endo CB, endocannabinoid. GluRs, glutamate receptors. MyT1, the zinc finger protein Myelin Transcription Factor. ORs, opioid receptors. BDNF, brain-derived neurotrophic factor. PLP, proteolipid protein. MOG, myelin oligodendrocyte glycoprotein. MAG, myelin-associated glycoprotein.

Figure 3.. White matter and gray matter myelin in different regions of the mouse brain.

A, White matter bundles revealed by anti-MBP staining in the anterior cingulate cortex of the WT B6 mouse (top). Its corpus callosum is shown in an enlarged image at the bottom (modified from ^[105]). Scale bars, 500 μm (top) and 100 μm (bottom). B, Gray matter myelin segments in the mouse hippocampus that was stained for neurofilament (red), MBP (green) and DAPI nuclear dye (blue). C, Gray matter myelin segments in the mouse somatosensory cortex that was stained for MBP (green) and Kv2.1 (red). Kv2.1, a Shab voltage-gated potassium channel mainly expressed in the somatodendritic region of cortical pyramidal neurons (Image courtesy of Farida Eid). Scale bars, 200 μm in B and 100 μm in C.