Cholesterol synthesis pathways in the PAG (and also in the DRN; McClintick et al., 2015) were altered by binge drinking (Table 4), with many genes having decreased expression. Hmgcr (3-hydroxy-3-methylglutaryl-CoA synthase 1, down 1.5-fold), catalyzes the rate limiting step for cholesterol production. Eight additional genes in the cholesterol pathway expression decreased by 1.3 to 1.5 fold. Alcohol consumption by P rats also decreased expression of cholesterol synthesis genes in the liver (Klein et al., 2014). Cholesterol is important for brain function, playing a major role in synaptogenesis, membranes, synaptic vesicles and myelin sheaths; 70–80% of the cholesterol in the brain is in the myelin sheaths. Since cholesterol cannot cross the blood-brain barrier, all cholesterol in the brain is synthesized there (Zhang and Liu, 2015). Cholesterol production peaks during development when myelination is heaviest. Cholesterol levels are tightly regulated, and levels are sensed by the sterol regulatory-element binding proteins (Srebp); the upstream regulator analysis indicates that Srebp and insulin signaling (which can also control expression of genes for cholesterol synthesis, uptake and transport) appear to be reduced. Decreases in brain cholesterol
