Are these stresses and dysfunctional changes related? Most of these stresses can be linked to NF-κB (Figure 2), which is connected to 25 of the differentially expressed genes in this dataset, including genes related to hypoxia, inflammation, neurogenesis, and myelin. Variations within NFKB1, a subunit of NF-κB, have been associated with alcoholism (Edenberg et al., 2008). One can conceptualize the inter-relationships as in Figure 3. Ethanol activates inflammation via the TLR4 pathway and NF-κB. Increased inflammation, via the toll-like receptor 4 (TLR4), can play a role in the loss of white matter seen in alcoholics (Alfonso-Loeches et al., 2012). Wild-type mice chronically treated with ethanol for 5 months had decreased expression of several myelin-related genes in multiple brain regions, and also a reduced number of oligodendrocytes, but Tlr4 knockout mice similarly treated did not show decreased expression of the myelin genes. The ER stress we have found, if unresolved, can also increase inflammation via TXNIP (strongly increased) and NF-κB.
