Genes affected by CIE fell into several pathways associated with neuronal development and/or plasticity (Supplementary Table S2). Fifty-eight genes in the axonal guidance pathway were affected, among which 38 were increased in expression (including frizzled and ephrin receptors, semaphorins and plexins), but the tubulins were decreased in expression. Tubulins make up microtubules necessary for development and movement of neurons (Breuss, Leca, Gstrein, Hansen, & Keays, 2017). Related pathways that share some of the same genes include reelin signaling in neurons, Ephrin A signaling, synaptogenesis signaling, and Wnt/β-catenin signaling. Reelin signaling is important in neuronal migration and modulation of synaptic functions (Lee & D’Arcangelo, 2016). TGF-β signaling, involved in late-stage adult neurogenesis (He et al., 2014), showed an overall increase in activity. All of these pathways except synaptogenesis were affected in at least one brain region of the CIE treated P rats (Supplementary Table S2) (McClintick et al., 2015, 2016, 2018). TGFβ signaling was also increased in the LCLs of alcoholics (McClintick et al., 2019). There is substantial overlap of genes within these pathways, including multiple Wnts and their Frizzled receptors, FGF receptors, ephrin receptors, semaphorins and adenylate cyclases.
