Astrocyte and microglial associated modules exhibited increased expression in AD subjects and were predominantly enriched with immune related processes. The immune signaling processes resulting from repeated alcohol abuse arise from activation of astrocytes and microglia; when coupled with alcohol-induced loss of neurogenesis, are thought to enhance the negative emotional states that lead to addiction [73]. In this study, M green was the module most significantly associated with these immune related processes, i.e. Toll-like receptor 4 (TLR4) signaling and inflammatory cytokine pathways. Injection of lipopolysaccharides (LPS) in mice has been shown to induce the expression of innate immune genes through activation of TLR4 in microglia and astrocytes, leading to depression-like behaviors [73]. LPS infusions in human studies were also reported to reduce reward responses and increase depressed mood [74]. Furthermore, induction of innate immune genes in mice resulted in increased ethanol consumption, whereas inactivation of such genes reduced drinking behavior [75, 76]. These observations highlight the role of immune signaling in the neurobiology of addiction and support our GSEA findings in astrocyte and microglial associated modules.
