NF-kB- and Smad3 networks were identified as highly connected in NAC. NF-kB is a ubiquitously expressed transcription factor family that controls the transcription of hundreds of genes that are involved in many processes, including inflammation, immunity, cell proliferation, and cell death [59, 60] and is known to be an important regulator of neuroinflammation [61]. A number of studies have identified genes that are related to inflammatory/immune responses and mediate their effects through NF-kB [40]. Smad3 (SMAD family member 3) mediates signaling from transforming growth factor beta (TGF-β) that is a regulator of cell proliferation, differentiation and death [62]. Smad3 knockout mice have impaired immune function, suggesting SMAD signaling is involved in regulating the immune response [63, 64]. Recently, alcohol-induced microglial changes were found to be over-represented in genes attributed to TGF-β/Smad3 receptor signaling and inflammatory response [65]. Given that TGF β is a cytokine expressed in brain that is capable of controlling microglial activation, this signaling pathway may have the potential to regulate alcohol consumption. MicroRNAs that targeted these hubs included miR-34a-5p, miR-17-5p, miR-181a-5p, miR-16-5p for Bcl2 in the AMY
