Given the large body of research examining the interaction between alcohol and the immune system, it is not surprising that over 60 of the 138 enriched BPs discovered in the differentially expressed gene network were related to immune signaling and immune system functioning. Similarly, C3ar1, Ccl6, Ccl9, and Cd59a, which are cell membrane receptors involved in innate immune signaling, were identified as hub genes in the differentially expressed gene network. Alcohol is known to activate Toll-like receptor 4 (TLR4) innate immune signaling pathways leading to NF-κB mediated transcription of pro-inflammatory cytokines and chemokines which may contribute to addictive processes such as escalation of intake, behavioral inflexibility, impulsivity, and negative affect (Crews et al. 2011; Crews et al. 2006; Montesinos et al. 2016; Zou & Crews 2010). Emerging evidence indicates cytokine and chemokine signaling also modulate synaptic transmission and plasticity. For instance, TNF-α, a cytokine produced upon TLR4 activation, drives AMPA receptor internalization in MSNs of the DS reducing AMPA/NMDA ratio driven currents (Lewitus et al. 2014). Our RNA-sequencing analysis provides further evidence that neuroimmune signaling is involved in the genetic
