Oxidative stress and inflammatory cytokines affect the human brain, increasing the risk for mood and cognitive disorders. Such risk might be selective to brain-specific regions. Here, we determined whether BXD recombinant inbred (RI) mice strains are more suitable than C57BL/6J mice for the understanding of the relationship between antioxidant response and inflammatory responses. We hypothesized that inflammatory responses could be independent of antioxidant response and be inherent to brain-specific regions. This hypothesis will be addressed by the analyses of mRNA expression. We explored, at 7-months-of-age, the innate activation of proinflammatory cytokines (tumor necrosis factor alpha (TNFα) and interleukin 6 (IL-6), as well as Kelch-like ECH-associating protein 1 (Keap1), nuclear factor erythroid 2 related factor 2 (Nrf2) and glutathione peroxidase 1 (Gpx1) mRNA in both male and female BXD84/RwwJ RI, BXD21/TyJ RI and control strain (C57BL/6J mice). We report that: (1) The cerebellum is more sensitive to antioxidant response in the BXD21/TyJ RI strain; (2) The cerebellum, hippocampus and striatum show increased levels of cytokines in the BXD21/TyJ RI strain; (3) The BXD RI strain has lower brain weight relative to control strain (C57BL/6 mice). In conclusion, our novel data show the utility of the BXD21/TyJ RI strain mice in offering mechanistic insight into Nrf2's role in the inflammatory system. Central nervous system (CNS) dysfunction is frequently accompanied by oxidative stress and inflammatory responses 1. Oxidative damage and inflammatory cytokines influence brain function and result in increased risk for mood, behavioral and cognitive disorders 2-4. Thus, the general hypothesis is that antioxidant defenses and inflammatory cytokines are key elements in CNS pathologies 5 and psychiatric disorders 3,4,6,7. Several studies have revealed the mechanism by which continued oxidative stress can lead to chronic inflammation, which, in turn, could mediate most chronic diseases 8. The disruption of the inflammatory and oxidative stress pathways is associated with multiple neurotoxic exposures 9-11. Oxidative stress acts activating a variety of transcription factors, including Nrf2. Upon oxidative stress generation, Nrf2 dissociates from Kelch-like ECH-associating protein 1 (Keap1), and translocates into the nucleus where it binds to the antioxidant response element (ARE), and initiates antioxidant gene transcription thus restoring cellular redox homeostasis 12-15. Activation of these transcription factors can lead to the expression of different genes, including those for inflammatory cytokines and anti-inflammatory molecules 8. Indeed, Nrf2 is essential for protection against oxidative stress and it has also been shown to attenuate inflammation 16. Consistent with these observations, published data have corroborated dysregulation of inflammatory and oxidative systems both in behavioral and psychiatric disorders as a consequence of altered Nrf2 pathway functioning 7,15. Neuroinflammatory processes are established...