The BXD21/TyJ recombinant inbred strain as a model for innate inflammatory response in distinct brain regions

Abstract

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...

Effects of oxidized soybean oil on the performance of sows and jejunum health of suckling piglets

“…It has been shown that exposure to oxidized soybean oil after a high oxidized diet results in oxidative stress in the intestinal mucosa (Liang et al, 2015). Sustained oxidative stress may result in the altered expression of certain genes involved in inflammatory pathways (Liu et al, 2021; López‐Granero et al, 2020). It was also confirmed in the present study that maternal feeding of oxidized soybean oil during late gestation and lactation resulted in abnormal mRNA levels of inflammatory‐regulating cytokines in the jejunum of the offspring.…”

BXD Recombinant Inbred Mice as a Model to Study Neurotoxicity

“…Interestingly, Phillips et al (1995) studied male BXD RI strains upon acute and repeated dosing with 2 g/kg ethanol. The authors found that both acute and repeated treatments led to changes in the initial ethanol response, which was attributed to the sensitization of locomotor stimulation; QTL analyses demonstrated an association with basal locomotor activity and acute locomotor response on chromosomes 3,4,7,11,12,13,15, and 17 to initial ethanol response [31]. Likewise, a study with 20 BXD RI murine strains and C57BL/6J and DBA/2J progenitor strains exposed to 2 g/kg of ethanol evaluated ethanol's ability to induce conditioned place preference, noting a significant association between ethanol-seeking behavior in BXD RI mice and genetic markers on chromosomes 4, 8, 9, 18 and 19 [32].…”

“…More recently, thanks to progress in genomic sequencing [ 5 ], the BXD RI mice were used to map complex traits. This advance has led to the use of BXD RI mice in addressing neurotoxicology and neurodegeneration [ 6 , 7 ]. Specifically, the relevance of the BXD RI family has been extended to the analysis of the genetics of behavioral phenotypes, including alcohol and drug addiction [ 8 , 9 , 10 , 11 , 12 , 13 , 14 ], neurodegenerative processes [ 4 , 6 , 15 , 16 , 17 ], heavy metals and pesticides [ 3 , 18 , 19 ], and changes related to the degeneration of the visual system [ 20 , 21 , 22 ].…”

“…Our research group has assessed BXD RI mice in the context of social preference, anxiety and depression-associated behaviors, along with changes in the inflammatory system in the brain cortex [ 6 ]. In addition, we reported on the utility of BXD RI mice as a model for innate inflammatory responses in distinct brain regions, such as the hippocampus, striatum, and cerebellum [ 7 ]. Our studies highlighted the need to identify an adequate animal model based on the neurotoxicology and behavioral objectives, with specific BXD RI mice strains providing unique, innate characteristics.…”