Project description:Adolescent sensitivity to alcohol is predictive of later alcohol use and is influenced by genetic background. Data from our laboratory suggested that adolescent C57BL/6J and DBA/2J inbred mice differed in susceptibility to dorsal hippocampus-dependent contextual fear learning deficits after acute alcohol exposure. To investigate the biological underpinnings of this strain difference, we examined dorsal hippocampus gene expression via RNA-sequencing after alcohol and/or fear conditioning across male and female C57BL/6J and DBA/2J adolescents. Strains exhibited dramatic differences in dorsal hippocampal gene expression. Specifically, C57BL/6J and DBA/2J strains differed in 3526 transcripts in males and 2675 transcripts in females. We identified pathways likely to be involved in mediating alcohol’s effects on learning, including networks associated with Chrna7 and Fmr1. These findings provide insight into the mechanisms underlying strain differences in alcohol’s effects on learning and suggest that different biological networks are recruited for learning based on genetics, sex, and alcohol exposure.
Project description:BACKGROUND: Human SP-A1 and SP-A2, encoded by SFTPA1 and SFTPA2 and their genetic variants differentially impact alveolar macrophage (AM) functions and regulation, including the miRNome. We investigated whether miRNome differences previously observed between AM from SP-A2 and SP-A1/SP-A2 mice are due to continued qualitative differences or a delayed response of mice carrying a single gene. METHODS: Human transgenic (hTG) mice, carrying SP-A2 or both SP-A genes and SP-A-KO mice were exposed to filtered air (FA) or O3. AM miRNA levels, target gene expression and pathways determined 18 h after O3 exposure. RESULTS: We found: (a) Differences in miRNome due to sex, SP-A genotype, and exposure; (b) miRNome of both sexes was largely downregulated by O3 ; co-ex had fewer changed (≥2X) miRNAs than either group. (c) the number and direction of expression of genes with significant changes in males and females in co-ex is almost the opposite of those in SP-A2; (iv) The same pathways were found in the studied groups; (e) O3 exposure attenuated sex differences; a higher number of genotype-dependent and genotype-independent miRNAs was common in both sexes after O3 exposure. CONCLUSION: Qualitative differences between SP-A2 and co-ex persist 18 h post-O3, and O3 attenuates sex differences.
Project description:Concerns about translation of findings across species and external validity of rodent models are often based on results from narrow investigations of populations with limited diversity. Sources of individual variation – including genetics and sex – are not often directly encompassed in model organism studies. Explicit inclusion of individual differences in rodent research has the potential to reveal conserved phenotypes and molecular systems relevant to human addiction. As with most complex diseases, risk for cocaine use disorder is subject to considerable inter-individual variation. We surveyed cocaine-related behavioral traits in both males and females of eight inbred mouse strains whose genomes collectively capture 90% of the genetic diversity of the mouse species. Across these strains, individual differences explained a substantial proportion of variance in cocaine-responsive or cocaine response-predictive behavioral and physiological phenotypes. The inclusion of wild-derived mouse strains often extended the phenotypic ranges of these behaviors beyond the range observed in conventional domestic laboratory mouse strains. Striatum transcriptional responses to cocaine were also highly dependent upon strain and sex differences, with most cocaine-responsive genes being differentially expressed in a manner moderated by strain, sex, or their combination. We compared the strain- and sex-mediated transcriptional responses to cocaine in mice to transcriptomic analysis of people with cocaine use disorder, finding that mouse similarity to humans was highly dependent upon mouse genetic background and sex. Specifically, male WSB/EiJ mice and female NOD/ShiLtJ mice exhibited the greatest extent of neural transcriptional consilience with humans with cocaine use disorder. Model organism diversity thus represents a crucial source of biological information that can substantially improve external validity of research into addiction risk mechanisms.