Consideration of genetic and sex effects in mice enhances consilience with human addiction studies. Consideration of genetic and sex effects in mice enhances consilience with human addiction studies

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. Overall design: This RNAseq dataset includes 128 mice from 8 inbred strains (129S1/SvImJ, A/J, C57BL/6J, NOD/ShiLtJ, NZO/HlLtJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ), two sexes (sex_chrY: M, F), and who received repeated injections of either cocaine (injection: cocaine, sham). Choroid plexus contamination was identified in some samples (choroid_plexus). Total RNA libraries were prepared using ribosomal depletion and sequenced to a median depth of 132M reads.

跨物种研究结果的可推广性以及啮齿类动物模型（rodent model）的外部效度问题，往往源于对多样性有限的群体所开展的窄化研究结果。个体差异的来源——包括遗传因素与性别因素——在模式生物（model organism）研究中往往未被直接纳入考量。在啮齿类动物研究中明确纳入个体差异，有望揭示与人类成瘾相关的保守表型与分子系统。与多数复杂疾病一致，可卡因使用障碍（cocaine use disorder）的患病风险存在显著的个体间差异。本研究针对8个近交系小鼠品系（inbred mouse strains）的雌雄个体开展了可卡因相关行为性状的调查，这些品系的基因组共同覆盖了小鼠物种90%的遗传多样性。在这些品系中，个体差异可解释可卡因应答性或可卡因应答预测性的行为与生理表型中相当大比例的变异。纳入野生来源的小鼠品系，往往能将这些行为的表型范围拓展至常规家养实验小鼠品系所观测到的范围之外。纹状体（striatum）对可卡因的转录应答同样高度依赖品系与性别差异，多数可卡因应答基因的差异表达模式受品系、性别或二者交互作用的调控。本研究将小鼠体内由品系与性别介导的可卡因转录应答，与可卡因使用障碍（cocaine use disorder）患者的转录组学（transcriptomic）分析结果进行对比，发现小鼠与人类的转录组相似性高度依赖小鼠的遗传背景与性别。具体而言，雄性WSB/EiJ小鼠与雌性NOD/ShiLtJ小鼠，在与可卡因使用障碍患者的神经转录组一致性方面表现最为突出。因此，模式生物（model organism）多样性是一类至关重要的生物学信息来源，可显著提升成瘾风险机制研究的外部效度。实验设计概述：本RNA测序（RNAseq）数据集包含来自8个近交系小鼠品系（129S1/SvImJ、A/J、C57BL/6J、NOD/ShiLtJ、NZO/HlLtJ、CAST/EiJ、PWK/PhJ及WSB/EiJ）的128只小鼠，涵盖两种性别（sex_chrY: M，雄性；F，雌性），且均接受了重复注射可卡因（注射分组：cocaine）或假注射（注射分组：sham）处理。部分样本中检测到脉络丛（choroid_plexus）污染。总RNA文库采用核糖体RNA去除法构建，测序的中位深度为132M reads（1.32亿条读段）。