Bagley Jared R, Bailey Lauren S, Gagnon Leona H, He Hao, Philip Vivek M, Reinholdt Laura G, Tarantino Lisa M, Chesler Elissa J, Jentsch James D
Department of Psychology, Binghamton University, Binghamton, NY, USA.
Center for Systems Neurogenetics of Addiction at The Jackson Laboratory, Bar Harbor, ME, USA.
Addict Neurosci. 2022 Dec;4. doi: 10.1016/j.addicn.2022.100045. Epub 2022 Nov 4.
Impulsive behavior and impulsivity are heritable phenotypes that are strongly associated with risk for substance use disorders. Identifying the neurogenetic mechanisms that influence impulsivity may also reveal novel biological insights into addiction vulnerability. Our past studies using the BXD and Collaborative Cross (CC) recombinant inbred mouse panels have revealed that behavioral indicators of impulsivity measured in a reversal-learning task are heritable and are genetically correlated with aspects of intravenous cocaine self-administration. Genome-wide linkage studies in the BXD panel revealed a quantitative trait locus (QTL) on chromosome 10, but we expect to identify additional QTL by testing in a population with more genetic diversity. To this end, we turned to Diversity Outbred (DO) mice; 392 DO mice (156 males, 236 females) were phenotyped using the same reversal learning test utilized previously. Our primary indicator of impulsive responding, a measure that isolates the relative difficulty mice have with reaching performance criteria under reversal conditions, revealed a genome-wide significant QTL on chromosome 7 (max LOD score = 8.73, genome-wide corrected p<0.05). A measure of premature responding akin to that implemented in the 5-choice serial reaction time task yielded a suggestive QTL on chromosome 17 (max LOD score = 9.14, genome-wide corrected <0.1). Candidate genes were prioritized ( based upon expression QTL data we collected in DO and CC mice and analyses using publicly available gene expression and phenotype databases. These findings may advance understanding of the genetics that drive impulsive behavior and enhance risk for substance use disorders.
冲动行为和冲动性是可遗传的表型，与物质使用障碍风险密切相关。确定影响冲动性的神经遗传机制可能也会揭示成瘾易感性的新生物学见解。我们过去使用BXD和协作杂交（CC）重组近交小鼠品系进行的研究表明，在反转学习任务中测量的冲动性行为指标是可遗传的，并且与静脉注射可卡因自我给药的某些方面存在遗传相关性。在BXD品系中进行的全基因组连锁研究在10号染色体上发现了一个数量性状基因座（QTL），但我们期望通过在具有更多遗传多样性的群体中进行测试来识别其他QTL。为此，我们转向了多样性远交（DO）小鼠；使用之前同样的反转学习测试对392只DO小鼠（156只雄性，236只雌性）进行了表型分析。我们冲动反应的主要指标是一种衡量在反转条件下小鼠达到性能标准相对困难程度的方法，该指标在7号染色体上发现了一个全基因组显著的QTL（最大LOD分数 = 8.73，全基因组校正p<0.05）。一种类似于在5选串行反应时间任务中实施的过早反应的测量方法在17号染色体上产生了一个提示性QTL（最大LOD分数 = 9.14，全基因组校正<0.1）。根据我们在DO和CC小鼠中收集的表达QTL数据以及使用公开可用的基因表达和表型数据库进行的分析，对候选基因进行了优先级排序。这些发现可能会促进对驱动冲动行为并增加物质使用障碍风险的遗传学的理解。
