Dickson Price E, Roy Tyler A, McNaughton Kathryn A, Wilcox Troy D, Kumar Padam, Chesler Elissa J
Center for Systems Neurogenetics of Addiction, The Jackson Laboratory, Bar Harbor, Maine.
Genes Brain Behav. 2019 Mar;18(3):e12519. doi: 10.1111/gbb.12519. Epub 2018 Oct 8.
Sensation seeking is a multifaceted, heritable trait which predicts the development of substance use and abuse in humans; similar phenomena have been observed in rodents. Genetic correlations among sensation seeking and substance use indicate shared biological mechanisms, but the genes and networks underlying these relationships remain elusive. Here, we used a systems genetics approach in the BXD recombinant inbred mouse panel to identify shared genetic mechanisms underlying substance use and preference for sensory stimuli, an intermediate phenotype of sensation seeking. Using the operant sensation seeking (OSS) paradigm, we quantified preference for sensory stimuli in 120 male and 127 female mice from 62 BXD strains and the C57BL/6J and DBA/2J founder strains. We used relative preference for the active and inactive levers to dissociate preference for sensory stimuli from locomotion and exploration phenotypes. We identified genomic regions on chromosome 4 (155.236-155.742 Mb) and chromosome 13 (72.969-89.423 Mb) associated with distinct behavioral components of OSS. Using publicly available behavioral data and mRNA expression data from brain regions involved in reward processing, we identified (a) genes within these behavioral QTL exhibiting genome-wide significant cis-eQTL and (b) genetic correlations among OSS phenotypes, ethanol phenotypes and mRNA expression. From these analyses, we nominated positional candidates for behavioral QTL associated with distinct OSS phenotypes including Gnb1 and Mef2c. Genetic covariation of Gnb1 expression, preference for sensory stimuli and multiple ethanol phenotypes suggest that heritable variation in Gnb1 expression in reward circuitry partially underlies the widely reported relationship between sensation seeking and substance use.
寻求刺激是一种多方面的、可遗传的特质，它能预测人类物质使用和滥用行为的发展；在啮齿动物中也观察到了类似现象。寻求刺激与物质使用之间的遗传相关性表明存在共同的生物学机制，但这些关系背后的基因和网络仍不清楚。在这里，我们在BXD重组近交小鼠品系中采用系统遗传学方法，以确定物质使用和对感觉刺激的偏好（寻求刺激的一种中间表型）背后的共同遗传机制。使用操作性寻求刺激（OSS）范式，我们对来自62个BXD品系以及C57BL/6J和DBA/2J创始品系的120只雄性和127只雌性小鼠对感觉刺激的偏好进行了量化。我们使用对活动杆和非活动杆的相对偏好，将对感觉刺激的偏好与运动和探索表型区分开来。我们在4号染色体（155.236 - 155.742 Mb）和13号染色体（72.969 - 89.423 Mb）上鉴定出与OSS不同行为成分相关的基因组区域。利用公开可用的行为数据和来自参与奖励处理的脑区的mRNA表达数据，我们确定了：（a）这些行为QTL内表现出全基因组显著顺式eQTL的基因，以及（b）OSS表型、乙醇表型和mRNA表达之间的遗传相关性。通过这些分析，我们提名了与不同OSS表型相关的行为QTL的定位候选基因，包括Gnb1和Mef2c。Gnb1表达、对感觉刺激的偏好和多种乙醇表型之间的遗传共变表明，奖励回路中Gnb1表达的遗传变异部分构成了寻求刺激与物质使用之间广泛报道的关系的基础。
