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Systems genetic analysis of nicotine withdrawal deficits in hippocampus-dependent learning
Genes, Brain and Behavior ( IF 2.5 ) Pub Date : 2021-04-02 , DOI: 10.1111/gbb.12734
Lisa R. Goldberg 1 , Munir Gunes Kutlu 1 , Dana Zeid 1 , Laurel R. Seemiller 1 , Thomas J. Gould 1
Affiliation  

Cognitive deficits, such as disrupted learning, are a major symptom of nicotine withdrawal. These deficits are heritable, yet their genetic basis is largely unknown. Our lab has developed a mouse model of nicotine withdrawal deficits in learning, using chronic nicotine exposure via osmotic minipumps and fear conditioning. Here, we utilized the BXD genetic reference panel to identify genetic variants underlying nicotine withdrawal deficits in learning. Male and female mice (n = 6–11 per sex per strain, 31 strains) received either chronic saline or nicotine (6.3 mg/kg per day for 12 days), and were then tested for hippocampus-dependent learning deficits using contextual fear conditioning. Quantitative trait locus (QTL) mapping analyses using GeneNetwork identified a significant QTL on Chromosome 4 (82.13 Mb, LRS = 20.03, p < 0.05). Publicly available hippocampal gene expression data were used to identify eight positional candidates (Snacpc3, Mysm1, Rps6, Plaa, Lurap1l, Slc24a2, Hacd4, Ptprd) that overlapped with our behavioral QTL and correlated with our behavioral data. Overall, this study demonstrates that genetic factors impact cognitive deficits during nicotine withdrawal in the BXD recombinant inbred panel and identifies candidate genes for future research.

中文翻译:

海马依赖性学习中尼古丁戒断缺陷的系统遗传分析

认知缺陷,例如学习中断,是尼古丁戒断的主要症状。这些缺陷是可遗传的,但它们的遗传基础在很大程度上是未知的。我们的实验室开发了一种学习中尼古丁戒断缺陷的小鼠模型,通过渗透性微型泵和恐惧条件使用慢性尼古丁暴露。在这里,我们利用 BXD 遗传参考面板来确定学习中尼古丁戒断缺陷的遗传变异。雄性和雌性小鼠 ( n = 6-11 每个性别每个菌株,31 个菌株)接受慢性盐水或尼古丁(每天 6.3 毫克/千克,持续 12 天),然后使用情境恐惧条件反射测试海马依赖性学习缺陷。使用 GeneNetwork 进行的数量性状基因座 (QTL) 定位分析确定了染色体 4 上的一个重要 QTL(82.13 Mb,LRS = 20.03,p  < 0.05)。公开可用的海马基因表达数据被用于鉴定八个候选位置(Snacpc3Mysm1Rps6PlaaLurap1lSlc24a2Hacd4Ptprd) 与我们的行为 QTL 重叠并与我们的行为数据相关。总的来说,这项研究表明,在 BXD 重组近交组中,遗传因素影响尼古丁戒断期间的认知缺陷,并确定了未来研究的候选基因。
更新日期:2021-04-02
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