Center for Sleep and Circadian Biology, Northwestern University, Evanston, IL 60208-3520, USA.
Genes Brain Behav. 2012 Feb;11(1):113-24. doi: 10.1111/j.1601-183X.2011.00737.x. Epub 2011 Nov 17.
Both human beings and animals exhibit substantial inter-individual variation in voluntary physical activity, and evidence indicates that a significant component of this variation is because of genetic factors. However, little is known of the genetic basis underlying central regulation of voluntary physical activity in mammals. In this study, using an F(2) intercross population and interval-specific congenic strains (ISCS) derived from the C57BL/6J strain and a chromosome 13 substitution strain, C57BL/6J-Chr13A/J/NA/J, we identified a 3.76-Mb interval on chromosome 13 containing 25 genes with a significant impact on daily voluntary wheel running activity in mice. Brain expression and polymorphisms between the C57BL/6J and A/J strains were examined to prioritize candidate genes. As the dopaminergic pathway regulates motor movement and motivational behaviors, we tested its function by examining cocaine-induced locomotor responses in ISCS with different levels of activity. The low-activity ISCS exhibited a significantly higher response to acute cocaine administration than the high-activity ISCS. Expression analysis of key dopamine-related genes (dopamine transporter and D1, D2, D3, D4 and D5 receptors) revealed that expression of D1 receptor was higher in the low-activity ISCS than in the high-activity ISCS in both the dorsal striatum and nucleus accumbens. Pathway analysis implicated Tcfap2a, a gene found within the 3.76-Mb interval, involved in the D1 receptor pathway. Using a luciferase reporter assay, we confirmed that the transcriptional factor, Tcfap2a, regulates the promoter activity of the D1 receptor gene. Thus, Tcfap2a is proposed as a candidate genetic regulator of the level of voluntary physical activity through its influence on a dopaminergic pathway.
人类和动物在自愿体力活动方面表现出很大的个体间差异，有证据表明，这种差异的一个重要组成部分是由于遗传因素。然而，对于哺乳动物自愿体力活动的中枢调节的遗传基础知之甚少。在这项研究中，我们使用了一个 F(2) 杂交群体和来自 C57BL/6J 品系和 13 号染色体替代品系 C57BL/6J-Chr13A/J/NA/J 的区间特异性同源导入系（ISCS），鉴定出 13 号染色体上的一个 3.76-Mb 区间，其中包含 25 个基因，这些基因对小鼠的每日自愿轮跑活动有显著影响。检查了 C57BL/6J 和 A/J 品系之间的脑表达和多态性，以确定候选基因。由于多巴胺能途径调节运动和动机行为，我们通过检查具有不同活动水平的 ISCS 对可卡因诱导的运动反应来测试其功能。低活性 ISCS 对急性可卡因给药的反应明显高于高活性 ISCS。关键多巴胺相关基因（多巴胺转运体和 D1、D2、D3、D4 和 D5 受体）的表达分析表明，在背侧纹状体和伏隔核中，低活性 ISCS 的 D1 受体表达高于高活性 ISCS。通路分析表明，在 3.76-Mb 区间内发现的基因 Tcfap2a 参与了 D1 受体途径。使用荧光素酶报告基因检测，我们证实转录因子 Tcfap2a 调节 D1 受体基因的启动子活性。因此，Tcfap2a 通过其对多巴胺能途径的影响，被提议作为自愿体力活动水平的候选遗传调节剂。
