Impulsive choices in mice lacking imprinted Nesp55
Impulsive choices in mice lacking imprinted Nesp55
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DOI：
10.1111/gbb.12316
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发表时间：
2016-11-01
影响因子：
2.5
通讯作者：
Isles, A. R.
中科院分区：
文献类型：
--
作者：
Dent, C. L.;Humby, T.;Isles, A. R.
基因组印记是种系表观遗传事件导致许多关键哺乳动物基因的亲本特异性单等位基因表达的过程。印记基因 Nesp 仅从母体等位基因表达并编码 Nesp55 蛋白。在大脑中，Nesp55 主要存在于下丘脑和中脑的离散区域。之前，我们已经证明 Nesp55 的缺失会引起新奇相关行为的改变。在这里，我们扩展了这些发现，并使用 Nesp(m/+) 小鼠模型证明，通过延迟强化任务测量，Nesp55 的缺失会导致冲动选择，其中 Nespm/+ 小鼠不太愿意等待延迟的、较大的奖励，而是更愿意选择立即的、较小的奖励。这些效果是高度具体的，因为冲动行为的另一个组成部分的表现，即停止信号反应时间任务中测定的一旦开始就停止反应的能力，与对照组相当。我们还显示了血清素系统的变化，这是介导冲动行为的关键神经递质途径。首先，我们证明了 Nesp55 与血清素共定位，然后进一步证明，在 Nesp(m/+) 小鼠的中脑区域，血清素特异性基因 Tph2 和 Slc6a4 的 mRNA 表达减少，但多巴胺特异性基因 Th 的 mRNA 表达没有减少；这表明血清素系统的改变可能在一定程度上导致冲动行为的改变。这些数据为大脑中的基因组印记提供了一种新的作用模式，并可能对以适应不良反应控制为特征的病理状况产生影响。
Genomic imprinting is the process whereby germline epigenetic events lead to parent-of-origin specific monallelic expression of a number of key mammalian genes. The imprinted gene Nesp is expressed from the maternal allele only and encodes for Nesp55 protein. In the brain, Nesp55 is found predominately in discrete areas of the hypothalamus and midbrain. Previously, we have shown that loss of Nesp55 gives rise to alterations in novelty-related behaviour. Here, we extend these findings and demonstrate, using the Nesp(m/+) mouse model, that loss of Nesp55 leads to impulsive choices as measured by a delayed-reinforcement task, whereby Nespm/+ mice were less willing to wait for a delayed, larger reward, preferring instead to choose an immediate, smaller reward. These effects were highly specific as performance in another component of impulsive behaviour, the ability to stop a response once started as assayed in the stop-signal reaction time task, was equivalent to controls. We also showed changes in the serotonin system, a key neurotransmitter pathway mediating impulsive behaviour. First, we demonstrated that Nesp55 is co-localized with serotonin and then went on to show that in midbrain regions there were reductions in mRNA expression of the serotonin-specific genes Tph2 and Slc6a4, but not the dopamine-specific gene Th in Nesp(m/+) mice; suggesting an altered serotonergic system could contribute, in part, to the changes in impulsive behaviour. These data provide a novel mode of action for genomic imprinting in the brain and may have implications for pathological conditions characterized by maladaptive response control.