Reactivation of Tert in the medial prefrontal cortex and hippocampus rescues aggression and depression of Tert(-/-) mice.
Reactivation of Tert in the medial prefrontal cortex and hippocampus rescues aggression and depression of Tert(-/-) mice.
复制标题
内侧前额皮质和海马中 Tert 的重新激活可挽救 Tert(-/-) 小鼠的攻击性和抑郁症
DOI：
10.1038/tp.2016.106
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发表时间：
2016-06-14
影响因子：
6.8
通讯作者：
Suh H
中科院分区：
文献类型：
--
作者：
Zhou QG;Wu HY;Zhou H;Liu MY;Lee HW;Liu X;Devkota S;Ro EJ;Zhu DY;Suh H
端粒酶逆转录酶（TERT）在衰老和癌症中的作用已被广泛研究。有趣的是，Tert−/−小鼠表现出额外的但意想不到的攻击性和抑郁行为，这意味着TERT功能可能参与情绪控制。我们的条件拯救实验表明，Tert−/−小鼠的抑郁和攻击行为源于两种不同大脑结构的Tert缺陷。海马中Tert的重新激活足以使Tert−/−小鼠的抑郁行为正常化，但不能使其攻击行为正常化。相反，内侧前额叶皮层（mPFC）中Tert的重新表达逆转了Tert−/−小鼠的攻击性行为，但没有逆转其抑郁行为。从机制上讲，海马中的多巴胺能信号传导减少和一氧化氮（NO）传递增加将Tert缺乏症转化为抑郁症，我们的观察结果证明，向海马中输注5-羟色胺受体1a（5-HTR 1A）的药理学激动剂和神经元NO合酶的选择性拮抗剂成功地使Tert−/−小鼠的抑郁行为正常化。此外，mPFC中5-HTR 1A激动剂增加的多巴胺能传递足以挽救Tert−/−小鼠的攻击行为。因此，我们的研究揭示了一个新的功能，在抑郁症和侵略性的脑结构特异性的方式，提供直接证据的情绪控制的贡献，端粒酶逆转录酶的病理。
The role of telomerase reverse transcriptase (TERT) has been extensively investigated in the contexts of aging and cancer. Interestingly, Tert−/− mice exhibit additional but unexpected aggressive and depressive behaviors, implying the potential involvement of TERT function in mood control. Our conditional rescue experiments revealed that the depressive and aggressive behaviors of Tert−/− mice originate from Tert deficiency in two distinct brain structures. Reactivation of Tert in the hippocampus was sufficient to normalize the depressive but not the aggressive behaviors of Tert−/− mice. Conversely, re-expression of Tert in the medial prefrontal cortex (mPFC) reversed the aggressive but not the depressive behavior of Tert−/− mice. Mechanistically, decreased serotonergic signaling and increased nitric oxide (NO) transmission in the hippocampus transduced Tert deficiency into depression as evidenced by our observation that the infusion of a pharmacological agonist for serotonin receptor 1a (5-HTR1A) and a selective antagonist for neuronal NO synthase into the hippocampus successfully normalized the depressive behavior of Tert−/− mice. In addition, increased serotonergic transmission by the 5-HTR1A agonist in the mPFC was sufficient to rescue the aggressive behavior of Tert−/− mice. Thus, our studies revealed a novel function of TERT in the pathology of depression and aggression in a brain structure-specific manner, providing direct evidence for the contribution of TERT to emotional control.