Lack of adrenomedullin in the mouse brain results in behavioral changes, anxiety, and lower survival under stress conditions
Lack of adrenomedullin in the mouse brain results in behavioral changes, anxiety, and lower survival under stress conditions
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DOI：
10.1073/pnas.0803174105
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发表时间：
2008-08-26
影响因子：
11.1
通讯作者：
Martinez, Alfredo
中科院分区：
文献类型：
--
作者：
Fernandez, Ana P.;Serrano, Julia;Martinez, Alfredo
肾上腺髓质素 (AM) 基因 adm 在中枢神经系统 (CNS) 中广泛表达，并且大脑 AM 具有多种功能。到目前为止，由于系统性 adm 敲除会导致胚胎致死，因此使用遗传模型对这些作用进行正式确认一直难以实现。我们使用 Cre/loxP 方法构建了条件敲除小鼠模型。当与在微管蛋白 T α-1 启动子下表达 Cre 重组酶的转基因小鼠杂交时，我们获得了中枢神经系统中没有 AM 表达但其他器官中表达正常水平的动物。这些动物过着正常的生活，没有任何明显的形态缺陷。缺乏 CNS AM 的动物大脑的特定区域含有高聚微管蛋白，这是 AM 下调的结果。行为分析表明，与野生型同窝小鼠相比，大脑中没有 AM 的小鼠运动协调能力受损，并且过度活跃和过度焦虑。哌醋甲酯、氟哌啶醇和地西泮治疗没有显示出基因型之间的差异。基因敲除小鼠和野生型小鼠中促肾上腺皮质激素和皮质酮的循环水平相似。与野生型小鼠相比，没有大脑 AM 的动物对低压缺氧的抵抗力较差，这证明了 AM 在中枢神经系统中的神经保护功能。总之，AM 通过在正常和压力条件下维持体内平衡而对大脑发挥有益作用。
The adrenomedullin (AM) gene, adm, is widely expressed in the central nervous system (CNS) and several functions have been suggested for brain AM. Until now, a formal confirmation of these actions using genetic models has been elusive since the systemic adm knockout results in embryo lethality. We have built a conditional knockout mouse model using the Cre/loxP approach. When crossed with transgenic mice expressing the Cre recombinase under the tubulin T alpha-1 promoter, we obtained animals with no AM expression in the CNS but normal levels in other organs. These animals lead normal lives and do not present any gross morphological defect. Specific areas of the brain of animals lacking CNS AM contain hyperpolymerized tubulin, a consequence of AM down-regulation. Behavioral analysis shows that mice with no AM in their brain have impaired motor coordination and are hyperactive and overanxious when compared to their wild-type littermates. Treatment with methylphenidate, haloperidol, and diazepam did not show differences between genotypes. Circulating levels of adrenocorticotropic hormone and corticosterone were similar in knockout and wild-type mice. Animals with no brain AM were less resistant to hypobaric hypoxia than wild-type mice, demonstrating the neuroprotective function of AM in the CNS. In conclusion, AM exerts a beneficial action in the brain by maintaining homeostasis both under normal and stress conditions.