Department of Physiology, University of Melbourne, Melbourne, Victoria 3010, Australia.
J Neurosci. 2012 Feb 8;32(6):2051-61. doi: 10.1523/JNEUROSCI.5360-11.2012.
The rise in blood pressure during an acute aversive stress has been suggested to involve activation of angiotensin type 1A receptors (AT(1A)Rs) at various sites within the brain, including the rostral ventrolateral medulla. In this study we examine the involvement of AT(1A)Rs associated with a subclass of sympathetic premotor neurons of the rostral ventrolateral medulla, the C1 neurons. The distribution of putative AT(1A)R-expressing cells was mapped throughout the brains of three transgenic mice with a bacterial artificial chromosome-expressing green fluorescent protein under the control of the AT(1A)R promoter. The overall distribution correlated with that of the AT(1A)Rs mapped by other methods and demonstrated that the majority of C1 neurons express the AT(1A)R. Cre-recombinase expression in C1 neurons of AT(1A)R-floxed mice enabled demonstration that the pressor response to microinjection of angiotensin II into the rostral ventrolateral medulla is dependent upon expression of the AT(1A)R in these neurons. Lentiviral-induced expression of wild-type AT(1A)Rs in C1 neurons of global AT(1A)R knock-out mice, implanted with radiotelemeter devices for recording blood pressure, modulated the pressor response to aversive stress. During prolonged cage-switch stress, expression of AT(1A)Rs in C1 neurons induced a greater sustained pressor response when compared to the control viral-injected group (22 ± 4 mmHg for AT(1A)R vs 10 ± 1 mmHg for GFP; p < 0.001), which was restored toward that of the wild-type group (28 ± 2 mmHg). This study demonstrates that AT(1A)R expression by C1 neurons is essential for the pressor response to angiotensin II and that this pathway plays an important role in the pressor response to aversive stress.
急性厌恶应激期间血压升高被认为涉及大脑内各种部位的血管紧张素 1 型受体 (AT(1A)R) 的激活，包括头侧腹外侧髓质。在这项研究中，我们检查了与头侧腹外侧髓质中交感节前神经元的一个亚类，即 C1 神经元相关的 AT(1A)R 的参与。通过在 AT(1A)R 启动子控制下表达绿色荧光蛋白的细菌人工染色体，在三只转基因小鼠的整个大脑中绘制了假定的 AT(1A)R 表达细胞的分布。总体分布与通过其他方法绘制的 AT(1A)R 分布相关，并表明大多数 C1 神经元表达 AT(1A)R。在 AT(1A)R 基因敲除小鼠的 C1 神经元中表达 Cre 重组酶，使人们能够证明向头侧腹外侧髓质内微注射血管紧张素 II 引起的升压反应依赖于这些神经元中 AT(1A)R 的表达。在植入用于记录血压的无线电遥测设备的全身 AT(1A)R 基因敲除小鼠的 C1 神经元中，慢病毒诱导表达野生型 AT(1A)R 可调节对厌恶应激的升压反应。在长时间的笼切换应激期间，与对照病毒注射组相比（AT(1A)R 为 22 ± 4 mmHg，GFP 为 10 ± 1 mmHg；p < 0.001），C1 神经元中 AT(1A)R 的表达诱导了更大的持续升压反应，这与野生型组的反应（28 ± 2 mmHg）相似。这项研究表明，C1 神经元中 AT(1A)R 的表达对于血管紧张素 II 的升压反应是必需的，并且该途径在厌恶应激的升压反应中起着重要作用。
