Stark Neurosciences Research Institute, Indiana University School of Medicine, 320 W. 15th Street, Indianapolis, IN 46202, USA; Graduate Program in Medical Neuroscience, Indiana University School of Medicine, 320 W. 15th Street, Indianapolis, IN 46202, USA.
Stark Neurosciences Research Institute, Indiana University School of Medicine, 320 W. 15th Street, Indianapolis, IN 46202, USA; Department of Anatomy Cellular Biology & Physiology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202, USA.
Neuroscience. 2021 Nov 21;477:40-49. doi: 10.1016/j.neuroscience.2021.08.031. Epub 2021 Sep 4.
Repeated exposure to stress has been implicated in inducing chronic anxiety states. Stress related increases in anxiety responses are likely mediated by activation of corticotropin-releasing factor receptors (CRFR) in the amygdala, particularly the basolateral amygdala (BLA). Within the BLA, acute injections of the CRFR agonist urocortin 1 (Ucn1) leads to acute anxiety, whereas repeated daily injections of subthreshold-doses of Ucn1 produces a long-lasting, persistent anxiety-like phenotype, a phenomenon referred to as Ucn1-priming. Relative gene expressions from the BLA of vehicle and Ucn1-primed rats were analyzed with quantitative RT-PCR using a predesigned panel of 82 neuroscience-related genes. Compared to vehicle-primed rats, only expression of the somatostatin receptor 2 gene (Sstr2) was significantly reduced in the BLA of Ucn1-primed rats. The contribution of Sstr2 on an anxiety phenotype was tested by injecting a Sstr2 antagonist into the BLA in un-primed rats. The Sstr2 antagonist increased anxiety-like behavior. Notably, pretreatment with Sstr2 agonist injected into the BLA blocked anxiety-inducing effects of acute Ucn1 BLA-injections and delayed anxiety expression during Ucn1-priming. However, concomitant Sstr2 agonist pretreatment during Ucn-1 priming did not prevent either the development of a chronic anxiety state or a reduction of BLA Sstr2 expression induced by priming. The data demonstrate that the persistent anxiety-like phenotype observed with Ucn1-priming in the BLA is associated with a selective reduction of Sstr2 gene expression. Although Sstr2 activation in the BLA blocks acute anxiogenic effects of stress and down-regulation of BLA Sstr2, it does not suppress the long-term consequences of prolonged exposure to stress-related challenges.
反复暴露于应激下与诱导慢性焦虑状态有关。应激相关的焦虑反应增加可能是通过激活杏仁核中的促肾上腺皮质释放因子受体（CRFR）介导的，特别是基底外侧杏仁核（BLA）。在 BLA 内，CRFR 激动剂孤啡肽 1（Ucn1）的急性注射会导致急性焦虑，而亚阈值剂量 Ucn1 的重复每日注射会产生持久的、持续的类似焦虑的表型，这种现象称为 Ucn1 引发。使用预先设计的 82 种神经科学相关基因的定量 RT-PCR 分析了来自载体和 Ucn1 引发的大鼠 BLA 的相对基因表达。与载体引发的大鼠相比，只有 Ucn1 引发的大鼠 BLA 中的生长抑素受体 2 基因（Sstr2）的表达明显降低。通过在未引发的大鼠的 BLA 中注射 Sstr2 拮抗剂来测试 Sstr2 在焦虑表型中的作用。Sstr2 拮抗剂增加了焦虑样行为。值得注意的是，BLA 中 Sstr2 激动剂的预处理阻断了急性 Ucn1 BLA 注射的焦虑诱导作用，以及 Ucn1 引发期间的延迟焦虑表达。然而，在 Ucn-1 引发期间同时进行 Sstr2 激动剂预处理既不能预防慢性焦虑状态的发展，也不能预防引发引起的 BLA Sstr2 表达的减少。数据表明，Ucn1 引发在 BLA 中观察到的持续的类似焦虑的表型与 Sstr2 基因表达的选择性降低有关。尽管 BLA 中的 Sstr2 激活可阻断应激的急性致焦虑作用和 BLA Sstr2 的下调，但它不能抑制与应激相关挑战的长期暴露的长期后果。
