Background

Stress produces differential behavioral responses through select molecular modifications to specific neurocircuitry elements. The orexin (Orx) system targets key components of this neurocircuitry in the basolateral amygdala (BLA).

Methods

We assessed the contribution of intra-BLA Orx₁ receptors (Orx₁Rs) in the expression of stress-induced phenotypes of mice. Using the Stress Alternatives Model, a social stress paradigm that produces two behavioral phenotypes, we characterized the role of intra-BLA Orx₁R using acute pharmacological inhibition (SB-674042) and genetic knockdown (AAV-U6-Orx₁R-shRNA) strategies.

Results

In the BLA, we observed that Orx₁R (Hcrtr1) messenger RNA is predominantly expressed in CamKIIα⁺ glutamatergic neurons and rarely in GABAergic (gamma-aminobutyric acidergic) cells. While there is a slight overlap in Hcrtr1 and Orx₂ receptor (Hcrtr2) messenger RNA expression in the BLA, we find that these receptors are most often expressed in separate cells. Antagonism of intra-BLA Orx₁R after phenotype formation shifted behavioral expression from stress-sensitive (Stay) to stress-resilient (Escape) responses, an effect that was mimicked by genetic knockdown. Acute inhibition of Orx₁R in the BLA also reduced contextual and cued fear freezing responses in Stay animals. This phenotype-specific behavioral change was accompanied by biased molecular transcription favoring Hcrtr2 over Hcrtr1 and Mapk3 over Plcb1 cell signaling cascades and enhanced Bdnf messenger RNA.

Conclusions

Functional reorganization of intra-BLA gene expression is produced by antagonism of Orx₁R, which promotes elevated Hcrtr2, greater Mapk3, and increased Bdnf expression. Together, these results provide evidence for a receptor-driven mechanism that balances pro- and antistress responses within the BLA.

中文翻译：

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基底外侧杏仁核中的食欲素 1 受体拮抗作用将平衡从促应激信号和行为转变为抗应激信号和行为

背景

压力通过对特定神经电路元件的选择分子修饰产生不同的行为反应。食欲素 (Orx) 系统以基底外侧杏仁核 (BLA) 中该神经回路的关键组件为目标。

方法

我们评估了 BLA 内 Orx ₁受体 (Orx ₁ Rs) 在应激诱导的小鼠表型表达中的作用。使用压力替代模型，一种产生两种行为表型的社会压力范式，我们使用急性药理学抑制 (SB-674042) 和基因敲低 (AAV-U6-Orx ₁ R-shRNA) 来表征 BLA 内 Orx ₁ R的作用策略。

结果

在 BLA 中，我们观察到 Orx ₁ R ( H crtr 1 ) 信使 RNA 主要在 CamKIIα ⁺谷氨酸能神经元中表达，很少在 GABA 能（γ-氨基丁酸能）细胞中表达。虽然 BLA 中的H crtr 1和 Orx ₂受体 ( H crtr 2 ) 信使 RNA 表达略有重叠，但我们发现这些受体最常在不同的细胞中表达。BLA 内 Orx _{1的拮抗作用}表型形成后的 R 将行为表达从压力敏感 (Stay) 转变为压力恢复 (Escape) 反应，这种效应被基因敲除所模仿。BLA 中Orx ₁ R的急性抑制也减少了 Stay 动物的背景和暗示恐惧冻结反应。这种表型特异性行为变化伴随着有利于H crtr 2超过H crtr 1和M apk 3超过P lcb 1细胞信号级联和增强的B dnf信使 RNA 的偏向分子转录。

结论

BLA 内基因表达的功能重组是由 Orx ₁ R 的拮抗作用产生的，它促进H crtr 2升高、M apk 3增强和B dnf表达增加。总之，这些结果为平衡 BLA 内的促应激反应和抗应激反应的受体驱动机制提供了证据。