Department of Biology, University of South Dakota, Vermillion, South Dakota; Neuroscience Group, Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, South Dakota; Veterans Affairs Research Service, Sioux Falls VA Health Care System, Sioux Falls, South Dakota.
Department of Biology, University of South Dakota, Vermillion, South Dakota; Neuroscience Group, Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, South Dakota.
Biol Psychiatry. 2022 May 1;91(9):841-852. doi: 10.1016/j.biopsych.2021.12.019. Epub 2022 Jan 19.
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).
We assessed the contribution of intra-BLA Orx receptors (OrxRs) 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 OrxR using acute pharmacological inhibition (SB-674042) and genetic knockdown (AAV-U6-OrxR-shRNA) strategies.
In the BLA, we observed that OrxR (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 Orx receptor (Hcrtr2) messenger RNA expression in the BLA, we find that these receptors are most often expressed in separate cells. Antagonism of intra-BLA OrxR 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 OrxR 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.
Functional reorganization of intra-BLA gene expression is produced by antagonism of OrxR, 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.
应激通过对特定神经回路元件的选择性分子修饰产生不同的行为反应。食欲素（Orx）系统靶向外侧杏仁核（BLA）中该神经回路的关键组成部分。
我们评估了 BLA 内 Orx 受体（OrxR）在表达应激诱导的小鼠表型中的作用。使用应激替代模型，这是一种产生两种行为表型的社交应激范式，我们使用急性药理学抑制（SB-674042）和基因敲低（AAV-U6-OrxR-shRNA）策略来研究 BLA 内 OrxR 的作用。
在 BLA 中，我们观察到 OrxR（Hcrtr1）信使 RNA 主要在 CamKIIα 谷氨酸能神经元中表达，而在 GABA 能（γ-氨基丁酸能）细胞中很少表达。虽然 BLA 中 Hcrtr1 和 Orx 受体（Hcrtr2）信使 RNA 表达有轻微重叠，但我们发现这些受体通常在不同的细胞中表达。表型形成后 BLA 内 OrxR 的拮抗作用将行为表达从应激敏感（Stay）转变为应激抵抗（Escape）反应，这种效应被基因敲低模拟。BLA 中 OrxR 的急性抑制也降低了 Stay 动物的情境和线索恐惧冻结反应。这种表型特异性的行为变化伴随着偏向性的分子转录，有利于 Hcrtr2 而不是 Hcrtr1，有利于 Mapk3 而不是 Plcb1 细胞信号级联，以及 Bdnf 信使 RNA 的增加。
OrxR 的拮抗作用导致 BLA 内基因表达的功能重组，促进了 Hcrtr2 的升高、Mapk3 的增加和 Bdnf 表达的增加。总之，这些结果为 BLA 内平衡促应激和抗应激反应的受体驱动机制提供了证据。
