Institute of Physiology 1, Westfälische Wilhelms-University, Robert-Koch-Str. 27 a, 48149, Münster, Germany.
Department of Pharmacology, Medical University Innsbruck, 6020, Innsbruck, Austria.
Psychopharmacology (Berl). 2019 Jan;236(1):281-291. doi: 10.1007/s00213-018-5080-8. Epub 2018 Nov 15.
Return of fear by re-exposure to an aversive event is a major obstacle in the treatment of fear-related disorders. Recently, we demonstrated that local pharmacological stimulation of neuropeptide Y type 2 receptors (Y2R) in anteroventral bed nucleus of stria terminalis (BNSTav) facilitates fear extinction and attenuates retrieval of remote fear with or without concomitant extinction training. Whether Y2R activation could also protect against re-exposure to traumatic events is still unknown.
Therefore, we investigated reinstatement of remote fear following early Y2R manipulation in BNSTav in relation to concomitant extinction training in mice.
We combined local pharmacological manipulation of Y2Rs in BNSTav with or without extinction training and tested for reinstatement of remote fear 15 days later. Furthermore, we employed immediate early gene mapping to monitor related local brain activation.
Y2R stimulation by local injection of NPY into BNSTav facilitated extinction, reduced fear reinstatement at remote stages, and mimicked the influence of extinction in groups without prior extinction training. In contrast, Y2R antagonism (JNJ-5207787) delayed extinction and increased reinstatement. Y2R treatment immediately before remote fear tests had no effect. Concomitantly, Y2R activation at early time points reduced the number of c-Fos positive neurons in BNSTav during testing of reinstated remote fear.
Local Y2R stimulation in BNSTav promotes fear extinction and stabilizes suppression of reinstated fear through a long-term influence, even without extinction training. Thus, Y2Rs in BNST are crucial pharmacological targets for extinction-based remote fear suppression.
通过重新暴露于厌恶事件来恢复恐惧是治疗与恐惧相关的障碍的主要障碍。最近，我们证明了在前终纹床核（BNSTav）中局部药理学刺激神经肽 Y 型 2 受体（Y2R）可促进恐惧消退，并减轻远程恐惧的检索，无论是否伴有同时的消退训练。Y2R 激活是否也能防止重新暴露于创伤性事件仍然未知。
因此，我们研究了 BNSTav 中 Y2R 的早期操作与同时的消退训练在与远程恐惧的重新出现有关的情况下，对远程恐惧的重新出现的影响。
我们将 BNSTav 中的 Y2R 的局部药理学操作与有无消退训练相结合，并在 15 天后测试远程恐惧的重新出现。此外，我们采用即时早期基因映射来监测相关的局部大脑激活。
通过将 NPY 局部注射到 BNSTav 中刺激 Y2R，促进了消退，减少了远程阶段的恐惧再出现，并模拟了没有预先进行消退训练的组中的消退的影响。相比之下，Y2R 拮抗作用（JNJ-5207787）延迟了消退并增加了再出现。Y2R 治疗在远程恐惧测试前没有效果。同时，Y2R 激活在早期时间点减少了 BNSTav 中的 c-Fos 阳性神经元的数量，在重新出现的远程恐惧的测试中。
BNSTav 中的局部 Y2R 刺激通过长期影响促进了恐惧消退，并稳定了抑制重新出现的恐惧，即使没有消退训练也是如此。因此，BNST 中的 Y2R 是基于消退的远程恐惧抑制的关键药理学靶标。
