Verma Dilip, Tasan Ramon, Sperk Guenther, Pape Hans-Christian
Institute of Physiology 1, Westfälische Wilhelms-University, D-48149 Münster, Germany.
Institute of Pharmacology, Medical University Innsbruck, 6020 Innsbruck, Austria.
Neurobiol Learn Mem. 2018 Mar;149:144-153. doi: 10.1016/j.nlm.2018.01.011. Epub 2018 Feb 27.
The anterior bed nucleus of stria terminalis (BNST) is involved in reinstatement of extinguished fear, and neuropeptide Y2 receptors influence local synaptic signaling. Therefore, we hypothesized that Y2 receptors in anteroventral BNST (BNSTav) interfere with remote fear memory and that previous fear extinction is an important variable. C57BL/6NCrl mice were fear-conditioned, and a Y2 receptor-specific agonist (NPY) or antagonist (JNJ-5207787) was applied in BNSTav before fear retrieval at the following day. Remote fear memory was tested on day 16 in two groups of mice, which had (experiment 1) or had not (experiment 2) undergone extinction training after conditioning. In the group with extinction training, tests of remote fear memory revealed partial retrieval of extinction, which was prevented after blockade of Y2 receptors in BNSTav. No such effect was observed in the group with no extinction training, but stimulation of Y2 receptors in BNSTav mimicked the influence of extinction during tests of remote fear memory. Pharmacological manipulation of Y2 receptors in BNSTav before fear acquisition (experiment 3) had no effect on fear memory retrieval, extinction or remote fear memory. Furthermore, partial retrieval of extinction during tests of remote fear memory was associated with changes in number of c-Fos expressing neurons in BNSTav, which was prevented or mimicked upon Y2 blockade or stimulation in BNSTav. These results indicate that Y2 receptor manipulation in BNSTav interferes with fear memory and extinction retrieval at remote stages, likely through controlling neuronal activity in BNSTav during extinction training.
终纹床核前部（BNST）参与消退恐惧的恢复，神经肽Y2受体影响局部突触信号传导。因此，我们推测腹侧前BNST（BNSTav）中的Y2受体干扰远期恐惧记忆，且先前的恐惧消退是一个重要变量。对C57BL/6NCrl小鼠进行恐惧条件训练，并在次日恐惧再现前于BNSTav中应用Y2受体特异性激动剂（NPY）或拮抗剂（JNJ-5207787）。在两组小鼠中于第16天测试远期恐惧记忆，这两组小鼠在条件训练后（实验1）或未（实验2）接受消退训练。在接受消退训练的组中，远期恐惧记忆测试显示消退的部分再现，在BNSTav中阻断Y2受体后这种再现被阻止。在未接受消退训练的组中未观察到这种效应，但在远期恐惧记忆测试期间，BNSTav中Y2受体的刺激模拟了消退的影响。在恐惧习得前（实验3）对BNSTav中Y2受体进行药理学操作对恐惧记忆再现、消退或远期恐惧记忆没有影响。此外，远期恐惧记忆测试期间消退的部分再现与BNSTav中c-Fos表达神经元数量的变化有关，在BNSTav中进行Y2阻断或刺激时这种变化被阻止或模拟。这些结果表明，BNSTav中Y2受体的操作在远期阶段干扰恐惧记忆和消退再现，可能是通过在消退训练期间控制BNSTav中的神经元活动来实现的。
