Regulation of learned fear expression through the MgN-amygdala pathway
Regulation of learned fear expression through the MgN-amygdala pathway
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DOI：
10.1016/j.nlm.2021.107526
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发表时间：
2021-09-25
影响因子：
2.7
通讯作者：
Helmstetter, Fred J.
中科院分区：
文献类型：
--
作者：
Ferrara, Nicole C.;Trask, Sydney;Helmstetter, Fred J.
恐惧反应增强是恐惧和焦虑相关疾病的特征，包括创伤后应激障碍。杏仁核的神经可塑性对于初始恐惧学习和恐惧表达至关重要，而内侧膝状核（MgN）和杏仁核之间突触连接的加强对于听觉恐惧学习至关重要。然而，人们对恐惧回忆和消退期间 MgN-杏仁核通路中发生的情况知之甚少，其中条件性恐惧随着单独听觉刺激的重复呈现而减少。在本研究中，我们发现在恐惧恢复和消退过程中，光遗传学抑制 MgN-杏仁核通路的活性可减少条件性恐惧的表达。虽然这种效应在通路抑制后持续至少两周，但它是特定于发生光遗传学抑制的环境，将 MgN-BLA 抑制与促进类灭绝过程联系起来。通过抑制 MgN-杏仁核通路来减少恐惧表达的进一步特征是，与对照组相比，GluA1 和 GluA2 AMPA 受体亚基的突触表达相似。抑制还降低了杏仁核中 CREB 的磷酸化，类似于听觉恐惧消退后的报道。然后我们证明，通过抑制含有 GluN2B 的 NMDA 受体可以降低这种效应。这些结果证明了 MgN-杏仁核通路在类灭绝过程中的新的重要作用，并表明抑制该通路的活动会导致恐惧行为的持续减少。
Heightened fear responding is characteristic of fear- and anxiety-related disorders, including post-traumatic stress disorder. Neural plasticity in the amygdala is essential for both initial fear learning and fear expression, and strengthening of synaptic connections between the medial geniculate nucleus (MgN) and amygdala is critical for auditory fear learning. However, very little is known about what happens in the MgN-amygdala pathway during fear recall and extinction, in which conditional fear decreases with repeated presentations of the auditory stimulus alone. In the present study, we found that optogenetic inhibition of activity in the MgN-amygdala pathway during fear retrieval and extinction reduced expression of conditional fear. While this effect persisted for at least two weeks following pathway inhibition, it was specific to the context in which optogenetic inhibition occurred, linking MgN-BLA inhibition to facilitation of extinction-like processes. Reduced fear expression through inhibition of the MgN-amygdala pathway was further characterized by similar synaptic expression of GluA1 and GluA2 AMPA receptor subunits compared to what was seen in controls. Inhibition also decreased CREB phosphorylation in the amygdala, similar to what has been reported following auditory fear extinction. We then demonstrated that this effect was reduced by inhibition of GluN2B-containing NMDA receptors. These results demonstrate a new and important role for the MgN-amygdala pathway in extinction-like processes, and show that suppressing activity in this pathway results in a persistent decrease in fear behavior.