Fear extinction requires ASIC1a-dependent regulation of hippocampal-prefrontal correlates.
Fear extinction requires ASIC1a-dependent regulation of hippocampal-prefrontal correlates.
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恐惧消退需要 ASIC1a 依赖的海马-前额叶相关调节
DOI：
10.1126/sciadv.aau3075
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发表时间：
2018-10
期刊：
影响因子：
13.6
通讯作者：
Xu TL
中科院分区：
文献类型：
--
作者：
Wang Q;Wang Q;Song XL;Jiang Q;Wu YJ;Li Y;Yuan TF;Zhang S;Xu NJ;Zhu MX;Li WG;Xu TL
学习消除创伤记忆取决于通过ASIC 1a通道对前额叶-前额叶连接的微调。条件性恐惧的消退需要海马体、内侧前额叶皮层（mPFC）和基底外侧杏仁核（BLA）的动态参与，但调节这些回路以实现恐惧消退的关键分子仍然很大程度上未知。在这里，我们报告说，酸敏感离子通道1a（ASIC 1a）是一个关键的分子调节器的恐惧消退，这一功能需要ASIC 1a在腹侧海马（vHPC），而不是背侧海马，mPFC，或BLA。虽然vHPC中ASIC 1a的遗传破坏或药理学抑制减弱了条件性恐惧的消退，但该区域通道的过度表达促进了恐惧消退。视紫红质-2辅助的电路映射显示，恐惧消退涉及ASIC 1a依赖的修改的远程前额叶皮层相关的投影特定的方式。基因表达谱分析和验证实验确定了几个神经元活动调节和记忆相关的基因，包括Fos，Npas 4和Bdnf，作为ASIC 1a调节恐惧消退的潜在介质。从机制上讲，vHPC中脑源性神经营养因子（BDNF）的基因过表达或mPFC中BDNF蛋白的补充都挽救了vHPC中Asic 1a基因失活引起的恐惧消退缺陷和大脑前额叶相关的防御驱动适应缺陷。总之，这些结果确立了ASIC 1a作为恐惧消退回路中的关键成分，因此是管理适应性行为的有希望的目标。
Learning to extinguish traumatic memory depends on fine-tuning of hippocampal-prefrontal connections via the ASIC1a channel. Extinction of conditioned fear necessitates the dynamic involvement of hippocampus, medial prefrontal cortex (mPFC), and basolateral amygdala (BLA), but key molecular players that regulate these circuits to achieve fear extinction remain largely unknown. Here, we report that acid-sensing ion channel 1a (ASIC1a) is a crucial molecular regulator of fear extinction, and that this function requires ASIC1a in ventral hippocampus (vHPC), but not dorsal hippocampus, mPFC, or BLA. While genetic disruption or pharmacological inhibition of ASIC1a in vHPC attenuated the extinction of conditioned fear, overexpression of the channel in this area promoted fear extinction. Channelrhodopsin-2–assisted circuit mapping revealed that fear extinction involved an ASIC1a-dependent modification of the long-range hippocampal-prefrontal correlates in a projection-specific manner. Gene expression profiling analysis and validating experiments identified several neuronal activity–regulated and memory-related genes, including Fos, Npas4, and Bdnf, as the potential mediators of ASIC1a regulation of fear extinction. Mechanistically, genetic overexpression of brain-derived neurotrophic factor (BDNF) in vHPC or supplement of BDNF protein in mPFC both rescued the deficiency in fear extinction and the deficits on extinction-driven adaptations of hippocampal-prefrontal correlates caused by the Asic1a gene inactivation in vHPC. Together, these results establish ASIC1a as a critical constituent in fear extinction circuits and thus a promising target for managing adaptive behaviors.
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DOI：
10.1523/jneurosci.3907-08.2008
发表时间：
2008-12-17
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Coryell MW;Wunsch AM;Haenfler JM;Allen JE;McBride JL;Davidson BL;Wemmie JA
通讯作者：
Wemmie JA
影响因子：
16.2
作者：
Duvarci S;Pare D
通讯作者：
Pare D
影响因子：
25
作者：
Kreple, Collin J.;Lu, Yuan;Wemmie, John A.
通讯作者：
Wemmie, John A.
影响因子：
15.9
作者：
Sun X;Lin Y
通讯作者：
Lin Y
影响因子：
16.2
作者：
Senn, Verena;Wolff, Steffen B. E.;Luethi, Andreas
通讯作者：
Luethi, Andreas