Targeting ASIC1a reduces innate fear and alters neuronal activity in the fear circuit
Targeting ASIC1a reduces innate fear and alters neuronal activity in the fear circuit
复制标题
DOI：
10.1016/j.biopsych.2007.05.008
复制
发表时间：
2007-11-15
影响因子：
10.6
通讯作者：
Wemmie, John A.
中科院分区：
文献类型：
--
作者：
Coryell, Matthew W.;Ziemann, Adam E.;Wemmie, John A.
背景：先天性恐惧的分子机制目前还知之甚少。先前的研究表明酸敏感离子通道ASIC 1a在条件反射范式中影响恐惧行为。然而，这些差异可能会导致从ASIC 1的学习，记忆，或表达的fear.Methods：要测试的假设，ASIC 1a影响表达的恐惧或焦虑的经典conditioning. Methods，我们研究了破坏小鼠ASIC 1a基因对无条件恐惧的影响，在开放的领域测试，无条件声惊吓，和恐惧引起的捕食气味三甲基噻唑啉（TMT）。此外，我们测试了用狼蛛毒中的ASIC 1a拮抗剂PcTx急性抑制ASIC 1a的效果。我们的免疫组化结果表明，ASIC 1a在终纹床核、内侧杏仁核和导水管周围灰质中表达，这些区域被认为在先天性恐惧的产生和表达中起重要作用。因此，我们还测试了ASIC 1中断是否改变了这些结构中的c-fos表达以下TMT exposition.Results：我们发现，ASIC 1的损失减少了恐惧在开放领域的测试，减少声惊吓，并抑制恐惧反应TMT。类似地，侧脑室注射PcTx减少了ASIC 1a（+/+）小鼠中TMT诱发的冻结，但对ASIC 1a（-/-）小鼠没有影响。此外，ASIC 1的损失改变了TMT诱发的c-fos在内侧杏仁核和背侧导水管周围gray.Conclusions表达：这些研究结果表明，ASIC 1的调制活动的电路固有的恐惧。此外，数据表明，靶向ASIC 1a基因或急性抑制ASIC 1a抑制恐惧和焦虑，而不依赖于条件反射。
Background: The molecular mechanisms underlying innate fear are poorly understood. Previous studies indicated that the acid sensing ion channel ASIC1 a influences fear behavior in conditioning paradigms. However,these differences may have resulted from an ASIC1 a effect on learning, memory, or the expression of fear.Methods: To test the hypothesis that ASIC1a influences the expression of fear or anxiety independent of classical conditioning, we examined the effects of disrupting the mouse ASIC1a gene on unconditioned fear in the open field test, unconditioned acoustic startle, and fear evoked by the predator odor trimethylthiazoline (TMT). In addition, we tested the effects of acutely inhibiting ASIC1 a with PcTx, an ASIC1a antagonist in tarantula venom. Our immunohistochemistry suggested ASIC1a is expressed in the bed nucleus of the stria terminalis, medial amygdala, and periaqueductal gray, which are thought to play important roles in the generation and expression of innate fear. Therefore, we also tested whether ASIC1 a disruption altered c-fos expression in these structures following TMT exposure.Results: We found that the loss of ASIC1 a reduced fear in the open field test, reduced acoustic startle, and inhibited the fear response to TMT. Similarly, intracerebroventricular administration of PcTx reduced TMT-evoked freezing in ASIC1a(+/+) mice but not ASIC1a(-/-) mice. In addition, loss of ASIC1 a altered TMT-evoked c-fos expression in the medial amydala and dorsal periaqueductal gray.Conclusions: These findings suggest that ASIC1 a modulates activity in the circuits underlying innate fear. Furthermore, the data indicate that targeting the ASIC1a gene or acutely inhibiting ASIC1 a suppresses fear and anxiety independent of conditioning.