CO2 inhalation enhances the lability of fear memory

项目概要/摘要 过度的恐惧记忆，例如创伤后应激障碍（PTSD），可能会造成严重后果。 然而，恐惧记忆也可能对生存至关重要。因此，发展意味着要么擦除，要么 强化恐惧记忆有助于理解记忆是如何形成的， 治疗策略最近关于改变恐惧记忆的研究集中在重新巩固窗口上。 在再巩固过程中，恐惧记忆被恢复并变得不稳定。随后的重新整合 已经被用来试图取代原来的记忆。然而， 恢复和灭绝模式的结合是有争议的。原来的记忆很难 被完全移除。我们最近的研究表明，质子是神经递质和酸敏感 离子通道（ASICs）是突触后受体，在神经传递和突触传递中起关键作用。 杏仁核是恐惧记忆形成的关键部位。我们还发现吸入二氧化碳 杏仁核细胞外pH值降低和ASIC活化。因此，我们询问是否通过 CO2吸入和ASICs的激活可以改变再巩固过程中恐惧记忆的不稳定性 窗口我们的研究结果表明，当一个检索事件给予小鼠，而他们呼吸10%， 二氧化碳，以下灭绝引起更大的记忆擦除。手术，重新调节增强 更多的内存。CO2诱导的记忆改变在ASIC基因敲除小鼠中被消除，这表明 通过降低pH和激活ASIC来介导作用。这些结果表明CO2吸入 作为一种可行的方法来增加恐惧记忆的不稳定性， 对擦除或增强的敏感性。我们的目标是阐明二氧化碳 吸入和ASIC调节恐惧记忆的不稳定性。该提案描述了三个不同的目标， 达到这个目标。第一个目标是了解CO2和ASIC如何调节记忆痕迹 与原始记忆相关的信息第二个目标将确定二氧化碳的特异性 吸入和ASIC对恐惧记忆不稳定性的影响。第三个目标将进一步审查 CO2和ASIC在调节AMPA受体的改变中起作用，这被认为是一种新的机制。 记忆不稳定的机制揭示了CO2的细胞和分子机制 吸入和ASIC介导的恐惧记忆的不稳定性是至关重要的，特别是因为它涉及到许多 精神障碍阐明这一机制将进一步促进制定充分的 在临床上治疗这些疾病的策略。

PROJECT SUMMARY / ABSTRACT Excessive fear memories, in post-traumatic stress disorder (PTSD) for example, can be crippling. However, fear memories can also be critical for survival. Thus, developing means to either erase or to strengthen fear memory could aid understanding of how memories are formed and may suggest novel therapeutic strategies. Recent research on altering fear memory has focused on a reconsolidation window. During reconsolidation, fear memories are retrieved and become labile. The subsequent reconsolidation with extinction has been used to attempt replacing the original memory. However, outcomes of the combination of retrieval and extinction paradigms are controversial. The original memory is difficult to be completely removed. Our recent studies revealed that protons are neurotransmitters and acid-sensing ion channels (ASICs) are postsynaptic receptors that play key roles in neurotransmission and synaptic plasticity in the amygdala, a critical site for fear memory formation. We also showed that CO2 inhalation reduced extracellular pH in the amygdala and activated ASICs. Therefore, we asked if manipulating pH via CO2 inhalation and activation of ASICs could alter the lability of fear memories within the reconsolidation window. Our findings indicated that when a retrieval event was given to mice while they breathed 10% CO2, the following extinction induced greater memory erasure. Oppositely, re-conditioning augmented more memory. The CO2-induced memory changes were eliminated in ASIC-null mice, suggesting that the effects were mediated by reduced pH and activation of ASICs. These results implicated CO2 inhalation during memory retrieval as a viable method to increase the lability of fear memories and increase susceptibility to either erasure or enhancement. Our goal is to elucidate the mechanisms by which CO2 inhalation and ASICs modulate the lability of fear memories. This proposal describes three distinct aims to reach this goal. The first aim focuses on understanding how CO2 and ASICs regulate the memory trace that is associated with the original memory. The second aim will determine the specificity of CO2 inhalation and ASIC effects on the lability of fear memory. The third aim will further examine the role that CO2 and ASICs play in regulating the alteration of AMPA receptors, which has been suggested as a mechanism of memory destabilization. Uncovering the cellular and molecular mechanisms by which CO2 inhalation and ASICs mediate the lability of fear memories is critical, especially as it relates to many mental disorders. Elucidation of this mechanism would further facilitate the development of sufficient strategies for treating these disorders in clinics.