CO2 inhalation enhances the lability of fear memory

项目摘要/摘要

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.