# CO2 inhalation enhances the lability of fear memory

> **NIH NIH R01** · UNIVERSITY OF TENNESSEE HEALTH SCI CTR · 2021 · $372,825

## Abstract

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.

## Key facts

- **NIH application ID:** 10242956
- **Project number:** 5R01MH113986-04
- **Recipient organization:** UNIVERSITY OF TENNESSEE HEALTH SCI CTR
- **Principal Investigator:** Jianyang Du
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $372,825
- **Award type:** 5
- **Project period:** 2020-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242956

## Citation

> US National Institutes of Health, RePORTER application 10242956, CO2 inhalation enhances the lability of fear memory (5R01MH113986-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10242956. Licensed CC0.

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