Understanding fear responses and their attenuation is critical to addressing anxiety disorders and PTSD. A recent study, published in Biological Psychiatry: Global Open Science, investigates the role of carbon dioxide reactivity in predicting fear expression following extinction and retrieval-extinction in rats. The research, led by Professor Marie Monfils, looks at how individual differences in carbon dioxide reactivity may determine the efficacy of extinction-based therapies.
In the study, male rats were subjected to a carbon dioxide test, fear conditioning, and then a standard extinction or retrieval-extinction protocol. Standard extinction involves repeated exposure to a conditioned stimulus without the aversive unconditioned stimulus, leading to a gradual reduction in fear responses. Retrieval-extinction, on the other hand, involves brief re-exposure to the conditioned stimulus to destabilize fear memory, followed by extinction training. This method aims to overwrite the original fear memory more effectively.
Professor Monfils’ team found that retrieval-extinction resulted in significantly lower fear responses compared to standard extinction. This was evident during extinction training, long-term memory testing, and reinstatement testing. Furthermore, carbon dioxide reactivity – as measured by behaviours such as wandering, grooming, rearing posture, and laboured breathing during a carbon dioxide challenge – was a strong predictor of fear memory retention. Specifically, high carbon dioxide reactivity was associated with better extinction outcomes, indicating that rats with higher carbon dioxide reactivity retained less fear memory, although this association was stronger in rats that underwent extinction than in those that underwent retrieval-extinction.
Marissa Raskin, the study’s first author, highlighted the importance of these findings. “Our most important conclusion is that carbon dioxide reactivity could serve as a screening tool to identify people who might benefit most from extinction-based therapies,” she said. This knowledge is particularly valuable, as it suggests that carbon dioxide reactivity could help tailor treatments to individual needs, potentially improving therapeutic outcomes for patients with anxiety and PTSD.
The study also highlighted the differential efficacy of extinction and retrieval-extinction. While both methods reduced fear responses, retrieval-extinction was more robust in preventing the return of fear, as originally discovered by Monfils et al in 2009. This is also consistent with previous findings that retrieval-extinction activates both extinction and reconsolidation mechanisms, leading to more persistent fear attenuation.
The implications of this research extend to the clinical setting. Carbon dioxide reactivity testing could be integrated into diagnostic procedures to identify patients who are likely to respond well to extinction-based therapies. Furthermore, retrieval-extinction could be adopted as a more effective method for long-term fear reduction in therapeutic practices.
Future research will aim to expand these studies to include female subjects and diverse cue modalities to examine the generalizability of the results. The research group has also partnered with clinical collaborators to begin testing the application of carbon dioxide reactivity as a predictive tool in human clinical trials.
In summary, the study by Professor Monfils and colleagues provides compelling evidence that carbon dioxide reactivity can predict fear memory retention and highlights the superior efficacy of retrieval-extinction over standard extinction. These findings open the way to more personalized and effective treatments for anxiety and PTSD, potentially improving the quality of life for many patients.
Journal reference
Raskin, M., Keller, N. E., Agee, L. A., Shumake, J., Smits, J. A. J., Telch, M. J., Otto, M. W., Lee, H. J., & Monfils, M.-H. (2024). Carbon dioxide reactivity differentially predicts fear expression following extinction and retrieval-extinction in rats. Biological Psychiatry: Global Open Science. https://doi.org/10.1016/j.bpsgos.2024.100310
About the Author
Professor Marie Monfils She received her PhD in behavioural neuroscience from the Canadian Centre for Behavioural Neuroscience and completed a postdoctoral fellowship at New York University. She is currently a professor at the University of Texas at Austin, where she and her team are pursuing three lines of research:
- investigating post-consolidation manipulations that can persistently attenuate fear memories,
- isolate the factors underlying affiliative kinship and the social transmission of information,
- assess individual differences and their impact on fear attenuation.
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