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Closed-loop brain stimulation augments fear extinction in male rats

Sierra, Rodrigo Ordoñez, Pedraza, Lizeth Katherine, Barcsai, Lívia, Pejin, Andrea, Li, Qun, Kozák, Gábor, Takeuchi, Yuichi, Nagy, Anett J., Lőrincz, Magor L., Devinsky, Orrin, Buzsáki, György and Berényi, Antal 2023. Closed-loop brain stimulation augments fear extinction in male rats. Nature Communications 14 (1) , 3972. 10.1038/s41467-023-39546-7

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Dysregulated fear reactions can result from maladaptive processing of trauma-related memories. In post-traumatic stress disorder (PTSD) and other psychiatric disorders, dysfunctional extinction learning prevents discretization of trauma-related memory engrams and generalizes fear responses. Although PTSD may be viewed as a memory-based disorder, no approved treatments target pathological fear memory processing. Hippocampal sharp wave-ripples (SWRs) and concurrent neocortical oscillations are scaffolds to consolidate contextual memory, but their role during fear processing remains poorly understood. Here, we show that closed-loop, SWR triggered neuromodulation of the medial forebrain bundle (MFB) can enhance fear extinction consolidation in male rats. The modified fear memories became resistant to induced recall (i.e., ‘renewal’ and ‘reinstatement’) and did not reemerge spontaneously. These effects were mediated by D2 receptor signaling-induced synaptic remodeling in the basolateral amygdala. Our results demonstrate that SWR-triggered closed-loop stimulation of the MFB reward system enhances extinction of fearful memories and reducing fear expression across different contexts and preventing excessive and persistent fear responses. These findings highlight the potential of neuromodulation to augment extinction learning and provide a new avenue to develop treatments for anxiety disorders.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Biosciences
Additional Information: License information from Publisher: LICENSE 1: URL:, Type: open-access
Publisher: Nature Research
Date of First Compliant Deposit: 7 July 2023
Date of Acceptance: 16 June 2023
Last Modified: 10 Oct 2023 21:23

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