Closed-loop brain stimulation augments fear extinction in male rats

Rodrigo Ordoñez Sierra, Lizeth Katherine Pedraza, Lívia Barcsai, Andrea Pejin, Qun Li, Gábor Kozák, Yuichi Takeuchi, Anett J. Nagy, Magor L. Lőrincz, Orrin Devinsky, György Buzsáki and Antal Berényi ()
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Rodrigo Ordoñez Sierra: University of Szeged
Lizeth Katherine Pedraza: University of Szeged
Lívia Barcsai: University of Szeged
Andrea Pejin: University of Szeged
Qun Li: University of Szeged
Gábor Kozák: University of Szeged
Yuichi Takeuchi: University of Szeged
Anett J. Nagy: University of Szeged
Magor L. Lőrincz: University of Szeged
Orrin Devinsky: NYU Grossman School of Medicine
György Buzsáki: New York University
Antal Berényi: University of Szeged

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-39546-7

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