CLOSED-LOOP MANIPULATION OF HIPPOCAMPAL RIPPLES REDUCE PERSISTENT FEAR EXPRESSION IN ANIMAL MODEL OF POSTTRAUMATIC-STRESS DISORDER
Lizeth Pedraza1, Rodrigo Sierra1, Yuichi Takeuchi1, Gábor Kozák1, Andrea Peijin1, Lívia Barcsai1, Antal Berényi1, 2
1 MTA-SZTE ‘Momentum’ Oscillatory Neuronal Networks Research Group, Department of Physiology, University of Szeged, Szeged H-6720, Hungary; 2Neuroscience Institute, New York University, New York, New York 10016, USA
Traumatic experiences can trigger psychiatric disturbances such as post-traumatic stress disorder (PTSD). Resistance to extinction has been reported as a hallmark of pathological fear memories, increasing the rate of relapse after psychotherapy and pharmacological treatments. Hippocampal sharp wave ripples (SPW-R) play a causal role in memory consolidation during sleep and rest, in particular, after contextual learning. Fear extinction is a highly context-dependent process and the lack of extinction generalization is underpinning the recovery of fear responses. Using a closed-loop electrical stimulation approach, we demonstrate that SPW-Rs manipulation after extinction sessions is sufficient to reduce persistent fear memories. After high intensity fear conditioning training (CS + 1mA foot shock), animals were exposed to extinction sessions (CS, 20x) until achieving 80% freezing reduction (remission criterion) compared to the original fear response. After each extinction session, animals were stimulated in their home-cages for 1h in a closed-loop fashion, using medial forebrain bundle (MFB) stimulation triggered by real-time SPW-R detection. As MFB is considered the primary pathway of the reward system, our stimulation protocol was able to induce conditioning place preference, consistent with previous reports. The closed-loop intervention enhanced fear extinction, reducing the days necessary to achieve the extinction criterion (3 days compared to 7 for open loop and non-stimulated groups). Importantly, lower freezing persisted even 25 days after the end of extinction sessions and after an immediate foot-shock reinstatement protocol. This robust therapeutic effect could be prevented by the inhibition of Rac1 in the basolateral amygdala (BLA), a key-protein of dendritic spine remodeling and also by the antagonism of amygdalar D2 dopamine receptors. Our results suggest that SPW-R triggered MFB stimulation modulate dopaminergic signaling through D2 receptor and induce synaptic remodeling in BLA resulting in long-lasting fear reduction of aversive memories. We consider this finding as a possible translational therapeutic target for the non-pharmaceutical treatment of post-traumatic stress disorder (PTSD).