Hippocampal sharp wave ripples mediate generalization and subsequent fear attenuation via closed-loop brain stimulation in rats

The balance between stimulus generalization and discrimination is essential in modulating behavioral responses across different contexts. Excessive fear generalization is linked to neuropsychiatric disorders such as generalized anxiety disorder (GAD) and PTSD. While hippocampal sharp wave-ripples (SWRs) and concurrent neocortical oscillations are central to the consolidation of contextual memories, their involvement in non-hippocampal dependent memories remains poorly understood. Here we show that closed-loop disruption of SWRs, after the consolidation of a cued fear conditioning, leads to atypical memory discrimination that would normally be generalized. Furthermore, SWR-triggered closed-loop stimulation of the basolateral amygdala (BLA) during memory reconsolidation inhibits fear generalization and enhances subsequent extinction. Comparable effects were observed when stimulating the infralimbic cortex either post-training or after a brief memory reactivation. A consistent increase in gamma incidence within the amygdala was identified in animals subjected to closed-loop BLA or infralimbic cortex neuromodulation. Our findings highlight the functional role of hippocampal SWRs in modulating the qualitative aspects of amygdala-dependent memories. Targeting the amygdala activity via prefrontal cortex with closed-loop SWR triggered stimulation presents a potential foundation of a non-invasive therapy for GAD and PTSD. ### Competing Interest Statement A.B. is the owner of Amplipex Llc. Szeged, Hungary a manufacturer of signal-multiplexed neuronal amplifiers. A.B is the CEO of Neunos ZRt, Szeged, Hungary, a company developing neurostimulator devices.