CLOSED-LOOP INFRALIMBIC CORTEX STIMULATION REDUCES ANXIETY AND PREVENTS FEAR GENERALIZATION DURING MEMORY CONSOLIDATION AND RECONSOLIDATION

Fear memory generalization is a hallmark of fear-related disorders. Our laboratory has shown that fear memories can be attenuated with closed-loop (CL) neurostimulation guided by real-time detection of dorsal hippocampal sharp-wave ripples (dSWRs) during extinction. Here, dSWRs triggered infralimbic cortex (IL) stimulation. Using Wistar rats, we applied high-intensity cue fear conditioning to induce fear generalization. Immediately after learning, or after short memory reactivation, animals received a 3 h intervention in which real-time dSWR detection triggered IL stimulation. Twenty-four hours later, rats were tested with conditioned (CS+) or neutral (CS-) stimuli. To assess effects during fear extinction, animals were exposed to 20 non-reinforced CS+ presentations and, 24 h later, to a renewal test. Animals receiving CL stimulation immediately after training expressed fear to CS+ but not CS-, indicating discrimination, whereas open-loop (OL) and non-stimulated groups showed fear generalization. CL stimulation lost efficacy when applied 48 h after training; however, efficacy was restored by short memory reactivation before CL intervention. This reactivation promoted protein-synthesis-dependent reconsolidation, as fear expression was disrupted by intra-BLA anisomycin infusion. CL-induced fear discrimination also promoted fear reduction during extinction. CL, but not OL, stimulation increased BLA gamma power and gamma incidence after stimulation. Both CL and OL IL stimulation reduced anxiety-like behavior in the elevated plus maze. These results suggest that dSWRs participate in cued fear discrimination. CL-IL stimulation increases BLA gamma activity, contributing to discrimination and enhanced fear extinction. These findings support reconsolidation-based approaches and open avenues for electrical neuromodulation to attenuate aversive memory traces after retrieval.