Spatiotemporally precise targeting of memory processes to prevent and ameliorate maladaptive fear responses

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Posttraumatic stress disorder (PTSD) is an incapacitating chronic disorder that results from direct or indirect exposure to stressful events compromising physical or mental safety. Memory features like fear generalization and resistance to the extinction, prevents the effectiveness of current psychotherapy and pharmacological treatments in PTSD. Pavlovian fear conditioning has been consistently used over decades to study factors contributing to adaptive and pathological fear memories. Sharp-wave ripples (SWRs) are well known to play a critical role in spatial memory consolidation. However, how SWRs mediates the consolidation of emotional memories is poorly understood. In this thesis, I present our experiments providing the first demonstration of a Closed-Loop (CL) intervention to update the emotional information of fear memory traces through intracranial electrical stimulation in male rats. We found the feasibility of this method in various memory processes with high translational value: CL-SWRs triggered neuromodulation of the Infralimbic cortex during consolidation prevents fear generalization and enhances extinction. CL-SWRs triggered neuromodulation of the Basolateral Amygdala after memory reactivation reverses fear generalization via reconsolidation dependent-mechanism. CL-SWRs triggered neuromodulation of the Medial Forebrain Bundle accelerates fear extinction and finally the disruption of SWRs impairs cued fear memory extinction, proving its causal role in fear processing. These results suggests that fear memories could be updated using high precision electrical stimulation inducing reward and anxiolytic signals. We discuss a new framework where PTSD can be considered as memory-based disorder and the strategies to reduce the invasiveness of the stimulation and detection procedures for future human testing.

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