Extinction-restraint intervention eradicates fear memory encoded in BLA engram cells via D2 receptor-mediated dopaminergic modulation from locus coeruleus

Abstract Despite undergoing exposure therapy, individuals with post-traumatic stress disorder (PTSD) frequently experience relapses when confronted with trauma reminders. This study examined the impact of extinction-restraint intervention (Ext-Res) in a PTSD-related fear relapse model. We found that reactivation of basolateral amygdala engram cells (BLA engram ) correlates with relapse following fear reinstatement. Post-extinction BLA engram activation induced fear relapse, whereas Ext-Res effectively protected relapse and facilitated BLA engram reactivation. Our investigation into the neural circuitry connecting the tyrosine hydroxylase (TH)-positive locus coeruleus neurons (LC TH ) and BLA engram revealed that dopamine release, but not norepinephrine, is crucial for the deactivation of BLA engram following Ext-Res. Manipulation of the LC-BLA circuit could either replicate or reverse the therapeutic effects of Ext-Res. Notably, dopamine D2 receptors emerged as vital mediators of these effects. Overall, we reveal that Ext-Res intervention disrupts fear memory encoded in BLA engram through dopamine D2 receptor-dependent manner, providing new insights into potential therapeutic strategies for preventing relapse in PTSD.