Post-retrieval noradrenergic activation impairs subsequent memory depending on cortico-hippocampal reactivation

Abstract

AbstractWhen retrieved, seemingly stable memories can become sensitive to modification through significant events, such as acute stress. While memory dynamics after retrieval have profound implications, for instance, in eyewitness testimony or aberrant memory in mental disorders, the mechanisms underlying these dynamics remain poorly understood. Here, we show in healthy humans that increases in noradrenaline after memory retrieval impairs subsequent remembering, depending on hippocampal and cortical reactivation during retrieval. In a three-day fMRI study, we measured brain activity during initial encoding (Day 1), 24h-delayed memory cueing accompanied by administration of placebo, hydrocortisone, or the α2-adrenoceptor antagonist yohimbine (Day 2), and final recall, 24h later (Day 3). While post-retrieval hydrocortisone did not affect subsequent memory (i.e., final recall), the impairing effect of yohimbine on final recall depended on the strength of hippocampal reactivation and category-level reinstatement in ventral temporal cortex during Day 2 retrieval. Notably, the effect of yohimbine on subsequent memory was contingent specifically on the neural reactivation during retrieval. While patterns from online reactivation were also reinstated in the post-retrieval rest-period, this offline reinstatement did not interact with the pharmacological manipulation. Additionally, the original memory trace from encoding was not significantly reactivated during retrieval and not reinstated offline during rest, further supporting the critical dependency of post-retrieval manipulations on the neural signal emerging during retrieval-related reactivation. Our findings demonstrate that, depending on the neural reactivation of memories, noradrenergic arousal after retrieval can alter the future accessibility of consolidated memories.Impact StatementWe show that pharmacological elevations of noradrenergic but not glucocorticoid activity after retrieval impair subsequent remembering. These impairments were bound to strong hippocampal and cortical neural reactivation before drug action.