Dynamics of memory retrieval in health and diseases

Abstract

Memory retrieval is not a static readout of fixed traces but a dynamic regulatory process where the accessibility of engrams, neuronal ensembles that are active during learning, fluctuates with internal and external states. Recent studies suggest that such variability may support adaptive, selective access to behaviorally relevant memories. Here, we review how contextual, stress-related, bodily, and brain-state factors regulate retrieval via engram state transitions and network-level control. Retrieval is facilitated when the external context or affective state at test matches that at encoding, which enhances reactivation of engram cells. In contrast, social stress can transiently shift engrams into a silent state that is not responsive to natural cues, thereby impairing retrieval. Bodily state also plays a key role: reduced arousal weakens prefrontal top-down suppression of task-irrelevant representations, whereas metabolic hormones such as ghrelin, leptin, and insulin family factors modulate synaptic plasticity and thus the efficiency of engram reactivation. In addition, ultra-slow brain dynamics and inappropriate activation of the default mode network (DMN) can disrupt switching to task-positive networks and lower effective access to stored memories. We discuss how failures of these dynamic regulatory mechanisms may underlie core symptoms of psychiatric and neurological disorders, including trauma-related flashbacks in post-traumatic stress disorder (PTSD), negative memory bias in depression, and cognitive fluctuations in dementia with Lewy bodies. We argue that these insights provide a useful framework for understanding the pathophysiology of these disorders and for developing future interventions that selectively target engram accessibility.