One leading hypothesis suggests that memories are stored in ensembles of neurons (or 'engram cells') and that successful recall involves reactivation of these ensembles. A logical extension of this idea is that forgetting occurs when engram cells cannot be reactivated. Forms of 'natural forgetting' vary considerably in terms of their underlying mechanisms, time course and reversibility. However, we suggest that all forms of forgetting involve circuit remodelling that switches engram cells from an accessible state (where they can be reactivated by natural recall cues) to an inaccessible state (where they cannot). In many cases, forgetting rates are modulated by environmental conditions and we therefore propose that forgetting is a form of neuroplasticity that alters engram cell accessibility in a manner that is sensitive to mismatches between expectations and the environment. Moreover, we hypothesize that disease states associated with forgetting may hijack natural forgetting mechanisms, resulting in reduced engram cell accessibility and memory loss.
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