Figure 3.

Model for reinstatement of a weak memory trace following reactivation by a hidden engram. Despite the reversal of threat-related plasticity, fear sometimes paradoxically returns and this can be accompanied by reinstatement of its synaptic substrates [24, 52, 53]. The conditions under which this relapse is observed requires that some residual trace of previous learning is retained in the brain, since animals were not re-exposed to the US and therefore had no opportunity to relearn the threat association. One possibility is a hidden engram (depicted as a nested layer) where such a trace can persist in an inactive state, while retaining strengthened connections to other CS-responsive engram cells, here termed the primary engram. The hidden engram might also receive CS input, but for the purpose of simplicity this has not been depicted. As in the conventional model of relapse (Fig. 1), the return of high fear is elicited by the detection of a new intero/exteroceptive state that has not been associated with fear attenuation. However, in contrast to unlearning or new learning, the recruitment of a hidden engram is sufficient, together with CS inputs, to reactivate primary engram cells due to the retention of synaptic strengthening in their connectivity with the hidden engram (bidirectional arrows). This reactivation might destabilize CS connections and permit their repotentiation through Hebbian synaptic strengthening or reconsolidation-based mechanisms.