Figure 1.

The conventional view of discrete plasticity processes leading to temporary and persistent threat memory attenuation via new learning and unlearning. The threat memory engram is depicted as a set of active nodes (green) that correspond to single neurons or ensembles with potentiated CS-evoked firing. Two types of inputs contribute to engram cell firing that are modulated by the following neural representations: sensory regions encoding basic attributes of the CS (sensory representation) and multimodal regions that represent the exteroceptive and interoceptive state of the animal (state representation) [87]. The exteroceptive state at the time of stimulus presentation includes the spatial and temporal context (both external variables), while the internal state is defined as the emotional and cognitive state of the animal (for example, the presence of stress- or drug-induced brain states). In most accounts, both forms of state representation are ascribed to the hippocampus and medial prefrontal cortex [86]. High fear develops when strengthening of excitatory inputs occurs within the sensory pathway. When fear is attenuated through new learning, such as extinction, a new engram is encoded (green nodes) and becomes linked to a new state representation through excitatory plasticity (denoted by thicker lines). Conversely, increased inhibition develops onto the threat-encoding neurons. Consequently, when the CS is encountered in this new configuration, defensive responses diminish. However, relapse occurs when the animal re-encounters the CS in a different state, such as in the context in which the original learning took place. Because the encoding of both threat- and safety-related ensembles are preserved, alternation between high and low fear can occur without any additional plasticity and is governed according to which state the animal detects at the time of test. In contrast to new learning, unlearning through protocols such as reconsolidation blockade is considered to destabilize and reverse potentiation of engram cell pathways. Resulting erasure of information precludes the return of threat memory, regardless of the state in which the CS is encountered.