Feedforward inhibition lets protein synthesis inhibitors block natural but spare optogenetic recall

Protein synthesis inhibition (PSI) following contextual fear conditioning preserves engram connectivity, enabling optogenetic hippocampal stimulation to trigger amygdalar-driven fear recall; however, natural cues fail to evoke recall, rendering engrams silent, with empirical descriptions falling short on circuit barriers that block natural but spare optogenetic recall. Replicating empirical data, our entorhinal-hippocampal-amygdalar computational model unveils feedforward inhibition, established during encoding, as the key barrier keeping natural cue-evoked sequential hippocampal activity below the amygdalar activation threshold under PSI. Strong optogenetic-like stimulation synchronizes engram firing, boosting hippocampal outputs to overcome amygdalar inhibition and restore recall, while weak stimulation yields asynchronous patterns that fail to evoke recall, akin to natural sequences. Without PSI, offline replay strengthens synapses, facilitating silent-to-active engram conversion that enables contextual sequences to surpass inhibition for natural recall. The model predicts calibrated disinhibition as an energy-efficient, precise, and hyperexcitability-safe strategy to recover amnesic memories, offering insights for disorders like Alzheimer's disease. This work extends the computational model developed in our previous study (bioRxiv: https://doi.org/10.64898/2025.12.09.693276).