Differential Encoding of Trace and Delay Fear Memory in the Entorhinal Cortex.

Trace fear conditioning is characterized by a stimulus-free trace interval (TI) between the conditioned stimulus (CS) and the unconditioned stimulus (US), which requires an array of brain structures to support the formation and storage of associative memory. The entorhinal cortex (EC) has been proposed to provide essential neural code for resolving temporal discontinuity in conjunction with the hippocampus. However, how the CS and TI are encoded at the neuronal level in the EC is not clear. In Exp. 1, we tested the effect of bilateral pre-training electrolytic lesions of EC on trace vs. delay fear conditioning using rats as subjects. We found that the lesions impaired the acquisition of trace but not delay fear conditioning confirming that EC is a critical brain area for trace fear memory formation. In Exp. 2, single-unit activities from EC were recorded during the pre-training baseline and post-training retention sessions following trace or delay conditioning. The recording results showed that a significant proportion of the EC neurons modulated their firing during TI after the trace conditioning, but not after the delay fear conditioning. Further analysis revealed that the majority of modulated units decreased the firing rate during the TI or the CS. Taken together, these results suggest that EC critically contributes to trace fear conditioning by modulating neuronal activity during the TI to facilitate the association between the CS and US across a temporal gap.

Increased tone-offset response in the lateral nucleus of the amygdala underlies trace fear conditioning.

Accumulating evidence suggests that the lateral nucleus of the amygdala (LA) stores associative memory in the form of enhanced neural response to the sensory input following classical fear conditioning in which the conditioned stimulus (CS) and the unconditioned stimulus (US) are presented in a temporally continuous manner. However, little is known about the role of the LA in trace fear conditioning where the CS and the US are separated by a temporal gap. Single-unit recordings of LA neurons before and after trace fear conditioning revealed that the short-latency activity to the CS offset, but not that to the onset, increased significantly and accompanied the conditioned fear response. The increased short-latency activity was evident in two aspects: the number of offset-responsive neurons was increased and the latency of the neuronal response to the CS offset was shortened. On the contrary, changes in the firing rate to either the onset or the offset were negligible following unpaired presentations of the CS and US. In sum, our results suggest that increased synaptic efficacy in the CS offset pathway in the LA might underlie the association between temporally distant stimuli in trace fear conditioning.