Neural circuit mechanism for associative fear memory persistence

Abstract

Plastic changes in lateral amygdala (LA) are thought as an underlying mechanism of associative fear memory. Consistent with this idea, previous findings demonstrated that direct optogenetic activation of auditory inputs to LA (optCS), instead of tone, is sufficient to form associative memory in mice, tested at 1 d after learning. However, since optCS is restricted to axonal terminal in LA, such artificial memory trace unlikely involves upstream auditory pathways, which are activated by tone CS. It raises a question of whether artificial CS could support persistent fear memory like natural auditory CS. In this study, I found optCS does not support remote memory formation, as induction of conditioned response was impaired at 20 d after learning. In vivo recording demonstrated that memory decay is correlated with decay of long-term potentiation (LTP) at optCS inputs, which is thought to support memory retrieval, as optogenetic induction of LTP restored decayed memory expression. While activation of auditory inputs in LA was not, activation of auditory soma was sufficient to form long-lasting memory. I inferred that brain-wide memory trace, which are activated by stimulation of auditory soma, is necessary for remote fear memory formation, probably through triggering offline reactivation of memory trace. Artificial reactivation by optCS prevented decay of both memory and LTP at optCS inputs, supporting above thought. In addition, pharmacological inactivation of dorsal hippocampus (DH), which is known as a key brain structure to drive offline reactivation, selectively impaired formation of remote auditory fear memory, while did not affect initial encoding and retrieval process. Besides, memory reactivation with tone CS compensated DH inactivation, as reactivated mice showed intact fear memory at remote time. Taken together, this study proposes synaptic reinforcement at CS inputs in LA, through offline reactivation of brain-wide memory trace including hippocampus, as an underlying mechanism of associative memory persistence.