UC Davis

Trace fear conditioning (TFC) is a variant of Pavlovian conditioning in which the CS and US are separated by a temporal gap (aka trace interval). The hippocampus is commonly assumed to facilitate this type of learning by maintaining a memory of the CS until the US occurs. Prior work from our lab and others has demonstrated that optogenetic inhibition of CA1 during the tone and trace interval impairs the acquisition of TFC. However, there is currently little to no evidence that individual hippocampal neurons reliably maintain a memory of the CS during the trace interval. Here, we used fiber photometry to record bulk calcium activity in CA1 as mice underwent TFC. Similar to previous work, we found that the footshock US produced a large and prolonged increase in CA1 activity. To determine if this activity was important for learning, we optogenetically silenced CA1 after footshock and found that trace fear memory was significantly impaired. In contrast, silencing CA1 for an equivalent period during the intertrial interval had no effect, indicating that immediate, but not delayed post-shock activity is essential for memory formation. However, this was only true for new learning, as post-shock silencing on the second day of training did not disrupt a previously formed trace fear memory. Similar patterns of activity in CA1 have been observed in spatial studies when a reward US is encountered on a maze. In that case, reward induces replay during sharp wave-ripples that travel backwards in time to reactivate the path leading to food. We hypothesize that something similar may happen during TFC: the aversive US activates CA1 and causes it to replay the sequence of events that lead to footshock. This allows the animal to associate the aversive outcome with predictive stimuli that occurred tens of seconds earlier. Implications for models of trace conditioning and hippocampal function are discussed.