Remembering the gist of an event over a lifetime depends on the hippocampus

Abstract

AbstractA well–accepted view in memory research is that retrieving the gist of a memory over time depends on the cortex, typically the prefrontal cortex, while retrieving its precision relies on the hippocampus. More recent advances indicate that the hippocampal subfield CA1, as opposed to CA3, remains engaged even for retrieving very remote memories and that this engagement coincides with a maximal recruitment of parahippocampal cortical areas (LEC, MEC, PER and POR)1. Using a time-window comparable to that used in human long-term memory studies, here we show that CA1 is necessary for retrieving the gist of a memory independently of its age while memory precision specifically depends on CA3 in a time-dependent manner. The precision for the memory of a context-footshock association was tested in mice after one day or very remotely (i.e. after 6 months or one year) allowing for the natural fading of the memory trace. Retrieving recent memories engaged both CA1 and CA3 in control mice as revealed by high levels of RNA of the immediate-early gene Arc, strongly tied to synaptic plasticity and memory function. Optogenetic inhibition of CA3 cell firing led to the loss of memory precision, i.e. the retrieval of the gist memory selectively supported by CA1. In contrast, CA1 inhibition abolished memory retrieval and reduced both CA1 and CA3’s activity. At very remote tests, controls retrieved only the gist of the event by recruiting CA1 and parahippocampal areas. Retrieving this gist was selectively abrogated upon CA1 optogenetic inactivation that dramatically reduced parahippocampal activity. Our findings indicate that the hippocampus, specifically CA1, is required for gist memory retrieval even for very remote memories that were previously reported to be hippocampal-independent, while CA3 is necessary for recalling precise memories in a time-dependent manner.