Sequential transcriptional gates in the thalamo-cortical circuit support memory stabilization [ATAC]

The molecular mechanisms that enable memories to persist over long time-scales from days to weeks and months are still poorly understood. To develop insights, we created a behavioral task where by varying the frequency of learned associations, mice formed multiple memories, but only consolidated some while forgetting others, over the span of weeks. We then monitored circuit-specific molecular programs that diverge between consolidated and forgotten memories. We identified multiple distinct waves of transcription, i.e., cellular macrostates, specifically in the thalamo-cortical circuit, that defined memory persistence. Notably, a small set of transcriptional regulators appeared sufficient to orchestrate broad molecular programs that enabled entry into these macrostates. Targeted CRISPR-manipulations of these transcriptional regulators revealed that while they had no effects on memory formation, they had prominent, causal, and strikingly time-dependent roles in memory stabilization. In particular, the calmodulin-dependent transcription factor Camta1 was required for initial memory maintenance over days, while Tcf4 and the histone methyl-transferase Ash1L were required later to maintain memory over weeks. These results identify a critical Camta1-Tcf4-Ash1L thalamo-cortical transcriptional cascade required for memory stabilization, and puts forth a model where the sequential, multi-step, recruitment of circuit-specific transcriptional programs enable memory maintenance over progressively longer time-scales.