Single-cell resolution spatial transcriptomic signature of the retrosplenial cortex during memory consolidation

The retrosplenial cortex (RSC) is a critical brain region activated during spatial memory tasks and plays an underlying role in long-term memory consolidation. The RSC comprises multiple cell types, including different classes of excitatory neurons across laminar layers. These layer-specific cells form the hub of neuronal connection between the RSC and other brain regions, including the hippocampus. Despite the established role of the RSC in spatial memory, the transcriptomic signature of the neuronal sub-types in the RSC during spatial memory consolidation remained elusive. Here we used both unbiased and targeted spatial transcriptomic approaches to illuminate the transcriptional signature of the RSC following a spatial memory task. We found that genes related to transcription regulation, protein folding, and mitogen-activated protein kinase pathways were upregulated in the RSC after spatial learning during an early time window of memory consolidation. Further, cell type and excitatory neuronal layer-specific changes in gene expression were resolved using Xenium spatial transcriptomics. The distinct signatures of memory-responsive genes were observed in excitatory neurons across the laminar layers of the RSC following learning. Finally, we observed that blocking RSC excitatory neurons during the early temporal window after learning using a chemogenetic approach impaired long-term spatial memory. Overall, our results uncover a molecular signature of the RSC after learning and demonstrate the role of RSC excitatory neurons during the early time points of memory consolidation. This study underscores the importance of the learning-induced transcriptional signature of the RSC in long-term spatial memory consolidation and reveals a cell-type specific signature of memory-responsive gene expression.