Mapping the spatial transcriptomic signature of the hippocampus during memory consolidation

Snehajyoti Chatterjee

doi:10.1002/alz.071988

Abstract Background Memory consolidation relies on discrete spatial patterns of transcriptional events in the hippocampus. Despite the emergence of single‐cell transcriptomic profiling techniques, defining learning‐responsive gene expression across sub‐regions of the hippocampus has remained challenging. Method We utilized unbiased spatial sequencing to elucidate transcriptome‐wide changes in gene expression in the hippocampus following a learning experience, enabling us to define molecular signatures unique to each hippocampal subregion. Result We find that the CA1 pyramidal layer, CA1 stratum radiatum, CA1 stratum oriens, CA2/3 pyramidal layer, and dentate gyrus (DG) granular and molecular layers of the dorsal hippocampus exhibit distinct yet overlapping transcriptomic signatures. While the CA1 region exhibited increased expression of genes related to transcription regulation, the dentate gyrus (DG) showed upregulation of genes associated with protein folding. We demonstrate the functional relevance of subregion‐specific gene expression by genetic manipulation of the Nr4a transcription factor subfamily members selectively in the CA1 hippocampal subregion, leading to long‐term memory deficits. We have also shown that the hippocampus from postmortem Alzheimer’s disease and related dementia (ADRD) and a mutant tau mouse model of ADRD exhibit downregulation of Nr4a family members. We demonstrate the functional relevance of subregion‐specific gene expression by genetic manipulation of a transcription factor selectively in the CA1 hippocampal subregion, leading to long‐term memory deficits and connecting these findings with ADRD. Conclusion Our work demonstrates the power of spatial molecular approaches to reveal that the subregions of the dorsal hippocampus respond to learning by exhibiting distinct transcriptomic signatures. Our attempt to elucidate the spatial transcriptomic signature of memory provides the groundwork for future studies to understand the precise gene expression patterns underlying memory consolidation, and whether these signatures are affected in neurodegenerative diseases associated with memory impairments.

Mapping the spatial transcriptomic signature of the hippocampus during memory consolidation

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