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

Savannah R Bliese; Budhaditya Basu; Stacy E Beyer; Muhammad Elsadany; Jacob J Michaelson; Snehajyoti Chatterjee

doi:10.1038/s41380-025-03331-3

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

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

Savannah R Bliese, Budhaditya Basu, Stacy E Beyer, Muhammad Elsadany, Jacob J Michaelson and Snehajyoti Chatterjee

Molecular psychiatry, Vol.31(4), pp.1845-1856

04/2026

DOI: 10.1038/s41380-025-03331-3

PMCID: PMC12645481

PMID: 41188622

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Abstract

The retrosplenial cortex (RSC) is a critical brain region that is activated during spatial memory tasks and plays a crucial role in the consolidation of long-term memory. Various classes of RSC excitatory neurons across different laminar layers serve as the central hub for neuronal connections between the RSC and other brain regions, such as the hippocampus. Despite the established role of the RSC in spatial memory, the transcriptomic signature of the neuronal subtypes in the RSC during spatial memory consolidation remained elusive. Here, we used unbiased and targeted spatial transcriptomics to identify the RSC transcriptional signature after a spatial memory task. Genes related to transcription regulation, protein folding, and mitogen-activated protein kinase pathways were upregulated in the RSC during an early time window of memory consolidation. Furthermore, cell-type and excitatory neuronal layer-specific changes in gene expression were resolved using Xenium spatial transcriptomics. A deep learning computational tool uncovered cell-type-specific molecular activation patterns within the RSC after learning. Conversely, in a mouse model of Alzheimer's disease and related dementia (ADRD) exhibiting tau hyperphosphorylation in the RSC, there was a reduction in predicted neuronal activation following learning. Notably, learning-induced Fos expression was decreased in excitatory neurons of the RSC in the ADRD mice. Finally, we observed that blocking RSC excitatory neurons during the early temporal window after learning using a chemogenetic approach impaired long-term spatial memory in adult mice. Our results reveal a molecular signature of the RSC after learning and emphasize the role of RSC excitatory neurons during spatial memory consolidation.

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Details

Title: Subtitle: Single-cell resolution spatial transcriptomic signature of the retrosplenial cortex during memory consolidation
Creators: Savannah R Bliese - University of Iowa
Budhaditya Basu - University of Iowa
Stacy E Beyer - University of Iowa
Muhammad Elsadany - University of Iowa Hospitals and Clinics
Jacob J Michaelson - University of Iowa Hospitals and Clinics
Snehajyoti Chatterjee - University of Iowa
Resource Type: Journal article
Publication Details: Molecular psychiatry, Vol.31(4), pp.1845-1856
DOI: 10.1038/s41380-025-03331-3
PMID: 41188622
PMCID: PMC12645481
NLM abbreviation: Mol Psychiatry
ISSN: 1359-4184
eISSN: 1476-5578
Publisher: Springer Nature
Grant note: AG068306 / U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)
Language: English
Electronic publication date: 11/04/2025
Date published: 04/2026
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Communication Sciences and Disorders; Psychiatry; Iowa Neuroscience Institute; Neuroscience and Pharmacology
Record Identifier: 9985024256302771

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