Novel environment exposure drives temporally defined and region-specific chromatin accessibility and gene expression changes in the hippocampus

Lisa Traunmüller, Erin E. Duffy, Hanqing Liu, Stella Sanalidou, Sebastian Krüttner, Elena G. Assad, Senmiao Sun, Naeem S. Pajarillo, Nancy Niu, Eric C. Griffith and Michael E. Greenberg ()
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Lisa Traunmüller: Harvard Medical School
Erin E. Duffy: Harvard Medical School
Hanqing Liu: Harvard Medical School
Stella Sanalidou: Harvard Medical School
Sebastian Krüttner: Harvard Medical School
Elena G. Assad: Harvard Medical School
Senmiao Sun: Harvard Medical School
Naeem S. Pajarillo: Harvard Medical School
Nancy Niu: Harvard Medical School
Eric C. Griffith: Harvard Medical School
Michael E. Greenberg: Harvard Medical School

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Exposure to novel environments (NE) induces structural and functional changes in multiple brain areas, including the hippocampus, driven in part by changes in gene expression. However, the cell-type-specific transcriptional and chromatin responses to NE remain poorly understood. We employed single-nucleus multiomics and bulk RNA-seq of the hippocampal DG, CA3, and CA1 regions of male mice to profile gene expression and chromatin accessibility following NE exposure. We observed region-specific responses in excitatory neurons and diverse transcriptional changes in inhibitory and non-neuronal cells. NE-regulated genes were enriched for secreted factors, and their cell-type-specific receptor expression highlighted candidate signaling pathways involved in learning and memory. We identified thousands of cell-type-specific chromatin accessibility changes, with coordinated expression and accessibility patterns implicating FOS/AP-1 as a key regulator. These data provide a rich resource of chromatin accessibility and gene expression profiles across hippocampal cell types in response to NE, a physiological stimulus affecting learning and memory.

Date: 2025
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DOI: 10.1038/s41467-025-63029-6

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