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Effects of SSRIs on the spatial transcriptome of dorsal raphe serotonin neurons.

Overview

Authors: Charlotta Henningson1, Jakub Mlost1, Iskra Pollak Dorocic1
ORCID iDs: Iskra Pollak Dorocic
  1. Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University,Stockholm, Sweden
Institutions: Stockholm University (Sweden)
Journal: Molecular psychiatry, volume 31, issue 10, pages 5607-5618
Dates: received 18 July 2025; accepted 30 April 2026; published online 15 May 2026; in print 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1038/s41380-026-03644-x · PMID 42141080 · PMCID PMC13569412 · OpenAlex W4403376306
Open access: hybrid, a free copy (OpenAlex)
Preprint: doi:10.1101/2024.10.10.617388
Status: code on request
Categories: genetics / omics (modality), mouse (organism), depression (population), cellular / molecular (subfield)
Methods: Statistics, Smoothing, state filtering, decompositions
Keywords: Neuroscience, Depression, Molecular biology
MeSH: Dorsal Raphe Nucleus*, Selective Serotonin Reuptake Inhibitors*, Serotonergic Neurons*, Animals, Fluoxetine, Male, Mice, Mice, Inbred C57BL, Neuropeptides, Receptor, Serotonin, 5-HT1A, Serotonin, Signal Transduction, Spatial Transcriptomics, Transcriptome (* major topic)
Topic: Adipose Tissue and Metabolism (Physiology, Medicine), according to OpenAlex
Funding: Science for Life Laboratory; Vetenskapsrådet; Polska Akademia Nauk (Polish Academy of Sciences)
Citations: cited by 3 papers (Europe PMC); 85 references in the paper

Abstract

The serotonin system is the main therapeutic target for selective serotonin reuptake inhibitors (SSRIs) in treating depression, yet the mechanism of action of SSRIs remains incompletely understood. To investigate the molecular and transcriptional effects of SSRI administration on serotonin neurons, we performed spatial transcriptomics, a spatially resolved RNA-sequencing method in intact brain tissue. Mouse brain sections containing the dorsal raphe nucleus and adjacent midbrain structures were analyzed, revealing six distinct serotonergic subpopulations with unique molecular signatures and spatial distributions. Both acute and chronic fluoxetine treatment induced a large number of changes in gene expression in the dorsal raphe nucleus. Notably, Htr1a expression increased following acute treatment but decreased after chronic administration, supporting previous findings on serotonin transporter blockade effects on 5-HT1A autoreceptors. Gene enrichment and network analysis identified key pathways modulated by SSRI administration, including Ras, MAPK and cAMP signaling pathways as well as pathways involved in axonal guidance. Additionally, we observed treatment-dependent opposing transcriptional changes in neuropeptides, particularly Thyrotropin-releasing hormone (Trh) and Prodynorphin (Pdyn), with distinct spatial localization within the dorsal raphe nucleus. Collectively, our transcriptomic and in situ hybridization analyses reveal spatial and cell-type-specific heterogeneity in SSRI action within the dorsal raphe nucleus, providing new insights into the molecular basis of SSRI treatment effects.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

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The paper's code and data availability statement is in the Data section.

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Data

Datasets cited

Data availability

Data has been deposited at https://doi.org/10.5281/zenodo.14859692 and is also accessible through an interactive app available at https://st-ssri.serve.scilifelab.se/app/st-ssri. Any additional information and code details are available from the lead contacts upon request.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

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Version 2, 28 September 2026

  • Publisher: n/a → Springer Nature

Version 1, 28 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 3 authors, 3 keywords, 14 MeSH terms, 3 funders, 83 references.

Cite

This paper

Henningson, C., Mlost, J., & Pollak Dorocic, I. (2026). Effects of SSRIs on the spatial transcriptome of dorsal raphe serotonin neurons. Molecular psychiatry, 31(10), 5607-5618. https://doi.org/10.1038/s41380-026-03644-x

BibTeX

@article{henningson2026effects,
author = {Henningson, Charlotta and Mlost, Jakub and Pollak Dorocic, Iskra},
title = {{Effects of SSRIs on the spatial transcriptome of dorsal raphe serotonin neurons}},
journal = {Molecular psychiatry},
year = {2026},
month = may,
volume = {31},
number = {10},
pages = {5607--5618},
publisher = {Springer Nature},
issn = {1359-4184},
doi = {10.1038/s41380-026-03644-x},
url = {https://doi.org/10.1038/s41380-026-03644-x},
pmid = {42141080},
pmcid = {PMC13569412}
}

RIS

TY - JOUR
AU - Henningson, Charlotta
AU - Mlost, Jakub
AU - Pollak Dorocic, Iskra
TI - Effects of SSRIs on the spatial transcriptome of dorsal raphe serotonin neurons
T2 - Molecular psychiatry
J2 - Mol Psychiatry
PY - 2026
DA - 2026/05/15
VL - 31
IS - 10
SP - 5607
EP - 5618
SN - 1359-4184
PB - Springer Nature
DO - 10.1038/s41380-026-03644-x
UR - https://doi.org/10.1038/s41380-026-03644-x
LA - en
ER -

CSL-JSON

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