Elevated glucocorticoid alters the developmental dynamics of hypothalamic neurogenesis in zebrafish

Helen Eachus; Min-Kyeung Choi; Anna Tochwin; Johanna Kaspareit; May Ho; Soojin Ryu

doi:10.1038/s42003-024-06060-5

Elevated glucocorticoid alters the developmental dynamics of hypothalamic neurogenesis in zebrafish

Helen Eachus
, Min-Kyeung Choi
, Anna Tochwin
, Johanna Kaspareit
, May Ho
, Soojin Ryu^*

^*Corresponding author for this work

Aston Pharmacy School

University of Exeter, Living Systems Institute & Department of Clinical and Biomedical Sciences, Stocker Road, Exeter, EX4 4QD, UK, ROR: https://ror.org/03yghzc09, GRID: grid.8391.3, ISNI: 0000 0004 1936 8024
University Medical Center, Johannes Gutenberg University Mainz, Institute of Human Genetics, Langenbeckstraße 1, Mainz, 55131, Germany, GRID: grid.410607.4
Nanyang Technological University, 50 Nanyang Avenue, Singapore, 639798, Singapore, ROR: https://ror.org/02e7b5302, GRID: grid.59025.3b, ISNI: 0000 0001 2224 0361

Research output: Contribution to journal › Article › peer-review

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Abstract

Exposure to excess glucocorticoid (GC) during early development is implicated in adult dysfunctions. Reduced adult hippocampal neurogenesis is a well-known consequence of exposure to early life stress or elevated GC, however the effects on neurogenesis during development and effects on other brain regions are not well understood. Using an optogenetic zebrafish model, here we analyse the effects of GC exposure on neurogenesis during development in the whole brain. We identify that the hypothalamus is a highly GC-sensitive region where elevated GC causes precocious development. This is followed by failed maturation and early decline accompanied by impaired feeding, growth, and survival. In GC-exposed animals, the developmental trajectory of hypothalamic progenitor cells is strikingly altered, potentially mediated by direct regulation of transcription factors such as rx3 by GC. Our data provide cellular and molecular level insight into GC-induced alteration of the hypothalamic developmental trajectory, a process crucial for health across the life-course.

Original language	English
Article number	416
Number of pages	14
Journal	Communications Biology
Volume	7
Issue number	1
Early online date	5 Apr 2024
DOIs	https://doi.org/10.1038/s42003-024-06060-5
Publication status	Published - 5 Apr 2024

Bibliographical note

Copyright © The Authors, 2024. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit https://creativecommons.org/licenses/by/4.0/.

Data Access Statement

All sequenced reads for RNA-seq were deposited in European Nucleotide Archive as part of our other study21 (ENA, PRJEB53713). The run accession IDs for the RNA-seq data reported in this study are: TU WT 6 dpf: ERR10476787 - ERR104767 91, star:bPAC positive 6 dpf: ERR10476 807 - ERR10476 811; TU WT 13 dpf: ERR104767 92 - ERR104767 96; star:bPAC positive 13 dpf: ERR10476 812 - ERR10476 816. Source data for figures are available in Supplementary data file 1. All other data are available from the corresponding author on reasonable request.
The code used for bioinformatic analysis of the RNA sequencing data is available in an online methods repository79.

Funding

This project is supported by an award from The Dennis and Mireille Gillings Foundation to S.R. and the German Federal Office for Education Research (grant number 01GQ1404) to S.R. H.E. received support from the Society for Endocrinology and Wellcome Trust Institutional Strategic Support Fund 3 scheme (ISSF3) to Translational Research Exchange @ Exeter. M.H. received support from the CN Yang Scholars Programme at Nanyang Technological University. We would like to acknowledge the support of Ms. Kathrin Domdera at the University of Mainz and the Exeter Aquatic Resources Centre staff at the University of Exeter for expert zebrafish care as well as Dr Corin Liddle at Exeter Bioimaging Centre for microscopy. We are grateful to Dr Elina Jacobs, Dr Kate Ellacott, Dr Steffen Scholpp, and Professor Gil Levkowitz for feedback on the manuscript. We are grateful to Dr Sara Kuntz for the generation of the Tg(star:bPAC-2A-tdTomato)uex300 transgenic line.

Funders	Funder number
Society for Endocrinology
The Wellcome Trust
Dennis and Mireille Gillings Foundation
University of Mainz
Nanyang Technological University
University of Exeter
Wellcome Trust
German Federal Office for Education Research	01GQ1404

Keywords

Animals
Glucocorticoids/pharmacology
Zebrafish
Hypothalamus
Neurogenesis/physiology
Hippocampus

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10.1038/s42003-024-06060-5Licence: CC BY 4.0

Eachus et al Elevated glucocorticoid alters the developmental dynamics of hypothalamic neurogenesis in zebrafish
Copyright © The Authors, 2024. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit https://creativecommons.org/licenses/by/4.0/.
Final published version, 1.88 MBLicence: CC BY 4.0

Cite this

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abstract = "Exposure to excess glucocorticoid (GC) during early development is implicated in adult dysfunctions. Reduced adult hippocampal neurogenesis is a well-known consequence of exposure to early life stress or elevated GC, however the effects on neurogenesis during development and effects on other brain regions are not well understood. Using an optogenetic zebrafish model, here we analyse the effects of GC exposure on neurogenesis during development in the whole brain. We identify that the hypothalamus is a highly GC-sensitive region where elevated GC causes precocious development. This is followed by failed maturation and early decline accompanied by impaired feeding, growth, and survival. In GC-exposed animals, the developmental trajectory of hypothalamic progenitor cells is strikingly altered, potentially mediated by direct regulation of transcription factors such as rx3 by GC. Our data provide cellular and molecular level insight into GC-induced alteration of the hypothalamic developmental trajectory, a process crucial for health across the life-course.",

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Elevated glucocorticoid alters the developmental dynamics of hypothalamic neurogenesis in zebrafish

Abstract

Bibliographical note

Data Access Statement

Funding

Keywords

Access to Document

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Elevated glucocorticoid alters the developmental dynamics of hypothalamic neurogenesis

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