BACKGROUND: Glucocorticoid (GC) receptor (GR) signaling in the hypothalamus (Hyp) and in the superordinate limbic structures, such as the hippocampus (Hip), conveys feedback regulation of the neuroendocrine stress response and acts upon other neurobiological functions that ultimately influence mental health. These responses are strongly influenced by sex, but the molecular causes are still largely unexplored. METHODS: To investigate GR targets and their GC sensitivity in the Hyp and Hip, we treated juvenile male and female piglets with 10 (D10) or 60 (D60) µg/kg dexamethasone (DEX), a selective GR agonist, and analyzed transcriptome responses compared to a saline control group using RNA sequencing. RESULTS: Both doses influenced similar biological functions, including cellular response to lipid and immune cell-related functions, but the transcriptional response to D10 was considerably weaker, particularly in the Hip. Weighted Gene Co-expression Network Analysis revealed a network of genes coordinately regulated by DEX in both structures, among which the alpha-arrestin ARRDC2 takes a central position. Distinct functional groups of genes were differentially regulated by DEX between sexes depending on the dose; at D10, these included particularly mitochondrial genes, whereas at D60 interferon signaling and lipid homeostasis genes were enriched. The general and sex-specific transcriptional responses to DEX highlight microglia as the prominent target. Several key marker genes of disease-associated microglia were regulated by DEX depending on sex, such as TREM2 and LPL. CONCLUSION: The discovered expression signatures suggest that DEX induced a dysfunctional state of microglia in males, while in females microglia were primed, which could entail predisposition for different mental disorders. The Author(s). Published by S. Karger AG, Basel.
BACKGROUND: Glucocorticoid (GC) receptor (GR) signaling in the hypothalamus (Hyp) and in the superordinate limbic structures, such as the hippocampus (Hip), conveys feedback regulation of the neuroendocrine stress response and acts upon other neurobiological functions that ultimately influence mental health. These responses are strongly influenced by sex, but the molecular causes are still largely unexplored. METHODS: To investigate GR targets and their GC sensitivity in the Hyp and Hip, we treated juvenile male and female piglets with 10 (D10) or 60 (D60) µg/kg dexamethasone (DEX), a selective GR agonist, and analyzed transcriptome responses compared to a saline control group using RNA sequencing. RESULTS: Both doses influenced similar biological functions, including cellular response to lipid and immune cell-related functions, but the transcriptional response to D10 was considerably weaker, particularly in the Hip. Weighted Gene Co-expression Network Analysis revealed a network of genes coordinately regulated by DEX in both structures, among which the alpha-arrestin ARRDC2 takes a central position. Distinct functional groups of genes were differentially regulated by DEX between sexes depending on the dose; at D10, these included particularly mitochondrial genes, whereas at D60 interferon signaling and lipid homeostasis genes were enriched. The general and sex-specific transcriptional responses to DEX highlight microglia as the prominent target. Several key marker genes of disease-associated microglia were regulated by DEX depending on sex, such as TREM2 and LPL. CONCLUSION: The discovered expression signatures suggest that DEX induced a dysfunctional state of microglia in males, while in females microglia were primed, which could entail predisposition for different mental disorders. The Author(s). Published by S. Karger AG, Basel.
Authors: Nadine Provençal; Janine Arloth; Annamaria Cattaneo; Christoph Anacker; Nadia Cattane; Tobias Wiechmann; Simone Röh; Maik Ködel; Torsten Klengel; Darina Czamara; Nikola S Müller; Jari Lahti; Katri Räikkönen; Carmine M Pariante; Elisabeth B Binder Journal: Proc Natl Acad Sci U S A Date: 2019-08-09 Impact factor: 11.205
Authors: Julia K Götzl; Matthias Brendel; Georg Werner; Samira Parhizkar; Laura Sebastian Monasor; Gernot Kleinberger; Alessio-Vittorio Colombo; Maximilian Deussing; Matias Wagner; Juliane Winkelmann; Janine Diehl-Schmid; Johannes Levin; Katrin Fellerer; Anika Reifschneider; Sebastian Bultmann; Peter Bartenstein; Axel Rominger; Sabina Tahirovic; Scott T Smith; Charlotte Madore; Oleg Butovsky; Anja Capell; Christian Haass Journal: EMBO Mol Med Date: 2019-06 Impact factor: 12.137
Authors: Cheryl E G Leyns; Jason D Ulrich; Mary B Finn; Floy R Stewart; Lauren J Koscal; Javier Remolina Serrano; Grace O Robinson; Elise Anderson; Marco Colonna; David M Holtzman Journal: Proc Natl Acad Sci U S A Date: 2017-10-09 Impact factor: 11.205