Astrocytic CREB in nucleus accumbens promotes susceptibility to chronic stress.

CREB RNA-sequencing astrocytes depression nucleus accumbens stress

Journal

Biological psychiatry
ISSN: 1873-2402
Titre abrégé: Biol Psychiatry
Pays: United States
ID NLM: 0213264

Informations de publication

Date de publication:
04 Oct 2024
Historique:
received: 15 01 2024
revised: 18 09 2024
accepted: 25 09 2024
medline: 7 10 2024
pubmed: 7 10 2024
entrez: 6 10 2024
Statut: aheadofprint

Résumé

Increasing evidence implicates astrocytes in stress and depression in both rodent models and human Major Depressive Disorder (MDD). Despite this, little is known about the transcriptional responses to stress of astrocytes within the nucleus accumbens (NAc), a key brain reward region, and their influence on behavioral outcomes. We used whole cell sorting, RNA-sequencing, and bioinformatic analyses to investigate the NAc astrocyte transcriptome in male mice in response to chronic social defeat stress (CSDS). Immunohistochemistry was used to determine stress-induced changes in astrocytic CREB within the NAc. Finally, astrocytic regulation of depression-like behavior was investigated using viral-mediated manipulation of CREB in combination with CSDS. We found a robust transcriptional response in NAc astrocytes to CSDS in stressed mice, with changes seen in both stress-susceptible and stress-resilient animals. Bioinformatic analysis revealed CREB, a transcription factor widely studied in neurons, as one of the top-predicted upstream regulators of the NAc astrocyte transcriptome, with opposite activation states implicated in resilient vs. susceptible mice. This bioinformatic deduction was confirmed at the protein level with immunohistochemistry. Moreover, NAc astrocyte morphological complexity correlated with CREB activation and was reduced selectively in astrocytes of resilient mice. Viral overexpression of CREB selectively in NAc astrocytes promoted susceptibility to chronic stress. Together, our data demonstrate that the astrocyte transcriptome responds robustly to CSDS and that transcriptional regulation in astrocytes contributes to depressive-like behaviors. A better understanding of transcriptional regulation in astrocytes may reveal unknown molecular mechanisms underlying neuropsychiatric disorders.

Sections du résumé

BACKGROUND BACKGROUND
Increasing evidence implicates astrocytes in stress and depression in both rodent models and human Major Depressive Disorder (MDD). Despite this, little is known about the transcriptional responses to stress of astrocytes within the nucleus accumbens (NAc), a key brain reward region, and their influence on behavioral outcomes.
METHODS METHODS
We used whole cell sorting, RNA-sequencing, and bioinformatic analyses to investigate the NAc astrocyte transcriptome in male mice in response to chronic social defeat stress (CSDS). Immunohistochemistry was used to determine stress-induced changes in astrocytic CREB within the NAc. Finally, astrocytic regulation of depression-like behavior was investigated using viral-mediated manipulation of CREB in combination with CSDS.
RESULTS RESULTS
We found a robust transcriptional response in NAc astrocytes to CSDS in stressed mice, with changes seen in both stress-susceptible and stress-resilient animals. Bioinformatic analysis revealed CREB, a transcription factor widely studied in neurons, as one of the top-predicted upstream regulators of the NAc astrocyte transcriptome, with opposite activation states implicated in resilient vs. susceptible mice. This bioinformatic deduction was confirmed at the protein level with immunohistochemistry. Moreover, NAc astrocyte morphological complexity correlated with CREB activation and was reduced selectively in astrocytes of resilient mice. Viral overexpression of CREB selectively in NAc astrocytes promoted susceptibility to chronic stress.
CONCLUSIONS CONCLUSIONS
Together, our data demonstrate that the astrocyte transcriptome responds robustly to CSDS and that transcriptional regulation in astrocytes contributes to depressive-like behaviors. A better understanding of transcriptional regulation in astrocytes may reveal unknown molecular mechanisms underlying neuropsychiatric disorders.

Identifiants

DOI: 10.1016/j.biopsych.2024.09.021 PMID: 39369762
pubmed: 39369762
pii: S0006-3223(24)01626-3
doi: 10.1016/j.biopsych.2024.09.021
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Auteurs

Leanne M Holt (LM)

Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, USA.

Trevonn M Gyles (TM)

Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, USA.

Eric M Parise (EM)

Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, USA.

Angelica Minier-Toribio (A)

Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, USA.

Matthew Rivera (M)

Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, USA.

Tamara Markovic (T)

Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, USA.

Szu-Ying Yeh (SY)

Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, USA.

Eric J Nestler (EJ)

Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, USA. Electronic address: eric.nestler@mssm.edu.

Classifications MeSH