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Histone 3 Trimethylation Patterns are Associated with Resilience or Stress Susceptibility in a Rat Model of Major Depression Disorder

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Abstract

Major Depressive Disorder (MDD) is a severe and multifactorial psychiatric condition. Evidence has shown that environmental factors, such as stress, significantly explain MDD pathophysiology. Studies have hypothesized that changes in histone methylation patterns are involved in impaired glutamatergic signaling. Based on this scenario, this study aims to investigate histone 3 involvement in depression susceptibility or resilience in MDD pathophysiology by investigating cellular and molecular parameters related to i) glutamatergic neurotransmission, ii) astrocytic functioning, and iii) neurogenesis. For this, we subjected male Wistar rats to the Chronic Unpredictable Mild Stress (CUMS) model of depression. We propose that by evaluating the sucrose consumption, open field, and object recognition test performance from animals submitted to CUMS, it is possible to predict with high specificity rats with susceptibility to depressive-like phenotype and resilient to the depressive-like phenotype. We also demonstrated, for the first time, that patterns of H3K4me3, H3K9me3, H3K27me3, and H3K36me3 trimethylation are strictly associated with the resilient or susceptible to depressive-like phenotype in a brain-region-specific manner. Additionally, susceptible animals have reduced DCx and GFAP and resilient animals present increase of AQP-4 immunoreactivity. Together, these results provide evidence that H3 trimethylations are related to the development of the resilient or susceptible to depressive-like phenotype, contributing to further advances in the pathophysiology of MDD and the discovery of mechanisms behind resilience.

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Data Availability

The datasets generated during and/or analysed during the current study are not publicly available but are available from the corresponding author on reasonable request.

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Acknowledgements

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS), Programa Pesquisa para o SUS (PPSUS)/FAPERGS and Pró-reitora de Pesquisa (PROPESQ‐UFRGS) that supported this study. Programa de Pós-Graduação em Biologia Celular e Molecular (PPGBCM).All authors have read and agree with authority.

Funding

This study was supported by: FAPERGS PPSUS (21/2551-0000090-2), FAPERGS PRONEX (16/2551-0000499-4), CNPq, CAPES and PROPESQ/UFRGS.

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Authors and Affiliations

  1. Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

    Lucas Santos, Luiza Behrens, Camila Barbosa, Camila Tiefensee-Ribeiro, Helen Rosa-Silva, Nauana Somensi, Alexandre Kleber Silveira, Daniel Pens Gelain & José Cláudio Fonseca Moreira

  2. Programa de Pós-Graduação em Biologia Celular e Molecular, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

    Lucas Santos, Daniel Pens Gelain & José Cláudio Fonseca Moreira

  3. Max Perutz Labs, Vienna BioCenter, University of Vienna, Vienna, Austria

    Pedro Ozorio Brum

  4. Laboratório de Investigação de Desordens Metabólicas e Doenças Neurodegenerativas, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

    Matheus Scarpatto Rodrigues & Jade de Oliveira

  5. Centro de Ciências Químicas Farmacêuticas e de Alimentos, Universidade Federal de Pelotas, Pelotas, RS, Brazil

    Roberto F Almeida

  6. Programa de Pós-Graduação em Bioquímica e Bioprospecção, Universidade Federal de Pelotas, Pelotas, RS, Brazil

    Roberto F Almeida

Authors
  1. Lucas Santos
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  2. Luiza Behrens
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  3. Camila Barbosa
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  13. José Cláudio Fonseca Moreira
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Contributions

Lucas Santos: the central idea of ​​research, animal handling and experimentation, behavioural tests, immunofluorescence, biochemical and molecular analyses, writing and reviewing the manuscript.

Luiza Behrens: animal handling and experimentation, behavioural tests, biochemical and molecular analyses.

Camila Barbosa: animal handling and experimentation and behavioural tests.

Camila Tiefensee-Ribeiro: animal handling and experimentation and euthanasia.

Helen Rosa-Silva: animal management and experimentation and DNA damage and repair techniques.

Nauana Somensi: animal handling and experimentation and biochemical analyses.

Pedro Ozorio Brum: euthanasia and immunofluorescence.

Alexandre Kleber Silveira: animal handling and experimentation and euthanasia.

Matheus Scarapatto Rodrigues: euthanasia and immunofluorescence.

Jade de Oliveira: manuscript review and immunofluorescence.

Daniel Gelain: a manuscript review.

Roberto Almeida: the central idea of ​​the manuscript's research, writing and review.

José Cláudio Fonseca Moreira: the central idea of ​​the manuscript's research, writing and review.

Corresponding author

Correspondence to Lucas Santos.

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All applicable international, national, and institutional guidelines for the care and use of the animals were followed. The Animal Experimentation Ethics Committee (CONCEA) of the UFRGS approved the research protocol under authorization number 35277.

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Santos, L., Behrens, L., Barbosa, C. et al. Histone 3 Trimethylation Patterns are Associated with Resilience or Stress Susceptibility in a Rat Model of Major Depression Disorder. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-03912-3

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