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Inflammatory, synaptic, motor, and behavioral alterations induced by gestational sepsis on the offspring at different stages of life

BACKGROUND: The term sepsis is used to designate a systemic condition of infection and inflammation associated with hemodynamic changes that result in organic dysfunction. Gestational sepsis can impair the development of the central nervous system and may promote permanent behavior alterations in th...

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Autores principales: Granja, Marcelo Gomes, Alves, Letícia Pires, Leardini-Tristão, Marina, Saul, Michelle Edelman, Bortoni, Letícia Coelho, de Moraes, Flávia Maciel, Ferreira, Erica Camila, de Moraes, Bianca Portugal Tavares, da Silva, Victória Zerboni, dos Santos, Adrielle Ferreira Ribeiro, Silva, Adriana Ribeiro, Gonçalves-de-Albuquerque, Cassiano Felippe, Bambini-Junior, Victorio, Weyrich, Andrew S., Rondina, Matthew T., Zimmerman, Guy A., de Castro-Faria-Neto, Hugo Caire
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905683/
https://www.ncbi.nlm.nih.gov/pubmed/33632243
http://dx.doi.org/10.1186/s12974-021-02106-1
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author Granja, Marcelo Gomes
Alves, Letícia Pires
Leardini-Tristão, Marina
Saul, Michelle Edelman
Bortoni, Letícia Coelho
de Moraes, Flávia Maciel
Ferreira, Erica Camila
de Moraes, Bianca Portugal Tavares
da Silva, Victória Zerboni
dos Santos, Adrielle Ferreira Ribeiro
Silva, Adriana Ribeiro
Gonçalves-de-Albuquerque, Cassiano Felippe
Bambini-Junior, Victorio
Weyrich, Andrew S.
Rondina, Matthew T.
Zimmerman, Guy A.
de Castro-Faria-Neto, Hugo Caire
author_facet Granja, Marcelo Gomes
Alves, Letícia Pires
Leardini-Tristão, Marina
Saul, Michelle Edelman
Bortoni, Letícia Coelho
de Moraes, Flávia Maciel
Ferreira, Erica Camila
de Moraes, Bianca Portugal Tavares
da Silva, Victória Zerboni
dos Santos, Adrielle Ferreira Ribeiro
Silva, Adriana Ribeiro
Gonçalves-de-Albuquerque, Cassiano Felippe
Bambini-Junior, Victorio
Weyrich, Andrew S.
Rondina, Matthew T.
Zimmerman, Guy A.
de Castro-Faria-Neto, Hugo Caire
author_sort Granja, Marcelo Gomes
collection PubMed
description BACKGROUND: The term sepsis is used to designate a systemic condition of infection and inflammation associated with hemodynamic changes that result in organic dysfunction. Gestational sepsis can impair the development of the central nervous system and may promote permanent behavior alterations in the offspring. The aim of our work was to evaluate the effects of maternal sepsis on inflammatory cytokine levels and synaptic proteins in the hippocampus, neocortex, frontal cortex, and cerebellum of neonatal, young, and adult mice. Additionally, we analyzed the motor development, behavioral features, and cognitive impairments in neonatal, young and adult offspring. METHODS: Pregnant mice at the 14(th) embryonic day (E14) were intratracheally instilled with saline 0.9% solution (control group) or Klebsiella spp. (3 × 10(8) CFU) (sepsis group) and started on meropenem after 5 h. The offspring was sacrificed at postnatal day (P) 2, P8, P30, and P60 and samples of liver, lung, and brain were collected for TNF-α, IL-1β, and IL-6 measurements by ELISA. Synaptophysin, PSD95, and β-tubulin levels were analyzed by Western blot. Motor tests were performed at all analyzed ages and behavioral assessments were performed in offspring at P30 and P60. RESULTS: Gestational sepsis induces a systemic pro-inflammatory response in neonates at P2 and P8 characterized by an increase in cytokine levels. Maternal sepsis induced systemic downregulation of pro-inflammatory cytokines, while in the hippocampus, neocortex, frontal cortex, and cerebellum an inflammatory response was detected. These changes in the brain immunity were accompanied by a reduction of synaptophysin and PSD95 levels in the hippocampus, neocortex, frontal cortex, and cerebellum, in all ages. Behavioral tests demonstrated motor impairment in neonates, and depressive-like behavior, fear-conditioned memory, and learning impairments in animals at P30 and P60, while spatial memory abilities were affected only at P60, indicating that gestational sepsis not only induces an inflammatory response in neonatal mouse brains, but also affects neurodevelopment, and leads to a plethora of behavioral alterations and cognitive impairments in the offspring. CONCLUSION: These data suggest that maternal sepsis may be causatively related to the development of depression, learning, and memory impairments in the litter. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-021-02106-1.
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spelling pubmed-79056832021-02-25 Inflammatory, synaptic, motor, and behavioral alterations induced by gestational sepsis on the offspring at different stages of life Granja, Marcelo Gomes Alves, Letícia Pires Leardini-Tristão, Marina Saul, Michelle Edelman Bortoni, Letícia Coelho de Moraes, Flávia Maciel Ferreira, Erica Camila de Moraes, Bianca Portugal Tavares da Silva, Victória Zerboni dos Santos, Adrielle Ferreira Ribeiro Silva, Adriana Ribeiro Gonçalves-de-Albuquerque, Cassiano Felippe Bambini-Junior, Victorio Weyrich, Andrew S. Rondina, Matthew T. Zimmerman, Guy A. de Castro-Faria-Neto, Hugo Caire J Neuroinflammation Research BACKGROUND: The term sepsis is used to designate a systemic condition of infection and inflammation associated with hemodynamic changes that result in organic dysfunction. Gestational sepsis can impair the development of the central nervous system and may promote permanent behavior alterations in the offspring. The aim of our work was to evaluate the effects of maternal sepsis on inflammatory cytokine levels and synaptic proteins in the hippocampus, neocortex, frontal cortex, and cerebellum of neonatal, young, and adult mice. Additionally, we analyzed the motor development, behavioral features, and cognitive impairments in neonatal, young and adult offspring. METHODS: Pregnant mice at the 14(th) embryonic day (E14) were intratracheally instilled with saline 0.9% solution (control group) or Klebsiella spp. (3 × 10(8) CFU) (sepsis group) and started on meropenem after 5 h. The offspring was sacrificed at postnatal day (P) 2, P8, P30, and P60 and samples of liver, lung, and brain were collected for TNF-α, IL-1β, and IL-6 measurements by ELISA. Synaptophysin, PSD95, and β-tubulin levels were analyzed by Western blot. Motor tests were performed at all analyzed ages and behavioral assessments were performed in offspring at P30 and P60. RESULTS: Gestational sepsis induces a systemic pro-inflammatory response in neonates at P2 and P8 characterized by an increase in cytokine levels. Maternal sepsis induced systemic downregulation of pro-inflammatory cytokines, while in the hippocampus, neocortex, frontal cortex, and cerebellum an inflammatory response was detected. These changes in the brain immunity were accompanied by a reduction of synaptophysin and PSD95 levels in the hippocampus, neocortex, frontal cortex, and cerebellum, in all ages. Behavioral tests demonstrated motor impairment in neonates, and depressive-like behavior, fear-conditioned memory, and learning impairments in animals at P30 and P60, while spatial memory abilities were affected only at P60, indicating that gestational sepsis not only induces an inflammatory response in neonatal mouse brains, but also affects neurodevelopment, and leads to a plethora of behavioral alterations and cognitive impairments in the offspring. CONCLUSION: These data suggest that maternal sepsis may be causatively related to the development of depression, learning, and memory impairments in the litter. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-021-02106-1. BioMed Central 2021-02-25 /pmc/articles/PMC7905683/ /pubmed/33632243 http://dx.doi.org/10.1186/s12974-021-02106-1 Text en © The Author(s) 2021 Open AccessThis 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 http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Granja, Marcelo Gomes
Alves, Letícia Pires
Leardini-Tristão, Marina
Saul, Michelle Edelman
Bortoni, Letícia Coelho
de Moraes, Flávia Maciel
Ferreira, Erica Camila
de Moraes, Bianca Portugal Tavares
da Silva, Victória Zerboni
dos Santos, Adrielle Ferreira Ribeiro
Silva, Adriana Ribeiro
Gonçalves-de-Albuquerque, Cassiano Felippe
Bambini-Junior, Victorio
Weyrich, Andrew S.
Rondina, Matthew T.
Zimmerman, Guy A.
de Castro-Faria-Neto, Hugo Caire
Inflammatory, synaptic, motor, and behavioral alterations induced by gestational sepsis on the offspring at different stages of life
title Inflammatory, synaptic, motor, and behavioral alterations induced by gestational sepsis on the offspring at different stages of life
title_full Inflammatory, synaptic, motor, and behavioral alterations induced by gestational sepsis on the offspring at different stages of life
title_fullStr Inflammatory, synaptic, motor, and behavioral alterations induced by gestational sepsis on the offspring at different stages of life
title_full_unstemmed Inflammatory, synaptic, motor, and behavioral alterations induced by gestational sepsis on the offspring at different stages of life
title_short Inflammatory, synaptic, motor, and behavioral alterations induced by gestational sepsis on the offspring at different stages of life
title_sort inflammatory, synaptic, motor, and behavioral alterations induced by gestational sepsis on the offspring at different stages of life
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905683/
https://www.ncbi.nlm.nih.gov/pubmed/33632243
http://dx.doi.org/10.1186/s12974-021-02106-1
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