Dataset Information

Altered Hippocampal Epigenetic Regulation Underlying Reduced Cognitive Development in Response to Early Life Environmental Insults.

ABSTRACT: The hippocampus is involved in learning and memory and undergoes significant growth and maturation during the neonatal period. Environmental insults during this developmental timeframe can have lasting effects on brain structure and function. This study assessed hippocampal DNA methylation and gene transcription from two independent studies reporting reduced cognitive development stemming from early life environmental insults (iron deficiency and porcine reproductive and respiratory syndrome virus (PRRSv) infection) using porcine biomedical models. In total, 420 differentially expressed genes (DEGs) were identified between the reduced cognition and control groups, including genes involved in neurodevelopment and function. Gene ontology (GO) terms enriched for DEGs were associated with immune responses, angiogenesis, and cellular development. In addition, 116 differentially methylated regions (DMRs) were identified, which overlapped 125 genes. While no GO terms were enriched for genes overlapping DMRs, many of these genes are known to be involved in neurodevelopment and function, angiogenesis, and immunity. The observed altered methylation and expression of genes involved in neurological function suggest reduced cognition in response to early life environmental insults is due to altered cholinergic signaling and calcium regulation. Finally, two DMRs overlapped with two DEGs, VWF and LRRC32, which are associated with blood brain barrier permeability and regulatory T-cell activation, respectively. These results support the role of altered hippocampal DNA methylation and gene expression in early life environmentally-induced reductions in cognitive development across independent studies.

SUBMITTER: Schachtschneider KM

PROVIDER: S-EPMC7074491 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Altered Hippocampal Epigenetic Regulation Underlying Reduced Cognitive Development in Response to Early Life Environmental Insults.

Schachtschneider Kyle M KM Welge Michael E ME Auvil Loretta S LS Chaki Sulalita S Rund Laurie A LA Madsen Ole O Elmore Monica R P MRP Johnson Rodney W RW Groenen Martien A M MAM Schook Lawrence B LB

Genes 20200204 2

The hippocampus is involved in learning and memory and undergoes significant growth and maturation during the neonatal period. Environmental insults during this developmental timeframe can have lasting effects on brain structure and function. This study assessed hippocampal DNA methylation and gene transcription from two independent studies reporting reduced cognitive development stemming from early life environmental insults (iron deficiency and porcine reproductive and respiratory syndrome vir ...[more]

PMID: 32033187

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Project description:Background: Most neurodegenerative diseases are sporadic and develop with age. Degenerative neural tissues often contain intra- and extracellular protein aggregates, suggesting that the proteostasis network that combats protein misfolding could be dysfunctional in the setting of neurodegenerative disease. Binding immunoglobulin protein (BiP) is an endoplasmic reticulum (ER) chaperone that is crucial for protein folding and modulating the adaptive response in early secretory pathways. The interaction between BiP and unfolded proteins is mediated by the substrate-binding domain and nucleotide-binding domain with ATPase activity. The interaction facilitates protein folding and maturation. BiP has a recovery motif at the carboxyl terminus. The aim of this study is to examine cognitive function in model mice with an impaired proteostasis network by expressing a mutant form of BiP lacking the recovery motif. We also investigated if impairments of cognitive function were exacerbated by exposure to environmental insults, such as inhaled anesthetics. Methods: We examined cognitive function by performing radial maze testing with mutant BiP mice and assessed the additional impact of general anesthesia in the context of proteostasis dysfunction. Testing over 8 days was performed 10 weeks, 6 months, and 1 year after birth. Results: Age-related cognitive decline occurred in both forms of mice. The mutant BiP and anesthetic exposure promoted cognitive dysfunction prior to the senile period. After senescence, when mice were tested at 6 months of age and at 1 year old, there were no significant differences between the two genotypes in terms of the radial maze testing; furthermore, there was no significant difference when tested with and without anesthetic exposure. Conclusion: Our data suggest that aging was the predominant factor underlying the impairment of cognitive function in this study. Impairment of the proteostasis network may promote age-related neurodegeneration, and this is exacerbated by external insults.

Dataset Information

Altered Hippocampal Epigenetic Regulation Underlying Reduced Cognitive Development in Response to Early Life Environmental Insults.

Publications

Altered Hippocampal Epigenetic Regulation Underlying Reduced Cognitive Development in Response to Early Life Environmental Insults.

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