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Hippocampal subfield transcriptomic profiles: Regional vulnerability to age and cognitive impairment

ABSTRACT: The current study employed next-generation RNA sequencing to examine gene expression related to brain aging and cognitive decline. Young and aged rats were trained on a spatial episodic memory task. Hippocampal regions CA1, CA3 and the dentate gyrus (DG) were isolated. Poly-A mRNA was examined using two different platforms, Illumina and Ion Proton. The Illumina platform was used to generate lists of genes that were differentially expressed across regions, ages, and in association with cognitive function. The gene lists were then retested using the Ion Proton platform. The results describe regional differences in gene expression and point to regional differences in vulnerability to aging. Aging was associated with increased expression of immune response related genes, particularly in the dentate gyrus. Finally, for the memory task used, impaired performance of aged animals was linked to the regulation of Ca2+ and synaptic function in region CA1.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE97608 | GEO | 2017/12/08

SECONDARY ACCESSION(S): PRJNA382422

REPOSITORIES: GEO

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Project description:Metabolic, mitochondrial and behavioral correlations with transcriptional profiles from the CA1 and DG hippocampal regions of young and aged rhesus macaque. Increasing evidence indicates that obesity correlates with impaired cognitive performance during normal aging and is a major risk factor for Alzheimer’s disease. However, little is known regarding how peripheral metabolic variables affect cellular pathways in brain regions important for memory. Brain inflammation, mitochondrial dysregulation, and altered transcriptional regulation have all been found to occur with aging, and recent microarray analyses in rodent models have linked these processes and others to age-related memory impairment. However, whether these brain changes are also associated with metabolic variables is not known. Aging monkeys exhibit several metabolic changes similar to those seen in humans. Here, we tested peripheral-brain relationships in six young (7.0 +/- 0.3 years) and six aged (23.5 +/- 0.7 years) female rhesus monkeys. Animal cognition was gauged with a variable delay task; blood constituents were assessed with a serum chemistry panel emphasizing markers of metabolic dysfunction; mitochondrial function was measured from the hippocampus of one hemisphere; and the CA1 and dentate gyrus regions of the other hippocampus were dissected out for gene expression microarray analysis. Aged animals showed reduced performance on the behavioral task, exhibited aspects of metabolic dysregulation including increased insulin, triglyceride, and chylomicron levels (consolidated into a peripheral metabolic index), and showed a significant age-related reduction in State III oxidation, a measure of mitochondrial function. Microarray analyses revealed hundreds of genes that correlated with the peripheral metabolic index. However, DAVID statistical pathway analyses showed that upregulated inflammatory genes in CA1 and downregulated transcriptional regulation genes in dentate gyrus and CA1 were particularly overrepresented among genes correlated with the peripheral index. Thus, the association of metabolic variables with specific neuropathological processes in different regions of the hippocampal formation may have implications for mechanisms through which peripheral metabolism alters the risk for Alzheimer’s disease. Keywords: Rhesus hippocampal aging

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Hippocampal subfield transcriptomic profiles: Regional vulnerability to age and cognitive impairment

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