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Microarray analysis of aging-associated immune system alterations in the Rostral Ventral Lateral Medulla of F344 rats

ABSTRACT: Progressive aging is associated with changes in sympathetic nervous system (SNS) regulation, suggesting an effect of advancing age on the functionality of central sympathetic premotor neurons. The rostral ventral lateral medulla (RVLM) contains sympathetic premotor neurons and plays a key role in SNS regulation, and it is plausible to speculate that age-related changes in the molecular mechanisms in the RVLM may contribute to alterations in SNS regulation. The present study tested the hypothesis that aging is associated with altered gene expression in the RVLM with emphasis on immune system associated gene transcripts. RVLM tissue punches from young, middle-aged, and aged F344 rats were analyzed using Agilent’s whole rat genome microarray. The RVLM gene expression profile varied with age and an association between chronological age and specific RVLM gene expression patterns was observed (p<0.05, FDR<0.3). Functional analysis of RVLM microarray data via gene ontology profiling and pathway analysis has identified up-regulation of genes associated with immune- and stress- related responses, and down-regulation of genes associated with lipid biosynthesis and neurotransmission in aged compared with middle-aged and young rats. Differentially expressed genes associated with complement system and microglial cells were further validated by quantitative PCR with separate RVLM samples (p<0.05, FDR<0.1). The present results are the first to demonstrate age-related changes in the RVLM molecular mechanisms, modifications that may provide the molecular backdrop for understanding immune-associated changes in SNS regulation.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE90956 | GEO | 2016/12/07

SECONDARY ACCESSION(S): PRJNA356440

REPOSITORIES: GEO

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Project description:The rostral ventrolateral medulla (RVLM), a part of the medullary reticular formation, plays a major role in several physiological responses, including cardiovascular and sympathetic nervous system functions. Although aging causes disturbances in the responses of these physiological systems, RVLM involvement in these age-related changes is not clear. Previous work using high-throughput gene expression analysis of the RVLM in aged animals suggested that chemical neurotransmission-related genes might be downregulated with advancing age. Since the RVLM function involves a balance of inhibitory and excitatory inputs, which is largely mediated by gamma-aminobutyric acid (GABA) and excitatory amino acid (EAA) neurotransmission, we hypothesized that aging is associated with altered excitatory and/or inhibitory neurotransmission-related gene expression in the RVLM. To test this hypothesis, we micropunched an RVLM-containing area from young (3–5 months), middle-aged (12–14 months), and aged (22–26 months) Fischer 344 male rats. RNA purified from these micropunches was analyzed using GABA and Glutamate RT2 Profiler PCR arrays (n= 8–10). In addition, the expression of selected genes was validated at the RNA level using TaqMan® based- qPCR and at the protein level using western blotting. All the genes that displayed significant differential expression (1.5-fold, p < .05, FDR < .05) were identified to be downregulated in the RVLM of aged and middle-aged rats compared to young rats. Among the downregulated genes, the percentage of glutamate neurotransmission-related genes was higher than GABA neurotransmission-related genes. Solute carrier family 1 member 6 (Slc1a6) gene showed the highest fold downregulation at the RNA level in the RVLM of aged compared to young rats, and its protein product, Excitatory amino acid transporter 4 (EAAT4), showed a downregulatory trend in the RVLM of aged and middle-aged rats. These results suggest that molecular constituents of both GABA and glutamate neurotransmission might be altered in the RVLM of aged and middle-aged rats, and the changes in glutamate neurotransmission might be more prominent. Investigating age-associated anatomical and functional changes in RVLM GABA and glutamate neurotransmission might provide a foundation for understanding the effects of aging on physiological function.

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Microarray analysis of aging-associated immune system alterations in the Rostral Ventral Lateral Medulla of F344 rats

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