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Transcriptomic analysis of dynamic dysregulation in brainstem autonomic nuclei during the development of hypertension

ABSTRACT: Neurogenic hypertension stems from an imbalance in autonomic function that shifts the central cardiovascular control circuits towards a state of dysfunction. Using the female spontaneously hypertensive rat (SHR) and the normotensive Wistar Kyoto (WKY) rat model, we compared the transcriptomic changes in three autonomic nuclei in the brainstem, the nucleus of the solitary tract (NTS), caudal ventrolateral medulla (CVLM), and rostral ventrolateral medulla (RVLM) in a time series at 8, 10, 12, 16, and 24 weeks of age, spanning the pre-hypertensive stage through extended chronic hypertension.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE234784 | GEO | 2024/01/30

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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Transcriptomic analysis of dynamic dysregulation in brainstem autonomic nuclei during the development of hypertension

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