Age‐associated Downregulation of GABAergic and Glutamatergic Synapse‐related Gene Expression in the Rostral Ventrolateral Medulla of Male Rats

Obese Zucker rats (OZR) have elevated sympathetic nerve activity (SNA) and mean arterial pressure (MAP) compared with lean Zucker rats (LZR). We examined whether altered tonic glutamatergic, angiotensinergic, or GABAergic inputs to the rostral ventrolateral medulla (RVLM) contribute to elevated SNA and MAP in OZR. Male rats (14–18 wk) were anesthetized with urethane (1.5 g/kg iv), ventilated, and paralyzed to record splanchnic SNA, heart rate (HR), and MAP. Inhibition of the RVLM by microinjections of muscimol eliminated SNA and evoked greater decreases in MAP in OZR vs. LZR ( P < 0.05). Antagonism of angiotensin AT1 receptors in RVLM with losartan yielded modest decreases in SNA and MAP in OZR but not LZR ( P < 0.05). However, antagonism of ionotropic glutamate receptors in RVLM with kynurenate produced comparable decreases in SNA, HR, and MAP in OZR and LZR. Antagonism of GABAA receptors in RVLM with gabazine evoked smaller rises in SNA, HR, and MAP in OZR vs. LZR ( P < 0.05), whereas responses to microinjections of GABA into RVLM were comparable. Inhibition of the caudal ventrolateral medulla, a major source of GABA to the RVLM, evoked attenuated rises in SNA and HR in OZR ( P <0.05). Likewise, inhibition of nucleus tractus solitarius, the major excitatory input to caudal ventrolateral medulla, produced smaller rises in SNA and HR in OZR. These results suggest the elevated SNA and MAP in OZR is derived from the RVLM and that enhanced angiotensinergic activation and reduced GABAergic inhibition of the RVLM may contribute to the elevated SNA and MAP in the OZR.

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Activation of corticotropin-releasing factor receptors in the rostral ventrolateral medulla is required for glucose-induced sympathoexcitation

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00291.2014 ◽

2014 ◽

Vol 307 (10) ◽

pp. E944-E953 ◽

Cited By ~ 14

Author(s):

Megan E. Bardgett ◽

Amanda L. Sharpe ◽

Glenn M. Toney

Keyword(s):

Energy Expenditure ◽

Neuronal Activity ◽

Rostral Ventrolateral Medulla ◽

Corticotropin Releasing Factor ◽

Glucose Infusion ◽

Neural Mechanisms ◽

Male Rats ◽

Ventrolateral Medulla ◽

Sympathetic Activation ◽

Gaba A

Energy expenditure is determined by metabolic rate and diet-induced thermogenesis. Normally, energy expenditure increases due to neural mechanisms that sense plasma levels of ingested nutrients/hormones and reflexively increase sympathetic nerve activity (SNA). Here, we investigated neural mechanisms of glucose-driven sympathetic activation by determining contributions of neuronal activity in the hypothalamic paraventricular nucleus (PVN) and activation of corticotropin-releasing factor (CRF) receptors in the rostral ventrolateral medulla (RVLM). Glucose was infused intravenously (150 mg/kg, 10 min) in male rats to raise plasma glucose concentration to a physiological postprandial level. In conscious rats, glucose infusion activated CRF-containing PVN neurons and TH-containing RVLM neurons, as indexed by c-Fos immunofluorescence. In α-chloralose/urethane-anesthetized rats, glucose infusion increased lumbar and splanchnic SNA, which was nearly prevented by prior RVLM injection of the CRF receptor antagonist astressin (10 pmol/50 nl). This cannot be attributed to a nonspecific effect, as sciatic afferent stimulation increased SNA and ABP equivalently in astressin- and aCSF-injected rats. Glucose-stimulated sympathoexcitation was largely reversed during inhibition of PVN neuronal activity with the GABA-A receptor agonist muscimol (100 pmol/50 nl). The effects of astressin to prevent glucose-stimulated sympathetic activation appear to be specific to interruption of PVN drive to RVLM because RVLM injection of astressin prior to glucose infusion effectively prevented SNA from rising and prevented any fall of SNA in response to acute PVN inhibition with muscimol. These findings suggest that activation of SNA, and thus energy expenditure, by glucose is initiated by activation of CRF receptors in RVLM by descending inputs from PVN.

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Microarray analysis of aging-associated immune system alterations in the rostral ventrolateral medulla of F344 rats

Physiological Genomics ◽

10.1152/physiolgenomics.00131.2016 ◽

2017 ◽

Vol 49 (8) ◽

pp. 400-415 ◽

Cited By ~ 5

Author(s):

Sivasai Balivada ◽

Chanran K. Ganta ◽

Yongqing Zhang ◽

Hitesh N. Pawar ◽

Richard J. Ortiz ◽

...

Keyword(s):

Gene Expression ◽

Immune System ◽

Neural Substrates ◽

Rostral Ventrolateral Medulla ◽

Ventrolateral Medulla ◽

Middle Aged ◽

Transcriptomic Profile ◽

Age Related ◽

F344 Rats ◽

Age Related Changes

The rostral ventrolateral medulla (RVLM) is an area of the brain stem that contains diverse neural substrates that are involved in systems critical for physiological function. There is evidence that aging affects some neural substrates within the RVLM, although age-related changes in RVLM molecular mechanisms are not well established. The goal of the present study was to characterize the transcriptomic profile of the aging RVLM and to test the hypothesis that aging is associated with altered gene expression in the RVLM, with an emphasis on immune system associated gene transcripts. RVLM tissue punches from young, middle-aged, and aged F344 rats were analyzed with 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, false discovery rate (FDR) < 0.3]. Functional analysis of RVLM microarray data via gene ontology profiling and pathway analysis identified upregulation of genes associated with immune- and stress-related responses and downregulation of genes associated with lipid biosynthesis and neurotransmission in aged compared with middle-aged and young rats. Differentially expressed genes associated with the complement system and microglial cells were further validated by quantitative PCR with separate RVLM samples ( P < 0.05, FDR < 0.1). The present results have identified age-related changes in the transcriptomic profile of the RVLM, modifications that may provide the molecular backdrop for understanding age-dependent changes in physiological regulation.

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Gene expression of NMDA receptor subunits using laser capture microdissection in the rostral ventrolateral medulla (RVLM) of sedentary versus physically active rats.

The FASEB Journal ◽

10.1096/fasebj.27.1_supplement.1118.24 ◽

2013 ◽

Vol 27 (S1) ◽

Author(s):

Madhan Subramanian ◽

Avril G Holt ◽

Patrick J Mueller

Keyword(s):

Gene Expression ◽

Nmda Receptor ◽

Laser Capture Microdissection ◽

Rostral Ventrolateral Medulla ◽

Ventrolateral Medulla ◽

Physically Active ◽

Nmda Receptor Subunits ◽

Laser Capture

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Gene Expression Networks in Rostral Ventrolateral Medulla (RVLM) of Rats with Angiotensin‐salt Hypertension

The FASEB Journal ◽

10.1096/fasebj.22.1_supplement.1168.10 ◽

2008 ◽

Vol 22 (S1) ◽

Author(s):

Lihui Yuan ◽

Xia Li ◽

Judith Sved ◽

Alan Sved ◽

Mohan Raizada ◽

...

Keyword(s):

Gene Expression ◽

Rostral Ventrolateral Medulla ◽

Ventrolateral Medulla ◽

Salt Hypertension

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DOCA/salt hypertension alters Period1 and orexin-related gene expression in the medulla and hypothalamus of male rats: Diurnal influences

Autonomic Neuroscience ◽

10.1016/j.autneu.2017.12.003 ◽

2018 ◽

Vol 210 ◽

pp. 34-43 ◽

Cited By ~ 1

Author(s):

M.E. Hernandez ◽

J.M. Watkins ◽

J. Vu ◽

L.F. Hayward

Keyword(s):

Gene Expression ◽

Male Rats ◽

Related Gene ◽

Salt Hypertension

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Swimming training reduces iNOS expression, augments the antioxidant defense and reduces sympathetic responsiveness in the rostral ventrolateral medulla of normotensive male rats

Brain Research Bulletin ◽

10.1016/j.brainresbull.2021.02.023 ◽

2021 ◽

Vol 170 ◽

pp. 225-233

Author(s):

Hiviny de Ataides Raquel ◽

Carla Fabiana Souza Guazelli ◽

Waldiceu A. Verri ◽

Lisete C. Michelini ◽

Marli Cardoso Martins-Pinge

Keyword(s):

Antioxidant Defense ◽

Rostral Ventrolateral Medulla ◽

Inos Expression ◽

Male Rats ◽

Ventrolateral Medulla ◽

Swimming Training

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Chronic estrogen exposure affects gene expression in the rostral ventrolateral medulla of young and aging rats: Possible role in hypertension

Brain Research ◽

10.1016/j.brainres.2015.09.007 ◽

2015 ◽

Vol 1627 ◽

pp. 134-142 ◽

Cited By ~ 10

Author(s):

Madhan Subramanian ◽

Coral Hahn-Townsend ◽

Kimberly A Clark ◽

Sheba M.J. MohanKumar ◽

P.S. MohanKumar

Keyword(s):

Gene Expression ◽

Rostral Ventrolateral Medulla ◽

Ventrolateral Medulla ◽

Aging Rats ◽

Estrogen Exposure

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Sex differences in angiotensin signaling in bulbospinal neurons in the rat rostral ventrolateral medulla

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.90485.2008 ◽

2008 ◽

Vol 295 (4) ◽

pp. R1149-R1157 ◽

Cited By ~ 18

Author(s):

Gang Wang ◽

Teresa A. Milner ◽

Robert C. Speth ◽

Andrea C. Gore ◽

Di Wu ◽

...

Keyword(s):

Sex Differences ◽

Nadph Oxidase ◽

Rostral Ventrolateral Medulla ◽

Female Rats ◽

Male Rats ◽

Ventrolateral Medulla ◽

Ros Production ◽

Ang Ii ◽

Dual Label

Sex differences may play a significant role in determining the risk of hypertension. Bulbospinal neurons in the rostral ventrolateral medulla (RVLM) are involved in the tonic regulation of arterial pressure and participate in the central mechanisms of hypertension. Angiotensin II (ANG II) acting on angiotensin type 1 (AT1) receptors in RVLM neurons is implicated in the development of hypertension by activating NADPH oxidase and producing reactive oxygen species (ROS). Therefore, we analyzed RVLM bulbospinal neurons to determine whether there are sex differences in: 1) immunolabeling for AT1 receptors and the key NADPH oxidase subunit p47 using dual-label immunoelectron microscopy, and 2) the effects of ANG II on ROS production and Ca2+ currents using, respectively, hydroethidine fluoromicrography and patch-clamping. In tyrosine hydroxylase-positive RVLM neurons, female rats displayed significantly more AT1 receptor immunoreactivity and less p47 immunoreactivity than male rats ( P < 0.05). Although ANG II (100 nM) induced comparable ROS production in dissociated RVLM bulbospinal neurons of female and male rats ( P > 0.05), an effect mediated by AT1 receptors and NADPH oxidase, it triggered significantly larger dihydropyridine-sensitive long-lasting (L-type) Ca2+ currents in female RVLM neurons ( P < 0.05). These observations suggest that an increase in AT1 receptors in female RVLM neurons is counterbalanced by a reduction in p47 levels, such that ANG II-induced ROS production does not differ between females and males. Since the Ca2+ current activator Bay K 8644 induced larger Ca2+ currents in females than in male RVLM neurons, increased ANG II-induced L-type Ca2+ currents in females may result from sex differences in calcium channel densities or dynamics.

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