Microglial activation induced by LPS mediates excitation of neurons in the hypothalamic paraventricular nucleus projecting to the rostral ventrolateral medulla.
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ABSTRACT:
SUBMITTER: Han TH
PROVIDER: S-EPMC8728541 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:An imbalance of excitatory and inhibitory functions has been shown to contribute to numerous pathological disorders. Accumulating evidence supports the idea that a change in hypothalamic gamma-aminobutyric acid (GABA)-ergic inhibitory and glutamatergic excitatory synaptic functions contributes to exacerbated neurohumoral drive in prevalent cardiovascular disorders, including hypertension. However, the precise underlying mechanisms and neuronal substrates are still not fully elucidated. In the present study, we combined quantitative immunohistochemistry with neuronal tract tracing to determine whether plastic remodeling of afferent GABAergic and glutamatergic inputs into identified RVLM-projecting neurons of the hypothalamic paraventricular nucleus (PVN-RVLM) contributes to an imbalanced excitatory/inhibitory function in renovascular hypertensive rats (RVH). Our results indicate that both GABAergic and glutamatergic innervation densities increased in oxytocin-positive, PVN-RVLM (OT-PVN-RVLM) neurons in RVH rats. Despite this concomitant increase, time-dependent and compartment-specific differences in the reorganization of these inputs resulted in an altered balance of excitatory/inhibitory inputs in somatic and dendritic compartments. A net predominance of excitatory over inhibitory inputs was found in OT-PVN-RVLM proximal dendrites. Our results indicate that, along with previously described changes in neurotransmitter release probability and postsynaptic receptor function, remodeling of GABAergic and glutamatergic afferent inputs contributes as an underlying mechanism to the altered excitatory/inhibitory balance in the PVN of hypertensive rats.
| S-EPMC4428175 | biostudies-literature
Project description:The periaqueductal gray (PAG) modulates nociception via a descending pathway that relays in the rostral ventromedial medulla (RVM) and terminates in the spinal cord. Previous behavioral pharmacology and electrophysiological evidence suggests that brain-derived neurotrophic factor (BDNF) plays an important role in descending pain modulation, likely through the PAG-RVM pathway. However, detailed information is still lacking on the distribution of BDNF, activation of BDNF-containing neurons projecting to RVM in the condition of pain, and neurochemical properties of these neurons within the PAG. Through fluorescent in situ hybridization (FISH) and immunofluorescent staining, the homogenous distributions of BDNF mRNA and protein were observed in the four subregions of PAG. Both neurons and astrocytes expressed BDNF, but not microglia. By combining retrograde tracing methods and formalin pain model, there were more BDNF-containing neurons projecting to RVM being activated in the ventrolateral subregion of PAG (vlPAG) than other subregions of PAG. The neurochemical properties of BDNF-containing projection neurons in the vlPAG were investigated. BDNF-containing projection neurons expressed the autoreceptor TrkB in addition to serotonin (5-HT), neurotensin (NT), substance P (SP), calcitonin gene related peptide (CGRP), nitric oxide synthase (NOS), and parvalbumin (PV) but not tyrosine decarboxylase (TH). It is speculated that BDNF released from projection neurons in the vlPAG might participate in the descending pain modulation through enhancing the presynaptic release of other neuroactive substances (NSs) in the RVM.
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Project description:Excess dietary salt intake contributes to or exacerbates some forms of hypertension by increasing sympathetic nerve activity (SNA) and arterial blood pressure (ABP) through angiotensin II (Ang II) type 1 receptor activation in the rostral ventrolateral medulla (RVLM). Despite this interaction among dietary salt, Ang II, and the RVLM, no studies have directly examined whether dietary salt by itself alters Ang II-dependent responses and regulation of RVLM neurons, SNA, and ABP. Therefore, the present study directly tested this hypothesis. Male Sprague-Dawley rats were fed normal chow and given access to water or 0.9% NaCl solution for 14 days. Unilateral injection of Ang II (0.6, 6, and 60 pmol) into the RVLM produced a significantly greater increase in renal SNA and mean ABP of rats drinking 0.9% NaCl versus water. However, dietary salt did not alter mRNA levels of RVLM Ang II type 1a receptors or the SNA and ABP responses to stimulation of the dorsolateral funinculus. Additional experiments demonstrate that blockade of RVLM Ang II type 1 receptors significantly reduced renal SNA, splanchnic SNA, and mean ABP of rats drinking 0.9% NaCl but not water. Blockade of iontotropic glutamate receptors had no effect. Altogether, these findings suggest that elevated dietary salt enhances the sympathoexcitatory actions of Ang II in the RVLM via changes in the intrinsic properties of RVLM neurons. Moreover, elevated dietary salt intake differentially affects the tonic activity of the peripheral versus brain RVLM Ang II type 1 receptors to regulate baseline SNA and ABP.
| S-EPMC2635570 | biostudies-literature
Project description:Increases in sympathetic nerve activity (SNA) have been implicated in obesity-induced risk for cardiovascular diseases, especially hypertension. Previous studies indicate that oxidative stress in the rostral ventrolateral medulla (RVLM), a key brain stem region that regulates sympathetic outflow to peripheral tissues, plays a pathogenic role in obesity-mediated sympathoexcitation. However, the molecular mechanisms underlying this phenomenon are not clear. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that regulates the expression of antioxidant and anti-inflammatory genes and confers cytoprotection against oxidative stress. The present study was designed to investigate whether Nrf2 dysfunction was associated with obesity-induced oxidative stress in the RVLM and sympathoexcitation. C57BL/6J mice were fed with chow or a high-fat diet (HFD) for 16 wk. Blood pressure parameters were assessed by radiotelemeters in conscious freely moving mice. SNA was measured by heart rate variability analysis and also through assessment of depressor response to ganglionic blockade. The RVLM was microdissected for gene expression and protein analysis (Western blot analysis and activity assay) related to Nrf2 signaling. Our results showed that HFD-induced obesity resulted in significant increases in SNA, although we only observed a mild increase in mean arterial pressure. Obesity-induced oxidative stress in the RVLM was associated with impaired Nrf2 signaling marked by decreased Nrf2 activity, downregulation of Nrf2 mRNA, its target genes [NAD(P)H quinone dehyrogenase 1 (Nqo1) and superoxide dismutase 2 (Sod2)], and inflammation. Our findings suggest that obesity results in Nrf2 dysfunction, which likely causes maladaptation to oxidative stress and inflammation in the RVLM. These mechanisms could potentially contribute to obesity-induced sympathoexcitation.
| S-EPMC7052598 | biostudies-literature
Project description:Hyperinsulinemia increases sympathetic nerve activity (SNA) and has been linked to cardiovascular morbidity in obesity. The rostral ventrolateral medulla (RVLM) plays a key role in the regulation of SNA and arterial blood pressure (ABP). Many sympathoexcitatory responses are mediated by glutamatergic receptor activation within the RVLM, and both the central renin-angiotensin and melanocortin systems are implicated in the sympathoexcitatory response to hyperinsulinemia. Therefore, we hypothesized that one or more of these neurotransmitters in the RVLM mediate the sympathoexcitatory response to insulin. Hyperinsulinemic-euglycemic clamps were performed in alpha-chloralose anesthetized, male Sprague-Dawley rats by infusion of insulin (3.75 mU/kg per minute, IV) and 50% dextrose solution for 120 minutes. Physiological increases in plasma insulin elevated lumbar SNA, with no change in renal SNA, ABP, or blood glucose. Microinjection of the ionotropic glutamate receptor antagonist kynurenic acid into the RVLM significantly reduced lumbar SNA and ABP. Selective blockade of NMDA but not non-NMDA glutamate receptors resulted in similar reductions of lumbar SNA. In marked contrast, microinjection of the angiotensin II type 1 receptor antagonist losartan or the melanocortin 3/4 antagonist SHU9119 had no effect on lumbar SNA or ABP. Western blot analysis showed that insulin receptor expression is significantly lower in the RVLM than the hypothalamus, and direct microinjection of insulin into the RVLM did not significantly increase lumbar SNA. These findings suggest that hyperinsulinemia increases lumbar SNA by activation of a glutamatergic NMDA-dependent projection to the RVLM.
| S-EPMC2861553 | biostudies-literature
Project description:Oxidative stress in the rostral ventrolateral medulla (RVLM), a key region for blood pressure (BP) regulation, has been demonstrated to be responsible for the overactivity of the sympathetic nervous system in hypertension and heart failure. Nuclear factor-erythroid-2-related factor 2 (Nrf2) is a key transcription factor that maintains redox homeostasis by governing a broad array of antioxidant genes in response to oxidative stress. β-Arrestin1 is a multifunctional scaffold protein with the ability to interact with diverse signaling molecules independent of G protein-coupled receptors (GPCRs), and its overexpression in the RVLM could reduce BP and renal sympathetic nerve activity (RSNA) in spontaneously hypertensive rats (SHR). The goal of this study was to investigate whether Nrf2-mediated antioxidative stress is involved in the antihypertensive effect of β-arrestin1 in the RVLM. It was found that the activation level of Nrf2 in the RVLM of SHR was significantly reduced, compared with normotensive Wistar-Kyoko (WKY) rats. Overexpression of β-arrestin1 in the RVLM significantly decreased ROS production and facilitated the Nrf2 activation in the RVLM of SHR, accompanied by upregulating the expression of HO-1 and NQO-1. However, Nrf2 knockdown attenuated the antioxidant effect of β-arrestin1 overexpression in the RVLM by downregulating HO-1 and NQO-1 expression levels. In conclusion, the current results suggested that the antihypertensive effect of β-arrestin1 overexpression in the RVLM is mediated by decreased ROS production, which is associated with Nrf2 activation.
| S-EPMC8059792 | biostudies-literature
Project description:Elevated NaCl concentrations of the cerebrospinal fluid increase sympathetic nerve activity (SNA) in salt-sensitive hypertension. Neurons of the rostral ventrolateral medulla (RVLM) play a pivotal role in the regulation of SNA and receive mono- or polysynaptic inputs from several hypothalamic structures responsive to hypernatremia. Therefore, the present study investigated the contribution of RVLM neurons to the SNA and pressor response to cerebrospinal fluid hypernatremia. Lateral ventricle infusion of 0.15 mol/L, 0.6 mol/L, and 1.0 mol/L NaCl (5 µL/10 minutes) produced concentration-dependent increases in lumbar SNA, adrenal SNA, and arterial blood pressure, despite no change in splanchnic SNA and a decrease in renal SNA. Ganglionic blockade with chlorisondamine or acute lesion of the lamina terminalis blocked or significantly attenuated these responses, respectively. RVLM microinjection of the gamma-aminobutyric acid (GABAA) agonist muscimol abolished the sympathoexcitatory response to intracerebroventricular infusion of 1 mol/L NaCl. Furthermore, blockade of ionotropic glutamate, but not angiotensin II type 1, receptors significantly attenuated the increase in lumbar SNA, adrenal SNA, and arterial blood pressure. Finally, single-unit recordings of spinally projecting RVLM neurons revealed 3 distinct populations based on discharge responses to intracerebroventricular infusion of 1 mol/L NaCl: type I excited (46%; 11/24), type II inhibited (37%; 9/24), and type III no change (17%; 4/24). All neurons with slow conduction velocities were type I cells. Collectively, these findings suggest that acute increases in cerebrospinal fluid NaCl concentrations selectively activate a discrete population of RVLM neurons through glutamate receptor activation to increase SNA and arterial blood pressure.
| S-EPMC5065924 | biostudies-literature
Project description:The paraventricular hypothalamic nucleus (PVH) contains many neurons that innervate the brainstem, but information regarding their target sites remains incomplete. Here we labeled neurons in the rat PVH with an anterograde axonal tracer, Phaseolus vulgaris leucoagglutinin (PHAL), and studied their descending projections in reference to specific neuronal subpopulations throughout the brainstem. While many of their target sites were identified previously, numerous new observations were made. Major findings include: 1) In the midbrain, the PVH projects lightly to the ventral tegmental area, Edinger-Westphal nucleus, ventrolateral periaqueductal gray matter, reticular formation, pedunculopontine tegmental nucleus, and dorsal raphe nucleus. 2) In the dorsal pons, the PVH projects heavily to the pre-locus coeruleus, yet very little to the catecholamine neurons in the locus coeruleus, and selectively targets the viscerosensory subregions of the parabrachial nucleus. 3) In the ventral medulla, the superior salivatory nucleus, retrotrapezoid nucleus, compact and external formations of the nucleus ambiguous, A1 and caudal C1 catecholamine neurons, and caudal pressor area receive dense axonal projections, generally exceeding the PVH projection to the rostral C1 region. 4) The medial nucleus of the solitary tract (including A2 noradrenergic and aldosterone-sensitive neurons) receives the most extensive projections of the PVH, substantially more than the dorsal vagal nucleus or area postrema. Our findings suggest that the PVH may modulate a range of homeostatic functions, including cerebral and ocular blood flow, corneal and nasal hydration, ingestive behavior, sodium intake, and glucose metabolism, as well as cardiovascular, gastrointestinal, and respiratory activities.
| S-EPMC2868510 | biostudies-literature
Project description: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.
| S-EPMC5582943 | biostudies-literature
Project description:AimsAngiotensin(1-7) (Ang1-7) acting at the level of the rostral ventrolateral medulla (RVLM) affects arterial pressure. The cellular substrate of Ang1-7 remains unknown. We sought to determine which cell types in RVLM could mediate its actions and whether these are altered in the spontaneously hypertensive rat (SHR).Methods and resultsAstrocytes, catecholaminergic (CA-ergic) and non-CA-ergic neurones were targeted with adenoviral vectors in organotypic slice cultures from Wistar rats and SHR. Astrocytic Ca(2+) signalling was monitored using a genetically engineered Ca(2+) sensor Case12. CA-ergic neurones expressed enhanced green fluorescent protein (EGFP) under control of the PRS x 8 promoter, whereas non-CA-neurones expressed EGFP under control of the synapsin-1 promoter. Neurones were recorded in whole cell mode while [Ca(2+)](i) was monitored using Rhod-2. RVLM astrocytes responded to Ang1-7 (200-1000 nM) with concentration-dependent [Ca(2+)](i) elevation. In SHR, the response to 1000 nM was significantly attenuated. The competitive Ang1-7 receptor antagonist A779, but not the AT(1) receptor blocker (losartan), suppressed Ang1-7-induced [Ca(2+)](i) elevations, which were also antagonized by blocking intracellular Ca(2+) stores. Ang1-7 evoked no consistent changes in [Ca(2+)](i) or membrane excitability in CA-ergic or non-CA-ergic neurones in either rat strain.ConclusionAstroglia are a plausible cellular target of Ang1-7 in RVLM. Our data suggest that astrocytic responsiveness to Ang1-7 is reduced in SHR. We hypothesise that Ang1-7 modulates astrocytic signalling which in vivo may affect local metabolism and microcirculation, resulting in changes in activity of RVLM pre-sympathetic neurones and hence blood pressure.
| S-EPMC2904658 | biostudies-literature