Rostral Ventrolateral Medullary Neurons Research Articles

Mechanisms Contributing to the Generation of Mayer Waves.

Mayer waves may synchronize overlapping propriobulbar interneuronal microcircuits constituting the respiratory rhythm and pattern generator, sympathetic oscillators, and cardiac vagal preganglionic neurons. Initially described by Sir Sigmund Mayer in the year 1876 in the arterial pressure waveform of anesthetized rabbits, authors have since extensively observed these oscillations in recordings of hemodynamic variables, including arterial pressure waveform, peripheral resistance, and blood flow. Authors would later reveal the presence of these oscillations in sympathetic neural efferent discharge and brainstem and spinal zones corresponding with sympathetic oscillators. Mayer wave central tendency proves highly consistent within, though the specific frequency band varies extensively across, species. Striking resemblance of the Mayer wave central tendency to the species-specific baroreflex resonant frequency has led the majority of investigators to comfortably presume, and generate computational models premised upon, a baroreflex origin of these oscillations. Empirical interrogation of this conjecture has generated variable results and derivative interpretations. Sinoaortic denervation and effector sympathectomy variably reduces or abolishes spectral power contained within the Mayer wave frequency band. Refractorines of Mayer wave generation to barodeafferentation lends credence to the hypothesis these waves are chiefly generated by brainstem propriobulbar and spinal cord propriospinal interneuronal microcircuit oscillators and likely modulated by the baroreflex. The presence of these waves in unitary discharge of medullary lateral tegmental field and rostral ventrolateral medullary neurons (contemporaneously exhibiting fast sympathetic rhythms [2–6 and 10 Hz bands]) in spectral variability in vagotomized pentobarbital-anesthetized and unanesthetized midcollicular (i.e., intercollicular) decerebrate cats supports genesis of Mayer waves by supraspinal sympathetic microcircuit oscillators. Persistence of these waves following high cervical transection in vagotomized unanesthetized midcollicular decerebrate cats would seem to suggest spinal sympathetic microcircuit oscillators generate these waves. The widespread presence of Mayer waves in brainstem sympathetic-related and non-sympathetic-related cells would seem to betray a general tendency of neurons to oscillate at this frequency. We have thus presented an extensive and, hopefully cohesive, discourse evaluating, and evolving the interpretive consideration of, evidence seeking to illumine our understanding of origins of, and insight into mechanisms contributing to, the genesis of Mayer waves. We have predicated our arguments and conjectures in the substance and matter of empirical data, though we have occasionally waxed philosophical beyond these traditional confines in suggesting interpretations exceeding these limits. We believe our synthesis and interpretation of the relevant literature will fruitfully inspire future studies from the perspective of a more intimate appreciation and conceptualization of network mechanisms generating oscillatory variability in neuronal and neural outputs. Our evaluation of Mayer waves informs a novel set of disciplines we term quantum neurophysics extendable to describing subatomic reality. Beyond informing our appreciation of mechanisms generating sympathetic oscillations, Mayer waves may constitute an intrinsic property of neurons extant throughout the cerebrum, brainstem, and spinal cord or reflect an emergent property of interactions between arteriogenic and neuronal oscillations.

Enhanced catabolism to acetaldehyde in rostral ventrolateral medullary neurons accounts for the pressor effect of ethanol in spontaneously hypertensive rats.

We have previously shown that ethanol microinjection into the rostral ventrolateral medulla (RVLM) elicits sympathoexcitation and hypertension in conscious spontaneously hypertensive rats (SHRs) but not in Wistar-Kyoto (WKY) rats. In this study, evidence was sought to implicate the oxidative breakdown of ethanol in this strain-dependent hypertensive action of ethanol. Biochemical experiments revealed significantly higher catalase activity and similar aldehyde dehydrogenase (ALDH) activity in the RVLM of SHRs compared with WKY rats. We also investigated the influence of pharmacological inhibition of catalase (3-aminotriazole) or ALDH (cyanamide) on the cardiovascular effects of intra-RVLM ethanol or its metabolic product acetaldehyde in conscious rats. Compared with vehicle, ethanol (10 μg/rat) elicited a significant increase in blood pressure in SHRs that lasted for the 60-min observation period but had no effect on blood pressure in WKY rats. The first oxidation product, acetaldehyde, played a critical role in ethanol-evoked hypertension because 1) catalase inhibition (3-aminotriazole treatment) virtually abolished the ethanol-evoked pressor response in SHRs, 2) intra-RVLM acetaldehyde (2 μg/rat) reproduced the strain-dependent hypertensive effect of intra-RVLM ethanol, and 3) ALDH inhibition (cyanamide treatment) uncovered a pressor response to intra-RVLM acetaldehyde in WKY rats similar to the response observed in SHRs. These findings support the hypothesis that local production of acetaldehyde, due to enhanced catalase activity, in the RVLM mediates the ethanol-evoked pressor response in SHRs.

Correlation of discharges of rostral ventrolateral medullary neurons with the low-frequency sympathetic rhythm in rats

The rostral ventrolateral medulla (RVLM) is critically important in the generation of sympathetic activity. The purpose of this study was to investigate whether discharges of RVLM neurons contribute to low-frequency (LF) sympathetic rhythms. Blood pressure (BP), renal sympathetic nerve activity (SNA), and neuronal activity in the RVLM were simultaneously recorded in seven anesthetized, paralyzed, and artificially ventilated rats. Fifty-one RVLM neurons were recorded and classified into three differential functional groups according to their activities related to baroreceptor input. Those in the category of spike firing inhibited by a BP increase (BP I) and which excited sympathetic discharges was the most abundant (24%). Coherence analysis was used to examine the relationship of the firing frequency of RVLM neurons with the LF (0.2–0.8 Hz) rhythm of SNA. Forty-one percent of RVLM neurons showed a significant correlation to LF rhythms, and BP I neurons with sympathoexcitatory properties were the major contributors. In another 4 baroreceptor-denervated rats, 36 RVLM neurons were recorded. In these rats, RVLM neuronal activities no longer changed with BP fluctuations. Nevertheless, more than 40% of RVLM neurons were sympathoexcitatory, and 36% of RVLM neurons were still correlated with the LF SNA rhythm. Our results suggest that there are RVLM neurons involved in generating the LF rhythm in SNA and that the baroreflex can induce the participation of more neurons in LF rhythm generation.

Systemic Cholecystokinin Differentially Affects Baro-activated GABAergic Neurons in Rat Caudal Ventrolateral Medulla

Cholecystokinin (CCK) is released after a meal to promote digestion and satiety. Circulating CCK inhibits splanchnic sympathetic nerve activity (sSNA), which may contribute to postprandial increases in mesenteric blood flow. The CCK-induced sympathoinhibition occurs by activation of vagal afferent nerves and inhibition of a subset of presympathetic rostral ventrolateral medullary (RVLM) neurons. The present study sought to determine whether the caudal ventrolateral medulla (CVLM) may also play a role in the CCK-induced changes in sSNA. Rats were anesthetized with chloralose, artificially ventilated, paralyzed, and prepared for recording arterial pressure (AP), heart rate (HR), sSNA, and activity of individual CVLM neurons. Injection of CCK-8 (8-10 microg/kg, iv) decreased sSNA, AP, and HR. Most baro-activated CVLM neurons were excited by CCK (n = 25, 3.4-fold increase), whereas other baro-activated CVLM neurons were not affected (n = 7) or were inhibited (n = 3). A subset of baro-activated CVLM neurons that were activated (n = 8) or unaffected (n = 2) was confirmed to be GABAergic by the presence of GAD67 mRNA. Bilateral inhibition of the CVLM by microinjections of muscimol reversed the decreases in sSNA and AP to a prominent sympathoactivation and increase in AP (n = 18). These data suggest that systemic injection of CCK leads to the activation of most baro-activated GABAergic CVLM neurons and that the CVLM is essential for the production of CCK-induced inhibition of sSNA. The differential responses of baro-activated GABAergic CVLM neurons to CCK may contribute to the diverse responses of presympathetic RVLM neurons and sympathetic outflows observed with systemic CCK.

The role of the medullary lateral tegmental field in the generation and baroreceptor reflex control of sympathetic nerve discharge in the cat.

Data from experiments with single neuron recordings as well as central microinjections of N-methyl-D-aspartate (NMDA) and non-NMDA excitatory amino receptor antagonists that have led to a model of central sympathetic pathways that includes synaptic relays in the medullary lateral tegmental field (LTF) of the cat are summarized. Evidence is presented that (1) the LTF contains a population of tonically active sympathoexcitatory neurons that drive rostral ventrolateral medullary neurons, (2) blockade of non-NMDA receptors in the LTF significantly reduces basal levels of sympathetic nerve discharge (SND) and mean arterial pressure in baroreceptor-denervated cats, and (3) blockade of NMDA-mediated neurotransmission in the LTF prevents baroreceptor reflex control of SND. Thus, LTF neurons play an important role in the generation and baroreceptor reflex control of SND in the cat.

Identification of an efferent projection from the paraventricular nucleus of the hypothalamus terminating close to spinally projecting rostral ventrolateral medullary neurons

The paraventricular nucleus of the hypothalamus is increasingly being viewed as an important site for cardiovascular integration because of its connections to regions in the brain and spinal cord which are known to be important in cardiovascular control. Like the vasomotor neurons of the rostral ventrolateral medulla, descending axons from paraventricular neurons can be identified that form synapses on sympathetic preganglionic neurons in the thoracic spinal cord. The purpose of this study was to determine whether paraventricular axons project to the rostral ventrolateral medulla and whether they are closely apposed to reticulospinal neurons in this region. Descending paraventricular axons were labelled with biotin dextran amine, while rostral ventrolateral medullary neurons were retrogradely labelled from the spinal cord with wheat germ agglutinin conjugated to horseradish peroxidase. This revealed, within the rostral ventrolateral medulla, paraventricular axon and terminal varicosities closely apposed to and apparently contiguous with retrogradely labelled spinally projecting neurons. Thus our study at the light microscopical level has shown the potential for the paraventricular nucleus to directly influence rostral ventrolateral reticulospinal neurons. We suggest these connections, if confirmed by electron microscopy, could be one means by which activation of paraventricular neurons elicits alterations in blood pressure.

Subgroups of Rostral Ventrolateral Medullary and Caudal Medullary Raphe Neurons Based on Patterns of Relationship to Sympathetic Nerve Discharge and Axonal Projections

This study was designed to answer three questions concerning rostral ventrolateral medullary (RVLM) and caudal medullary raphe (CMR) neurons with activity correlate to sympathetic nerve discharge (SND). 1) What are the proportions of RVLM and CMR neurons that have activity correlated to both the cardiac-related and 10-Hz rhythms in SND, to only the 10-Hz rhythm, and to only the cardiac-related rhythm? 2) Which of these cell types project to the spinal cord? 3) Do the outputs of the cardiac-related and 10-Hz rhythm generators converge at the level of bulbospinal neurons or their antecedent interneurons? To address these issues we recorded from 44 RVLM and 48 CMR neurons with sympathetic nerve-related activity in urethan-anesthetized cats with intact carotid sinus nerves, but sectioned aortic depressor and vagus nerves. Spike-triggered averaging, arterial pulse-triggered analysis, and coherence analysis revealed that the naturally occurring discharges of 24 of these RVLM neurons and 41 of these CMR neurons were correlated to both the 10-Hz and cardiac-related rhythms in inferior cardiac postganglionic SND. The discharges of the other neurons were correlated to only the 10-Hz rhythm (15 RVLM and 6 CMR neurons) or to only the cardiac-related rhythm (5 RVLM neurons and 1 CMR neuron) in SND. The time-controlled collision test verified that 16 of 18 RVLM and 31 of 34 CMR neurons with activity correlated to both rhythms were antidromically activated by stimulation of the white matter of the first thoracic (T1) segment of the spinal cord. In contrast, only 1 of 10 RVLM neurons and 0 of 4 CMR neurons with activity correlated to only the 10-Hz rhythm could be antidromically activated by stimulation at T1. Also 0 of 3 RVLM neurons with activity correlated to only the cardiac-related rhythm in SND were antidromically activated by spinal stimulation. These data show for the first time that bulbospinal sympathetic pathways emanating from the RVLM and CMR are comprised almost exclusively of neurons whose discharges are correlated to both the cardiac-related and 10-Hz rhythms in SND. Moreover, the data support the hypothesis that the outputs of the cardiac-related and 10-Hz rhythm generators converge on RVLM and CMR bulbospinal neurons rather than on their antecedent interneurons. Finally, the data demonstrate that a substantial proportion of RVLM neurons and a small group of CMR neurons with activity correlated to SND do not project to the thoracic spinal cord. Their discharges were correlated to only one of the rhythms in SND. Their axonal trajectories and functions are unknown.

Neurons in the barosensory area of the caudal ventrolateral medulla project monosynaptically on to sympathoexcitatory bulbospinal neurons in the rostral ventrolateral medulla.

Neurons in the caudal ventrolateral medulla may function as interneurons in the baroreceptor reflex are by inhibiting sympathoexcitatory bulbospinal neurons in rostral ventrolateral medulla. While some caudal ventrolateral medullary neurons are excited orthodromically by baroreceptors and antidromically from the rostral ventrolateral medulla, there is no anatomical evidence to prove that these barosensory neurons of the caudal ventrolateral medulla monosynaptically innervate the bulbospinal neurons in the rostral ventrolateral medulla. To establish the presence of such a direct projection, barosensory neurons were identified in the rostral caudal ventrolateral medulla of anesthetized rats by criteria that they spontaneously discharged with a cardiac rhythm and were excited by baroreceptor stimulation. The anterograde tracer biocytin was iontophoresed onto these neurons and, in the same animal, the retrograde tracer wheatgerm-agglutinated apo-horseradish peroxidase conjugated to gold particles was injected by micropressure into the ipsilateral spinal (thoracic level 3) intermediolateral cell column to label bulbospinal neurons. After 18-24 h, rats were killed and sections through the rostral ventrolateral medulla were processed for both markers. By light microscopy, numerous biocytin-labeled varicose processes overlapped rostral ventrolateral medullary neurons containing wheatgerm-agglutinated apo-horseradish peroxidase conjugated to gold particles. By electron microscopy, biocytin was found in axons and terminals. The terminals (n = 76) were large (0.6-1.2 microns in diameter), contained numerous small, clear vesicles and formed primarily symmetric synapses on perikarya and large (1.5-4.5 microns) dendrites within the rostral ventrolateral medulla. Some of these target neurons contained wheatgerm-agglutinated apo-horseradish peroxidase conjugated to gold particles associated with lysosomes and multivesicular bodies in the cytoplasm. The results indicate that: (i) neurons in the barosensory sympathoinhibitory region of the caudal ventrolateral medulla directly synapse on bulbospinal neurons in the rostral ventrolateral medulla; and (ii) the synaptic profile (symmetric synapse) and location (perikarya and large dendrites) is consistent with the conclusion that baroreceptor neurons of the caudal ventrolateral medulla potently and monosynaptically inhibit sympathoexcitatory neurons of the rostral ventrolateral medulla. The findings support the hypothesis that the barosensory region of the rostral caudal ventrolateral medulla is an intermediate relay in the baroreceptor reflex are.

Differential drives from rostral ventrolateral medullary neurons to three identified sympathetic outflows

Simultaneous recordings were made in chloralose-anesthetized cats from muscle vasoconstrictor (MVC), visceral vasoconstrictor (VVC), and renal (RSN) sympathetic fibers. Their barosensitivity was demonstrated, after which all baroreceptor nerves were cut. Multiple microinjections of sodium glutamate (5 nl, 0.1 M) were made in a grid pattern covering the rostral ventrolateral medulla (RVLM) pressor area on seven sides of four animals. Injections increased blood pressure by up to 87 +/- 22 mmHg and MVC, VVC, and RSN activities by up to 169 +/- 55, 62 +/- 23, and 67 +/- 36%, respectively. The relative responses between nerves (taken in pairs) showed significant inhomogeneity across injections into 5/7, 6/7, and 1/7 RVLMs for MVC vs. VVC, MVC vs. RSN, and VVC vs. RSN, respectively. Calculation showed that overall, less than half the response spikes due to RVLM glutamate injections could be accounted for by a hypothetical population of neurons that excited MVC, VVC, and RSN outflows in fixed proportion. Sites that exclusively drove MVC, VVC, or RSN outflows were found in 7/7, 3/7, and 5/7 RVLMs, respectively. Sites that selectively drove either nerve of a given pair were ubiquitous. The RVLM territories from which the three outflows could be activated overlapped but showed clear differences. Their shapes and sizes differed between animals and even between sides. They covered the subretrofacial (SRF) nucleus plus a variable rostromedial extension. The data support the view that the RVLM neurons driving these three sympathetic outflows are largely, perhaps entirely, separate populations.

Stimulation of the rostral ventrolateral medullary neurons increases cortical cerebral blood flow via activation of the intracerebral neural pathway

In urethane-anesthetized, artificially ventilated rats, electrical or chemical (by l-glutamate) focal stimulations of the rostral ventrolateral medulla (RVLM) produced an increase in cortical cerebral blood flow (CBF). The RVLM-induced cortical vasodilative response was present in animals with spinal cords sectioned at levels of Th 3–4 and with bilateral extracerebral cervical sympathetic trunks (CSTs) severed. The RVLM-induced cortical vasodilative response was totally eliminated by an α 2 adrenergic blocker, but not by blockers for muscarinic, nicotinic, α 1 and β receptors. It was concluded that there is an intracerebral vasodilative neural pathway including an α 2 adrenergic receptor originating in the RVLM for regulation of cortical blood vessels.

Rostral ventrolateral medullary neurons with intrinsic pacemaker properties are not catecholaminergic

Neurons of the rat rostral ventrolateral medulla with intrinsic pacemaker properties and immediately adjacent silent neurons were recorded in tissue slices, labeled intracellularly with the fluorescent dye Lucifer yellow, and the tissue was subsequently processed for the immunocytochemical detection of the catecholamine-synthesizing enzyme tyrosine-hydroxylase. Forty-five percent (9/20) of the silent neurons were tyrosine hydroxylase-immunoreactive, but none of the pacemaker cells were (0/15). We conclude that the ventrolateral reticular neurons with intrinsic pacemaker properties are not the C 1 adrenergic cells.

Patterns of sympathetic neuron activity associated with Mayer waves.

Patterns of sympathetic neuron activity associated with Mayer waves.

Sympathetic unit activity associated with Mayer waves in the spinal dog.

Sympathetic unit activity associated with Mayer waves in the spinal dog.