Ventrolateral Medullary Research Articles

Lesion of NPY Receptor-expressing Neurons in Perifornical Lateral Hypothalamus Attenuates Glucoprivic Feeding.

Glucoprivic feeding is one of several counterregulatory responses (CRRs) that facilitates restoration of euglycemia following acute glucose deficit (glucoprivation). Our previous work established that glucoprivic feeding requires ventrolateral medullary (VLM) catecholamine (CA) neurons that coexpress neuropeptide Y (NPY). However, the connections by which VLM CA/NPY neurons trigger increased feeding are uncertain. We have previously shown that glucoprivation, induced by an anti-glycolygic agent 2-deoxy-D-glucose (2DG), activates perifornical lateral hypothalamus (PeFLH) neurons and that expression of NPY in the VLM CA/NPY neurons is required for glucoprivic feeding. We therefore hypothesized that glucoprivic feeding and possibly other CRRs require NPY-sensitive PeFLH neurons. To test this, we used the ribosomal toxin conjugate NPY-saporin (NPY-SAP) to selectively lesion NPY receptor-expressing neurons in the PeFLH of male rats. We found that NPY-SAP destroyed a significant number of PeFLH neurons, including those expressing orexin, but not those expressing melanin-concentrating hormone. The PeFLH NPY-SAP lesions attenuated 2DG-induced feeding but did not affect 2DG-induced increase in locomotor activity, sympathoadrenal hyperglycemia, or corticosterone release. The 2DG-induced feeding response was also significantly attenuated in NPY-SAP-treated female rats. Interestingly, PeFLH NPY-SAP lesioned male rats had reduced body weights and decreased dark cycle feeding, but this effect was not seen in female rats. We conclude that a NPY projection to the PeFLH is necessary for glucoprivic feeding, but not locomotor activity, hyperglycemia, or corticosterone release, in both male and female rats.

Rostral Ventrolateral Medullary Compression: A Rare but a Cardinal Cause of Refractory Hypertension (RfHTN)

Rostral Ventrolateral Medullary Compression: A Rare but a Cardinal Cause of Refractory Hypertension (RfHTN)

1132 Bradypnea and Central Sleep Apnea Due to Ventrolateral Medullary Infarction

1132 Bradypnea and Central Sleep Apnea Due to Ventrolateral Medullary Infarction

Revisiting the link between hypertension and hemifacial spasm.

The relationship between hypertension and hemifacial spasm (HFS) has been debated. Microvascular decompression surgery is effective in some HFS patients with uncontrolled hypertension. To address current gaps in knowledge, we conducted a meta-analysis of case-control studies that have examined the prevalence of hypertension in HFS patients compared to non-HFS controls. We also evaluated the implications and limitations of the pooled studies. We identified 62 studies from PubMed, The Cochrane Library, Web of Science and Scholar.google.com and six studies that fit our inclusion criteria were included. A random-effects model was used to derive the pooled estimate of the Odds Ratio. The data was plotted on a Forest plot. A pooled analysis involving 51585 subjects, 549 cases, 720 neurological controls and 50316 controls from the general population, showed that HFS patients had a higher chance of developing hypertension (OR = 1.72, 95% CI = (1.12, 2.31), p-value <0.001). The prevalence of hypertension was higher in HFS patients as compared to non-HFS patients. This meta-analysis highlights a positive correlation between hypertension and HFS. Blood pressure should be closely monitored during the follow-up of HFS patients. Preliminary links between ventrolateral medullary (VLM) compression and HFS should be further evaluated in future studies.

NPY is Co‐localized with TH in Ventrolateral Medullary Neurons Projecting to the Hypothalamus in Mice

The catecholamine (CA) neurons of the ventrolateral medulla (VLM) are activated by many visceral stressors, including hypovolemia, hypoxia, hypoglycemia and infection and their activation results in equally diverse physiological output, including elevated BP, ventilation, arousal and neuroendocrine activation. In the rat, we previously described two subsets of VLM‐CA neurons: spinal‐ and hypothalamic‐projecting. In the current study we have identified the same subsets in mice. We distinguished between two VLM‐CA subtypes by rostral‐caudal location and neuropeptide Y (NPY) expression. In mice, Fluorogold (FG) was injected into either the spinal cord or paraventricular nucleus of the hypothalamus to identify spinal‐projecting and hypothalamic‐projecting VLM‐CA neurons, respectively. After allowing 5‐7 days for retrograde transport, the mice were perfused and brains processed for combined immunohistochemistry and in situ hybridization (ISH) to visualize VLM‐CA neuronal somata (TH‐ir) containing FG and NPY (ISH). We found that more than half (66.1 ± 2.5 %, n = 8) of the VLM‐CA neurons are positive for NPY mRNA. Spinal‐projecting VLM‐CA neurons generally resided more rostral, just behind and medial to the facial nucleus, and did not express NPY mRNA (0.5 ± 0.3 %, n = 4).Conversely, hypothalamic‐projecting VLM‐CA neurons were located slightly more caudal and most expressed NPY mRNA (63.8 ± 19.6 %, n = 3). In addition, over 90 % (n = 8) of NPY‐positive neurons co‐expressed TH, indicating that, within the mouse VLM, NPY is predominantly expressed by VLM‐CA neurons. NPY expression is a selective marker for hypothalamic‐projecting VLM‐CA neurons in mice as well as rats.

Role of Rostral Ventrolateral Medullary ERK/JNK/p38 MAPK Signaling in the Pressor Effects of Ethanol and Its Oxidative Product Acetaldehyde

We tested the hypothesis that alterations of the phosphorylation/dephosphorylation profile of mitogen-activated protein kinases (MAPKs) in the rostral ventrolateral medulla (RVLM) underlie the pressor response elicited by ethanol (EtOH) microinjection into the RVLM of spontaneously hypertensive rats (SHRs). The studies were extended to determine whether acetaldehyde (ACA), the primary oxidative product of EtOH, replicates the molecular effects of EtOH within the RVLM and the consequent pressor response. Effects of EtOH or ACA on blood pressure (BP) were evaluated in the absence or presence of selective JNK (SP600125), ERK (PD98059), p38 (SB203580), or ser/thr phosphatases (okadaic acid [OKA]) inhibitor. Intra-RVLM EtOH (10μg/rat) or ACA (2μg/rat) caused a similar ERK2-dependent pressor response because EtOH or ACA-evoked increases in BP and in RVLM p-ERK2 level were abolished after pharmacologic inhibition of ERK phosphorylation. SP600125 abrogated the pressor action of EtOH, but not ACA, thus implicating JNK in EtOH action on BP. Despite EtOH enhancement of p38 phosphorylation, pharmacological studies argued against a causal role for this kinase in EtOH-evoked pressor response. RVLM phosphatase catalytic activity was not influenced by EtOH or ACA. Interestingly, pharmacologic phosphatase inhibition (OKA), which increased RVLM p-ERK2 and BP, abrogated the pressor effect of subsequently administered EtOH or ACA. Enhancement of RVLM ERK2 phosphorylation constitutes a major molecular mechanism for the pressor response elicited by intra-RVLM EtOH or its metabolite, ACA, in conscious SHRs. Further, RVLM kinases dephosphorylation does not contribute to intra-RVLM EtOH- or ACA-evoked pressor response.

Evidence That Adrenergic Ventrolateral Medullary Cells Are Activated whereas Precerebellar Lateral Reticular Nucleus Neurons Are Suppressed during REM Sleep

Rapid eye movement sleep (REMS) is generated in the brainstem by a distributed network of neurochemically distinct neurons. In the pons, the main subtypes are cholinergic and glutamatergic REMS-on cells and aminergic REMS-off cells. Pontine REMS-on cells send axons to the ventrolateral medulla (VLM), but little is known about REMS-related activity of VLM cells. In urethane-anesthetized rats, dorsomedial pontine injections of carbachol trigger REMS-like episodes that include cortical and hippocampal activation and suppression of motoneuronal activity; the episodes last 4–8 min and can be elicited repeatedly. We used this model to determine whether VLM catecholaminergic cells are silenced during REMS, as is typical of most aminergic neurons studied to date, and to investigate other REMS-related cells in this region. In 18 anesthetized, paralyzed and artificially ventilated rats, we obtained extracellular recordings from VLM cells when REMS-like episodes were elicited by pontine carbachol injections (10 mM, 10 nl). One major group were the cells that were activated during the episodes (n = 10). Their baseline firing rate of 3.7±2.1 (SD) Hz increased to 9.7±2.1 Hz. Most were found in the adrenergic C1 region and at sites located less than 50 µm from dopamine β-hydroxylase-positive (DBH+) neurons. Another major group were the silenced or suppressed cells (n = 35). Most were localized in the lateral reticular nucleus (LRN) and distantly from any DBH+ cells. Their baseline firing rates were 6.8±4.4 Hz and 15.8±7.1 Hz, respectively, with the activity of the latter reduced to 7.4±3.8 Hz. We conclude that, in contrast to the pontine noradrenergic cells that are silenced during REMS, medullary adrenergic C1 neurons, many of which drive the sympathetic output, are activated. Our data also show that afferent input transmitted to the cerebellum through the LRN is attenuated during REMS. This may distort the spatial representation of body position during REMS.

Central CO2chemoreception in cardiorespiratory control

Central CO₂chemoreception in cardiorespiratory control

Inhibition of the commissural nucleus of the solitary tract inhibits peripheral but not central chemoreflex in rats

A large variety of sensory afferents converges to the nucleus of the solitary tract (NTS) and influences the activity of ventrolateral medullary (VLM) neurons involved in cardiovascular and respiratory regulations. Here, we investigated the effects of inhibition of the commissural NTS (commNTS) on cardiovascular and respiratory responses to chemoreflex activation in conscious and anesthetized male Holtzman rats (280‐300g, n = 7/group). In conscious rats, electrolytic lesions of the commNTS eliminated the increase in mean arterial pressure (MAP) (Δ= +8±4, vs. sham: +45±18 mmHg) and reduced the increase in ventilation (404±43, vs. sham: 773±28 ml/min/kg) produced by activation of peripheral chemoreflex with KCN (40 μg/rat) intravenously (iv). However, electrolytic lesion of the commNTS did not change the increase in ventilation produced by activation of central chemoreceptors with increased levels of CO2 (7%) (1189±32, vs. sham: 1055±53 ml/min/kg). In urethane anesthetized animals, the injection of the GABA‐A agonist muscimol (2 mM ‐ 60 nL) into the commNTS eliminated the increase in MAP (Δ= +6±3, vs. saline: +23±18 mmHg), on phrenic nerve discharge (PND) and on splanchnic sympathetic nerve discharge (sSND). Muscimol into the commNTS did not change the activation of central chemoreceptors with CO2 (7%) on PND and sSND. In conclusion, the integrity of commNTS is important for the cardiorespiratory responses elicited by peripheral but not central chemoreflex activation.

Recurrent Connections between the Pontine Respiratory Group and Ventrolateral Medullary Respiratory Column through Parallel Functional Pathways

We have previously identified correlational neuronal assemblies within the medullary raphe nuclei and dorsolateral pons (PRG) as well as evidence for their influences on a ‘core’ network within the ventrolateral medullary respiratory column (VRC) (Nuding et al. 2002 & 2004). To identify extended correlational linkages, multi-electrode arrays were placed concurrently in these three areas in 10 decerebrated, vagotomized, ventilated cats. Up to 118 neurons were recorded simultaneously and evaluated for respiratory modulation and other unit characteristics, yielding a database with 685 single neurons [VRC: 272; PRG: 123; raphe: 290] and cross-correlograms from 20,697 pairs of neurons. The results provide support for PRG-VRC neural interactions proposed in a recent pontine-medullary respiratory network model (Lindsey et al. 2005). Moreover, multiple neuron correlations are consistent with recurrent pathways between the VRC and the PRG that include intervening raphe cells. Evidence has been found for 26 PRG→raphe→VRC and 34 VRC→raphe→PRG ‘serial’ connections. More than half of these ‘A-to-B-to-C trios’ involve a non-respiratory modulated cell (NRM), and 11 include an additional C-to-A inferred recurrent loop connection. These parallel functional pathways and NRM cell involvement must be considered in future models of the respiratory brainstem. Support: NIH grants NS46062 (under the NSF-NIH CRCNP) & NS19814.

Breathing of awake goats during prolonged dysfunction of caudal M ventrolateral medullary neurons.

Cooling the caudal M ventrolateral medullary (VLM) surface for 30 s results in a sustained apnea in anesthetized goats but only a 30% decrease in breathing in awake goats. The purpose of the present study was to determine, in the awake state, the effect of prolonged (minutes, hours) caudal M neuronal dysfunction on eupneic breathing and CO2 sensitivity. Dysfunction was created by ejecting excitatory amino acid receptor antagonists or a neurotoxin on the VLM surface through guide tubes chronically implanted bilaterally on a 10- to 12-mm2 portion of the caudal M VLM surface of 12 goats. Unilateral and bilateral ejections (1 microliter) of selective antagonists for N-methyl-D-aspartic acid or non-N-methyl-D-aspartic acid receptors had no significant effect on eupneic breathing or CO2 sensitivity. Unilateral ejection of a nonselective excitatory amino acid receptor antagonist generally had no effect on eupneic breathing or CO2 sensitivity. However, bilateral ejection of this antagonist resulted in a significant 2-Torr hypoventilation during eupnea and a significant reduction in CO2 sensitivity to 60 +/- 9% of control. Unilateral ejection of the neurotoxin kainic acid initially stimulated breathing; however, breathing then returned to near control with no incidence of apnea. After the kainic acid ejection, CO2 sensitivity was reduced significantly to 60 +/- 7% of control. We conclude that in the awake state a prolonged dysfunction of caudal M VLM neurons results in compensation by other mechanisms (e.g., carotid chemoreceptors, wakefulness) to maintain near-normal eupneic breathing, but compensation is more limited for maintaining CO2 sensitivity.

Sites Other Than Ventrolateral Medullary Chemoreceptive Regions Contribute to Hypercapnic Responses During Development. † 1492

During postnatal maturation, development of respiratory activity and hypercapnic responses is controlled by a network of chemosensory cells that senses changes in CO2 and H+ ion concentration. The ventrolateral medulla is considered the primary site for central chemosensitivity, however, brain stem midline neurons have also been shown to contribute to ventilatory control of upper airway and chest wall muscle activities. In this study we sought to characterize the role of specific neurons within the midline brainstem at the so-called raphe obscurus on phrenic and hypoglossal nerve responses to hypercapnia during development. Studies were performed in ten decorticate, vagotomized, paralyzed and mechanically ventilated 14 to 20 day old piglets. Blockade of raphe obscurus neuronal activity induced by microinjections of lidocaine was associated with a significant reduction of phrenic and hypoglossal nerve responses to progressive hypercapnia. At any given end-tidal CO2, peak phrenic and hypoglossal nerve activities were significantly lower following blockade than in the control period. For example, at 7.5% CO2 phrenic activity (in arbitrary units) was 33.9±1.9 vs 18.3±4.1 (p<0.005, mean ± SEM) prior to vs following lidocaine blockade respectively. Corresponding hypoglossal activity was preferentially reduced to a greater degree than phrenic activity. for example, at 7.5% CO2 hypoglossal activity was 20.8±3.6 vs 5.6±2.1 (p<0.005) prior to vs following lidocaine blockade respectively. Injection of saline (control) solution at the same site had no effect. We conclude that impaired function of raphe obscurus midline neurons reduces respiratory responses to central chemosensory stimulation. We speculate that specific neuronal sites within the midline region of the brainstem are required for full expression of ventilatory responses to hypercapnia, and raise the possibility that alteration in their function may contribute to respiratory instability during early postnatal life.

Static muscle contraction elicits a baroreflex-dependent increase in glutamate concentration in the ventrolateral medulla

In anesthetized cats, static contraction of the hindlimb reflexly increases mean arterial pressure (MAP). This cardiovascular adjustment is reduced by the arterial baroreflex. Both of these reflex responses are mediated through activation of ventrolateral medullary (VLM) regions. We tested the hypothesis that the concentration of glutamate (Glu) increases in the caudal ventrolateral medulla (cVLM) during static hindlimb contractions in anesthetized cats, and that barodenervation reduces this elevation in Glu levels. Static contractions of the triceps surae muscle of one hindlimb were evoked by electrical stimulation of the peripheral ends of cut L7 and S1 ventral roots. After the insertion of the microdialysis probes and a 3-h recovery period, a 2-min static contraction increased MAP by 47±7 mmHg. The concentration of Glu increased from 606±189 to 1042±228 nM. These results were repeatable in that Glu, as well as MAP, rose by a similar amount in two subsequent contractions. By contrast, in a subset of cats paralyzed prior to the third contraction, neither MAP nor Glu were significantly increased over baseline levels during the third stimulation period. In a third group of cats, hindlimb contraction increased MAP and Glu levels. However, the Glu release was attenuated in subsequent contractions after these cats were barodenervated. During the same periods of stimulation, the denervation accentuated the rise in MAP. These data demonstrate that static contraction of the hindlimb increases the extracellular concentration of Glu in the cVLM. Further, our study implicates this neurotransmitter in the baroreflex mediated reduction of the pressor reflex response to static muscle contraction.

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.

Effects of cooling the ventrolateral medulla on diaphragm activity during NREM sleep

Dysfunction through cooling of neurons near the ventrolateral medullary (VLM) surface results in apnea in the anesthetized state, whereas similar neuronal dysfunction in the awake state only modestly decreases breathing. The purpose of this study was to investigate effects on breathing, as measured by diaphragm electromyogram (EMG di), of VLM neuronal dysfunction during NREM sleep, a naturally occurring change in state. In six goats, thermodes for cooling were chronically implanted between the first hypoglossal rootlet and the pontomedullary junction (area M and area S). During wakefulness and NREM sleep, bilateral VLM cooling (thermode temp = 20°C) for 30 sec decreased EMG di mean activity and minute EMG di ( p < 0.05) and lengthened the time between diaphragm contractions. During NREM sleep, reductions in mean and minute EMG di during cooling tended to be greater than during waking, but not significantly. However, following carotid body denervation, VLM cooling caused prolonged apnea during NREM sleep but only a brief apnea in the awake state. The data suggest that either intact VLM neuronal mechanisms or intact carotid afferents are necessary for sustained EMG di activity during NREM sleep.

Effects of Angiotensin II on the Spontaneous Activity of Rostral Ventrolateral Medullary Cardiovascular Neurons and Blood Pressure in Spontaneously Hypertensive Rats

Effects of Angiotensin II on the Spontaneous Activity of Rostral Ventrolateral Medullary Cardiovascular Neurons and Blood Pressure in Spontaneously Hypertensive Rats

Differential effect of ventrolateral medullary cooling on respiratory muscles of goats.

The objective was to determine whether there is an inhomogeneous response of respiratory muscles during cooling-induced ventrolateral medullary (VLM) neuronal dysfunction in anesthetized and awake goats. Thermodes for cooling were chronically implanted on all or portions of rostral, intermediate, and caudal areas of the VLM of 16 adult goats. Electromyograms (EMGs) were obtained from chronically implanted wires in the diaphragm (di), transversus abdominis (TA), and triangularis sterni (TS) muscles. During some periods of cooling in 9 of 16 anesthetized airway-intubated goats, complete cessation of EMGdi coincided with a reduced yet sustained inspiratory flow. In six awake tracheotomized goats, VLM cooling decreased (P < 0.05) EMGdi duration and minute activity more than inspiratory duration and minute ventilation. Cooling thus decreased activation of the diaphragm more than activation of other respiratory muscles. On the other hand, during VLM cooling in 3 of 10 airway-intact awake goats, cessation of inspiratory flow coincided with sustained EMGdi, suggesting that cooling decreased stimulation of the upper airway muscles more than stimulation of the diaphragm. Finally, VLM cooling in a majority of goats decreased EMGTA and EMGTS more than EMGdi. We conclude that VLM neuronal dysfunction has a differential effect on respiratory muscles of adult anesthetized and awake goats.

Hypotensive Effects of 5-HT1A Receptor Agonists on the Ventrolateral Medullary Pressor Area in Dogs

Hypotensive Effects of 5-HT1A Receptor Agonists on the Ventrolateral Medullary Pressor Area in Dogs

Hypotensive Effects of 5-HT1A Receptor Agonists on the Ventrolateral Medullary Pressor Area in Dogs

An attempt to determine the central site of the sympathoinhibitory effects of 8-hydroxy-2-(di-n-propyl-amino)tetralin (8-OH-DPAT), a 5-HT1A receptor agonist, has been made in normotensive anesthetized dogs. Intravenous and central (cisterna magna, vertebral artery) administration of 8-OH-DPAT induced dose-dependent decreases in blood pressure and sympathetic (splanchnic and renal) nerve activity in intact and baroreceptor denervated dogs. In contrast, 8-OH-DPAT was ineffective when injected into the nucleus tractus solitarii or into the raphe nuclei. Administration of 8-OH-DPAT into the ventrolateral pressor area (VLPA) decreased blood pressure and renal sympathetic nerve activity. The sympathoinhibitory effects of 8-OH-DPAT injected into the vertebral artery (v.a.) were antagonized by methiothepin and (+/-)pindolol injected into the v.a. Likewise, the effects of 8-OH-DPAT administered into the VLPA were antagonized by methiothepin injected into the same site. Depletion of central catecholamines and 5-HT content did not change the sympathoinhibitory effects of 8-OH-DPAT. These results suggested that 8-OH-DPAT has a direct effect on 5-HT1A receptors located in the VLPA in dogs.

The functional states of the thalamus and the associated neuronal interplay.

The functional states of the thalamus and the associated neuronal interplay.