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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects the upper and lower motor neurons, resulting in progressive paralysis of the limb, trunk, and orofacial muscles (Kiernan et al., [...], Purpose: The goals of this study were to (a) classify speech movements of patients with amyotrophic lateral sclerosis (ALS) in presymptomatic and symptomatic phases of bulbar function decline relying solely on kinematic features of lips and jaw and (b) identify the most important measures that detect the transition between early and late bulbar changes. Method: One hundred ninety-two recordings obtained from 64 patients with ALS were considered for the analysis. Feature selection and classification algorithms were used to analyze lip and jaw movements recorded with Optotrak Certus (Northern Digital Inc.) during a sentence task. A feature set, which included 35 measures of movement range, velocity, acceleration, jerk, and area measures of lips and jaw, was used to classify sessions according to the speaking rate into presymptomatic (> 160 words per minute) and symptomatic (< 160 words per minute) groups. Results: Presymptomatic and symptomatic phases of bulbar decline were distinguished with high accuracy (87%), relying only on lip and jaw movements. The best features that allowed detecting the differences between early and later bulbar stages included cumulative path of lower lip and jaw, peak values of velocity, acceleration, and jerk of lower lip and jaw. Conclusion: The results established a relationship between facial kinematics and bulbar function decline in ALS. Considering that facial movements can be recorded by means of novel inexpensive and easy-to-use, video-based methods, this work supports the development of an automatic system for facial movement analysis to help clinicians in tracking the disease progression in ALS. more...

Previous studies showed that the ventral medulla (vM) contains GABAergic neurons expressing the immediate early gene c-fos after deprivation-induced REM sleep rebound (11,12), suggesting REM sleep-related activity. To test the [...], Rapid eye movement (REM) sleep is a distinct brain state characterized by activated electroencephalogram and complete skeletal muscle paralysis, and is associated with vivid dreams (1-3). Transection studies by Jouvet first demonstrated that the brainstem is both necessary and sufficient for REM sleep generation (2), and the neural circuits in the pons have since been studied extensively (4-8). The medulla also contains neurons that are active during REM sleep (9-13), but whether they play a causal role in REM sleep generation remains unclear. Here we show that a GABAergic (γ-aminobutyric-acid-releasing) pathway originating from the ventral medulla powerfully promotes REM sleep in mice. Optogenetic activation of ventral medulla GABAergic neurons rapidly and reliably initiated REM sleep episodes and prolonged their durations, whereas inactivating these neurons had the opposite effects. Optrode recordings from channelrhodopsin-2-tagged ventral medulla GABAergic neurons showed that they were most active during REM sleep ([REM.sub.max]), and during wakefulness they were preferentially active during eating and grooming. Furthermore, dual retrograde tracing showed that the rostral projections to the pons and midbrain and caudal projections to the spinal cord originate from separate ventral medulla neuron populations. Activating the rostral GABAergic projections was sufficient for both the induction and maintenance of REM sleep, which are probably mediated in part by inhibition of REM-suppressing GABAergic neurons in the ventrolateral periaqueductal grey. These results identify a key component of the pontomedullary network controlling REM sleep. The capability to induce REM sleep on command may offer a powerful tool for investigating its functions. more...

Initiation of natural movement depends on the function of descending pathways to the spinal cord. This critical need is strikingly obvious in patients with complete spinal cord injury who lack [...], Translating the behavioural output of the nervous system into movement involves interaction between brain and spinal cord. The brainstem provides an essential bridge between the two structures, but circuit-level organization and function of this intermediary system remain poorly understood. Here we use intersectional virus tracing and genetic strategies in mice to reveal a selective synaptic connectivity matrix between brainstem substructures and functionally distinct spinal motor neurons that regulate limb movement. The brainstem nucleus medullary reticular formation ventral part (MdV) stands out as specifically targeting subpopulations of forelimb-innervating motor neurons. Its glutamatergic premotor neurons receive synaptic input from key upper motor centres and are recruited during motor tasks. Selective neuronal ablation or silencing experiments reveal that MdV is critically important specifically for skilled motor behaviour, including accelerating rotarod and single-food-pellet reaching tasks. Our results indicate that distinct premotor brainstem nuclei access spinal subcircuits to mediate task-specific aspects of motor programs. more...

Author(s): Corey N. Miller [sup.1] [sup.2] , Irina Proekt [sup.1] [sup.2] , Jakob von Moltke [sup.2] [sup.3] [sup.4] [sup.9] , Kristen L. Wells [sup.5] , Aparna R. Rajpurkar [sup.5] , [...], The thymus is responsible for generating a diverse yet self-tolerant pool of T cells.sup.1. Although the thymic medulla consists mostly of developing and mature AIRE.sup.+ epithelial cells, recent evidence has suggested that there is far greater heterogeneity among medullary thymic epithelial cells than was previously thought.sup.2. Here we describe in detail an epithelial subset that is remarkably similar to peripheral tuft cells that are found at mucosal barriers.sup.3. Similar to the periphery, thymic tuft cells express the canonical taste transduction pathway and IL-25. However, they are unique in their spatial association with cornified aggregates, ability to present antigens and expression of a broad diversity of taste receptors. Some thymic tuft cells pass through an Aire-expressing stage and depend on a known AIRE-binding partner, HIPK2, for their development. Notably, the taste chemosensory protein TRPM5 is required for their thymic function through which they support the development and polarization of thymic invariant natural killer T cells and act to establish a medullary microenvironment that is enriched in the type 2 cytokine, IL-4. These findings indicate that there is a compartmentalized medullary environment in which differentiation of a minor and highly specialized epithelial subset has a non-redundant role in shaping thymic function.A comprehensive analysis of the thymic medulla identifies a tuft-cell-like thymic epithelial cell population that is necessary for shaping thymic function. more...

Hypertonicity increases urea transport independently of, as well as synergistically with, vasopressin in the inner medullary collect duct (IMCD). We previously showed that hypertonicity does not increase the level of cAMP in the IMCD, but it does increase the level of intracellular calcium. Since we also showed that hypertonicity increases both the phosphorylation and biotinylation of the urea transporters UT-A1 and UT-A3, this would suggest involvement of a calcium-dependent protein kinase in the regulation of urea transport in the inner medulla. In this study, we investigated whether protein kinase C (PKC), which is present in the IMCD, is a regulator of urea permeability. We tested the effect of PKC inhibitors and activators on urea permeability in the isolated, perfused rat terminal IMCD. Increasing osmolality from 290 to 690 mosmol/kg[H.sub.2]O significantly stimulated (doubled) urea permeability; it returned to control levels on inhibition of PKC with either 10 [micro]M chelerythrine or 50 [micro]M rottlerin. To determine the potential synergy between vasopressin and PKC, phorbol dibutyrate (PDBu) was used to stimulate PKC. Vasopressin stimulated urea permeability 247%. Although PDBu alone did not change basal urea permeability, in the presence of vasopressin, it significantly increased urea permeability an additional 92%. The vasopressin and PDBu-stimulated urea permeability was reduced to AVP alone levels by inhibition of PKC. We conclude that hypertonicity stimulates urea transport through a PKC-mediated phosphorylation. Whether PKC directly phosphorylates UT-A1 and/or UT-A3 or phosphorylates it as a consequence of a cascade of activations remains to be determined. tubule perfusion; calcium signaling; urine concentration; vasopressin; hypertonicity doi: 10.1152/ajprenal.00322.2010 more...

Previous studies have shown that in proximal and distal tubule nephron segments, peritubular ANG II stimulates sodium chloride transport. However, ANG II inhibits chloride transport in the medullary thick ascending limb (mTAL). Because ANG II and catecholamines are both stimulated by a decrease in extracellular fluid volume, the purpose of this study was to examine whether there was an interaction between ANG II and catecholamines to mitigate the inhibition in chloride transport by ANG II. In isolated perfused rat mTAL, [10.sup.-8] M bath ANG II inhibited wansport (from a basal transport rate of 165.6 [+ or -] 58.8 to 58.8 [+ or -] 29.4 pmol*[mm.sup.-1]*[min.sup.-1]; p < 0.0l). Bath norepinephrine stimulated chloride transport (from a basal transport rate of 298.1 [+ or -] 31.7 to 425.2 [+ or -] 45.8 pmol*[mm.sup.-1]*[min.sup.-1]; P < 0.05) and completely prevented the inhibition in chloride transport by ANG II. The stimulation of chloride transport by norepinephrine was mediated entirely by its [beta]-adrenergic effect; however, both the [beta]- and [alpha]-adrenergic agonists isoproterenol and phenylephrine prevent the ANG II-mediated inhibition in chloride transport. In the presence of [10.sup.-5] M propranolol, the effect of norepinephrine to prevent the inhibition of chloride transport by ANG II was still present. These data are consistent with an interaction of both [alpha]- and [beta]-catecholamines and ANG II on net chloride transport in the mTAL. NKCC2; norepinephrine; isoproterenol doi: 10.1152/ajpregu.00758.2009. more...

The mammalian kidney is particularly vulnerable to hypoperfusion, because the [O.sub.2] supply to the renal medulla barely exceeds its [O.sub.2] requirements. In this study, we examined the impact of the complex structural organization of the rat outer medulla (OM) on [O.sub.2] distribution. We extended the region-based mathematical model of the rat OM developed by Layton and Layton (Am J Physiol Renal Physiol 289: F1346-F1366, 2005) to incorporate the transport of RBCs, Hb, and [O.sub.2]. We considered basal cellular [O.sub.2] consumption and [O.sub.2] consumption for active transport of NaCl across medullary thick ascending limb epithelia. Our model predicts that the structural organization of the OM results in significant P[O.sub.2] gradients in the axial and radial directions. The segregation of descending vasa recta, the main supply of [O.sub.2], at the center and immediate periphery of the vascular bundles gives rise to large radial differences in P[O.sub.2] between regions, limits [O.sub.2] reabsorption from long descending vasa recta, and helps preserve [O.sub.2] delivery to the inner medulla. Under baseline conditions, significantly more [O.sub.2] is transferred radially between regions by capillary flow, i.e., advection, than by diffusion. In agreement with experimental observations, our results suggest that 79% of the [O.sub.2] supplied to the medulla is consumed in the OM and that medullary thick ascending limbs operate on the brink of hypoxia. region-based model; red blood cells; medullary thick ascending limbs; active sodium transport more...

In the companion study (Am J Physiol Renal Physiol. First published April 29, 2009; doi:10.1152/ajprenal.90496.2008), we extended the region-based mathematical model of the urine-concentrating mechanism in the rat outer medulla (OM) developed by Layton and Layton (Am J Physiol Renal Physiol 289: F1346-F1366, 2005) to examine the impact of the complex structural organization of the OM on [O.sub.2] transport and distribution. In the present study, we investigated the sensitivity of predicted P[O.sub.2] profiles to several parameters that characterize the degree of OM regionalization, boundary conditions, structural dimensions, transmural transport properties, and relative positions and distributions of tubules and vessels. Our results suggest that the fraction of [O.sub.2] supplied to descending vasa recta (DVR) that reaches the inner medulla, i.e., a measure of the axial P[O.sub.2] gradient in the OM, is insensitive to parameter variations as a result of the sequestration of long DVR in the vascular bundles. In contrast, [O.sub.2] distribution among the regions surrounding the vascular core strongly depends on the radial positions of medullary thick ascending limbs (mTALs) relative to the vascular core, the degree of regionalization, and the distribution of short DVR along the corticomedullary axis. Moreover, if it is assumed that the mTAL active [Na.sup.+] transport rate decreases when mTAL P[O.sub.2] falls below a critical level, [O.sub.2] availability to mTALs has a significant impact on the concentrating capability of the model OM. The model also predicts that when the OM undergoes hypertrophy, its concentrating capability increases significantly only when anaerobic metabolism supports a substantial fraction of the mTAL active [Na.sup.+] transport and is otherwise critically reduced by low interstitial and mTAL luminal P[O.sub.2] in a hypertrophied OM. region-based model; medullary thick ascending limbs; red blood cells; active sodium transport more...

Heme oxygenase has been linked to the oxygen-sensing function of the carotid body, pulmonary vasculature, cerebral vasculature, and airway smooth muscle. We have shown previously that the cardiorespiratory regions of the rostral ventrolateral medulla are excited by local hypoxia and that heine oxygenase-2 (HO-2) is expressed in the hypoxia-chemosensitive regions of the rostral ventrolateral medulla (RVLM), the respiratory pre-Botzinger complex, and C1 sympathoexcitatory region. To determine whether heme oxygenase is necessary for the hypoxic-excitation of dissociated RVLM neurons (P1) cultured on confluent medullary astrocytes (P5), we examined their electrophysiological responses to hypoxia (NaCN and low [Po.sub.2]) using the whole-cell perforated patch clamp technique before and after blocking heme oxygenase with tin protoporphyrin-IX (SnPP-IX). Following the electrophysiological recording, immunocytocbemistry was performed on the recorded neuron to correlate the electrophysiological response to hypoxia with the expression of HO-2. We found that the responses to NaCN and hypoxia were similar. RVLM neurons responded to NaCN and low [Po.sub.2] with either depolarization or hyperpolarization and SnPP-IX blocked the depolarization response of hypoxia-excited neurons to both NaCN and low [Po.sub.2] but had no effect on the hyperpolarization response of hypoxia-depressed neurons. Consistent with this observation, HO-2 expression was present only in the hypoxia-excited neurons. We conclude that RVLM neurons are excited by hypoxia via a heme oxygenase-dependent mechanism. chemosensitivity; pre-Botzinger complex; C1 sympathoexcitatory region more...

The effects of activation and blockade of the neurokinin 1 (NK1) receptor in the rostral ventrolateral medulla (RVLM) on arterial blood pressure (ABP), splanchnic sympathetic nerve activity (sSNA), phrenic nerve activity, the somato-sympathetic reflex, baroreflex, and chemoreflex were studied in urethane-anesthetized and artificially ventilated Sprague-Dawley rats. Bilateral microinjection of either the stable substance P analog (pGlu5, MePheS, Sar9)SP(5-11) (DiMe-SP) or the highly selective NK1 agonist [Sar9, Met ([O.sub.2])11]SP into the RVLM resulted in an increase in ABP, sSNA, and heart rate and an abolition of phrenic nerve activity. The effects of [Sar9, Met ([O.sub.2])11]SP were blocked by the selective nonpeptide NK1 receptor antagonist WIN 51708. NK1 receptor activation also dramatically attenuated the somato-sympathetic reflex elicited by tibial nerve stimulation, while leaving the baroreflex and chemoreflex unaffected. This effect was again blocked by WIN 51708. NK1 receptor antagonism in the RVLM, with WIN 51708 significantly attenuated the sympathoexcitatory response to hypoxia but had no effect on baseline respiratory function. Our findings suggest that substance P and the NK1 receptor play a significant role in the cardiorespiratory reflexes integrated within the RVLM. substance P; rostral ventrolateral medulla; baroreflex; brainstem; sympathetic nerve activity; neurokinin 1 more...

We tested whether luminal perfusion and pressurization induce an endothelial cytoplasmic [Ca.sup.2+] ([[[Ca.sup.2+]].sub.CYT]) response in descending vasa recta (DVR). DVR isolated from the rat outer medulla were cannulated and subjected to free-flow microperfusion (5 nl/min); the onset of which increased [[[Ca.sup.2+]].sub.CYT] from a baseline of 76 [+ or -] 13 to 221 [+ or -] 65 nM. A graded increase in luminal pressure from 0 to 45 mmHg in stopped-flow experiments induced a parallel increase in [[[Ca.sup.2+]].sub.CYT] from a baseline of 74 [+ or -] 24 to 194 [+ or -] 33 nM at 45 mmHg, with a tendency for [[[Ca.sup.2+]].sub.CYT] to plateau at pressures >25 mmHg. The removal of extracellular [Ca.sup.2+] and blockade by either [La.sup.3+] (10 [micro]M) or SKF-96365 (100 [micro]M) eliminated the response. Luminal pressurization to 25 mmHg increased nitric oxide (NO) generation, a response blocked by NO synthase inhibition or removal of extracellular [Ca.sup.2+]. The NO generation was not affected by the superoxide dismutase mimetic tempol. We conclude that DVR endothelia are mechanosensitive and respond to luminal pressure by elevating [[[Ca.sup.2+]].sub.CYT] and generating NO. That response might augment medullary perfusion and saliuresis. medulla; kidney; microcirculation; shear; fura 2; 4,5-diaminofluoroscein more...

Byline: Laurent Ducros (1), Katayoun Vahedi (2), Thomas Similowski (3), Marie-Germaine Bousser (2), Didier Payen (1) Keywords: Medulla oblongata Hypercapnia Cerebral infarction Abstract: Background.. Medullary infarcts can be associated with breathing disorders that usually consist in central hypoventilation. Patient.. We describe the case of a 54-year-old man, fully conscious, presenting with an uncontrollable high frequency and shallow tachypnea (95/min) at the onset of a unilateral medial medullary infarct. This disorder disappeared under inspiratory pressure support mechanical ventilation. Measurements and results.. Respiratory drive (respiratory rate, occlusion pressure, and mean inspiratory flow), efferent pathway (transcranial and cervical magnetic stimulation), and afferent pathway (response to CO.sub.2 and to lung inflation) were investigated. The respiratory drive was increased. The phrenic nerve conduction time was normal. The sensitivity of the central pattern generator to lung inflation and to CO.sub.2 was preserved. The territory of the infarct was supplied by the spinal anterior artery. Conclusions.. An extremely rapid and shallow tachypnea due to the increase in respiratory drive can be associated with unilateral medullary infarction. Author Affiliation: (1) Departement d'Anesthesie-Reanimation-SMUR, Hopital Lariboisiere, Assistance Publique-Hopitaux de Paris, 2 rue Ambroise Pare, 75010, Paris, France (2) Service de Neurologie, Hopital Lariboisiere, Assistance Publique-Hopitaux de Paris, Paris, France (3) Laboratoire de Physiopathologie Respiratoire, Service de Pneumologie, Groupe Hospitalier Pitie-Salpetriere, Assistance Publique-Hopitaux de Paris, Paris, France Article History: Received Date: 09/08/2001 Accepted Date: 20/12/2002 Article note: Electronic Publication more...

Evidence suggests that transmission of barosensitive input from arterial baroreceptors and cardiac mechanoreceptors at nucleus tractus solitarius (NTS) neurons involves non-N-methyl-D-aspartate (NMDA) glutamate receptors, but there is a possibility that the contribution of NMDA receptors might increase during periods of increased afferent input, when enhanced neuronal depolarization could increase the activation of NMDA receptors by removal of a [Mg.sup.2+] block. Thus the effects of NMDA on cardiac mechanoreceptor-modulated NTS neuronal discharges were examined at different levels of arterial pressure used to change cardiac mechanoreceptor afferent input. To determine whether the response was specific to NMDA, ([+ or -])-[alpha]-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA) was also administered at different levels of neuronal discharge. In anesthetized dogs, neuronal activity was recorded from the NTS while NMDA or AMPA was picoejected at high versus low arterial stimulating pressures. NMDA, but not AMPA, produced a significantly greater discharge of mechanoreceptor-driven NTS neurons at higher versus lower levels of stimulating pressure. These data suggest that the role played by NMDA receptors is greater during periods of enhanced neuronal depolarization, which could be produced by increases in afferent barosensitive input. medulla; nucleus tractus solitarius; AMPA; baroreceptors more...

According to prior evidence opioid and serotonin release by lower brain stem neurons may contribute to hemorrhage-induced sympathoinhibition (HISI). Here we seek direct evidence for the activation of opioidergic, GABAergic, or serotonergic neurons by severe hemorrhage in the medulla oblongata. Blood was withdrawn from awake rats (40-50% total volume) causing hypotension and profound initial bradycardia. Other rats received the vasodilator hydralazine, causing tachycardia and hypotension. Neuronal activation was gauged by the presence of Fos-immunoreactive (ir) nuclei after 2 h. Serotonergic, enkephalinergic, and GABAergic neurons were identified by the presence of a diagnostic enzyme or mRNA. Hemorrhaged rats had 30% fewer non-GABAergic Fos-ir neurons in the rostral ventrolateral medulla (RVLM) than hydralazine-treated rats, but they had six times more Fos-ir neurons within the subependymal parapyramidal nucleus (SEPPN). Fos-labeled SEPPN neurons were serotonergic (40-60%), GABAergic (31%), enkephalinergic (15%), or had mixed phenotypes. The data suggest that a reduced sympathoexcitatory drive from RVLM may contribute to HISI. SEPPN neuronal activation may also contribute to HISI or could mediate defensive thermoregulatory mechanisms triggered by hemorrhage-induced hypothermia. neural control of blood pressure; hemorrhagic shock; rostral ventrolateral medulla; [gamma]-aminobutyric acid; opioid; serotonin more...

Chronic pain, whether the result of nerve trauma or persistent inflammation, is a debilitating condition that exerts a high social cost in terms of productivity, 7 economic impact and quality of life. Currently available therapies yield limited success in treating such pain, suggesting the need for new insight into underlying mechanism(s). Here, we examine the likelihood that sustained activation of descending modulatory pathways that facilitate pain transmission could underlie some states of chronic pain. Such activation of descending facilitatory pathways might be the result of neuroplastic changes that occur at medullary sites in response to persistent input of pain signals. Understanding the mechanisms of descending facilitation and the spinal effects of such discharge could provide new insights into the modulation of chronic pain. more...

A single bout of exercise results in a postexercise hypotension (PEH) that is accompanied by a reduced baroreflex function. Based on the role of rostral ventrolateral medulla (RVLM) neurons in controlling sympathetic nerve activity (SNA) and blood pressure, the role of [gamma]-aminobutyric acid (GABA) in controlling RVLM neuronal activity, and the reduced baroreflex-SNA relationship during PEH, we determined whether: 1) RVLM neuronal activity is decreased during PEH, 2) GAB[A.sub.A]-receptor mechanisms mediate the decrease, and 3) baroreflex control of RVLM activity is reduced. Spontaneously hypertensive rats (SHR) were subjected to 40 min of treadmill or sham exercise (Sham PEH). PEH lasted 10 h in conscious and anesthetized SHR, indicating that the anesthetics did not affect the expression of PEH. Extracellular RVLM neuronal activity having a cardiac and sympathetic rhythm, lumbar SNA, and blood pressure were recorded at rest and during baroreflex function curves. Resting RVLM neuronal activity was lower and was increased to a greater extent by GAB[A.sub.A]-receptor antagonism in PEH versus Sham PEH (P < 0.05). Baroreflex control of RVLM neuronal activity operated with a reduced gain (P < 0.05). Thus increased GABA signaling at RVLM neurons may contribute to PEH. spontaneously hypertensive rats; central sympathetic network; extracellular recording more...

Antunes, Vagner R., G. Cristina Brailoiu, Ernest H. Kwok, Phouangmala Scruggs, and Nae J. Dun. Orexins/ hypocretins excite rat sympathetic preganglionic neurons in vivo and in vitro. Am J Physiol Regulatory Integrative Comp Physiol 281: R1801-R1807, 2001.--The two recently isolated hypothalamic peptides orexin A and orexin B, also known as hypocretin 1 and 2, are reported to be important signaling molecules in feeding and sleep/wakefulness. Orexin-containing neurons in the lateral hypothalamus project to numerous areas of the rat brain and spinal cord including the intermediolateral cell column (IML) of the thoracohimbar spinal cord. An in vivo and in vitro study was undertaken to evaluate the hypothesis that orexins, acting on sympathetic preganglionic neurons (SPNs) in the rat spinal cord, increase sympathetic outflow. First, orexin A (0.3, 1, and 10 nmol) by intrathecal injection increased mean arterial pressure (MAP) and heart rate (HR) by an average of 5, 18, and 30 mmHg and 10, 42, and 85 beats/min in urethane-anesthetized rats. Intrathecal injection of saline had no significant effects. Orexin B (3 nmol) by intrathecal administration increased MAP and HR by an average of 11 mmHg and 40 beats/min. The pressor effects of orexin A were attenuated by prior intrathecal injection of orexin A antibodies (1:500 dilution) but not by normal serum albumin. Intravenous administration of the [alpha]l-adrenergic receptor antagonist prazosin (0.5 mg/kg) or the [beta]-adrenergic receptor antagonist propranolol (0.5 mg/kg) markedly diminished, respectively, the orexin A-induced increase of MAP and HR. Second, whole cell patch recordings were made from antidromically identified SPNs of spinal cord slices from 12- to 16-day-old rats. Superfusion of orexin A or orexin B (100 or 300 nM) excited 12 of 17 SPNs, as evidenced by a membrane depolarization and/or increase of neuronal discharges. Orexin A- or B-induced depolarizations persisted in TTX (0.5 [micro]M)-containing Krebs solution, indicating that the peptide acted directly on SPNs. Results from our in vivo and in vitro studies together with the previous observation of the presence of orexin A-immunoreactive fibers in the IML suggest that orexins, when released within the IML, augment sympathetic outflow by acting directly on SPNs. hypothalamus; intermediolateral cell column; medulla; obesity; rostral ventrolateral medulla; sleep; spinal cord; sympathetic nervous system Received 1 February 2001; accepted in final form August 2001 more...

Research was conducted to determine whether a monosynaptic connection from the nucleus tractus solitarius (NTS) or the depressor ventrolateral medulla (VLM) to the pressor region of the rostral VLM (RVLM) are part of the reflex pathway activated by cardiopulmonary baroreceptors. Although the central reflex pathways activated by volume expansion include the NTS and the depressor region of the VLM, there was no indication for the monosynaptic connection between those regions and the RVLM. more...

The regulation of intracellular pH (pHi) in individual neurons from chemosensitive and nonchemosensitive areas of the medulla was studied in greater detail to determine whether other differences in extracellular pH (pHo) is present. Results showed that intrinsic buffering power was not markedly different between chemosensitive and nonchemosensitive areas. It was also observed that neurons from the chemosensitive areas had a steeper pHi versus pHo slope than the neurons from the nonchemosensitive areas. more...

The rat rostral ventrolateral medulla (RVLM) catechol signal was studied in rats after mild systemic acidosis to test the idea that systemic acidosis causes activates RVLM adrenergic neurons. Findings showed that a catechol activation in the RVLM results when arterial pressure is maintained during isocapnic systemic metabolic acidosis. Adrenergic RVLM neurons may relay inputs from the central respiratory generator to the sympathetic system and/or assume the role of chemosensors for H+ next to the surface of the ventrolateral medulla. more...

Anesthetized pigs were used in the investigation of the role of nitric oxide in the central regulation of sympathetic activity in response to hypoxia. Hypoxia induces an elevation of the pulmonary artery arterial pressure while decreasing systemic arterial pressure and vascular resistance. Results of enzyme inhibition studies and manipulations of the autonomic nervous system reveal that peripheral chemoreceptors are responsible for the release of nitric oxide in the medulla and the subsequent regulation of sympathetic activity. more...

Cardiovascular parameters and renal sympathetic nerve activity were monitored in male Sprague-Dawley rats before and after microinjection of the alpha2 adrenoreceptor agonist clonidine at the caudal ventrolateral medulla (CVLM) with or without receptor blocking to determine the contribution of the alpha2 adrenoreceptor at the CVLM to autonomic regulation. Results suggest that clonidine inhibits neurons in the CVLM. more...

The hypotensive and sympathoinhibitory activity of the caudal midline medulla is mediated by the neurotransmitter gamma-amino butyric acid-based inhibition of the excitatory neurons on the rostral ventrolateral medulla as revealed in studies done on barointact and barodenervated rabbits. Blocking the sympathoinhibitory neurons in the caudal midline medulla revealed the presence of a population of excitatory neurons. more...

The long-term effects of losartan on rats with area postrema lesions (APx) are investigated three months after the induction of the lesion. Control animals exhibited significant hypotension by the eight day of losartan administration. This is attenuated in the APx group. Food intake is not a contributory factor in the observed hypotensive effects of losartan. Losartan is an antagonist of the type 1 angiotensin receptor. Its hypotensive effects are mediated in part at the area postrema. more...

The effects of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) on mean arterial pressure (MAP) and heart rate (HR) were analyzed in anesthetized rats during static muscle contractions. Administration of CNQX into the rostral and caudal ventrolateral medulla (cVLM) of anesthetized rats attenuated elevations in MAP and HR during static muscle contractions. Furthermore, blockade of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors within the cVLM inhibited exercise-pressor reflex. more...

The role of substance P (SP) in the dorsal vagal complex (DVC) on the modulation thyrotropin-releasing hormone (TRH) was analyzed during DVC-induced stimulation of gastric acid secretion in rats. Basal gastric secretion (GAS) response to a TRH analog was reduced in urethan-anesthetized rats by unilateral injections of the stable SP agonists, DiMe-C7, and RX77368. On the other hand, basal GAS was enhanced by the bilateral injection of an SP neurokinin receptor antagonist in rats. more...

Tissue slices of rat nucleus of the solitary tract (NTS) were analyzed by whole cell patch-clamp techniques to determine the presence and kinetics of nicotinic acetylcholine receptor (nAChR)-mediated signal transduction. Whole cell patch-clamp analysis of whole cell currents in rat medullary NTS slices indicated the presence of nAChRs that possessed similar properties to neuronal nAChR. Furthermore, nAChR-mediated signal transduction from afferent nerves to neurons in the NTS involved the diffusion of acetylcholine. more...

The caudal ventrolateral medulla of anesthetized and paralyzed rats were analyzed to determine the response of sympathetic baroreceptor reflex to alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA). Analysis of sympathetic baroreceptor reflex in paralyzed rats after the selective blockage of N-methyl-D-aspartate and AMPA/kainate receptors indicated the presence of elevated arterial blood pressure. Blockage of the inotropic excitatory amino acid receptors also increased splanchnic sympathetic nerve activity and attenuated sympathetic-baroreceptor reflex. more...

The cardiac sympathetic responses of the ipsilateral inferior cardiac nerve of chloralose-anesthetized cats were analyzed to determine the location of cardiac premotor neurons that regulate cardiac sympathetic supply. Analysis of cardiac sympathetic responses in feline ipsilateral inferior cardiac nerve indicated the presence of neurons that elicit selective activation on cardiac sympathetic flow. The neurons in the rostral ventrolateral medulla are organized topographically with a substantial region of overlap. more...

The effects of arginine vasopressin (AVP) microinjections or intravenous infusion on the response of nucleus of the solitary tract (NTS) neurons to vagus nerve inputs were analyzed in anesthetized rabbits. Analysis of sinoaortic and vagal denervated anesthetized rabbits after administration of AVP indicated the presence of augmented NTS neuronal response to aortic/vagal stimulation. AVP-mediated enhancement of sympathoinhibitory response to increases in arterial pressure can be inhibited by pretreatment of animals with AVP V1 receptor antagonists. more...

The effects of static muscle contraction on the expression of c-Fos and Fos-like immunoreactivity in the medulla were analyzed during induced contractions of the cat spinal L7 and S1 ventral roots. Static muscle contraction activated the phenylethanolamine-N-methyltrasferase-containing neurons in the ventrolateral medulla. Furthermore, static muscle contraction also enhanced the Fos-like immunoreactivity of the lateral reticular nucleus and vestibular nucleus of the cat medulla. more...

Medullary pathways that mediate cardiovascular responses to the activation of the nucleus of the solitary tract (NTS) were analyzed in male Wistar rats by utilizing Phaseolus vulgaris leucoagglutinin. Analysis of medullary responses that mediate the depressor responses on Na+-sensitive sites in the NTS of Wistar rats indicated the role of neurons from the ventrolateral medulla (VLM) in mediating brachycardic response. Furthermore, medial subnucleus of the NTS mediates depressor responses through innervations in the VLM. more...

The interaction between light and Fos expression in the suprachiasmatic nuclei (SCN) was analyzed in young, middle-aged and aging rats including middle-aged rats with transplants of fetal tissue. Middle-aged rats exhibited blunted SCN diurnal pattern activity while the transplantation of fetal SCN in middle-aged rats restored rhythmic functional capabilities. Furthermore, baseline Fos expression increased prematurely in middle-aged rats. more...

Isolated rostral ventrolateral medulla (RVLM) vasomotor neurons from cholarose-anesthetized Sprague-Dawley rats were analyzed to determine the effects of cholinergic agonist on rat bulbospinal C1 neurons. Administration of carbachol activated the RVLM vasomotor neurons which were inhibited by the iontophoresis of methylatropine. The post- and pre-synaptic effects of carbachol on RVLM sympathoexcitatory neurons were mediated by pharmacologic and muscarinic factors. more...

The effects of aortic nerve synaptic stimulation in the neurons of the ventrolateral medulla oblongata (VLM) were analyzed in Sprague-Dawley rats. Analysis of postsynaptic potentials during VLM response to the stimulation of the aortic nerve indicated the presence of inhibition, excitation and biphasic responses. Furthermore, the excitatory response of VLM neurons to aortic nerve stimulation indicated the role of the rostral VLM on baroreceptor input processing. more...

Neurons in the rat nucleus raphe obscurus (NRO) and nucleus raphe magnus (NRM) were chemically stimulated following electrical stimulation of the periaqueductal gray matter (PAG) to determine if there are afferent pathways that regulate the PAG-mediated cardiovascular defense reaction (CDF), which includes an increase in heart rate, blood pressure, respiration and femoral conductance and reduction in renal conductance. The results indicate that NRO and NRM neurons regulate the CDF by modulating the excitability of neurons of the midbrain defense area, its efferent pathway or both. more...

A study was conducted to determine the intrinsic characteristics of the bulbospinal cells (C1) of the rostral ventrolateral medulla oblongata in neonatal rats and to verify if they express functional alpha-2-adrenergic receptors. The results show that C1 cells have intrinsic pacemaker properties. Furthermore, C1 cells also possess alpha-2-adrenergic receptors that are coupled with potassium conductance. more...

The inhibitory effect of arginine vasopressin (AVP) is due to interconnections with area postrema (AP) neurons activated by the peptide. AP, a circumventricular organ present on the dorsal surface of the medulla is essential for cardiovascular regulation. Insertion of slices with aCSF containing V1 antagonist inhibit the excitatory responses of five AP cells to AVP indicating that influence of AVP on AP neurons is a V1 receptor-mediated excitatory action. more...

A study of the effect of chemical simulation of the nucleus raphe obscurus (NRO) with kainic acid on plasma concentration of glucose, glucagon and insulin shows that NRO helps in the central vagal regulation of endocrine pancreatic function in the rat. The increase in plasma concentration of glucagon and insulin is similar in time and magnitude as that to simulation of dorsal vagal complex. These effects are mediated by the vagus nerve. Electrical stimulation of the dorsal motor nucleus of the vagus enhances the insulin secretion. more...

Astudy of the interactions between G proteins and H+-ATPase through immunocytochemical studies of rat kidneys using a monoclonal antibody to H+-ATPase and polyclonal anti-G protein antibodies reveals that G-alpha(i-2), G-alpha(i-3), and G-alpha(q/11) associate with H-ATPase-containing cells, while the G-alpha(S) subunits do not. Staining for any G-alpha subunit is absent in some of the intercalated cell that stain for H+-ATPase. Guanosine 5'-O-(3-thiotriphosphate) enhances protein transport and guanine nucleotides do not influence the protein leak in vesicles, indicating that a few G proteins modulate the function of H+-ATPase by associating with it. more...

Transepithelial absorption of NH(super +)(sub 4) in rat medullary thick ascending limb (MTAL) is greater than NH3 absorption resulting in net ammonium absorption. Ammonium absorption determines pHi in the MTAL by increasing the acidification of cells. The transcellular absorption of NH(super +)(sub 4) is mediated by apical membrane ion transport which eliminates barium-sensitive NH(super +)(sub 4) entry. more...

The significance of endogenous angiotensin II (ANG II) in the ventrolateral medulla (VLM) of spontaneously hypertensive rats (SHR) was investigated by microinjection of an ANG II antagonist either in the rostral orcaudal VLM. Rostrally, the antagonist elicited depressor and bradicardic effects while the caudal microinjection induced the opposite effects. These results suggest a tonic excitatory effect function for endogenous ANG II on VLMvasomotor neurons. Further, ANG II blood pressure responses is much higher in SHRs than in normotensive rats. more...

The nucleus tractus solitarii (NTS) is an elongated nucleus extending from the caudal edge of the motor facial nucleus to the cervical spinal cord. This dorsomedial part of the medulla oblongata has cell bodies with peptidergic and nonpeptidergic neurotransmitters and modulators. Microinjection of antagonists and antisera as well as electrophysiological studies of the NTS showed that lesions in this area result in hypertension, blood pressure lability, and changes in heart rate and baroreflex sensitivity. more...