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Injection into the nucleus tractus solitarii (NTS) of toxins that target substance P (SP) receptors ablates neurons that express neurokinin-1 (NK1) receptors, attenuates baroreflexes, and results in increased lability of arterial pressure. We and others have shown that the toxin leads to loss of neurons containing SP receptors and loss of GABAergic neurons in the NTS; but given that neither type neuron is thought to be integral to baroreflex transmission in NTS, mechanisms responsible for the cardiovascular changes remained unclear. Because NK1 receptors colocalize with N-methyl-d-aspartate (NMDA) receptors and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in NTS and because glutamate transmission may be integral to baroreflex transmission in the NTS we hypothesized that the toxic lesions may interrupt mechanisms for glutamate transmission. Interruption of those mechanisms could be responsible for the cardiovascular effects. We tested the hypothesis by performing fluorescent immunohistochemistry, confocal microscopy and image analysis after injecting stabilized SP-SAP (SSP-SAP) unilaterally into the NTS. We assessed changes in immunoreactivity (IR) of NMDA receptor subunit 1 (NMDAR1), AMPA receptor subunit 2 (GluR2), and 3 types of vesicular glutamate transporters (VGluT) as well as IR of gamma-aminobutyric acid receptors type b (GABAb), neuronal nitric oxide synthase (nNOS), tyrosine hydroxylase (TH), and protein gene product 9.5 (PGP 9.5), a neuronal marker, in the NTS. When compared to that of the same section of the un-injected NTS, IR decreased significantly in the injected side for NMDAR1 (p<0.01), GluR2 (p<0.01), VGluT3 (p<0.01), GABAb (p<0.001), and PGP9.5 (p<0.001). In contrast, IR for VGluT1 (p<0.001), VGluT2 (p<0.001), nNOS (p<0.001), and TH (p<0.001) increased significantly. We conclude that pathologic effects following ablation of neurons with NK1 receptors in NTS may result from interruption of neurotransmission through other neurochemical systems associated with NK1 receptors-containing neurons., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background & Aims: Gastric electrical stimulation (GES) is an effective therapy to treat patients with chronic dyspepsia refractory to medical management. However, its mechanisms of action remain poorly understood., Methods: Gastric pain was induced by performing gastric distension (GD) in anesthetized rats. Pain response was monitored by measuring the pseudo-affective reflex (e.g., blood pressure variation), while neuronal activation was determined using c-fos immunochemistry in the central nervous system. Involvement of primary afferents was assessed by measuring phosphorylation of ERK1/2 in dorsal root ganglia., Results: GES decreased blood pressure variation induced by GD, and prevented GD-induced neuronal activation in the dorsal horn of the spinal cord (T9-T10), the nucleus of the solitary tract and in CRF neurons of the hypothalamic paraventricular nucleus. This effect remained unaltered within the spinal cord when sectioning the medulla at the T5 level. Furthermore, GES prevented GD-induced phosphorylation of ERK1/2 in dorsal root ganglia., Conclusions: GES decreases GD-induced pain and/or discomfort likely through a direct modulation of gastric spinal afferents reducing central processing of visceral nociception.

Growing evidence suggests that oxytocin plays an important role in the regulation of energy balance and that central oxytocin administration induces weight loss in diet-induced obese (DIO) animals. To gain a better understanding of how oxytocin mediates these effects, we examined feeding and neuronal responses to oxytocin in animals rendered obese following exposure to either a high-fat (HFD) or low-fat diet (LFD). Our findings demonstrate that peripheral administration of oxytocin dose-dependently reduces food intake and body weight to a similar extent in rats maintained on either diet. Moreover, the effect of oxytocin to induce weight loss remained intact in leptin receptor-deficient Koletsky (fa(k)/fa(k)) rats relative to their lean littermates. To determine whether systemically administered oxytocin activates hindbrain areas that regulate meal size, we measured neuronal c-Fos induction in the nucleus of the solitary tract (NTS) and area postrema (AP). We observed a robust neuronal response to oxytocin in these hindbrain areas that was unexpectedly increased in rats rendered obese on a HFD relative to lean, LFD-fed controls. Finally, we report that repeated daily peripheral administration of oxytocin in DIO animals elicited a sustained reduction of food intake and body weight while preventing the reduction of energy expenditure characteristic of weight-reduced animals. These findings extend recent evidence suggesting that oxytocin circumvents leptin resistance and induces weight-loss in DIO animals through a mechanism involving activation of neurons in the NTS and AP, key hindbrain areas for processing satiety-related inputs.

Ample animal studies demonstrate that neuropeptides NPY and α-MSH expressed in Arcuate Nucleus and Nucleus of the Tractus Solitarius, modulate glucose homeostasis and food intake. In contrast is the absence of data validating these observations for human disease. Here we compare the post mortem immunoreactivity of the metabolic neuropeptides NPY, αMSH and VGF in the infundibular nucleus, and brainstem of 11 type-2 diabetic and 11 non-diabetic individuals. α-MSH, NPY and tyrosine hydroxylase in human brain are localized in the same areas as in rodent brain. The similar distribution of NPY, α-MSH and VGF indicated that these neurons in the human brain may share similar functionality as in the rodent brain. The number of NPY and VGF immuno positive cells was increased in the infundibular nucleus of diabetic subjects in comparison to non-diabetic controls. In contrast, NPY and VGF were down regulated in the Nucleus of the Tractus Solitarius of diabetic patients. These results suggest an activation of NPY producing neurons in the arcuate nucleus, which, according to animal experimental studies, is related to a catabolic state and might be the basis for increased hepatic glucose production in type-2 diabetes.

Essential hypertension is idiopathic although it is accepted as a complex polygenic trait with underlying genetic components, which remain unknown. Our supposition is that primary hypertension involves activation of the sympathetic nervous system. One pivotal region controlling arterial pressure set point is nucleus tractus solitarii (NTS). We recently identified that pro-inflammatory molecules, such as junctional adhesion molecule-1, were over expressed in endothelial cells of the microvasculature supplying the NTS in an animal model of human hypertension (the spontaneously hypertensive rat: SHR) compared to normotensive Wistar Kyoto (WKY) rats. We have also shown endogenous leukocyte accumulation inside capillaries within the NTS of SHR but not WKY rats. Despite the inflammatory state in the NTS of SHR, transcripts of some inflammatory molecules such as chemokine (C-C motif) ligand 5 (Ccl5), and its receptors, chemokine (C-C motif) receptor 1 and 3 were down-regulated in the NTS of SHR compared to WKY rats. This may be compensatory to avoid further strong inflammatory activity. More importantly, we found that down-regulation of Ccl5 in the NTS of SHR may be pro-hypertensive since microinjection of Ccl5 into the NTS of SHR decreased arterial pressure but was less effective in WKY rats. Leukocyte accumulation of the NTS microvasculature may also induce an increase in vascular resistance and hypoperfusion within the NTS; the latter may trigger release of pro-inflammatory molecules which via paracrine signaling may affect central neural cardiovascular activity conducive to neurogenic hypertension. All told, we suggest that vascular inflammation within the brainstem contributes to neurogenic hypertension by multiple pathways., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Since the nucleus tractus solitarii (NTS) is a pivotal region for regulating the set-point of arterial pressure, we propose here its role in the development of neurogenic hypertension. Given the findings of recent studies suggesting that the NTS of spontaneously hypertensive rats (SHR) exhibits a specific inflammatory state characterized by leukocyte accumulation within the NTS microvasculature, we hypothesized that gene expression levels of apoptotic factors are altered in the NTS of SHR compared to normotensive Wistar-Kyoto rats (WKY). To test this hypothesis, we used RT(2) Profiler PCR arrays targeting apoptosis-related factors. We found that gene expression of the death receptor Fas (tumor necrosis factor receptor superfamily, member 6) and the cysteine-aspartic acid protease caspase 12 were down-regulated in the NTS of both adult hypertensive and young pre-hypertensive SHR compared to age-matched WKY. On the other hand, an anti-apoptotic factor, neuronal apoptosis inhibitory protein, was highly increased in the NTS of SHR. These results suggest that the NTS of SHR exhibits an anti-apoptotic condition. Furthermore, this profile appears not to be secondary to hypertension. Whether this differential gene expression in the NTS contributes to the hypertensive state of the SHR via alteration of neuronal circuitry regulating cardiovascular autonomic activity awaits elucidation., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: Based upon scarce clinical data in humans and experimental findings in animal studies, it has been postulated that the ascending gustatory projection from the nucleus tractus solitarii courses ipsilaterally through the pons and midbrain to the ipsilateral ventral posteromedial nucleus. Thus, it has been assumed that ischemic lesions affecting the secondary projection gustatory fibers would cause ipsilateral taste disorders., Description of Case: We report a case of bilateral ageusia following an acute right midbrain and thalamic infarction affecting the ipsilateral central trigeminal tract and ventral posteromedial nucleus in a right-handed man., Conclusion: The present case indicates that, in contrast to animal data, some secondary projection gustatory fibers may cross in humans and consequently unilateral right-sided posterior circulation ischemic lesions can cause bilateral gustatory deficits., (Copyright © 2011 by the American Society of Neuroimaging.)

Hydrogen sulfide (H2S), the colorless gas with the smell of rotten eggs, has been regarded as a novel gaseous signaling molecule. Although H2S has been proved been involved into the cardiovascular functions, the cardiovascular functions of H2S within the nucleus tractus solitarii (NTS) are not clear. Unilateral microinjection of NaHS (2 to 200 pmol), a H2S donor, into the NTS caused transient and dose-dependent hypotension and bradycardia (P<0.01). Microinjection of CBS allosteric activator S-ademetionine (SAM) into the NTS also produced significant decreases in BP (from 101 +/- 8 to 82 +/- 7 mmHg, P < 0.01) and HR (from 469 +/- 16 to 449 +/- 14 bpm, P<0.01), which was very similar to those of NaHS. Pretreatment with hydroxylamine, a CBS inhibitor, failed to affect the cardiovascular functions of intra-NTS NaHS. However, pretreatment with glibenclamide (10 nmol), a KATP channel blocker, eliminated the on BP (from -23 +/- 4 to -5 +/- 1 mmHg, P<0.01) and HR (from -24 +/- 2 to -5 +/- 1 bpm, P<0.01) by 78% and 79%, respectively, of intra-NTS NaHS (20 pmol). Likewise, pretreatment with kynurenic acid (Kyn, 5 nmol) also attenuated the effects of NaHS on BP (from -29 +/- 3 to -12 +/- 3 mmHg, P<0.01) and HR (from -19 +/- 2 to -9 +/- 2 bpm, P<0.01) by 59% and 53%, respectively, of intra-NTS NaHS (20 pmol). These data support the hypothesis that endogenous H2S produces cardiovascular inhibition functions in the NTS, mainly mediated by KATP channels regulation or/and glutamate receptors.

Major changes in arterial pressure, autonomic, and respiratory activity occur in response to hypoxia. We analyzed structural damage and increased vascular permeability in the ventrolateral medulla and nucleus tractus solitarius, which control autonomic, respiratory, and cardiovascular functions in adult Wistar rats subjected to 2 hours of hypoxia (7% oxygen + 93% nitrogen) for up to 14 days after hypoxicexposure. Brainstem tissue levels of vascular endothelial growth factor (VEGF), nitric oxide (NO), and glutamate were significantly increased over control levels after hypoxic injury. By electron microscopy, swollen neurons and dendrites, degenerating axons, disrupted myelin sheaths, and swollen astrocyte processes were observed in the nucleus tractus solitarius and ventrolateral medulla. Leakage of intravenously administered horseradish peroxidase was observed through vascular walls in hypoxic rats. These results suggest that increased VEGF and NO production in hypoxia resulted in increased vascular permeability, which, along with increased levels of glutamate, may have induced structural alterations of the neurons, dendrites, and axons. Administration of the antioxidant neurohormone melatonin (10mg/kg) before and after the hypoxia reduced VEGF, NO, and glutamate levels and improved ultrastructural abnormalities induced by hypoxia exposure, suggesting that it may have a therapeutic potential in reducing hypoxia-associated brainstem damage.

Hypoxic respiratory and cardiovascular responses in mammals are mediated by peripheral chemoreceptor afferents which are relayed centrally via the solitary tract nucleus (NTS) in dorsomedial medulla to other cardiorespiratory-related brainstem regions such as ventrolateral medulla (VLM). Here, we test the hypothesis that peripheral chemoafferents could also be relayed directly to the Kölliker-Fuse/parabrachial complex in dorsolateral pons, an area traditionally thought to subserve pneumotaxic and cardiovascular regulation. Experiments were performed on adult Sprague-Dawley rats. Brainstem neurons with axons projecting to the dorsolateral pons were retrogradely labeled by microinjection with choleras toxin subunit B (CTB). Neurons involved in peripheral chemoreflex were identified by hypoxia-induced c-Fos expression. We found that double-labeled neurons (i.e. immunopositive to both CTB and c-Fos) were localized mostly in the commissural and medial subnuclei of NTS and to a lesser extent in the ventrolateral NTS subnucleus, VLM and ventrolateral pontine A5 region. Extracellular recordings from the commissural and medial NTS subnuclei revealed that some hypoxia-excited NTS neurons could be antidromically activated by electrical stimulations at the dorsolateral pons. These findings demonstrate that hypoxia-activated afferent inputs are relayed to the Kölliker-Fuse/parabrachial complex directly via the commissural and medial NTS and indirectly via the ventrolateral NTS subnucleus, VLM and A5 region. These pontine-projecting peripheral chemoafferent inputs may play an important role in the modulation of cardiorespiratory regulation by dorsolateral pons., (Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.)

Structural neuronal plasticity is present in the nucleus para-retroambiguus (NPRA) and the commissural nucleus of the solitary tract/A2 group (NTScom/A2) in female hamsters. Both brainstem nuclei play a role in estrous cycle related autonomic adaptations. We investigated how aging affects the capillary condition in these adaptive brainstem regions. Senescent female hamsters (+/-95 weeks) were tested weekly for their 4-day estrous cycle. Subsequently morphological changes of NPRA and NTScom/A2 were compared with those of young (+/-20 weeks) females in an ultrastructural study. The medial tegmental field served as control area. In 841 capillaries (n=319 capillaries, young females (N=3); n=522 capillaries, aged females (N=4)) vascular aberrations were classified into 3 categories: endothelial and tight junction, basement membrane and pericyte aberrations. In old animals, capillaries showed marked endothelial changes, disrupted tight junctions, and thickening and splitting of basement membranes. Aberrations were found in 40-60% of all capillaries. About 70% of the pericytes contained degenerative inclusions. Despite this generalized vascular degeneration, the reproductive cycle of female hamsters was unaffected by vascular senescence. Perivascular fibrosis as reported in aging rats was never observed, which suggests the existence of species differences., (Copyright 2010 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.)

A very rare case of continuous hypertension and tachycardia after excision of a cerebellar hemangioblastoma at the dorsal medulla oblongata is presented. This 21-year-old man was admitted to the authors' hospital with a headache and dizziness. Radiological examination revealed a tumor located behind the dorsal medulla oblongata and compressing it substantially. The tumor was completely resected, but after the surgery the patient experienced prolonged hypertension and tachycardia. Postoperative MR imaging showed a small injury at the dorsocaudal medulla that was located at the caudal site of the nucleus of the tractus solitarius (NTS). Because the NTS has been reported to play a central role in cardiovascular regulation along with the rostral ventrolateral medulla, the authors considered it possible that the NTS injury was the cause of the prolonged elevation of sympathetic tone.

Chronic intermittent hypoxia (CIH) is a frequent concomitant of sleep apnea, which can increase sympathetic nerve activity through mechanisms involving chemoreceptor inputs to the commissural nucleus of the solitary tract (cNTS). These chemosensory inputs co-store glutamate and substance P (SP), an endogenous ligand for neurokinin-1 (NK(1)) receptors. Acute hypoxia results in internalization of NK(1) receptors, suggesting that CIH also may affect the subcellular distribution of NK(1) receptors in subpopulations of cNTS neurons, some of which may express tyrosine hydroxylase, the rate-limiting enzyme for catecholamine synthesis (TH). To test this hypothesis, we examined dual immunolabeling for the NK(1) receptor and TH in the cNTS of male mice subjected to 10days or 35days of CIH or intermittent air. Electron microscopy revealed that NK(1) receptors and TH were almost exclusively localized within separate somatodendritic profiles in cNTS of control mice. In dendrites, immunogold particles identifying NK(1) receptors were prevalent in the cytoplasm and on the plasmalemmal surface. Compared with controls, CIH produced a significant region-specific decrease in the cytoplasmic (10 and 35days, P<0.05, unpaired Student t-test) and extrasynaptic plasmalemmal (35days, P<0.01, unpaired Student t-test) density of NK(1) immunogold particles exclusively in small (<0.1microm) dendrites without TH immunoreactivity. These results suggest that CIH produces a duration-dependent reduction in the availability of NK(1) receptors preferentially in small dendrites of non-catecholaminergic neurons in the cNTS. The implications of our findings are discussed with respect to their potential involvement in the slowly developing hypertension seen in sleep apnea patients., (Copyright (c) 2009 Elsevier Inc. All rights reserved.)

The distribution of nitricoxideergic neurons and activity of neuronal NO-synthase (nNOS) was studied in some nuclei of the medulla oblongata in patients with the lifetime diagnosis of arterial hypertension, stages I-III (AG I-III). In AG I, the significant decrease of nNOS activity was observed in most nuclei, although the relative content of NO-neurons was not changed. The marked changes of these parameters were noted in the nucleus of solitary tract compared to those of the reticular formation. In AG II, a portion NO-neurons in the nuclei was markedly reduced, however the following decrease of nNOS activity was not found. In AG III, there was the augmentation of nNOS activity and the subtle decrease in the portion of NO-neurons. Therefore, in AG, there is the decrease of quantitative parameters that characterize the state of the oxide-ergic system. This is one of the causes of the hyperactivation of sympathetic nervous system and elevation of arterial pressure. The exception is the dorsal nucleus of the vagus nerve, in which the relatively larger number of NO-neurons and higher nNOS activity were found, that may be related with the cholinergic mechanism of compensatory activation of the nitric oxide-ergic system.

The aim of the present paper is to briefly review the changes occurring in the nucleus tractus solitarii and carotid body in response to hypoxic and hyperoxic injuries. Selective alterations of dendrites and Fos-immunoreactivity of neurons have been observed in the subnucleus gelatinosus of the nucleus tractus solitarii of adult subjects dying after hypoxic-ischaemic injury. The selective vulnerability of this portion of the nucleus tractus solitarii may be explained mainly with reference to the vascularization of medullary tegmentum. In the carotid body, chronic hypoxia and hyperoxia cause a series of morphological, cellular and biochemical changes which may play a major role during the first postnatal period and may have implications in the pathogenesis of Sudden Infant Death Syndrome. Intermittent hypoxia may cause hypersensitivity of the carotid body, possibly increasing the risk of unstable respiration. Conversely, hyperoxia exposure has been reported to cause hyposensitivity and reduction in volume of the carotid body, possibly leading to ineffective response.

Behavior ablation remains a powerful, if not cutting-edge, approach for localization of function within the nervous system. The initial discovery of the suprachiasmatic nuclei as the site of the mammalian light-entrainable circadian pacemaker is owed to this approach. Food-anticipatory activity (FAA), an output of a putative feeding-entrainable circadian pacemaker, is a behavior that has been surprisingly resilient to elimination by surgical lesion. Here we review this literature, with particular attention paid to recent studies aimed at defining the role of the dorsomedial hypothalamus in the generation of FAA. This literature is fraught with examples of inconsistent results among lesion studies, which in some cases can be accounted for by varied endpoint measures. The site of the feeding-entrainable circadian pacemaker, if it resides in a discrete structure at all, remains unknown.

We studied the effect of chronic hypobaric hypoxia (CHx; 10-11% O(2)) on the response to hypercapnia (15% CO(2)) of individual solitary complex (SC) neurons from adult rats. We simultaneously measured the intracellular pH and firing rate responses to hypercapnia of SC neurons in superfused medullary slices from control and CHx-adapted adult rats using the blind whole cell patch clamp technique and fluorescence imaging microscopy. We found that CHx caused the percentage of SC neurons inhibited by hypercapnia to significantly increase from about 10% up to about 30%, but did not significantly alter the percentage of SC neurons activated by hypercapnia (50% in control vs. 35% in CHx). Further, the magnitudes of the responses of SC neurons from control rats (chemosensitivity index for activated neurons of 166+/-11% and for inhibited neurons of 45+/-15%) were the same in SC neurons from CHx-adapted rats. This plasticity induced in chemosensitive SC neurons by CHx appears to involve intrinsic changes in neuronal properties since they were the same in synaptic blockade medium.

Exposure to chronic intermittent hypoxia (CIH) leads to significant autonomic and respiratory changes, similar to those observed in obstructive sleep apnea. The hypertension associated with CIH is due to sympathoexcitation triggered by long-term exposure to intermittent hypoxia. However, the mechanisms underlying these effects are unknown. Changes in central regulation of sympathetic activity may underlie CIH-induced hypertension. Since NO appears to be mainly sympathoinhibitory in the nucleus of the solitary tract (NTS), we hypothesized that CIH augments sympathetic activity, in part by reducing neuronal nitric oxide synthase (nNOS) expression and consequently nitric oxide (NO) production in this brain region. To test our hypothesis, juvenile male Wistar rats were exposed to CIH for 8 h/day for 10 days and sections of perfused brainstem were either stained to reveal nNOS-immunoreactivity or loaded with DAF 2-DA to label neurons containing NO. CIH rats showed a significant increase in mean arterial pressure and heart rate compared to controls. However, there was no significant difference in the distribution, staining intensity or numbers of nNOS-immunoreactive neurons in the NTS between experimental and control rats. We also found no significant change in NO content in the DAF 2-DA-loaded sections of NTS from CIH rats. Our data show that NO is not altered in the NTS of juvenile CIH rats, suggesting that nitrergic mechanisms, at least in the NTS, are unlikely to be involved in the sympathetic excitation that generates the hypertension observed after 10 days of CIH.

Commissural nucleus of the solitary tract (commNTS) lesions transitorily (first 5 days) reduce mean arterial pressure (MAP) in spontaneously hypertensive rats (SHR), and lesions of the tissue surrounding the anteroventral third ventricle (AV3V region) chronically reduce MAP in other models of hypertension. In the present study, we investigated the effects of combined AV3V+commNTS electrolytic lesions on MAP and heart rate (HR) in conscious SHR. Baseline MAP and HR were recorded in male SHR before and for the next 40 days after sham or AV3V lesions combined with sham or commNTS lesions. The AV3V lesions produced no change in MAP in SHR, while commNTS lesions reduced MAP acutely (121 +/- 2 to 127 +/- 3 mmHg in the 1st and 5th days, respectively, vs. prelesion: 192 +/- 4 mmHg) but not chronically (from 10 to 40 days). However, combined AV3V+commNTS lesions reduced MAP of SHR chronically (119 +/- 2 to 161 +/- 4 mmHg, in the 1st and 40th day, respectively, vs. prelesion levels: 186 +/- 4 mmHg) or sham-lesioned SHR (187 +/- 4 to 191 +/- 6 mmHg). Sympathetic and angiotensinergic blockade produced less reduction in MAP in SHR with AV3V+commNTS-lesions, and there was no relationship between changes on water and food intake, body weight, or urinary excretion produced by AV3V+commNTS lesions with the changes in MAP. The present findings suggest that in the absence of the commNTS, the AV3V region contributes to the hypertension observed in SHR by mechanisms that appear to involve enhanced angiotensinergic and sympathetic activity.

Glutamatergic synaptic currents elicited in second-order neurons in the nucleus of the solitary tract (nTS) by activation of chemosensory and other visceral afferent fibers are severely reduced following 10 days of chronic intermittent hypoxia (CIH). The mechanism by which this occurs is unknown. A strong candidate for producing the inhibition is dopamine, which is also released from the presynaptic terminals and which we have shown exerts a tonic presynaptic inhibition on glutamate release. We postulated that tonic activation of the D2 receptors inhibits presynaptic calcium currents to reduce transmitter release and that in CIH this occurs in conjunction with an increase in the dopamine inhibitory response due to the increase in presynaptic D2 receptors or an increase in dopamine release further suppressing the evoked excitatory postsynaptic current (eEPSC). Thus we predicted that blockade of the D2 receptors would return the EPSC to values of animals maintained under normoxic conditions. We found that dopamine and quinpirole, the selective D2-like agonist, inhibit calcium currents via the D2 receptors by acting on the N-type calcium channel in presynaptic neurons and their nTS central terminals. However, in brain slice studies from CIH animals, although the D2 antagonist sulpiride increased the CIH-reduced amplitude of synaptic currents, EPSCs were not restored to normal levels. This indicates that while the dopamine inhibitory effect remains intact in CIH, most of the reduction in the eEPSC amplitude occurs via alternative mechanisms.

Our previous studies have shown that morphine withdrawal increases the hypothalamic-pituitary-adrenocortical axis activity, which is dependent on a hyperactivity of noradrenergic pathways (nucleus tractus solitarius-A(2)) innervating the hypothalamic paraventricular nucleus. The extracellular signal-regulated kinase has been implicated in drug addiction, but its role in activation of paraventricular nucleus and nucleus tractus solitarius during morphine dependence remain poorly understood. We have determined the activation of extracellular signal-regulated kinase during morphine dependence and withdrawal as well as its involvement in morphine withdrawal-induced gene expression. We show that naloxone-induced morphine withdrawal activates extracellular signal-regulated kinases(1/2) and increases c-Fos expression in rat paraventricular nucleus and nucleus tractus solitarius-A(2) neurons. Activated extracellular signal-regulated kinases(1/2) was colocalized with c-Fos in both nuclei, and this response was blocked by SL327, a drug that prevents extracellular signal-regulated kinase activation. In the paraventricular nucleus from morphine-withdrawn rats, the number of neurons expressing CRF was increased. Immunohistochemical study showed a dramatic increase in c-Fos immunoreactivity within CRF-positive cells. These results suggest that extracellular signal-regulated kinases1/2 signaling pathway is necessary for morphine withdrawal-induced activation of brain areas associated with the stress system.

The possible effects of cervical lymphatic blockade (CLB) on a series of parameters in conscious freely moving rats were analysed. Blood pressure (BP) and heart rate (HR) for conscious male Sprague-Dawley rats at 1, 3, 7, 11, 15 and 21 days after a CLB or a sham operation were monitored continuously for 24 hours with a computerized recording system. Since BP and HR were subjected to spontaneous variations, blood pressure variability (BPV) and heart rate variability (HRV) were expressed as the standard deviation of beat-to-beat BP and HR values. The baroreflex sensitivities (BRS) were determined by measuring the heart period (HP = 60,000/HR) prolongation in response to the elevation in BP induced by an intravenous administration of phenylephrine at 1, 7, 15 and 21 days after the CLB or sham operation. Compared with those in sham-operated rats, the values of systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial blood pressure (MAP), HR and BRS in CLB rats were significantly lower, whereas the values of BPV and HRV were markedly raised in CLB rats at different time points. Furthermore, the impaired ultrastructure in the dorsomedial nucleus of the solitary tract (dmNTS) including degeneration, apoptosis and necrosis in neurons and gliacytes, were apparent from the 1st to 15th day but the changes were most significant at 7th day after CLB operation. Structural changes appeared to be closely related to functional changes of the dmNTS at each time point. Thus, in CLB conscious rats, a significant decline in blood pressure accompanied by dysfunction in its regulation might be due to the impaired structure in the dmNTS.

We report a case of fatal neurogenic pulmonary edema in progressive multiple sclerosis (MS). The patient had one isolated relapse-like episode. Six years later progressive disease began, lasting 5 years until unexpected death during sleep. Medico-legal autopsy revealed pulmonary edema and neuropathological examination showed infiltrations with lymphocytes and microglia in the respiratory centers of the medulla. More classical demyelinated lesions were found in the white matter of spinal cord and in the gray matter of the brain along with disseminated perivascular lymphocytic infiltrates. Medullary inflammation in progressive MS may result in sudden fatal respiratory failure.

Hypoxic-ischemic (HI) injury in the preterm neonate incurs numerous functional deficits, however little is known about the neurochemically-defined brain nuclei that may underpin them. Key candidates are the brainstem catecholamine neurons. Using an immature animal model, the postnatal day (P)-3 (P3) rat pup, we investigated the effects of HI on brainstem catecholamine neurons in the locus coeruleus, nucleus tractus solitarius (NTS), and ventrolateral medulla (VLM). On P21, we found that prior P3 HI significantly reduced numbers of catecholaminergic neurons in the locus coeruleus, NTS, and VLM. Only locus coeruleus A6, NTS A2, and VLM A1 noradrenergic neurons, but not NTS C2 and VLM C1 adrenergic neurons, were lost. There was also an associated reduction in dopamine-beta-hydroxylase-positive immunolabeling in the forebrain. These findings suggest neonatal HI can affect specific neurochemically-defined neuronal populations in the brainstem and that noradrenergic neurons are particularly vulnerable to HI injury.

This study characterizes neural firing activity of the nucleus tractus solitarii (NTS) and baroreflex sensitivity (BRS) in streptozotocin (STZ)-induced diabetic rats relative to control rats by implantation of multi-wire electrode into rat NTS for direct monitoring of barosensitive NTS neurons before and after baroreflex system challenge by phenylephrine (PE) injection. NTS firing data is correlated with arterial pressure for both control and diabetic rats. In control rats, NTS firing rate and systolic arterial pressure correlate significantly with both pre-PE (baseline) and post-PE (p<0.01). In STZ-induced diabetic rats, positive correlation is observed only after PE injection (p<0.05). Although NTS firing rate was not significantly different between control and diabetic rats (p=0.085) in the baseline condition, it was significantly reduced in STZ-induced diabetic rats (p=0.042) with adjustment for BRS. After PE injection, NTS firing rate is significantly lower in diabetic rats relative to control rats (p<0.01). With adjustment for BRS, multivariate analysis shows that diabetes is independently associated with NTS firing rate after PE injection (p=0.034). Prior physiological and immunofluorescent studies found differing NTS data for control and diabetic rat only after PE challenge, but our data show diabetes-induced barosensitive NTS impairment in the baseline condition for STZ-induced diabetic rats. This latter finding suggests greater sensitivity of multi-wire electrode study of NTS relative to earlier methods.

Knowing that exercise training reduces arterial pressure in hypertensive individuals and that pressure fall is accompanied by blockade of brain renin-angiotensin system, we sought to investigate whether training (T) affects central renin-angiotensin system. Spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto controls (WKY) were submitted to training or kept sedentary (S) for 3 months. After functional recordings, brain was removed and processed for autoradiography (brain stem sequential slices hybridized with (35)S-oligodeoxynucleotide probes for angiotensinogen [Aogen] and angiotensin II type 1 [AT(1A)] receptors). Resting arterial pressure and heart rate were higher in SHR(S) (177+/-2 mm Hg, 357+/-12 bpm versus 121+/-1 mm Hg, 320+/-9 bpm in WKY(S); P<0.05). Training was equally effective to enhance treadmill performance and to cause resting bradycardia (-10%) in both groups. Training-induced blood pressure fall (-6.3%) was observed only in SHR(T). In SHR(S) (versus WKY(S)) AT(1A) and Aogen mRNA expression were significantly increased within the NTS and area postrema (average of +67% and +41% for AT(1A) and Aogen, respectively; P<0.05) but unchanged in the gracilis nucleus. Training did not change AT(1A) expression but reduced NTS and area postrema Aogen mRNA densities specifically in SHR(T) (P<0.05 versus SHR(S), with values within the range of WKY groups). In SHRs, NTS Aogen mRNA expression was correlated with resting pressure (y=5.95x +41; r=0.55; P<0.05), with no significant correlation in the WKY group. Concurrent training-induced reductions of both Aogen mRNA expression in brain stem cardiovascular-controlling areas and mean arterial pressure only in SHRs suggest that training is as efficient as the renin-angiotensin blockers to reduce brain renin-angiotensin system overactivity and to decrease arterial pressure.

Background: Baroreceptor reflexes are regulated by nerve terminals of the glossopharyngeal and vagal nerves. The body of pressure-sensitive neurons of these nerves is located in the petrosal ganglion of both nerves. We examined whether there is a relationship between the neuron numbers of the inferior ganglion of the glossopharyngeal nerve and blood pressure values., Methods: Petrosal ganglions were examined in 18 male hybrid rabbits divided into three equal groups: Group A normotensive (TA=90-100 mmHg), Group B hypertensive (TA>100 mmHg); and Group C hypotensive (TA<90 mmHg). After examination of blood pressure for one week, all animals were sacrificed, and the petrosal ganglions extracted bilaterally and examined histopathologically using the physical dissector method., Results: The mean (+/-SD) neuronal density was: Group A 8700+/-200, Group B 7800+/-250 and Group C 9800+/-300, respectively. The difference between the groups B and C as compared to A was significant (p<0.01) while the difference between Groups B and C was highly significant (p<0.001)., Conclusions: An inverse relationship was noticed between the neuronal density in the petrosal ganglion and blood pressure values with potential implications in the study of the etiology of hypertension.

Whole cell patch-clamp measurements were made in neurons enzymatically dispersed from the nucleus of the solitary tract (NTS) to determine if alterations occur in voltage-dependent potassium channels from rats made hypertensive (HT) by unilateral nephrectomy/renal wrap for 4 wk. Some rats had the fluorescent tracer DiA applied to the aortic nerve before the experiment to identify NTS neurons receiving monosynaptic baroreceptor afferent inputs. Mean arterial pressure (MAP) was greater in 4-wk HT (165 +/- 5 mmHg, n = 26, P < 0.001) rats compared with normotensive (NT) rats (109 +/- 3 mmHg measured in 10 of 69 rats). Transient outward currents (TOCs) were observed in 67-82% of NTS neurons from NT and HT rats. At activation voltages from -10 to +10 mV, TOCs were significantly less in HT neurons compared with those observed in NT neurons (P < 0.001). There were no differences in the voltage-dependent activation kinetics, the voltage dependence of steady-state inactivation, and the rise and decay time constants of the TOCs comparing neurons isolated from NT and HT rats. The 4-aminopyridine-sensitive component of the TOC was significantly less in neurons from HT compared with NT rats (P < 0.001), whereas steady-state outward currents, whether or not sensitive to 4-aminopyridine or tetraethylammonium, were not different. Delayed excitation, studied under current clamp, was observed in 60-80% of NTS neurons from NT and HT rats and was not different comparing neurons from NT and HT rats. However, examination of the subset of NTS neurons exhibiting somatic DiA fluorescence revealed that DiA-labeled neurons from HT rats had a significantly shorter duration delayed excitation (n = 8 cells, P = 0.022) than DiA-labeled neurons from NT rats (n = 7 cells). Neurons with delayed excitation from HT rats had a significantly broader first action potential (AP) and a slower maximal downstroke velocity of repolarization compared with NT neurons with delayed excitation (P = 0.016 and P = 0.014, respectively). The number of APs in the first 200 ms of a sustained depolarization was greater in HT than NT neurons (P = 0.012). These results suggest that HT of 4-wk duration reduces TOCs in NTS neurons, and this contributes to reduced delayed excitation and increased AP responses to depolarizing inputs. Such changes could alter baroreflex function in hypertension.

Intractable hiccup and nausea (IHN) was found in eight of 47 cases of relapsing neuromyelitis optica (NMO) (17%) but in none of 130 cases of multiple sclerosis (MS). IHN resolved with methylprednisolone. In six cases, MRI detected linear medullary lesions involving the pericanal region, the area postrema, and the nucleus tractus solitarius. Like long and centrally located myelitis, a linear medullary lesion causing IHN may distinguish NMO from MS.

Central sleep apnoea (CSA) is a breathing disorder characterized by repetitive central apnoeas with hypoxia interrupted by hyperventilation phases. In the literature, there are reports of CSA caused by brainstem infarcts. We report two patients (38 and 53 years old) with longstanding history of central sleep apnoea who died during sleep. In both cases the autopsy revealed acute bilateral hypoxic lesions at the level of the solitary tract nuclei. In one case, symmetrical selective neuronal necrosis was found in the dorsal part of the solitary tract nuclei. A chronic obstructive vasculopathy was also found, with thickening and fibrosis of the smallest vessels of the medullary tegmentum. In the other case, bilateral infarctions were found with the base at the ependymal lining of the 4th ventricle floor and the apex towards the solitary tract. An acute intramural hemorrhagic lesion in the premedullary segment of the left vertebral artery was also found. Episodes of hypoxemic hypoxia during sleep may worsen the effects of focal oligohemic hypoxia in the medullary tegmentum. Selective stroke of the solitary tract nuclei may be the acute fatal lesion in patients with both central sleep apnoea and lesions of the vertebro-basilar system. To the best of our knowledge, this is the first neuropathologic report of acute medullary ischemic-hypoxic lesions which may not be considered the cause of the CSA because of their recent onset. Our findings suggest that CSA, besides being caused by ischemic events at the level of the medulla, may also contribute to pathogenesis of strokes, through hypoxia or hemodynamic oscillations.

We measured the cross-sectional area (CSA) of the human tractus solitarius (HTS) with the help of an image-analyzer system on a cross section of the upper part of the medulla oblongata in 44 Japanese cadavers (22 males and 22 females) and examined the relationship between age, sex and whether the subjects were dentulous or edentulous. The results showed no significant differences between the left and right sides of the HTS in either male or female subjects. However, the size of HTS decreased slightly with age in males but not at all in females, whereas tooth loss had a definite incidence on the size of HTS in females but not in male, as the CSA was smaller in edentulous females but not in edentulous males. This would tend to indicate that a decreases in taste function is connected with the aging process in male, and with tooth loss in females.

Sudden infant death syndrome (SIDS) "gray zone" or borderline cases are defined as those cases in which it is difficult to establish whether the pathological findings are sufficiently severe to have caused the death. Examination of the brainstem in 103 cases of SIDS disclosed five SIDS "gray zone" cases in which only further investigations of serial sections successfully identified anatomico-pathological findings that likely represent the morphological substrates for a sudden reflexogenic death. A complete autopsy was performed, including close examination of the brainstem and cardiac conduction system, according to our guidelines. Our five cases are consistent with the triple-risk model of SIDS, a hypothesis postulating an underlying biological vulnerability to exogenous stressors or triggering factors in a critical developmental period. Inflammatory infiltrates (cases 1 and 2), necrotic focus of the solitary tract (case 3), hemangioendothelioma (case 4) and mild pneumonia (case 5) alone might or might not have accounted for the sudden deaths, if it had not been for the location and/or concomitant presence of brainstem abnormalities that could have had a triggering role in causing the sudden death of these babies.

The factors underlying the sudden infant death syndrome (SIDS) are still unknown, but in recent years much attention has been focused on the central cardiorespiratory control system. In the present work we analyzed the nucleus tractus solitarii (nTS) of 23 SIDS victims and 17 age-matched control cases. We studied the functional and morphological alterations of neurons and glial cells to evaluate the results of possible hypoxic-ischemic injury that could have led to sudden death. Morphometric and immunohistochemical analyses were performed on medullary sections. In the nTS of SIDS victims we observed modifications of both neuronal and glial cells. Brain injury triggers the activation of both astrocytes and microglia, which respond to neuronal damage by characteristic changes that could explain our observations in the nTS of SIDS victims. In our investigation of the nTS of SIDS victims we found a significant increase of reactive astrocytes density, a significantly higher percentage of necrotic cells, an increase of reactive microglial cells density, a significantly higher expression of substance P and the presence of NMDA receptors immunoreactivity. Our results support the hypothesis that there is injury of the nTS neurons in SIDS victims, even if the causes of this damage are still unknown. This neuronal damage may explain why adequate ventilation is often not maintained during hypoxia. Such histological findings have never been thought sufficient to explain SIDS, but the tissue findings could be an indication of the impairment of several pathophysiological mechanisms which may underlie brainstem dysfunction, affecting cardiorespiratory control.

The dorsal portion of the nucleus tractus solitarii (NTS) shows selective dendritic lesions in adults who died after an episode of acute heart failure, suggesting excitotoxic glutamate-induced neuronal death. Cerebral hypoxia and/or ischaemia also produce hyperexpression of specific genes (c-fos, c-jun) which may be involved, in vulnerable districts, in the mechanisms of excitotoxic neuronal death. In the present study, we examined NTS in 23 adults, who died shortly after an ischaemic and/or hypoxic event, on transverse serial sections of the medulla, stained with haematoxylineosin, Nissl, Klüver-Barrera and Luxol fast blue, and immunohistochemical staining by anti-tyrosine hydroxylase and anti-Fos. In 10 cases, at the level of the dorsal portion of the NTS, corresponding to the subnucleus gelatinosus, bilateral symmetrical hypereosinophilic areas and strong Fos-like immunoreactivity were detected. The hypoxic-ischaemic origin of these findings was supported by the strong hypereosinophilic appearance and shrinking of neurons, and by selective Fos-like immunoreactivity, the expression of Fos being mainly associated with cellular damage and subsequent death following hypoxic-ischaemic injury. In 7 other cases, Fos-like immunoreactivity was found at the level of the subnucleus gelatinosus, in the absence of hypereosinophilia or pyknosis in histological staining. The immediate-early gene expression induces to ascribe the absence of morphologically evident hypoxicischaemic lesions to the rapidity of death. The selective vulnerability of the subnucleus gelatinosus to hypoxic-ischaemic injury may not only be explained with reference to vascularization of the medullary tegmentum, but also to the structural and functional characteristics of the subnucleus itself.

The inhibitory amino acid GABA is released within the nucleus of the solitary tract (NTS) during hypoxia and modulates the respiratory response to hypoxia. To determine if responses of NTS neurons to activation of GABA(A) receptors are altered following exposure to chronic hypoxia, GABA(A) receptor-evoked whole cell currents were measured in enzymatically dispersed NTS neurons from normoxic and chronic hypoxic rats. Chronic hypoxic rats were exposed to 10% O(2) for 9-12 days. Membrane capacitance was the same in neurons from normoxic (6.9+/-0.5 pF, n=16) and hypoxic (6.3+/-0.5 pF, n=15) rats. The EC(50) for peak GABA-evoked current density was significantly greater in neurons from hypoxic (21.7+/-2.2 microM) compared to normoxic rats (12.2+/-0.9 microM) (p<0.001). Peak and 5-s adapted GABA currents evoked by 1, 3 and 10 microM were greater in neurons from normoxic compared to hypoxic rats (p<0.05) whereas peak and 5-s adapted responses to 30 and 100 microM GABA were not different comparing normoxic to hypoxic rats. Desensitization of GABA(A)-evoked currents was observed at concentrations greater than 3 microM and, measured as the ratio of the current 5 s after the onset of 100 microM GABA application to the peak GABA current, was the same in neurons from normoxic (0.37+/-0.03) and hypoxic rats (0.33+/-0.04). Reduced sensitivity to GABA(A) receptor-evoked inhibition in chronic hypoxia could influence chemoreceptor afferent integration by NTS neurons.

The expression of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor subunits GluR1-4 in the nucleus of the solitary tract (NTS) of adult Wistar rats was examined by polymerase chain reaction (PCR), and the neuronal localisation of these receptor subunits in the NTS were confirmed by immunohistochemistry using subunit-specific antibodies. Semi-quantitative PCR was used to investigate differences in AMPA receptor subunit expression between spontaneously hypertensive rats (SH) and age-matched normotensive Wistar Kyoto rats (WKY). All four receptor subunits were expressed in both strains, but compared to WKY, total AMPA receptor and the GluR3 mRNA expressions were significantly higher in SH. No differences were detected in cDNA form the cerebral cortex or cerebellum. Immunolabelling for GluRs 1, 2 and 2/3 in the neuropil relative to neuronal somata in the cardioregulatory areas of the NTS appeared to be increased in SH, with an overall increase in the density of GluR2/3 labelling in the medial and commissural NTS of SH. These results indicate a possible role for changes in AMPA receptor subunit expression in NTS neurones, involving an increase in GluR3 associated with development of hypertension in SH.

Acute electrolytic lesions of the commissural nucleus of the solitary tract (commNTS) reduce blood pressure (BP) in SHR but not in normotensive Wistar-Kyoto and Wistar rats and abolish the pressor response to intravenous injection of potassium cyanide. We investigated the chronic effect of commNTS lesions on mean arterial pressure (MAP), and on baroreceptor and chemoreceptor reflex responses in SHR. The contribution of the sympathetic nervous system and the hormones vasopressin and angiotensin II to maintenance of BP in lesioned SHR was also investigated. MAP fell to normotensive levels the day after lesioning the commNTS but returned to the hypertensive level 9 days later. The reflex tachycardia evoked by sodium nitroprusside remained attenuated for 10 days after commNTS lesions but became enhanced 30 days after commNTS lesions. The pressor component of the chemoreflex elicited by potassium cyanide remained blocked for 30 days after lesions. Vasopressin antagonist or ACE blocker did not change MAP in sham or commNTS-lesioned SHR. Ganglionic blockade with hexamethonium elicited similar reductions in MAP in sham and commNTS-lesioned SHR. Results demonstrated that commNTS lesions in SHR produce a transient fall in BP and a long-lasting inhibition of the pressor response of the chemoreflex. Therefore, the blockade of the pressor response to peripheral chemoreflex activation is not sufficient to chronically reduce MAP in SHR. In the chronic absence of the commNTS, other subnuclei of the NTS or other brain stem nuclei may reorganize to replace the function of commNTS neurons, restoring sympathetic activity and high BP in SHR.

Bilateral lesions of the nuclei prepositus hypoglossi produced a more than twofold decrease in the mean frequency discharges in the neurons of the nucleus coeruleus. The number of neurons with burst activity and the number of polymodal neurons substantially increased. Lesion of the nucleus tractus solitarius resulted in an increase in the number of neurons with regular activity and certain decrease in the mean discharge frequency of coeruleus neurons. The results confirm the suggestion about a substantial role of the nucleus prepositus hypoglossi in relaying afferent effects to the activity of locus coeruleus neurons.

We previously demonstrated that morphine withdrawal induced hyperactivity of noradrenergic pathways innervating the hypothalamic paraventricular nucleus (PVN) in rats, in parallel with an increase in the neurosecretory activity of the hypothalamus-pituitary-adrenocortical (HPA) axis, as evaluated by corticosterone release. These neuroendocrine effects were dependent on stimulation of alpha-adrenoceptors. In the present study, Fos immunostaining was used as a reflection of neuronal activity and combined with immunostaining for tyrosine hydroxylase (TH) for immunohistochemical identification of active neurones during morphine withdrawal. Dependence on morphine was induced by 7-day chronic subcutaneous implantation of six morphine pellets (75 mg). Morphine withdrawal was precipitated by administration of naloxone (5 mg/kg subcutaneously) on day 8. Fos immunoreactivity in the PVN and also in the nucleus tractus solitarius (NTS)-A2 and ventrolateral medulla (VLM)-A1 cell groups, which project to the PVN, increased during morphine withdrawal. Following withdrawal, Fos immunoreactivity was present in most of the TH-positive neurones of the A2 and A1 neurones. In a second study, the effects of administration of adrenoceptor antagonists on withdrawal-induced Fos expression in the PVN were studied. Pre-treatment with alpha1- or alpha2-adrenoceptor antagonists, prazosin (1 mg/kg intraperitoneally) and yohimbine (1 mg/kg intraperitoneally), respectively, 20 min before naloxone administration to morphine-dependent rats markedly reduced Fos expression in the PVN. Similarly, pre-treatment with the beta antagonist, propranolol (3 mg/kg intraperitoneally), significantly prevented withdrawal-induced Fos expression. Collectively, these results suggest the hypothesis that noradrenergic neurones in the brainstem innervating the PVN are active during morphine withdrawal, and that activation of transcriptional responses mediated by Fos in the HPA axis following withdrawal are dependent upon hypothalamic alpha- and beta-adrenoceptors.

Neurons in the commissural nucleus of the solitary tract (commNTS) play an important role in certain cardiovascular responses dependent on sympathetic vasoconstrictor activation, including the arterial chemoreceptor reflex. Electrolytic lesions of the commNTS elicit a fall in arterial pressure (AP) in spontaneously hypertensive rats (SHR). To determine whether the latter result 1) arose from elimination of commNTS neuronal activity rather than en passant axons and 2) was accompanied by a reduction in sympathetic nerve activity, we evaluated the effect of inhibition of neurons in the commNTS on basal splanchnic sympathetic nerve activity (SNA), AP, and heart rate (HR) in SHR, Wistar-Kyoto (WKY), and Sprague-Dawley (SD) rats. In chloralose-anesthetized, paralyzed, and artificially ventilated SHR, microinjection of GABA into the commNTS markedly decreased splanchnic SNA, AP, and HR. The reductions in SNA and AP following similar microinjections in WKY and SD rats were significantly less than those in SHR. Our findings suggest that tonically active neurons in the commNTS contribute to the maintenance of SNA and the hypertension in SHR. The level of tonic discharge of these commNTS neurons in normotensive WKY and SD rats may be lower than in SHR.

Infrared (IR) microspectroscopy was used to detect disease-associated molecular changes spatially resolved in cryosections of scrapie-infected tissue of the CNS. The results show that IR spectra can be used for the discrimination between normal and 263K scrapie-infected hamster nervous tissue not only in the terminal stage of the disease but also in early clinical and even in the preclinical stage at 90 d after oral infection. The nuclei of the cranial nerves located in the medulla oblongata were especially well suited for an early detection of the diseased state by IR microspectroscopy. The most prominent molecular changes indicated by the IR spectra were located between 1300 and 1000 cm(-1), a region that contains contributions primarily from carbohydrates and the phosphate backbones of nucleic acids but also from membrane constituents.

A 64-year-old man died in spite of surgery 4 days after attempting suicide. He first tried to hang himself with a rope and when the hanging did not succeed, he cut his throat with a knife. The autopsy showed four sutured cervical wounds with laryngeal wounds but without associated important vascular injury. The neuropathological study revealed two watershed-type haemorrhagic infarcts, involving the left occipital lobe and the left cerebellum. It also showed a symmetrical necrosis of solitary tract nuclei in the medullary tegmentum. Such a lesion is likely to result from sudden acute transient circulatory failure and might have played a role in the secondary autonomous cardiac and respiratory dysfunctions following a non-lethal trauma.

In this report we describe the respiratory patterns of six patients with Leigh syndrome, including two individual cases with accompanying clinical phenotypes of Alpers disease and mitochondrial encephalopathy with ragged red fibers. In five cases where sleep apnea was monitored, each one showed isolated or post-sigh central apnea, hiccup, apneusis-like breathing and obstructive apnea in various combinations. The remaining patient with Alpers/Leigh overlap syndrome showed an apneusis-like pattern of dyspnea. The sleep structure was examined in three patients. Two patients with brainstem lesions showed a decrease in the deep sleep stages and an absence of REM sleep. Medullary lesions were found in four patients by magnetic resonance imaging or at autopsy and involved predominantly the dorsal respiratory group (DRG) of medullary neurons. The role of DRG lesions in the pathophysiology of respiratory symptoms in Leigh syndrome is discussed.

It has been suggested that increased sympathetic activity and arterial chemoreceptors are important for the high blood pressure in spontaneously hypertensive rats (SHR). Electrolytic lesions of the commissural nucleus of the solitary tract (commNTS) abolish (1) the cardiovascular responses to chemoreflex activation with potassium cyanide (KCN) in normotensive rats and (2) the hypertension that follows acute aortic baroreceptor denervation in rats. Therefore, in this study we investigated the effects of electrolytic lesions of the commNTS on basal mean arterial pressure (MAP), baroreflex, and chemoreflex in SHR and in normotensive control Wistar-Kyoto (WKY) and Wistar rats. CommNTS lesions elicited a dramatic fall in MAP to normal levels during the period of study (from the first to fourth day following lesions) in SHR and almost no changes in WKY and Wistar rats. The pressor responses to chemoreflex activation with KCN tested in the days 1 and 4 after commNTS lesions were abolished in SHR and in normotensive strains. The reflex tachycardia induced by sodium nitroprusside was also attenuated in days 1 and 4 after commNTS lesions in SHR, WKY, and Wistar rats. The data suggest that the integrity of commNTS is important for the maintenance of high blood pressure in SHR and for the reflex responses dependent on sympathetic activation either in SHR or in normotensive strains.

Rats with ibotenic acid lesions of the parabrachial nucleus (PBN) failed to learn a taste aversion induced by lithium chloride (LiCl) toxicosis. The same rats also did not learn to prefer a taste that was paired with intragastric (IG) carbohydrate infusions during 22 hr/day trials. The PBN-lesioned rats did learn to prefer a flavor (odor + taste) paired with the IG carbohydrate infusions over a different flavor paired with IG water. The PBN-lesioned rats also learned to avoid a flavor paired with IG LiCl infusions during 22 hr/day trials. The flavor preference and aversion, however, were less pronounced than those displayed by control rats. These data indicate that the PBN is essential for forming orosensory-viscerosensory associations when taste is the primary cue but is less critical when more complex flavor cues are available.

Portal hypertension due to either prehepatic portal hypertension or cirrhosis is associated with cardiovascular derangement. We aimed to delineate regulatory mechanisms in the brain stem cardiovascular nuclei in rat models of prehepatic portal hypertension and cirrhosis. Neuronal activation in the nucleus of the solitary tract (NTS) and ventrolateral medulla (VLM) were assessed by immunohistochemical staining for the immediate-early gene product Fos. In the same sections, catecholaminergic neurons were counted by tyrosine hydroxylase (TH) staining. Ninety minutes after hypotensive hemorrhage (or no volume challenge), the animals were killed for Fos and TH medullary staining. These protocols were repeated after capsaicin administration. The NTS of unchallenged sham-operated rats had scant Fos-positive cells (3.6 +/- 0.4 cells/section), whereas hemorrhage significantly increased Fos staining (91.8 +/- 14). In contrast, the unchallenged portal hypertensive and cirrhotic groups showed increased Fos staining (14.3 +/- 5.8 and 32.8 +/- 2.8, respectively), which hemorrhage did not alter significantly. The numbers of TH-positive cells were similar in the three unchallenged groups; double labeling revealed that approximately 50% of TH-positive cells were activated by hemorrhage in the sham and cirrhotic rats but not the portal hypertensive rats. Similar patterns of Fos and TH staining were observed in the VLM. Capsaicin treatment not only significantly reduced the Fos-positive neuron numbers in portal hypertensive and cirrhotic rats but also attenuated hemorrhage-induced Fos and double-positive cells in both NTS and VLM. These results suggest that disordered trafficking in capsaicin-sensitive nerves and central dysregulation contribute to blunted cardiovascular responsiveness in cirrhosis and prehepatic portal hypertension.

Partial elimination of vagal sensory afferents by subdiaphragmatic vagal section has variously been reported to eliminate, to reduce, or to have no effect on fever produced by peripheral lipopolysaccharide and interleukin-1beta (IL-1beta). However, to adequately test the idea that vagal afferents convey immune information to the brain, all vagal input to the central nervous system must be eliminated. This was accomplished by bilateral electrolytic lesions of the nucleus tractus solitarius (NTS). Reflex bradycardia evoked by intravenous phenylbiguanide was eliminated in NTS-lesioned rats, verifying the lesion's effectiveness. IL-1beta (2 microg/kg) was given to conscious, unrestrained rats via an indwelling intraperitoneal catheter and produced rapid fever (approximately 1 degree C) with an onset latency of 15 min and peak response at 30 min, with a second, smaller peak at 130 min. NTS lesions attenuated the first fever peak, with a lesser, non-significant effect on the second peak. The thermogenic capacity of NTS-lesioned rats was evaluated using 3 different strategies: (1) thermogenesis evoked by CNS injections of prostaglandin E2, (2) 3 h exposure to a 4 degrees C environment, and (3) heat production of intrascapular brown fat produced by intravenous infusion of the beta3-adrenergic agonist BRL 37344. NTS-lesioned rats were equivalent, or even superior to control animals in their thermogenic response to these non-immune-related stimuli. Therefore, the impaired febrile response of NTS-lesioned rats to IL-1beta cannot be attributed to reduced thermogenic capacity. Finally, these results suggest that fever elicited by intraperitoneal IL-1beta is, at least in part, dependent on the integrity of NTS neurons, but also that mechanisms independent of vagal afferent projections to the NTS must also play a role in immune-to-brain signaling.

Background: A 52-year-old woman with metastases in brain and bone had clinical and radiological response to therapy but died about 10 weeks after diagnosis. General autopsy failed to identify a primary neoplasm or an anatomic cause of death. Investigation of sudden respiratory cessation was a consideration when undertaking an anatomic study of the brain., Methods: Review of patient records and careful examination of the brain following autopsy were carried out., Results: The patient had terminal episodes of hypersomnia but episodes of sleep apnea were not observed. She received no respiratory support and no respiratory difficulties were recorded until she was pronounced dead at 7 a.m. Autopsy revealed metastatic adenocarcinoma in a pattern suggestive of a primary pulmonary neoplasm, including multiple cerebral metastases, although no significant pulmonary lesions of any type were found. A 0.2 cm metastatic adenocarcinoma was found in the nucleus of the tractus solitarius (NTS). No other tumor was present in the brain stem., Conclusions: Unilateral destruction of the NTS in the medulla would have severely disturbed the most critical point of convergence of autonomic and voluntary respiratory control and of cardiocirculatory reflexes in the central autonomic network. It is postulated that this caused respiratory arrest during a state transition from sleeping to waking. Few metastases to the medulla are reported, most are relatively large, and several have caused respiratory symptoms before death. The very small metastasis in our patient could be the direct anatomic cause of death, and as such it is an unusual complication of metastatic disease of which clinicians should be aware. It is speculated that dysfunction of direct NTS connections to the pons or of connections passing close to the metastatic deposit resulted in terminal hypersomnia.