Area postrema and adjacent solitary nucleus in water and energy balance

Lesions of the area postrema (AP) and immediately adjacent nucleus tractus solitarii cause a syndrome of permanent weight loss with little disruption to behavioral controls of body weight regulation. There is also a permanent polydipsia and elevated salt appetite, which appear to be secondary to deficits in renal conservation of water and sodium. Neuroanatomical studies indicate that the immediately adjacent solitary nucleus and AP are sites of termination of visceral afferents from abdominal organs and the destination and origin of distant central afferent and efferent connections.     

Noradrenergic alpha 2 binding sites in vagal dorsal motor nucleus and nucleus tractus solitarius: autoradiographic localization

The distribution in the canine medulla oblongata of binding sites for p-[3H]aminoclonidine, a ligand specific for alpha 2-adrenergic receptors, was studied with light microscopic autoradiographic methods. Specific labelling was determined using unlabelled phentolamine as a displacer. The greatest density of sites was localized in the dorsal motor nucleus of the vagus nerve, the area postrema, and in several regions of the nucleus tractus solitarius. Less dense binding of the radioligand was also seen in the inferior olivary nucleus. Dorsomedial regions of the nucleus tractus solitarius were the most densely labelled in this nucleus, and dorsolateral and ventral regions were much less densely labelled. The region of the nucleus tractus solitarius shown in this study to be heavily labelled with alpha 2-adrenergic binding sites has been implicated in the autonomic control of blood pressure. The dorsal motor nucleus of the vagus, together with the nucleus tractus solitarius, may thus represent the site of the antihypertensive action of the drug clonidine, an alpha 2-adrenoreceptor agonist.     

Anorectic effect of calcitonin, neurotensin and bombesin infused in the area of the rostral part of the nucleus of the tractus solitarius in the rat

The three neuropeptides calcitonin, neurotensin and bombesin can decrease food intake in the rat when injected into the cerebral ventricles or into the paraventricular nucleus of the hypothalamus. The paraventricular nucleus of the hypothalamus is an important site for the integration of visceral and endocrine systems, and has connections with the nucleus of the tractus solitarius which is a major locus for visceral afferents. Since calcitonin, neurotensin and bombesin, or their receptors, have been found to be present in the nucleus of the tractus solitarius, we tested the effects of local infusions of these peptides on food intake. The peptides were microinjected in a 0.25 microliter volume in rats trained to eat for only 3 hours per day. The injections were made in the rostral part of the nucleus and surrounding areas, through the lateral vestibular nuclei, to avoid leakage of the peptides into the cerebrospinal fluid. In the nucleus of the tractus solitarius the three peptides decreased food intake by more than 50%. The peptides were also active in the spinal trigeminal nucleus oralis, and, for calcitonin and bombesin, in the reticular formation under the nucleus of the tractus solitarius. A local diffusion from the point of injection may explain some of these results. Therefore, the area of the nucleus of the tractus solitarius is a nonhypothalamic site where these peptides can act to produce anorexia.     

迷走神经背核的研究进展

迷走神经背核（ＤＭＶ）是一个重要的内脏运动核团和内脏感觉核团。ＤＭＶ与中枢及外周存在广泛的纤维联系。ＤＭＶ和孤束核、最后区一起构成了“迷走感觉运动中枢”。ＤＭＶ存在神经－体液回路,使ＤＭＶ神经元可以直接感受外周血及脑脊液中的信息。ＤＭＶ含乙酰胆碱、儿茶酚胺、神经肽类等多种递质及相应受体。ＤＭＶ参与中枢调节胃肠、心血管及内分泌等生理功能。     

Glutamatergic mechanisms in the nucleus tractus solitarius in blood pressure control

The nucleus tractus solitarius (NTS), the site of termination of visceral afferents of the ninth and tenth cranial nerves, mediates and integrates the reflex cardiovascular and noncardiovascular responses to stimulation of cardiopulmonary and other visceral afferents. On injection into the NTS, the amino acid L-glutamate (L-Glu) and its excitatory analogs produce dose-dependent hypotension and bradycardia, a baroreceptor reflex-like response. The L-Glu antagonist glutamate diethyl ester blocks the response both to L-Glu and to baroreceptor reflex activation. Electrical stimulation of vagal c-fibers selectively releases 3H into a push-pull cannula after preloading of the NTS with L-[3H]Glu or D-[3H]aspartate. The NTS contains a high-affinity uptake system for inactivation of L-Glu. Like L-Glu, acetylcholine and serotonin, which are also found in the NTS, both elicit a baroreceptor reflex-like response when microinjected into the NTS. However, cholinergic and serotonergic antagonists do not block the baroreceptor reflex. A glutamatergic neuron (or neurons) projecting into NTS appears to be an integral part of the baroreceptor reflex arc.     

Possible mechanisms of the anterior limbic cortex influence on the neuron activity of the vago-solitary complex

In ananesthetized cats, neurons of the nucleus of the tractus solitarius (NTS) and the dorsal motor nucleus of the vagus nerve (DMNV) revealed phasic excitatory responses to separate single vagal and cortical stimuli. Stimulation of the anterior limbic cortex combined with vagal stimulation resulted in inhibitory or excitatory modification of the vagal induced responses of the NTS and DMNV neurons. The data obtained suggest that complete inhibitory effects are related to general cortical mechanisms of control of the functional state of the brain stem visceral neurons. Selective inhibition of the vagal induced responses by limbic cortex stimulation is due to particular cortical mechanisms of the visceral sensory transmission control via the NTS neurons.     

孤束核内微量注射乙酰胆碱对刺激兔下丘脑诱发期前收缩的影响

电刺激兔下丘脑乳头体及其周围区域诱发期前收缩(HSE)。电刺激一侧颈迷走神经中枢端,或电刺激延髓孤束核区域(NTS),均使HSE数减少。而电刺激延髓最后区、网状结构内2/3区域的背侧部以及三叉脊束核等区域对HSE数影响不大。NTS内微量注射乙酰胆碱,使HSE数减少。NTS内微量注射阿托品,可减弱刺激迷走神经对HSE的抑制作用。上述结果提示:电刺激颈迷走神经中枢端对HSE有抑制作用,此作用可能与延髓孤束核内乙酰胆碱的释放有关。     

Sources of ascending afferent projections to the midbrain central tegmental area and centrum medianum thalami in cats

After microinjections of horseradish peroxidase into the central tegmental area of the midbrain and centrum medianum thalami in cats, labeled neurons were found in the nucleus of the tractus solitarius, gracile and cuneate nuclei, spinal nuclei of the trigeminal nerve, the external nucleus and nucleus of the brachium of the inferior colliculus, the medial pretectal region, nucleus of the posterior commissure and stratum intermediale of the superior colliculus, and reticular structures of the medulla and pons. Comparison of the location of the sources of ascending afferent projections in the central tegmental area of the midbrain and centrum medianum thalami showed that the reticular formation receives mainly visceral projections through the nucleus of the tractus solitarius, whereas the centrum medianum thalami is innervated mainly by the system of sensory somatic nuclei.I. P. Pavlov Institute of Physiology, Academy of Sciences of the USSR, Leningrad. Translated from Neirofiziologiya, Vol. 14, No. 2, pp. 172–178, March–April, 1982.     

Action of substance P and one of its synthetic antagonists on the nucleus tractus solitarius

The study aims to establish the nature of the chemical mediator which produces the IP (presynaptic inhibition) of the mechanoreceptive afferents reaching the NTS (nucleus tractus solitarius) of the frog. To this end we have examined the effects of the administration of SP (substance P) and of one of its antagonists in the IV ventricle, in both normal and unilaterally axotomized preparations at the level of the glossopharyngeal nerve. In particular we have examined the size of the afferent discharge of the glossopharyngeal-hypoglossus reflex arc and the PAD (primary afferent depolarization) phenomena recorded from the dorsal root of the XII. While in normal preparations the SP reduces the size of the reflex discharge, on the contrary the antagonist increases it; the electrical activity of PAD appears to be enhanced by SP and reduced by the antagonist. Lastly SP normalises the enhanced response produced by axotomy. All the observed effects favour the hypothesis that the IP, which appears in the NTS with the activation of the mechanoreceptive afferents, is brought about by the release of S.P. from their central endings.     

Ozone inhalation activates stress-responsive regions of the CNS

Ozone (O(3)), a major component of air pollution, has considerable impact on public health. Besides the well-described respiratory tract inflammation and dysfunctions, there is accumulating evidence indicating that O(3) exposure affects brain functions. However, the mechanisms through which O(3) exerts toxic effects on the brain remain poorly understood. This work aimed at precisely characterizing CNS neuronal activation after O(3) inhalation using Fos staining in adult rat. We showed that, together with lung inflammation, O(3) exposure caused a sustained time- and dose-dependent neuronal activation in the dorsolateral regions of the nucleus tractus solitarius overlapping terminal fields of lung afferents running in vagus nerves. Furthermore, we highlighted neuronal activation in interconnected central structures such as the caudal ventrolateral medulla, the parabrachial nucleus, the central nucleus of the amygdala, the bed nucleus of the stria terminalis and the paraventricular hypothalamic nucleus. In contrast, we did not detect any neuronal activation in the thoracic spinal cord where lung afferents running in spinal nerves terminate. Overall, our results demonstrate that O(3) challenge evokes a lung inflammation that induces the activation of nucleus tractus solitarius neurons through the vagus nerves and promotes neuronal activation in stress-responsive regions of the CNS.     

Characterization by stimulation of medullary mechanisms underlying gasping neurogenesis

Our purpose was to evaluate the hypothesis that neurons in the lateral tegmental field of the medulla comprise a pattern generator for neurogenesis of gasping. Stimulations in this area produced changes characteristic of pattern generators in other systems. These included shifts in gasping rhythm and refractory periods for eliciting gasps; the latter varied inversely with spontaneous gasping frequency. These responses were recorded from activities of phrenic and hypoglossal nerves of decerebrate, cerebellectomized, vagotomized, paralyzed, and ventilated cats. Gasping followed freezing the brain stem between pons and medulla. In addition to lateral tegmental loci, gasps were elicited by stimulating areas extending lateral to the nucleus ambiguus and medial to the contralateral medulla. These areas are envisaged to contain axons to or from the pattern generator of lateral tegmental field. Finally, stimulations in sites approximating nucleus tractus solitarius and nucleus ambiguus delayed spontaneous gasps and terminated ongoing gasps. Current required to terminate gasps fell during neural inspiration. Our data are consistent with the lateral tegmental field of medulla comprising a central pattern generator for gasping and pacemaker elements being a component of this pattern generator.     

Gastrointestinal hormones regulating appetite

The role of gastrointestinal hormones in the regulation of appetite is reviewed. The gastrointestinal tract is the largest endocrine organ in the body. Gut hormones function to optimize the process of digestion and absorption of nutrients by the gut. In this capacity, their local effects on gastrointestinal motility and secretion have been well characterized. By altering the rate at which nutrients are delivered to compartments of the alimentary canal, the control of food intake arguably constitutes another point at which intervention may promote efficient digestion and nutrient uptake. In recent decades, gut hormones have come to occupy a central place in the complex neuroendocrine interactions that underlie the regulation of energy balance. Many gut peptides have been shown to influence energy intake. The most well studied in this regard are cholecystokinin (CCK), pancreatic polypeptide, peptide YY, glucagon-like peptide-1 (GLP-1), oxyntomodulin and ghrelin. With the exception of ghrelin, these hormones act to increase satiety and decrease food intake. The mechanisms by which gut hormones modify feeding are the subject of ongoing investigation. Local effects such as the inhibition of gastric emptying might contribute to the decrease in energy intake. Activation of mechanoreceptors as a result of gastric distension may inhibit further food intake via neural reflex arcs. Circulating gut hormones have also been shown to act directly on neurons in hypothalamic and brainstem centres of appetite control. The median eminence and area postrema are characterized by a deficiency of the blood-brain barrier. Some investigators argue that this renders neighbouring structures, such as the arcuate nucleus of the hypothalamus and the nucleus of the tractus solitarius in the brainstem, susceptible to influence by circulating factors. Extensive reciprocal connections exist between these areas and the hypothalamic paraventricular nucleus and other energy-regulating centres of the central nervous system. In this way, hormonal signals from the gut may be translated into the subjective sensation of satiety. Moreover, the importance of the brain-gut axis in the control of food intake is reflected in the dual role exhibited by many gut peptides as both hormones and neurotransmitters. Peptides such as CCK and GLP-1 are expressed in neurons projecting both into and out of areas of the central nervous system critical to energy balance. The global increase in the incidence of obesity and the associated burden of morbidity has imparted greater urgency to understanding the processes of appetite control. Appetite regulation offers an integrated model of a brain-gut axis comprising both endocrine and neurological systems. As physiological mediators of satiety, gut hormones offer an attractive therapeutic target in the treatment of obesity.     

Efferent projections of the area postrema demonstrated by autoradiography

The efferents connections of the area postrema (AP) have been studied autoradiographically following iontophoretic injections of 3H-glycine or 3H-leucine into the area postrema. Precise control of the diffusion of the labelled amino acids injected iontophorectically into the AP was made using the technique of sectioning with a cryostat. AP projects to a great number of structures. Projections to nucleus tractus solitarius (NFS), dorsal vagal nucleus, nucleus intercalatus, nucleus praepositus hypoglossi, nucleus hypoglossal, the mesencephalic nucleus of V nerve, locus coeruleus and superior and inferior colliculi are shown bilaterally. The density of the efferents was greatest to the NFS and the LC. Corelations are suggested with functional mechanisms of cardiovascular regulation.     

Intracisternal administration of cholecystokinin-8 counteracts the central cardiovascular effects of adrenaline and NPY. A study based on the coexistence of cholecystokinin, phenylethanolamine N-methyltransferase and neuropeptide Y immunoreactivity in neurons of the nucleus tractus solitarius

(1) In the present study the occlusion method was employed to evaluate the overall coexistence of neuropeptide Y and phenylethanolamine-N-methyl transferase, neuropeptide Y and tyrosine hydroxylase as well as cholecystokinin and phenylethanolamine-N-methyl transferase immunoreactivity in nerve cell bodies of the dorsal subnuclei of the nucleus tractus solitarius of the male rat. A high degree of coexistence was established for neuropeptide Y/phenylethanolamine-N-methyl transferase, cholecystokinin/phenylethanolamine-N-methyl transferase and for tyrosine hydroxylase/neuropeptide Y immunoreactivity. (2) Sulfated [¹²I]cholecystokinin-8 was used as radioligand to study the densities of cholecystokinin-8 binding sites in the dorsal medulla oblongata by means of quantitative receptor autoradiography. High densities of binding sites were observed in parts of the nucleus tractus solitarius and in the area postrema. Labeling was also observed in the dorsal motor nucleus of the vagus. (3) In the physiological studies adrenaline (0.15–1.0 nmol), neuropeptide Y (0.075–0.75 nmol) and sulfated cholecystokinin-8 (0.3–3.0 nmol) were administered alone or in combination with neuropeptide Y or adrenaline intracisternally into -chloralose anaesthetized male rats. Especially the hypotensive and bradycardic responses of adrenaline were counteracted in the adrenaline/cholecystokinin co-treated animals, whereas the cardiovascular effects of neuropeptide Y when co-administered with cholecystokinin-8 (0.3 nmol) appeared to be more resistant to the antagonistic effect of cholecystokinin 8. In addition, cholecystokinin-8 further enhanced the neuropeptide Y-induced bradynpnea and increase in the tidal volume.

The present results indicate the existence of neuropeptide Y, adrenaline and cholecystokinin-8 immunoreactivity in the same neurons of the dorsal subnuclei of the nucleus tractus solitarius. Furthermore, binding sites for cholecystokinin-8 seem to at least partly co-distribute with -2 adrenergic and neuropeptide Y binding sites in the nucleus tractus solitarius. In the functional analysis, an antagonistic interaction between cholecystokinin-8 and adrenaline as well as between cholecystokinin and neuropeptide Y is demonstrated opening up the possibility that cholecystokinin peptides act as intrinsic modulators in the putative cholecystokinin/neuropeptide Y/adrenaline synapses in the nucleus tractus solitarius.     

The abdominal visceral innervation and the emetic reflex: pathways, pharmacology, and plasticity

In recent years the role of the area postrema in the emetic reflex has been predominant and the involvement of the abdominal visceral innervation has tended to be overlooked. This paper attempts to redress the balance reflex by reviewing aspects of the existing literature and complementing this with original studies from the ferret. In view of the widespread use of the ferret in studies of emesis and particularly in the characterization of the antiemetic actions of 5-HT3 receptor antagonist, the opportunity is taken to assess the suitability of this species for studies of emesis. It is concluded that the ferret is sensitive to a wide range of emetic stimuli including intragastric irritants, opiate and dopamine receptor agonists, many cytotoxic drugs, and radiation. For several stimuli it is more sensitive than other species and for radiation on the basis of its ED100 it appears to be the most sensitive of the laboratory animals studied. Using electrical stimulation of the central end of the dorsal vagal trunk in the abdomen in conscious and anaesthetized animals, the vagal afferents were shown to be capable of eliciting emesis. Using lesioning studies an involvement of the vagus in the emetic response to a number of cytotoxic drugs (e.g., cisplatinum, cyclophosphamide, mustine) and radiation was demonstrated, although the magnitude of the effect varied with the different stimuli. An attempt is made to reconcile these observations with previous studies of area postrema ablation. The problems of interpreting the effects of nerve lesions are critically discussed in light of preliminary evidence presented here that there may be a degree of plasticity in the emetic pathway following such lesions. The range of antiemetic effects of 5-HT3 receptor antagonists is reviewed and an attempt is made to identify the site(s) at which these agents act. Results are presented that suggest a link between the vagus and 5-HT3 receptor antagonism. These studies are discussed together with others and lead us to propose that (in the ferret) 5-HT3 receptor antagonists have their main antiemetic effect by acting on vagal afferent terminals in the wall of the upper gut with an additional minor site either in the nucleus tractus solitarius or presynaptically on the vagal afferent terminals in the medulla where binding sites for 5-HT3 receptor ligands have recently been demonstrated in this species.     

Baroreceptor reflex modulation by circulating angiotensin II is mediated by AT1 receptors in the nucleus tractus solitarius

Circulating ANG II modulates the baroreceptor reflex control of heart rate (HR), at least partly via activation of ANG II type 1 (AT1) receptors on neurons in the area postrema. In this study, we tested the hypothesis that the effects of circulating ANG II on the baroreflex also depend on AT1 receptors within the nucleus tractus solitarius (NTS). In confirmation of previous studies in other species, increases in arterial pressure induced by intravenous infusion of ANG II had little effect on HR in urethane-anesthetized rats, in contrast to the marked bradycardia evoked by equipressor infusion of phenylephrine. In the presence of a continuous background infusion of ANG II, the baroreflex control of HR was shifted to higher levels of HR but had little effect on the baroreflex control of renal sympathetic activity. The modulatory effects of circulating ANG II on the cardiac baroreflex were significantly reduced by microinjection of candesartan, an AT1 receptor antagonist, into the area postrema and virtually abolished by microinjections of candesartan into the medial NTS. After acute ablation of the area postrema, a background infusion of ANG II still caused an upward shift of the cardiac baroreflex curve, which was reversed by subsequent microinjection of candesartan into the medial NTS. The results indicate that AT1 receptors in the medial NTS play a critical role in modulation of the cardiac baroreflex by circulating ANG II via mechanisms that are at least partly independent of AT1 receptors in the area postrema.     

肾缺血引起大鼠儿茶酚胺神经元Fos表达

实验应用Fos蛋白和酪氨酸羟化酶（tyrosine hydroxylase,TH）的双重免疫组化方法,观察肾脏动脉阻断（renal artery occlusion,RAO）是否激活脑干中核团的儿荷酚胺能神经元。所得结果如下：（1）脑干中Fos样蛋白的基础性表达低;RAO可诱发孤束核（nucleus tractus solitarius,NTS）、最后区（area postrema,AP）、巨细胞旁外侧核（paragi-gantocellularis lateralis,PGL）和蓝斑（locus coeruleus,LC）核团中许多神经元显示Fos样免疫反应（Fos-like immunoreactivi-ty,FLI）。（2）NTS、AP、PGL和LC核团中含有较多的儿茶酚胺能神经元;RAO能激活其中的部分儿荷酚胺能神经元。（3）腺苷受体阻断剂8－苯茶碱可明显减弱RAO所致的上述效应。以上结果表明,肾脏短暂缺血能激活脑干内的一些神经核团以及其中的部分儿荷酚胺能神经元。此效应可能是肾缺血时腺苷释放作用于肾内腺苷受体后引起肾传入神经活动增加的结果。     

Central nervous system mechanisms of arterial pressure regulation

This paper provides a review of recent developments in the field of neural and humoral control of the cardiovascular system mediated through the central nervous system. The areas covered include central mechanism of baroreceptor reflex control, sites of origin of tonic vasomotor activity, interactions between forebrain and brain stem, central actions of humoral factors, the role of visceral and somatic afferents, and the potential for central selectivity of vasomotor control.     

Development of catecholaminergic neurons in the human medulla oblongata

Distribution and maturation of catecholaminergic (CA) neurons have been studied by tyrosine hydroxylase immunohistochemistry in the medulla oblongata of human fetuses aged 14.5-25 weeks of gestation. Already at 14.5 weeks, CA neurons were observed in two longitudinally oriented cell clusters, one located ventrolaterally in the area of the lateral reticular and ambiguous nuclei, the other one dorsomedially forming 4 groups related to the dorsal vagal nucleus, the commissural nucleus of the vagus, the nucleus of the tractus solitarius and the area postrema. CA neurons in the area postrema were often found close to blood vessels. Scattered intermediate CA neurons were seen between these two larger clusters. CA neurons still appeared immature exhibiting bipolar morphology with only one or two short stout processes, which hardly branched. At 21 weeks, CA neurons occupied essentially the same location, but had a more mature morphology. Though still bipolar in shape, they had thinner and much longer processes which frequently branched. Both in the ventrolateral and the dorsomedial cell clusters, these processes were frequently lying close to blood vessels. At 25 weeks, CA cells had matured into multipolar neurons with long thin processes forming fine fiber networks in the ventrolateral medulla as well as around and within the dorsal vagal and solitarius nuclei. Only at this stage, a distinct CA fiber tract was seen located in the region of the tractus solitarius. Our results indicate that CA neurons in the human medulla, which are presumably involved in the control of ventilation and blood pressure, though generated rather early during development, mature relatively late.     

Quantitative distribution of angiotensin II binding sites in rat brain by autoradiography

Angiotensin II binding sites were localized and quantified in individual brain nuclei from single rats by incubation of tissue sections with 1 nM 125I-[Sar1]-angiotensin II, [3H]-Ultrofilm autoradiography, computerized microdensitometry and comparison with 125I-standards. High angiotensin II binding was present in the circumventricular organs (organon vasculosum laminae terminalis, organon subfornicalis and area postrema), in selected hypothalamic nuclei (nuclei suprachiasmatis, periventricularis and paraventricularis) and in the nucleus tractus olfactorii lateralis, the nucleus preopticus medianus, the dorsal motor nucleus of the vagus and the nucleus tractus solitarii. High affinity (KA from 0.3 to 1.5 X 10(9) M-1) angiotensin II binding sites were demonstrated in the organon subfornicalis, the nucleus tractus solitarii and the area postrema after incubation of consecutive sections from single rat brains with 125I-[Sar1]-angiotensin II in concentrations from 100 pM to 5 nM. These results demonstrate and characterize brain binding sites for angiotensin II of variable high affinity binding both inside and outside the blood-brain barrier.