André Jean

Control of the central swallowing program by inputs from the peripheral receptors. A review

Swallowing is a complex motor sequence, usually divided into a buccopharyngeal stage (coordinated contractions of several muscles of the mouth, pharynx and larynx) and an esophageal stage, called primary peristalsis. This motor sequence depends on the activity of medullary interneurons belonging to the swallowing center which program through excitatory and inhibitory connections the sequential excitation of motoneurons and vagal preganglionic neurons responsible for the whole motor sequence. The activity of the medullary swallowing neurons can occur without feedback phenomena: it is truly a central activity indicating that swallowing depends on a central network which may function without afferent support. However, the swallowing neurons receive a strong afferent input suggesting the involvement of sensory feedbacks during swallowing. The swallowing neurons present a short latency activation on electrical stimulation of the peripheral afferent fibers supplying the region of the tract which is under their control. In addition, the neurons are activated by localized distensions of the swallowing tract, this distension having to be done more and more distally when the neuronal discharge occurs later and later during swallowing. Furthermore the swallowing discharge of the central neurons is increased either when a bolus is swallowed or during a slight distension of the corresponding region of the tract. Thus, under physiological conditions, swallowing neurons receive sensory information from pharyngeal and esophageal receptors and the central program may be modified by peripheral afferents that adjust the motor sequence to the size of the swallowed bolus. The inputs from the peripheral receptors can also exert inhibitory effects depending on the central connections between the swallowing neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Central serotonergic projections to the nucleus tractus solitarii: Evidence from a double labeling study in the rat

Projections from several brainstem serotonergic nuclei to the nucleus tractus solitarii were investigated in the rat. Experiments were performed using a double labeling method combining retrograde radioautographic tracing and serotonin immunohistochemistry. After injection of the radioactive tracer ([3H] wheat germ agglutinin) into the lateral nucleus tractus solitarii, nerve cell bodies exhibiting both radioautographic labeling and immunostaining were detected in all the serotonergic nuclei investigated, namely the nucleus raphe magnus, the ventromedial paragigantocellular nucleus, the nuclei raphe pontis, medianus and dorsalis, the medial lemniscus and the reticulotegmental nucleus of the pons. Most of the double labeled perikarya observed were in the nucleus raphe magnus, the adjacent part of the paragigantocellular nucleus and the nucleus raphe dorsalis. Nerve cell bodies retrogradely labeled but devoid of immunostaining were also observed, together with the double labeled perikarya, within serotonergic nuclei. These results provide direct evidence that brainstem serotonergic neurons contribute to the innervation of the nucleus tractus solitarii. They indicate that the nucleus raphe magnus and the nucleus raphe dorsalis constitute two major sources of central serotonergic projections to the nucleus tractus solitarii.

Prostaglandins and sickness behavior: Old story, new insights

Previous evidence has shown that prostaglandins play a key role in the development of sickness behavior observed during inflammatory states. In particular, prostaglandin E2 (PGE2) is produced in the brain by a variety of inflammatory signals such as endotoxins or cytokines. Its injection has been also shown to induce symptoms of sickness behavior. The role of cyclooxygenase enzymes (COX), the rate-limiting enzymes converting arachidonic acid into prostaglandins, in sickness behavior has been extensively studied, and it has been demonstrated that strategies aiming at inhibiting these enzymes limit anorexia, body weight loss and fever in animals with inflammatory diseases. However, inhibiting COX activity may lead to negative gastric or cardiovascular effects, since COX enzymes play a role in the synthesis of others prostanoids with various and sometimes contrasting properties. Recently, prostaglandin E synthases (PGES), which specifically catalyze the final step of PGE2 biosynthesis, were characterized. Among these enzymes, the microsomal prostaglandin E synthase-1 (mPGES-1) was of a particular interest since it was shown to be up-regulated by inflammatory signals in a variety of cell types. Moreover, mPGES-1 was shown to be crucial for correct immune-to-brain communication and induction of fever and anorexia by pro-inflammatory agents. This review takes stock of previous knowledge and recent advances in understanding the role of prostaglandins and of their specific synthesizing enzymes in the molecular mechanisms underlying sickness behavior. The review concludes with a short summary of key questions that remain to be addressed and points out therapeutic developments in this research field.

Evidence that activation of N-methyl-D-aspartate (NMDA) and non-NMDA receptors within the nucleus tractus solitarii triggers swallowing

Swallowing is a patterned motor activity generated by neurons located within the nucleus tractus solitarii (NTS). Previous experiments have shown that administration of excitatory amino acids within the NTS induces swallowing. The present study was undertaken to identify the receptor subtypes involved in this effect. Pressure microinjections of L-glutamate (10-100 pmol), quisqualate (0.1-10 pmol) and N-methyl-D-aspartate (NMDA, 0.1-10 pmol) were performed into the NTS of decerebrate rats. Glutamate and quisqualate microinjections elicited short series of swallows while NMDA microinjections induced long-lasting, rhythmic swallowing. Pretreatment with the selective NMDA antagonist, DL-2-amino-5-phosphonovalerate (50 pmol), almost completely suppressed the response elicited by NMDA (10 pmol) but did not induce a significant modification of swallowing triggered by either glutamate (25 pmol) or quisqualate (10 pmol). Pretreatment with 6-cyano-7-nitroquinoxaline-2,3-dione (50 pmol), a selective blocker of non-NMDA receptors, suppressed the swallows elicited by glutamate and strongly inhibited the response elicited by quisqualate microinjections. The same pretreatment induced only a slight modification of the swallowing elicited by NMDA. These data demonstrate that deglutition can be triggered by activating either NMDA or non-NMDA receptors localized within the NTS, and therefore suggest that both receptor subtypes may be involved in swallowing elicited under physiological conditions.

Immunohistochemical detection of glutamate in rat vagal sensory neurons

Vagal primary afferent neurons have their cell bodies located in the nodose (inferior) and jugular (superior) vagal ganglia and send terminals into the nucleus tractus solitarii (NTS) which lies in the dorsomedial medulla. The presence of glutamate (Glu)-containing neurons in the rat nodose ganglion was investigated using immunohistochemistry. Glu-immunoreactivity on nodose sections was found in neuronal perikarya and nerve fibers, but not in non-neuronal elements such as Schwann cells and satellite cells. Both immunoreactive and non-immunoreactive ganglion cells were observed. The immunoreactive ganglion cells amounted to about 60% of the nodose population. No specific intraganglionic localization was observed for the non-immunoreactive cells. Immunoreactive perikarya were slightly smaller than the non-immunoreactive ones, but no relationship was found between size and staining intensities of immunoreactive neurons. The present data indicate that immunodetectable Glu is present in a large population of vagal afferent neurons. They therefore add to a growing body of evidence suggesting that Glu may be the main neurotransmitter released by vagal afferent terminals within the nucleus tractus solitarii.

Connections between the ventral medullary swallowing area and the trigeminal motor nucleus of the sheep studied by tracing techniques

The anatomical connections between two regions involved in swallowing, the medullary reticular formation around the nucleus ambiguous (ventral group of swallowing interneurons) and the trigeminal motor nucleus (NMV) were studied in sheep using anterograde and retrograde tracing techniques. [3H]leucine and HRP were injected into the ventral medulla and the NMV respectively. These injections were performed according to stereotaxic coordinates previously established by electrophysiological recording tests. The results show bilateral connections between the ventral medulla, 2-4 mm rostral to the obex, and the trigeminal motor nucleus. In addition, the same area of the ventral medulla is connected with the homologous contralateral region and with the facial, vagal and hypoglossal nuclei that are also involved in swallowing. Some connections between the ventral medulla and the NMV must be monosynaptic since aggregates of silver grains typical of axon terminals were observed on the cell bodies of trigeminal motoneurons. Obviously, the various connections shown to exist in this study may serve other functions than swallowing. Nevertheless, most of the results are consistent with the view that the ventral group of medullary swallowing interneurons are switching neurons that distribute the programmed swallowing excitation to the various motoneuron pools involved in deglutition.

The Food-Contaminant Deoxynivalenol Modifies Eating by Targeting Anorexigenic Neurocircuitry

Physiological regulations of energy balance and body weight imply highly adaptive mechanisms which match caloric intake to caloric expenditure. In the central nervous system, the regulation of appetite relies on complex neurocircuitry which disturbance may alter energy balance and result in anorexia or obesity. Deoxynivalenol (DON), a trichothecene, is one of the most abundant mycotoxins found on contaminated cereals and its stability during processing and cooking explains its widespread presence in human food. DON has been implicated in acute and chronic illnesses in both humans and farm animals including weight loss. Here, we provide the first demonstration that DON reduced feeding behavior and modified satiation and satiety by interfering with central neuronal networks dedicated to food intake regulation. Moreover, our results strongly suggest that during intoxication, DON reaches the brain where it modifies anorexigenic balance. In view of the widespread human exposure to DON, the present results may lead to reconsider the potential consequences of chronic DON consumption on human eating disorders.

c-Fos immunoreactivity induced by intraperitoneal LPS administration is reduced in the brain of mice lacking the microsomal prostaglandin E synthase-1 (mPGES-1)

The aim of the present study was to investigate the impact of the deletion of the microsomal prostaglandin E synthase-1 (mPGES-1) gene on lipopolysaccharide (LPS)-induced neuronal activation in central nervous structures. The mPGES-1 catalyses the conversion of COX-derived PGH(2) to PGE(2) and has been described as a regulated enzyme whose expression is stimulated by proinflammatory agents. Using the immediate-early gene c-fos as a marker of neuronal activation, we determined whether deletion of the mPGES-1 gene altered the neuronal activation induced by LPS in structures classically recognized as immunosensitive regions. No significant difference in the c-Fos immunostaining was observed in the brain of saline-treated mPGES-1+/+, mPGES-1+/- and mPGES-1-/- mice. However, we observed that LPS-induced neuronal activation was reduced in most of the centres known as immunosensitive nuclei in mPGES-1-/- mice compared with heterozygous and wild-type mice. The decrease in the number of c-Fos positive nuclei occurred particularly in the caudal ventrolateral medulla, the medial, intermediate and central parts of the nucleus tractus solitarius, area postrema, parabrachial nucleus, locus coeruleus, paraventricular nucleus of the hypothalamus, ventromedial preoptic area, central amygdala, bed nucleus of the stria terminalis and to a lesser extent in the ventrolateral part of the nucleus tractus solitarius and rostral ventrolateral medulla. These results suggest that the mPGES-1 enzyme is strongly needed to provide sufficient PGE(2) production required to stimulate immunosensitive brain regions and they are discussed with regard to the recent works reporting impaired sickness behavior in mPGES-1-/- mice.

Inhibition of the swallowing reflex by local application of serotonergic agents into the nucleus of the solitary tract

Swallowing is a medullary polysynaptic reflex organized by an interneuronal network localized mainly within the nucleus of the solitary tract (NST). The existence of several putative neurotransmitters within the NST has been well demonstrated. The presence of serotonin (5-HT) in nerve terminals and fibers has been particularly well-documented. This study was therefore designed to determine the role of 5-HT in the swallowing reflex. The effects of serotonergic agents were investigated in the rat, on rhythmic swallowing elicited by long repetitive stimulation of the superior laryngeal nerve (SLN). The agents were microinjected by pressure application, within the swallowing region of the NST. Microinjections of 5-HT (0.3-5 nmol, 30-50 nl) significantly decreased the number and the amplitude of swallows elicited by stimulation of the ipsilateral SLN without changing the swallowing reflex induced by contralateral SLN stimulation. The decrease induced by 5-HT microinjections was dose-related. No significant modification of swallowing was induced by control injections of the vehicle within the active sites. Moreover, the effect of 5-HT microinjections was significantly antagonized by pretreatment with metitepine (0.4 nmol) applied locally in the NST and microinjections of quipazine (2.5 nmol) also decreased the number of swallows. It can therefore be concluded that the present findings suggest the existence within the NST of a serotonergic inhibition of the swallowing reflex elicited by laryngeal afferents.

Activation of N-methyl-d-aspartate Receptors Induces Endogenous Rhythmic Bursting Activities in Nucleus Tractus Solitarii Neurons: An Intracellular Study on Adult Rat Brainstem Slices.

A brainstem slice preparation and intracellular recording techniques were used to examine the effects of N‐methyl‐D‐aspartate (NMDA) application on neurons within the swallowing area of the nucleus tractus solitarii (NTS). According to their cellular properties, NTS neurons were classified into type I and type II neurons. The most striking difference was the occurrence of delayed excitation in type I but not in type II neurons, when they were depolarized from membrane potentials more negative than ‐60 mV. Bath application of NMDA (30–60 μM) elicited depolarization and triggered stable repetitive firing in all the NTS neurons but one. During the NMDA‐induced depolarization, hyperpolarization below ‐60 mV elicited, in some type I neurons, a rhythmic bursting pattern. The duration of the bursts (300–1000 ms) and their frequency (0.5–2 Hz) depended on the membrane potential. With hyperpolarizations below ‐75 mV, rhythmic bursting was converted into rhythmic single discharges, a pattern elicited directly in the other type I neurons. In all cases, rhythmic patterns were superimposed on cyclic depolarizations of the membrane potential characterized by an initial ramp‐shaped phase. In type II neurons, rhythmic bursting discharges, superimposed on rhythmic oscillations of the membrane potential, were also obtained upon hyperpolarization during the NMDA‐induced depolarization. In all type I neurons tested, NMDA‐induced cyclic ramp‐shaped depolarizations continued after addition of tetrodotoxin to the medium. Rhythmic bursting was not elicited by bath application of kainate (10–20 μM). Application of D‐2‐amino‐5‐phosphonovalerate (50 μM) blocked NMDA‐induced depolarizations without modifying those elicited by kainate, which were selectively depressed by 6‐cyano‐7‐nitroquinoxaline‐2, 3‐dione (10 μM). Moreover, removal of Mg2+ from the medium suppressed NMDA‐induced cyclic depolarizations. Results demonstrate that both NMDA and non‐NMDA receptors are present in NTS neurons and that selective activation of NMDA receptors induced rhythmic bursting and/or rhythmic single discharges. Rhythmic patterns were not driven by synaptic mechanisms but originated from endogenous properties of NTS neurons activated by NMDA. Thus, NTS neurons can be considered as conditional pacemakers. According to the location of the neurons, the conditional properties shown in these in vitro experiments might be involved in vivo in the generation of rhythmic motor activities set up at the NTS level, such as swallowing.