RESUMO
We investigated the participation of the nucleus of the tractus solitarius (NTS) in tonicâclonic seizures and postictal antinociception control mediated by NMDA receptors, the role of NTS GABAergic interneurons and noradrenergic pathways from the locus coeruleus (LC) in these phenomena. The NTS-lateral nucleus reticularis paragigantocellularis (lPGi)-LC pathway was studied by evaluating neural tract tracer deposits in the lPGi. NMDA and GABAergic receptors agonists and antagonists were microinjected into the NTS, followed by pharmacologically induced seizures. The effects of LC neurotoxic lesions caused by DSP-4, followed by NTS-NMDA receptor activation, on both tonicâclonic seizures and postictal antinociception were also investigated. The NTS is connected to lPGi neurons that send outputs to the LC. Glutamatergic vesicles were found on dendrites and perikarya of GABAergic interneurons in the NTS. Both tonicâclonic seizures and postictal antinociception are partially dependent on glutamatergic-mediated neurotransmission in the NTS of seizing rats in addition to the integrity of the noradrenergic system since NMDA receptor blockade in the NTS and intrathecal administration of DSP-4 decrease the postictal antinociception. The GABAA receptor activation in the NTS decreases both seizure severity and postictal antinociception. These findings suggest that glutamatergic inputs to NTS-GABAergic interneurons, in addition to ascending and descending noradrenergic pathways from the LC, are critical for the control of both seizures and postictal antinociception.
Assuntos
Benzilaminas , Locus Cerúleo , Receptores de N-Metil-D-Aspartato , Ratos , Animais , Locus Cerúleo/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Bulbo/metabolismo , Núcleo Solitário/metabolismo , Norepinefrina/metabolismo , Convulsões/metabolismoRESUMO
Both animals and humans have been studied to explore the impact of acute physical exercise (PE) on memory. In rats, a single session of PE enhances the persistence of novel object recognition (NOR) memory, which depends on dopamine and noradrenaline activity in the hippocampus. However, limited research has examined the involvement of other brain regions in this phenomenon. In this study, we investigated the role of the ventral tegmental area (VTA) and locus coeruleus (LC) in modulating the persistence of NOR memory induced by acute PE. After NOR training, some animals underwent a 30 min treadmill PE session, followed by infusion of either vehicle (VEH) or muscimol (MUS) in either the VTA or LC. Other animals did not undergo PE and only received VEH, MUS, or NMDA within the same time window. We evaluated memory recall 1, 7, and 14 days later. Acute PE promoted memory persistence for up to 14 days afterward, similar to NMDA glutamatergic stimulation of the VTA or LC. Moreover, only the LC region was required for the memory improvement induced by acute PE since blocking this region with MUS impaired NOR encoding. Our findings suggest that acute PE can improve learning within a closed time window, and this effect depends on LC, but not VTA, activity.
Assuntos
Locus Cerúleo , Área Tegmentar Ventral , Humanos , Ratos , Animais , Locus Cerúleo/fisiologia , N-Metilaspartato/farmacologia , Reconhecimento Psicológico , MemóriaRESUMO
At rest, inspiration is an active process while expiration is passive. However, high chemical drive (hypercapnia or hypoxia) activates central and peripheral chemoreceptors triggering reflex increases in inspiration and active expiration. The Locus Coeruleus contains noradrenergic neurons (A6 neurons) that increase their firing frequency when exposed to hypercapnia and hypoxia. Using recently developed neuronal hyperpolarising technology in conscious rats, we tested the hypothesis that A6 neurons are a part of a vigilance centre for controlling breathing under high chemical drive and that this includes recruitment of active inspiration and expiration in readiness for flight or fight. Pharmacogenetic inhibition of A6 neurons was without effect on resting and on peripheral chemoreceptors-evoked inspiratory, expiratory and ventilatory responses. On the other hand, the number of sighs evoked by systemic hypoxia was reduced. In the absence of peripheral chemoreceptors, inhibition of A6 neurons during hypercapnia did not affect sighing, but reduced both the magnitude and incidence of active expiration, and the frequency and amplitude of inspiration. These changes reduced pulmonary ventilation. Our data indicated that A6 neurons exert a CO2-dependent modulation of expiratory drive. The data also demonstrate that A6 neurons contribute to the CO2-evoked increases in the inspiratory motor output and hypoxia-evoked sighing.
Assuntos
Locus Cerúleo/fisiologia , Respiração , Neurônios Adrenérgicos/patologia , Neurônios Adrenérgicos/fisiologia , Animais , Dióxido de Carbono/metabolismo , Expiração , Hipercapnia/metabolismo , Hipercapnia/fisiopatologia , Hipóxia/metabolismo , Hipóxia/fisiopatologia , Inalação , Locus Cerúleo/fisiopatologia , Masculino , Ratos , Ratos WistarRESUMO
Central chemoreceptors are highly sensitive neurons that respond to changes in pH and CO2 levels. An increase in CO2/H+ typically reflects a rise in the firing rate of these neurons, which stimulates an increase in ventilation. Here, we present an ionic current model that reproduces the basic electrophysiological activity of individual CO2/H+-sensitive neurons from the locus coeruleus (LC). We used this model to explore chemoreceptor discharge patterns in response to electrical and chemical stimuli. The modeled neurons showed both stimulus-evoked activity and spontaneous activity under physiological parameters. Neuronal responses to electrical and chemical stimulation showed specific firing patterns of spike frequency adaptation, postinhibitory rebound, and post-stimulation recovery. Conversely, the response to chemical stimulation alone (based on physiological CO2/H+ changes), in the absence of external depolarizing stimulation, showed no signs of postinhibitory rebound or post-stimulation recovery, and no depolarizing sag. A sensitivity analysis for the firing-rate response to the different stimuli revealed that the contribution of an applied stimulus current exceeded that of the chemical signals. The firing-rate response increased indefinitely with injected depolarizing current, but reached saturation with chemical stimuli. Our computational model reproduced the regular pacemaker-like spiking pattern, action potential shape, and most of the membrane properties that characterize CO2/H+-sensitive neurons from the locus coeruleus. This validates the model and highlights its potential as a tool for studying the cellular mechanisms underlying the altered central chemosensitivity present in a variety of disorders such as sudden infant death syndrome, depression, and anxiety. In addition, the model results suggest that small external electrical signals play a greater role in determining the chemosensitive response to changes in CO2/H+ than previously thought. This highlights the importance of considering electrical synaptic transmission in studies of intrinsic chemosensitivity.
Assuntos
Dióxido de Carbono/metabolismo , Células Quimiorreceptoras/fisiologia , Locus Cerúleo/fisiologia , Modelos Neurológicos , Potenciais de Ação , Animais , Biologia Computacional , Estimulação Elétrica , Fenômenos Eletrofisiológicos , Humanos , Concentração de Íons de Hidrogênio , Hipercapnia/fisiopatologia , Hipocapnia/fisiopatologia , Locus Cerúleo/citologia , Transmissão SinápticaRESUMO
The mechanisms responsible for the onset of respiratory activity during fetal life are unknown. The onset of respiratory rhythm may be a consequence of the genetic program of each of the constituents of the respiratory network, so they start to interact and generate respiratory cycles when reaching a certain degree of maturation. Alternatively, generation of cycles might require the contribution of recently formed sensory inputs that will trigger oscillatory activity in the nascent respiratory neural network. If this hypothesis is true, then sensory input to the respiratory generator must be already formed and become functional before the onset of fetal respiration. In this review, we evaluate the timing of the onset of the respiratory rhythm in comparison to the appearance of receptors, neurotransmitter machinery, and afferent projections provided by two central chemoreceptive nuclei, the raphe and locus coeruleus nuclei.
Assuntos
Desenvolvimento Fetal/fisiologia , Locus Cerúleo/fisiologia , Neurônios/fisiologia , Núcleos da Rafe/fisiologia , Respiração , Mecânica Respiratória/fisiologia , Potenciais de Ação/fisiologia , Animais , HumanosRESUMO
Several evidences indicate that the locus coeruleus (LC) is involved in central chemoreception responding to CO2/pH and displaying a high percentage of chemosensitive neurons (>80%). However, there are no studies about the LC-mediated hypercapnic ventilation performed in females. Therefore, we assessed the role of noradrenergic LC neurons in non-ovariectomized (NOVX), ovariectomized (OVX) and estradiol (E2)-treated ovariectomized (OVX+E2) rats in respiratory response to hypercapnia, using a 6-hydroxydopamine (6-OHDA) - lesion model. A reduction in the number of tyrosine hydroxylase (TH) immunoreactive neurons (51-90% in 3 animals of NOVX group, 20-42% of lesion in 5 animals of NOVX females, 61.3% for OVX and 62.6% for OVX+E2 group) was observed seven days after microinjection of 6-OHDA in the LC. The chemical lesion of the LC resulted in decreased respiratory frequency under normocapnic conditions in OVX and OVX+E2 group. Hypercapnia increased ventilation in all groups as consequence of increases in respiratory frequency (fR) and tidal volume (VT). Nevertheless, the hypercapnic ventilatory response was significantly decreased in 6-OHDA-NOVX>50% rats compared with SHAM-NOVX group and with females that had 20-42% of LC lesion. In OVX and OVX+E2 lesioned groups, no difference in CO2 ventilatory response was observed when compared to SHAM-OVX and SHAM-OVX+E2 groups, respectively. Neither basal body temperature (Tb) nor Tb reduction in response to hypercapnia were affected by E2 treatment, ovariectomy or LC lesion. Thus, our data show that LC noradrenergic neurons seem to exert an excitatory role on the hypercapnic ventilatory response in female rats, as evidenced by the results in NOVX animals with LC lesioned more than 50%; however, this modulation is not observed in OVX and OVX+E2 rats. In addition, LC noradrenergic neurons of OVX females seem to provide a tonic excitatory drive to maintain breathing frequency in normocapnia, and this response may not to be functionally influenced by E2.
Assuntos
Locus Cerúleo/fisiologia , Neurônios/fisiologia , Respiração , Animais , Temperatura Corporal/fisiologia , Modelos Animais de Doenças , Estradiol/administração & dosagem , Estradiol/metabolismo , Ciclo Estral/fisiologia , Feminino , Hipercapnia/patologia , Hipercapnia/fisiopatologia , Locus Cerúleo/patologia , Locus Cerúleo/fisiopatologia , Neurônios/patologia , Norepinefrina/metabolismo , Ovariectomia , Oxidopamina , Pletismografia Total , Ratos Wistar , Telemetria , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Astrocytes perform various homeostatic functions in the nervous system beyond that of a supportive or metabolic role for neurons. A growing body of evidence indicates that astrocytes are crucial for central respiratory chemoreception. This review presents a classical overview of respiratory central chemoreception and the new evidence for astrocytes as brainstem sensors in the respiratory response to hypercapnia. We review properties of astrocytes for chemosensory function and for modulation of the respiratory network. We propose that astrocytes not only mediate between CO2/H+ levels and motor responses, but they also allow for two emergent functions: (1) Amplifying the responses of intrinsic chemosensitive neurons through feedforward signaling via gliotransmitters and; (2) Recruiting non-intrinsically chemosensitive cells thanks to volume spreading of signals (calcium waves and gliotransmitters) to regions distant from the CO2/H+ sensitive domains. Thus, astrocytes may both increase the intensity of the neuron responses at the chemosensitive sites and recruit of a greater number of respiratory neurons to participate in the response to hypercapnia.
Assuntos
Astrócitos/fisiologia , Dióxido de Carbono/metabolismo , Células Quimiorreceptoras/fisiologia , Hipercapnia/metabolismo , Neurônios/fisiologia , Centro Respiratório/fisiologia , Aminoácidos/metabolismo , Animais , Astrócitos/citologia , Sinalização do Cálcio , Células Quimiorreceptoras/citologia , Humanos , Hipercapnia/fisiopatologia , Locus Cerúleo/citologia , Locus Cerúleo/fisiologia , Núcleos da Rafe do Mesencéfalo/citologia , Núcleos da Rafe do Mesencéfalo/fisiologia , Neurônios/citologia , Neurotransmissores/metabolismo , Prótons , Centro Respiratório/citologia , Serotonina/metabolismo , Transmissão SinápticaRESUMO
The locus coeruleus (LC) is a pontine noradrenergic nucleus that acts as a central chemoreceptor to CO2/pH and has been implicated in the cognitive aspects of stress responses. This participation is in part mediated by the action of corticotropin-releasing factor (CRF), which when released in these situations increases the firing frequency of LC noradrenergic neurons. Nevertheless, the role of CRF1 receptors in the LC in breathing and temperature control is unknown. Therefore, we tested the involvement of CRF1 receptors located in the LC in room air ventilation and the ventilatory response induced by hypercapnia (7% CO2) in rats. To this end, we injected CRF-R1-selective antagonists (antalarmin-1.2 and 2.4mmol/0.1µL or CP-376395-5nmol/0.1µL) into the LC of male Wistar rats. Pulmonary ventilation (VE) and body temperature (Tb, dataloggers) were measured in air, followed by 7% CO2 in unanesthetized rats. Antalarmin (higher dose) and CP-376395 in the LC caused an increase in VE during normocapnia and hypercapnia, due to an increase in tidal volume. There were no differences in Tb between groups under normocapnia and hypercapnia. The results suggest that CRF acting on CRF1 receptors in the LC exerts a tonic inhibitory role in ventilation.
Assuntos
Hormônio Liberador da Corticotropina/metabolismo , Locus Cerúleo/fisiologia , Ventilação Pulmonar/fisiologia , Respiração , Aminopiridinas/farmacologia , Animais , Hormônio Liberador da Corticotropina/farmacologia , Relação Dose-Resposta a Droga , Hipercapnia/fisiopatologia , Locus Cerúleo/efeitos dos fármacos , Masculino , Microinjeções , Ventilação Pulmonar/efeitos dos fármacos , Pirimidinas/farmacologia , Pirróis/farmacologia , Ratos , Ratos Wistar , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Respiração/efeitos dos fármacos , Volume de Ventilação Pulmonar/efeitos dos fármacos , Volume de Ventilação Pulmonar/fisiologiaRESUMO
The heme oxygenase-carbon monoxide pathway has been shown to play an important role in many physiological processes and is capable of altering nociception modulation in the nervous system by stimulating soluble guanylate cyclase (sGC). In the central nervous system, the locus coeruleus (LC) is known to be a region that expresses the heme oxygenase enzyme (HO), which catalyzes the metabolism of heme to carbon monoxide (CO). Additionally, several lines of evidence have suggested that the LC can be involved in the modulation of emotional states such as fear and anxiety. The purpose of this investigation was to evaluate the activation of the heme oxygenase-carbon monoxide pathway in the LC in the modulation of anxiety by using the elevated plus maze test (EPM) and light-dark box test (LDB) in rats. Experiments were performed on adult male Wistar rats weighing 250-300 g (n=182). The results showed that the intra-LC microinjection of heme-lysinate (600 nmol), a substrate for the enzyme HO, increased the number of entries into the open arms and the percentage of time spent in open arms in the elevated plus maze test, indicating a decrease in anxiety. Additionally, in the LDB test, intra-LC administration of heme-lysinate promoted an increase on time spent in the light compartment of the box. The intracerebroventricular microinjection of guanylate cyclase, an sGC inhibitor followed by the intra-LC microinjection of the heme-lysinate blocked the anxiolytic-like reaction on the EPM test and LDB test. It can therefore be concluded that CO in the LC produced by the HO pathway and acting via cGMP plays an anxiolytic-like role in the LC of rats.
Assuntos
Ansiolíticos/farmacologia , Ansiedade/metabolismo , Comportamento Animal/efeitos dos fármacos , Monóxido de Carbono/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Locus Cerúleo/metabolismo , Transdução de Sinais/fisiologia , Animais , Monóxido de Carbono/fisiologia , Guanilato Ciclase/metabolismo , Locus Cerúleo/efeitos dos fármacos , Locus Cerúleo/fisiologia , Masculino , Aprendizagem em Labirinto , Ratos , Ratos WistarRESUMO
This study was designed to investigate brain connections among chemosensitive areas in newborn rats. Rhodamine beads were injected unilaterally into the locus coeruleus (LC) or into the caudal part of the nucleus tractus solitarius (cNTS) in Sprague-Dawley rat pups (P7-P10). Rhodamine-labeled neurons were patched in brainstem slices to study their electrophysiological responses to hypercapnia and to determine if chemosensitive neurons are communicating between LC and cNTS regions. After 7-10 days, retrograde labeling was observed in numerous areas of the brainstem, including many chemosensitive regions, such as the contralateral LC, cNTS and medullary raphe. Whole-cell patch clamp was done in cNTS. In 4 of 5 retrogradely labeled cNTS neurons that projected to the LC, firing rate increased in response to hypercapnic acidosis (15% CO2), even in synaptic blockade medium (SNB) (high Mg(2+)/low Ca(2+)). In contrast, 2 of 3 retrogradely labeled LC neurons that projected to cNTS had reduced firing rate in response to hypercapnic acidosis, both in the presence and absence of SNB. Extensive anatomical connections among chemosensitive brainstem regions in newborn rats were found and at least for the LC and cNTS, the connections involve some CO2-sensitive neurons. Such anatomical and functional coupling suggests a complex central respiratory control network, such as seen in adult rats, is already largely present in neonatal rats by at least day P7-P10. Since the NTS and the LC play a major role in memory consolidation, our results may also contribute to the understanding of the development of memory consolidation.