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1.
Brain Stimul ; 12(5): 1151-1158, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31129152

RESUMO

BACKGROUND: Electrical stimulation on select areas of the external auricular dermatome influences the autonomic nervous system. It has been postulated that activation of the Auricular Branch of the Vagus Nerve (ABVN) mediates such autonomic changes. However, the underlying neural pathways mediating these effects are unknown and, further, our understanding of the anatomical distribution of the ABVN in the auricle has now been questioned. OBJECTIVE: To investigate the effects of electrical stimulation of the tragus on autonomic outputs in the rat and probe the underlying neural pathways. METHODS: Central neuronal projections from nerves innervating the external auricle were investigated by injections of the transganglionic tracer cholera toxin B chain (CTB) into the right tragus of Wistar rats. Physiological recordings of heart rate, perfusion pressure, respiratory rate and sympathetic nerve activity were made in an anaesthetic free Working Heart Brainstem Preparation (WHBP) of the rat and changes in response to electrical stimulation of the tragus analysed. RESULTS: Neuronal tracing from the tragus revealed that the densest CTB labelling was within laminae III-IV of the dorsal horn of the upper cervical spinal cord, ipsilateral to the injection sites. In the medulla oblongata, CTB labelled afferents were observed in the paratrigeminal nucleus, spinal trigeminal tract and cuneate nucleus. Surprisingly, only sparse labelling was observed in the vagal afferent termination site, the nucleus tractus solitarius. Recordings made from rats at night time revealed more robust sympathetic activity in comparison to day time rats, thus subsequent experiments were conducted in rats at night time. Electrical stimulation was delivered across the tragus for 5 min. Direct recording from the sympathetic chain revealed a central sympathoinhibition by up to 36% following tragus stimulation. Sympathoinhibition remained following sectioning of the cervical vagus nerve ipsilateral to the stimulation site, but was attenuated by sectioning of the upper cervical afferent nerve roots. CONCLUSIONS: Inhibition of the sympathetic nervous system activity upon electrical stimulation of the tragus in the rat is mediated at least in part through sensory afferent projections to the upper cervical spinal cord. This challenges the notion that tragal stimulation is mediated by the auricular branch of the vagus nerve and suggests that alternative mechanisms may be involved.


Assuntos
Vértebras Cervicais , Frequência Cardíaca/fisiologia , Células Receptoras Sensoriais/fisiologia , Medula Espinal/fisiologia , Estimulação Elétrica Nervosa Transcutânea/métodos , Nervo Vago/fisiologia , Vias Aferentes/fisiologia , Animais , Tronco Encefálico/fisiologia , Masculino , Técnicas de Cultura de Órgãos , Ratos , Ratos Wistar , Núcleo Solitário/fisiologia , Estimulação do Nervo Vago/métodos
2.
Pharmacology ; 103(1-2): 76-81, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30517935

RESUMO

Dextromethorphan (DEX) presynaptically decreases glutamatergic transmission in second-order neurons of the nucleus tractus solitarius (TS). To clarify the inhibitory mechanism of DEX, the present study examined the interaction of DEX with cAMP. The effects of DEX on miniature and TS-evoked excitatory postsynaptic currents (mEPSCs and eEPSCs) were recorded under activation of the cAMP-dependent pathway using the brainstem slices. An increase in cAMP by forskolin counteracted the inhibitory effect of DEX on mEPSCs. Eight-Bromo-cAMP and N-ethylmaleimide also attenuated the DEX effect. However, forskolin had negligible effects on the DEX-induced inhibition of eEPSCs. This suggests that DEX decreases spontaneous glutamate release by inhibiting the cAMP-dependent pathway and synchronous release by another unknown mechanism.


Assuntos
AMP Cíclico/metabolismo , Dextrometorfano/farmacologia , Glutamatos/metabolismo , Neurônios/efeitos dos fármacos , Núcleo Solitário/efeitos dos fármacos , Núcleo Solitário/fisiologia , Transmissão Sináptica/efeitos dos fármacos , 8-Bromo Monofosfato de Adenosina Cíclica/farmacologia , Animais , Colforsina/farmacologia , Etilmaleimida/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Cobaias , Masculino , Potenciais Pós-Sinápticos em Miniatura/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/fisiologia , Núcleo Solitário/metabolismo , Transmissão Sináptica/fisiologia
3.
J Neurophysiol ; 121(2): 634-645, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30565959

RESUMO

Theories of neural coding in the taste system typically rely exclusively on data gleaned from taste-responsive cells. However, even in the nucleus tractus solitarius (NTS), the first stage of central processing, neurons with taste selectivity coexist with neurons whose activity is linked to motor behavior related to ingestion. We recorded from a large ( n = 324) sample of NTS neurons recorded in awake rats, examining both their taste selectivity and the association of their activity with licking. All subjects were implanted with a bundle of microelectrodes aimed at the NTS and allowed to recover. Following moderate water deprivation, rats were placed in an experimental chamber where tastants or artificial saliva (AS) were delivered from a lick spout. Electrophysiological responses were recorded, and waveforms from single cells were isolated offline. Results showed that only a minority of NTS cells responded to taste stimuli as determined by conventional firing-rate measures. In contrast, most cells, including taste-responsive cells, tracked the lick pattern, as evidenced by significant lick coherence in the 5- to 7-Hz range. Several quantitative measures of taste selectivity and lick relatedness showed that the population formed a continuum, ranging from cells dominated by taste responses to those dominated by lick relatedness. Moreover, even neurons whose responses were highly correlated with lick activity could convey substantial information about taste quality. In all, data point to a blurred boundary between taste-dominated and lick-related cells in NTS, suggesting that information from the taste of food and from the movements it evokes are seamlessly integrated. NEW & NOTEWORTHY Neurons in the rostral nucleus of the solitary tract (NTS) are known to encode information about taste. However, recordings from awake rats reveal that only a minority of NTS cells respond exclusively to taste stimuli. The majority of neurons track behaviors associated with food consumption, and even strongly lick-related neurons could convey information about taste quality. These findings suggest that the NTS integrates information from both taste and behavior to identify food.


Assuntos
Neurônios/fisiologia , Núcleo Solitário/fisiologia , Percepção Gustatória , Animais , Masculino , Ratos , Ratos Sprague-Dawley , Núcleo Solitário/citologia , Paladar
4.
J Neurophysiol ; 121(2): 602-608, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30565964

RESUMO

Activation of corticotropin-releasing hormone (CRH) type 2 receptors (CRHR2) in the nucleus of the solitary tract (NTS) contributes to the development of hypertension, but the source of CRH inputs to the NTS that increases blood pressure remains unknown. This study tested the hypothesis that activation of CRH-containing projections from the paraventricular nucleus of the hypothalamus (PVN) to the NTS increase blood pressure. We expressed channelrhodopsin 2 (ChR2), a light-sensitive ion channel, into CRH-containing neurons in the PVN. This was achieved by injecting Cre-inducible virus expressing ChR2 into the PVN of CRH-Cre mice. CRH-Cre mice are genetically modified mice expressing Cre recombinase only in neurons producing CRH. We found that optogenetic stimulation of CRH-containing somas in the PVN or CRH-containing fibers in the NTS originating from the PVN significantly increased blood pressure and heart rate. Microinjection of K-41498 (CRHR2 antagonist) into the NTS attenuated the pressor and tachycardiac responses induced by optogenetic stimulation of CRH-containing somas in the PVN. In vitro loose-patch recordings revealed that optogenetic stimulation of CRH-containing fibers in the NTS originating from the PVN significantly increased the discharge frequency of NTS neurons. This effect was attenuated by pretreatment of K-41498 and was abolished by pretreatment of kynurenic acid (nonselective glutamate receptor antagonist). These results suggest that activation of PVN-NTS CRH-containing projections increases blood pressure and heart rate. The cardiovascular responses may be mediated at least in part by the corelease of CRH and glutamate from NTS CRH-containing axons originating from the PVN. NEW & NOTEWORTHY Optogenetic stimulation of paraventricular nucleus of the hypothalamus (PVN) corticotropin-releasing hormone (CRH)-containing somas or nucleus of the solitary tract (NTS) CRH-containing fibers originating from the PVN increased blood pressure and heart rate. Corelease of CRH and glutamate from NTS CRH-containing axons originating from the PVN may contribute to the pressor and tachycardiac responses elicited by optogenetic stimulation of PVN CRH-containing somas.


Assuntos
Pressão Sanguínea , Hormônio Liberador da Corticotropina/metabolismo , Neurônios/fisiologia , Núcleo Hipotalâmico Paraventricular/fisiologia , Núcleo Solitário/fisiologia , Proteínas de Anfíbios/farmacologia , Animais , Channelrhodopsins/antagonistas & inibidores , Channelrhodopsins/genética , Channelrhodopsins/metabolismo , Antagonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Frequência Cardíaca , Ácido Cinurênico/farmacologia , Masculino , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Optogenética , Núcleo Hipotalâmico Paraventricular/citologia , Hormônios Peptídicos/farmacologia , Núcleo Solitário/citologia
5.
Physiol Rep ; 6(22): e13913, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30467998

RESUMO

Adenosine operating in the nucleus of the solitary tract (NTS) may inhibit or facilitate neurotransmitter release from nerve terminals and directly inhibit or facilitate central neurons via A1 and A2a pre- and postsynaptic receptors, respectively. However, adenosine A2a receptors, may also activate GABA-ergic neurons/terminals which in turn inhibit glutamatergic transmission in the NTS network. Our previous studies showed that adenosine operating via both A1 (inhibitor) and A2a (activator) receptors powerfully inhibits the cardiopulmonary chemoreflex (CCR) at the level of the caudal NTS. A1 receptors most likely inhibit glutamate release in the CCR network, whereas A2a receptors facilitate NTS GABA-ergic mechanisms which in turn inhibit CCR glutamatergic transmission. Therefore, we hypothesized that A2a receptors are located on NTS GABA-ergic neurons/terminals whereas A1 receptors may be located on NTS glutamatergic neurons/terminals. We investigated this hypothesis using double immunofluorescent staining for A2a or A1 adenosine receptors and GABA synthesizing enzyme, GAD67, in 30 µm thick, floating, medullary rat sections. We found that A2a adenosine receptors are localized within the GABA-ergic cells in the caudal NTS, whereas A1 adenosine receptors are absent from these neurons. Instead, A1 receptors were located on non-GABA-ergic (likely glutamatergic) neurons/terminals in the caudal NTS. These data support our functional findings and the hypothesis that adenosine A2a, but not A1 receptors are located on GABA-ergic neurons.


Assuntos
Neurônios GABAérgicos/metabolismo , Receptor A1 de Adenosina/metabolismo , Receptor A2A de Adenosina/metabolismo , Reflexo , Núcleo Solitário/fisiologia , Animais , Neurônios GABAérgicos/fisiologia , Ratos , Ratos Sprague-Dawley , Receptor A1 de Adenosina/genética , Receptor A2A de Adenosina/genética , Núcleo Solitário/citologia , Núcleo Solitário/metabolismo
6.
Neural Plast ; 2018: 8919347, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30363902

RESUMO

Electroacupuncture (EA) has been reported to benefit hypertension, but the underlying mechanisms are still unclear. We hypothesized that EA attenuates hypertension, in part, through modulation of γ-aminobutyric acid (GABA) receptor function in the nucleus tractus solitarii (NTS). In the present study, the long-term effect of EA on GABA receptor function and expression was examined in the NTS of two-kidney, one-clip (2K1C) renovascular hypertensive rats. EA (0.1-0.4 mA, 2 and 15 Hz) was applied at Zusanli (ST36) acupoints overlying the deep fibular nerve for 30 min once a day for two weeks. The results showed that long-term EA treatment improved blood pressure (BP) and markedly restored the baroreflex response in 2K1C hypertensive rats. The increased pressor and depressor responses to microinjection of GABAB receptor agonist and antagonist into the NTS in the hypertensive rats were blunted by the EA treatment. Moreover, EA treatment attenuated the increased GABAB receptor expression in the NTS of hypertensive rats. In contrast, EA had no significant effect on the GABAA receptor function and expression in the NTS of 2K1C hypertensive rats. These findings suggest that the beneficial effects of EA on renovascular hypertension may be through modulation of functional GABAB receptors in the NTS.


Assuntos
Barorreflexo/fisiologia , Eletroacupuntura/métodos , Hipertensão/fisiopatologia , Hipertensão/terapia , Receptores de GABA-B/fisiologia , Núcleo Solitário/fisiologia , Animais , Masculino , Ratos , Ratos Sprague-Dawley
7.
Exp Brain Res ; 236(10): 2661-2676, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29974148

RESUMO

Sensory-motor control of the pharyngeal swallow requires sensory afferent inputs from the pharynx and larynx evoked by introducing bolus into the pharynx. Patients with reduced sensitivity of the pharynx and larynx are likely to have a swallowing impairment, such as pre-swallow aspiration due to delayed swallow triggering. Interferential current stimulation applied to the neck is thought to improve the swallowing function of dysphagic patients, although the mechanism underlying the facilitatory effect of such stimulation remains unknown. In the present study, we examined the changes in the elicitability of swallowing due to the stimulation and the responses of the swallowing-related neurons in the nucleus tractus solitarius and in the area adjacent to the stimulation in decerebrate and paralyzed guinea pigs. The swallowing delay time was shortened by the stimulation, whereas the facilitatory effect of eliciting swallowing was attenuated by kainic acid injection into the nucleus tractus solitarius. Approximately half of the swallowing-related neurons responded to the stimulation. These data suggest that the interferential current stimulation applied to the neck could enhance the sensory afferent pathway of the pharynx and larynx, subserving excitatory inputs to the neurons of the swallowing pattern generator, thereby facilitating the swallowing reflex.


Assuntos
Vias Aferentes/fisiologia , Deglutição/fisiologia , Nervos Laríngeos/fisiologia , Faringe/fisiologia , Reflexo/fisiologia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Biofísica , Estimulação Elétrica , Eletromiografia , Agonistas de Aminoácidos Excitatórios/toxicidade , Cobaias , Ácido Caínico/toxicidade , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Tempo de Reação/fisiologia , Núcleo Solitário/citologia , Núcleo Solitário/lesões , Núcleo Solitário/fisiologia
8.
J Comp Neurol ; 526(14): 2149-2164, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30019398

RESUMO

Glutamatergic neurons that express pre-proglucagon (PPG) and are immunopositive (+) for glucagon-like peptide-1 (i.e., GLP-1+ neurons) are located within the caudal nucleus of the solitary tract (cNTS) and medullary reticular formation in rats and mice. GLP-1 neurons give rise to an extensive central network in which GLP-1 receptor (GLP-1R) signaling suppresses food intake, attenuates rewarding, increases avoidance, and stimulates stress responses, partly via GLP-1R signaling within the cNTS. In mice, noradrenergic (A2) cNTS neurons express GLP-1R, whereas PPG neurons do not. In this study, confocal microscopy in rats confirmed that prolactin-releasing peptide (PrRP)+ A2 neurons are closely apposed by GLP-1+ axonal varicosities. Surprisingly, GLP-1+ appositions were also observed on dendrites of PPG/GLP-1+ neurons in both species, and electron microscopy in rats revealed that GLP-1+ boutons form asymmetric synaptic contacts with GLP-1+ dendrites. However, RNAscope confirmed that rat GLP-1 neurons do not express GLP-1R mRNA. Similarly, Ca2+ imaging of somatic and dendritic responses in mouse ex vivo slices confirmed that PPG neurons do not respond directly to GLP-1, and a mouse crossbreeding strategy revealed that <1% of PPG neurons co-express GLP-1R. Collectively, these data suggest that GLP-1R signaling pathways modulate the activity of PrRP+ A2 neurons, and also reveal a local "feed-forward" synaptic network among GLP-1 neurons that apparently does not use GLP-1R signaling. This local GLP-1 network may instead use glutamatergic signaling to facilitate dynamic and potentially selective recruitment of GLP-1 neural populations that shape behavioral and physiological responses to internal and external challenges.


Assuntos
Peptídeo 1 Semelhante ao Glucagon/fisiologia , Rede Nervosa/fisiologia , Núcleo Solitário/citologia , Núcleo Solitário/fisiologia , Sinapses/fisiologia , Animais , Feminino , Receptor do Peptídeo Semelhante ao Glucagon 1/biossíntese , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Glutamato Descarboxilase , Masculino , Camundongos , Camundongos Transgênicos , Rede Nervosa/citologia , Proglucagon/metabolismo , Hormônio Liberador de Prolactina/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/fisiologia , Núcleo Solitário/ultraestrutura , Sinapses/ultraestrutura
9.
PLoS Comput Biol ; 14(7): e1006292, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29985917

RESUMO

Neurons process and convey information by transforming barrages of synaptic inputs into spiking activity. Synaptic inhibition typically suppresses the output firing activity of a neuron, and is commonly classified as having a subtractive or divisive effect on a neuron's output firing activity. Subtractive inhibition can narrow the range of inputs that evoke spiking activity by eliminating responses to non-preferred inputs. Divisive inhibition is a form of gain control: it modifies firing rates while preserving the range of inputs that evoke firing activity. Since these two "modes" of inhibition have distinct impacts on neural coding, it is important to understand the biophysical mechanisms that distinguish these response profiles. In this study, we use simulations and mathematical analysis of a neuron model to find the specific conditions (parameter sets) for which inhibitory inputs have subtractive or divisive effects. Significantly, we identify a novel role for the A-type Potassium current (IA). In our model, this fast-activating, slowly-inactivating outward current acts as a switch between subtractive and divisive inhibition. In particular, if IA is strong (large maximal conductance) and fast (activates on a time-scale similar to spike initiation), then inhibition has a subtractive effect on neural firing. In contrast, if IA is weak or insufficiently fast-activating, then inhibition has a divisive effect on neural firing. We explain these findings using dynamical systems methods (plane analysis and fast-slow dissection) to define how a spike threshold condition depends on synaptic inputs and IA. Our findings suggest that neurons can "self-regulate" the gain control effects of inhibition via combinations of synaptic plasticity and/or modulation of the conductance and kinetics of A-type Potassium channels. This novel role for IA would add flexibility to neurons and networks, and may relate to recent observations of divisive inhibitory effects on neurons in the nucleus of the solitary tract.


Assuntos
Potenciais de Ação/fisiologia , Modelos Neurológicos , Inibição Neural/fisiologia , Neurônios/fisiologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/fisiologia , Potenciais Sinápticos/fisiologia , Animais , Plasticidade Neuronal/fisiologia , Distribuição de Poisson , Núcleo Solitário/fisiologia , Sinapses/fisiologia
10.
J Comp Neurol ; 526(13): 2032-2047, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29888789

RESUMO

Astrocytes, the most abundant and structurally complex glial cells of the central nervous system, are proposed to play an important role in modulating the activities of neuronal networks, including respiratory rhythm-generating circuits of the preBötzinger complex (preBötC) located in the ventrolateral medulla of the brainstem. However, structural properties of astrocytes residing within different brainstem regions are unknown. In this study astrocytes in the preBötC, an intermediate reticular formation (IRF) region with respiratory-related function, and a region of the nucleus tractus solitarius (NTS) in adult rats were reconstructed and their morphological features were compared. Detailed morphological analysis revealed that preBötC astrocytes are structurally more complex than those residing within the functionally distinct neighboring IRF region, or the NTS, located at the dorsal aspect of the medulla oblongata. Structural analyses of the brainstem microvasculature indicated no significant regional differences in vascular properties. We hypothesize that high morphological complexity of preBötC astrocytes reflects their functional role in providing structural/metabolic support and modulation of the key neuronal circuits essential for breathing, as well as constraints imposed by arrangements of associated neurons and/or other local structural features of the brainstem parenchyma.


Assuntos
Astrócitos/fisiologia , Tronco Encefálico/citologia , Respiração , Fenômenos Fisiológicos Respiratórios , Animais , Astrócitos/ultraestrutura , Tronco Encefálico/irrigação sanguínea , Tronco Encefálico/fisiologia , Capilares/fisiologia , Masculino , Bulbo/citologia , Bulbo/fisiologia , Ratos , Ratos Sprague-Dawley , Formação Reticular/fisiologia , Núcleo Solitário/fisiologia
11.
Neuroscience ; 379: 219-227, 2018 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-29604384

RESUMO

During pregnancy, the progesterone metabolite, allopregnanolone (ALLO), becomes elevated and has been associated with altered levels within the CNS and resulting changes in GABAA receptor function. Pregnant animals poorly compensate reflexes for a decrease in blood pressure during hemorrhage. Previous works suggested that ALLO decreases baroreflex responses by central actions, however, the underlying mechanisms are poorly understood. In this study, we tested ALLO actions on visceral afferent synaptic transmission at second-order neurons within medial portions of the nucleus tractus solitarius (NTS) using hindbrain slices from non-pregnant female rats. Solitary tract (ST) stimulation-evoked excitatory postsynaptic currents (ST-eEPSCs) in NTS neurons directly connected to vagal afferents within the ST. ST-eEPSCs were functionally identified as monosynaptic by the latency characteristics (low jitter = standard deviation of latency, ≤200 µs) to ST stimulation. Such second-order neurons all displayed spontaneous inhibitory postsynaptic currents (sIPSCs), and low micromolar concentrations of ALLO increased frequency and decay time. At submicromolar concentrations, ALLO induced a tonic, GABAergic inhibitory current and suppressed ST-eEPSCs' amplitude. While GABAA receptor antagonist, bicuculline, blocked all ALLO effects, gabazine only blocked sIPSC actions. In current-clamp mode, ALLO perfusion increased failure of ST stimulation to trigger action potentials in most neurons. Thus, our results indicate that ALLO acts to suppress visceral afferent ST synaptic transmission at first synapses by activating pharmacologically distinct GABAA subtypes at different concentration ranges. This ALLO-mediated attenuated visceral afferent signal integration in NTS may underlie reflex changes in blood pressure during gestation.


Assuntos
Fármacos do Sistema Nervoso Central/farmacologia , Neurônios Aferentes/efeitos dos fármacos , Pregnanolona/farmacologia , Núcleo Solitário/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Animais , Bicuculina/farmacologia , Feminino , Neurônios Aferentes/fisiologia , Técnicas de Patch-Clamp , Piridazinas/farmacologia , Ratos Sprague-Dawley , Receptores de GABA-A/metabolismo , Núcleo Solitário/fisiologia , Transmissão Sináptica/fisiologia , Técnicas de Cultura de Tecidos , Ácido gama-Aminobutírico/metabolismo
12.
Brain Behav Immun ; 70: 398-422, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29601943

RESUMO

Transition periods (TPs) are brief stages in CNS development where neural circuits can exhibit heightened vulnerability to pathologic conditions such as injury or infection. This susceptibility is due in part to specialized mechanisms of synaptic plasticity, which may become activated by inflammatory mediators released under pathologic conditions. Thus, we hypothesized that the immune response to lung injury (LI) mediated synaptic changes through plasticity-like mechanisms that depended on whether LI occurred just before or after a TP. We studied the impact of LI on brainstem 2nd-order viscerosensory neurons located in the nucleus tractus solitarii (nTS) during a TP for respiratory control spanning (postnatal day (P) 11-15). We injured the lungs of Sprague-Dawley rats by intratracheal instillation of Bleomycin (or saline) just before (P9-11) or after (P17-19) the TP. A week later, we prepared horizontal slices of the medulla and recorded spontaneous and evoked excitatory postsynaptic currents (sEPSCs/eEPSCs) in vitro from neurons in the nTS that received monosynaptic glutamatergic input from the tractus solitarii (TS). In rats injured before the TP (pre-TP), neurons exhibited blunted sEPSCs and TS-eEPSCs compared to controls. The decreased TS-eEPSCs were mediated by differences in postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic-acid receptors (AMPAR). Specifically, compared to controls, LI rats had more Ca2+-impermeable AMPARs (CI-AMPARs) as indicated by: 1) the absence of current-rectification, 2) decreased sensitivity to polyamine, 1-Naphthyl-acetyl-spermine-trihydrochloride (NASPM) and 3) augmented immunoreactive staining for the CI-AMPAR GluA2. Thus, pre-TP-LI acts postsynaptically to blunt glutamatergic transmission. The neuroimmune response to pre-TP-LI included microglia hyper-ramification throughout the nTS. Daily intraperitoneal administration of minocycline, an inhibitor of microglial/macrophage function prevented hyper-ramification and abolished the pre-TP-LI evoked synaptic changes. In contrast, rat-pups injured after the TP (post-TP) exhibited microglia hypo-ramification in the nTS and had increased sEPSC amplitudes/frequencies, and decreased TS-eEPSC amplitudes compared to controls. These synaptic changes were not associated with changes in CI-AMPARs, and instead involved greater TS-evoked use-dependent depression (reduced paired pulse ratio), which is a hallmark of presynaptic plasticity. Thus we conclude that LI regulates the efficacy of TS → nTS synapses through discrete plasticity-like mechanisms that are immune-mediated and depend on whether the injury occurs before or after the TP for respiratory control.


Assuntos
Lesão Pulmonar/imunologia , Lesão Pulmonar/metabolismo , Fatores Etários , Animais , Animais Recém-Nascidos , Bleomicina/farmacologia , Depressão , Transtorno Depressivo , Fármacos atuantes sobre Aminoácidos Excitatórios , Potenciais Pós-Sinápticos Excitadores , Feminino , Ácido Glutâmico/fisiologia , Lesão Pulmonar/fisiopatologia , Masculino , Bulbo , Plasticidade Neuronal , Neurônios , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley , Núcleo Solitário/fisiologia , Sinapses/fisiologia , Transmissão Sináptica/fisiologia
13.
Physiol Rep ; 6(3)2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29388357

RESUMO

Obstructive sleep apnea (OSA) is the most common respiratory disturbance of sleep and is closely associated to cardiovascular diseases. In humans, apnea increases respiratory effort and elevates muscle sympathetic nerve activity (SNA), but the primary stimulus for the SNA activation has not been identified. We recently developed a model of apnea in rodents using acute airway obstruction. In this study, we employed this model to test whether the elevation in SNA was mediated by hypoxia, carotid chemoreceptors, or neurotransmission in the nucleus tractus solitarius (NTS). In anesthetized, male Sprague-Dawley rats, airway obstruction (20s) increased phrenic nerve activity (PNA), arterial blood pressure (ABP), and lumbar, renal, and splanchnic SNA. The changes in SNA were similar across all three sympathetic nerves. Inactivation of chemoreceptors by hyperoxia (100% O2 ) or surgical denervation of carotid chemoreceptors attenuated, but did not eliminate, the changes in SNA and ABP produced by airway obstruction. To interrupt afferent information from carotid chemoreceptor and extracarotid afferents to the hindbrain, airway obstruction was performed before and after NTS microinjection of the GABAA agonist muscimol or a cocktail of NMDA and non-NMDA antagonists. Inhibition of NTS neurons or blockade of glutamatergic receptors attenuated the increase in lumbar SNA, splanchnic SNA, renal SNA, and PNA. Collectively, these findings suggest that PNA and SNA responses induced by airway obstruction depend, in part, on chemoreceptors afferents and glutamatergic neurotransmission in the NTS.


Assuntos
Corpo Carotídeo/fisiologia , Hipóxia/fisiopatologia , Apneia Obstrutiva do Sono/fisiopatologia , Sistema Nervoso Simpático/fisiologia , Transmissão Sináptica , Animais , Ácido Glutâmico/metabolismo , Masculino , Nervo Frênico/fisiologia , Ratos , Ratos Sprague-Dawley , Núcleo Solitário/fisiologia
14.
J Neurophysiol ; 119(3): 771-785, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29093172

RESUMO

Neurons in the rostral nucleus of the solitary tract (rNST) convey taste information to both local circuits and pathways destined for forebrain structures. This nucleus is more than a simple relay, however, because rNST neurons differ in response rates and tuning curves relative to primary afferent fibers. To systematically study the impact of convergence and inhibition on firing frequency and breadth of tuning (BOT) in rNST, we constructed a mathematical model of its two major cell types: projection neurons and inhibitory neurons. First, we fit a conductance-based neuronal model to data derived from whole cell patch-clamp recordings of inhibitory and noninhibitory neurons in a mouse expressing Venus under the control of the VGAT promoter. We then used in vivo chorda tympani (CT) taste responses as afferent input to modeled neurons and assessed how the degree and type of convergence influenced model cell output frequency and BOT for comparison with in vivo gustatory responses from the rNST. Finally, we assessed how presynaptic and postsynaptic inhibition impacted model cell output. The results of our simulations demonstrated 1) increasing numbers of convergent afferents (2-10) result in a proportional increase in best-stimulus firing frequency but only a modest increase in BOT, 2) convergence of afferent input selected from the same best-stimulus class of CT afferents produced a better fit to real data from the rNST compared with convergence of randomly selected afferent input, and 3) inhibition narrowed the BOT to more realistically model the in vivo rNST data. NEW & NOTEWORTHY Using a combination of in vivo and in vitro neurophysiology together with conductance-based modeling, we show how patterns of convergence and inhibition interact in the rostral (gustatory) solitary nucleus to maintain signal fidelity. Although increasing convergence led to a systematic increase in firing frequency, tuning specificity was maintained with a pattern of afferent inputs sharing the best-stimulus compared with random inputs. Tonic inhibition further enhanced response fidelity.


Assuntos
Potenciais de Ação , Modelos Neurológicos , Neurônios/fisiologia , Núcleo Solitário/fisiologia , Vias Aferentes/fisiologia , Animais , Nervo da Corda do Tímpano/fisiologia , Neurônios GABAérgicos/fisiologia , Camundongos Transgênicos , Vias Neurais/fisiologia , Paladar/fisiologia
15.
Neurobiol Dis ; 109(Pt A): 25-32, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28927958

RESUMO

Rett syndrome (RTT) is a devastating neurodevelopmental disorder caused by loss-of-function mutations in the X-linked methyl-CpG binding protein 2 (Mecp2) gene. GABAergic dysfunction has been implicated contributing to the respiratory dysfunction, one major clinical feature of RTT. The nucleus tractus solitarius (NTS) is the first central site integrating respiratory sensory information that can change the nature of the reflex output. We hypothesized that deficiency in Mecp2 gene reduces GABAergic neurotransmission in the NTS. Using whole-cell patch-clamp recordings in NTS slices, we measured spontaneous inhibitory postsynaptic currents (sIPSCs), miniature IPSCs (mIPSCs), NTS-evoked IPSCs (eIPSCs), and GABAA receptor (GABAA-R) agonist-induced responses. Compared to those from wild-type mice, NTS neurons from Mecp2-null mice had significantly (p<0.05) reduced sIPSC amplitude, sIPSC frequency, and mIPSC amplitude but not mIPSC frequency. Mecp2-null mice also had decreased eIPSC amplitude with no change in paired-pulse ratio. The data suggest reduced synaptic receptor-mediated phasic GABA transmission in Mecp2-null mice. In contrast, muscimol (GABAA-R agonist, 0.3-100µM) and THIP (selective extrasynaptic GABAA-R agonist, 5µM) induced significantly greater current response in Mecp2-null mice, suggesting increased extrasynaptic receptors. Using qPCR, we found a 2.5 fold increase in the delta subunit of the GABAA-Rs in the NTS in Mecp2-null mice, consistent with increased extrasynaptic receptors. As the NTS was recently found required for respiratory pathology in RTT, our results provide a mechanism for NTS dysfunction which involves shifting the balance of synaptic/extrasynaptic receptors in favor of extrasynaptic site, providing a target for boosting GABAergic inhibition in RTT.


Assuntos
Potenciais Pós-Sinápticos Inibidores , Proteína 2 de Ligação a Metil-CpG/fisiologia , Neurônios/fisiologia , Síndrome de Rett/fisiopatologia , Núcleo Solitário/fisiologia , Transmissão Sináptica , Ácido gama-Aminobutírico/fisiologia , Animais , Modelos Animais de Doenças , Agonistas de Receptores de GABA-A , Proteína 2 de Ligação a Metil-CpG/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Potenciais Pós-Sinápticos em Miniatura , Neurônios/efeitos dos fármacos , RNA Mensageiro/metabolismo , Receptores de GABA-A/administração & dosagem , Receptores de GABA-A/fisiologia , Síndrome de Rett/metabolismo , Núcleo Solitário/metabolismo
16.
Neuropharmacology ; 128: 152-167, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28987939

RESUMO

Recent studies have demonstrated that a mild stimulation of the dorsomedian nucleus of the hypothalamus (DMH), a defense area, induces the inhibition of the carotid chemoreflex tachypnea. DMH activation reduces the cardiac chemoreflex response via the dorsolateral part of the periaqueductal grey matter (dlPAG) and serotonin receptors (5-HT3 subtype) in the nucleus tractus solitarius (NTS). The objectives of this study were to assess whether dlPAG and subsequent NTS 5-HT3 receptors are involved in chemoreflex tachypnea inhibition during mild activation of the DMH. For this purpose, peripheral chemoreflex was activated with potassium cyanide (KCN, 40 µg/rat, i.v.) during electrical and chemical minimal supra-threshold (mild) stimulation of the dlPAG or DMH. In both situations, changes in respiratory frequency (RF) following KCN administration were reduced. Moreover, pharmacological blockade of the dlPAG prevented DMH-induced KCN tachypnea inhibition. Activation of NTS 5-HT3 receptors also reduced chemoreflex tachypnea in a dose-dependent manner. In addition, blockade of NTS 5-HT3 receptors with granisetron (2.5 but not 1.25 mM), or the use of mice lacking the 5-HT3a receptor (5-HT3a KO), prevented dlPAG-induced KCN reductions in RF. A respiratory hypothalamo-midbrain-medullary pathway (HMM) therefore plays a crucial role in the inhibition of the hyperventilatory response to carotid chemoreflex.


Assuntos
Barorreflexo/efeitos dos fármacos , Células Quimiorreceptoras/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Cianeto de Potássio/farmacologia , Respiração/efeitos dos fármacos , Medula Suprarrenal , Animais , Biguanidas/farmacologia , Relação Dose-Resposta a Droga , Hipotálamo/efeitos dos fármacos , Hipotálamo/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores 5-HT3 de Serotonina/deficiência , Receptores 5-HT3 de Serotonina/genética , Agonistas do Receptor de Serotonina/farmacologia , Núcleo Solitário/efeitos dos fármacos , Núcleo Solitário/fisiologia
17.
J Physiol ; 596(3): 497-513, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29235097

RESUMO

KEY POINTS: In the rat nucleus of the solitary tract (NTS), activation of astrocytic proteinase-activated receptor 1 (PAR1) receptors leads to potentiation of neuronal synaptic activity by two mechanisms, one TRPV1-dependent and one TRPV1-independent. PAR1-dependent activation of presynaptic TRPV1 receptors facilitates glutamate release onto NTS neurons. The TRPV1-dependent mechanism appears to rely on astrocytic release of endovanilloid-like molecules. A subset of NTS neurons excited by PAR1 directly project to the rostral ventral respiratory group. The PAR1 initiated, TRPV1-dependent modulation of synaptic transmission in the NTS contributes to regulation of breathing. ABSTRACT: Many of the cellular and molecular mechanisms underlying astrocytic modulation of synaptic function remain poorly understood. Recent studies show that G-protein coupled receptor-mediated astrocyte activation modulates synaptic transmission in the nucleus of the solitary tract (NTS), a brainstem nucleus that regulates crucial physiological processes including cardiorespiratory activity. By using calcium imaging and patch clamp recordings in acute brain slices of wild-type and TRPV1-/- rats, we show that activation of proteinase-activated receptor 1 (PAR1) in NTS astrocytes potentiates presynaptic glutamate release on NTS neurons. This potentiation is mediated by both a TRPV1-dependent and a TRPV1-independent mechanism. The TRPV1-dependent mechanism appears to require release of endovanilloid-like molecules from astrocytes, which leads to subsequent potentiation of presynaptic glutamate release via activation of presynaptic TRPV1 channels. Activation of NTS astrocytic PAR1 receptors elicits cFOS expression in neurons that project to respiratory premotor neurons and inhibits respiratory activity in control, but not in TRPV1-/- rats. Thus, activation of astrocytic PAR1 receptor in the NTS leads to a TRPV1-dependent excitation of NTS neurons causing a potent modulation of respiratory motor output.


Assuntos
Astrócitos/fisiologia , Neurônios/fisiologia , Receptor PAR-1/metabolismo , Respiração , Núcleo Solitário/fisiologia , Transmissão Sináptica , Canais de Cátion TRPV/metabolismo , Potenciais de Ação , Animais , Astrócitos/citologia , Potenciais Pós-Sinápticos Excitadores , Masculino , Neurônios/citologia , Ratos , Ratos Sprague-Dawley , Núcleo Solitário/citologia
18.
Neuron ; 96(1): 190-206.e7, 2017 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-28957668

RESUMO

Sodium deficiency increases angiotensin II (ATII) and aldosterone, which synergistically stimulate sodium retention and consumption. Recently, ATII-responsive neurons in the subfornical organ (SFO) and aldosterone-sensitive neurons in the nucleus of the solitary tract (NTSHSD2 neurons) were shown to drive sodium appetite. Here we investigate the basis for NTSHSD2 neuron activation, identify the circuit by which NTSHSD2 neurons drive appetite, and uncover an interaction between the NTSHSD2 circuit and ATII signaling. NTSHSD2 neurons respond to sodium deficiency with spontaneous pacemaker-like activity-the consequence of "cardiac" HCN and Nav1.5 channels. Remarkably, NTSHSD2 neurons are necessary for sodium appetite, and with concurrent ATII signaling their activity is sufficient to produce rapid consumption. Importantly, NTSHSD2 neurons stimulate appetite via projections to the vlBNST, which is also the effector site for ATII-responsive SFO neurons. The interaction between angiotensin signaling and NTSHSD2 neurons provides a neuronal context for the long-standing "synergy hypothesis" of sodium appetite regulation.


Assuntos
Aldosterona/fisiologia , Angiotensina II/fisiologia , Relógios Biológicos/fisiologia , Neurônios/fisiologia , Transdução de Sinais , Sódio/fisiologia , Núcleo Solitário/fisiologia , Animais , Ingestão de Alimentos/fisiologia , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/fisiologia , Masculino , Camundongos , Camundongos Transgênicos , Canal de Sódio Disparado por Voltagem NAV1.5/fisiologia , Vias Neurais/fisiologia , Núcleos Septais/fisiologia , Sódio/deficiência
19.
Neuroscience ; 360: 18-27, 2017 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-28757247

RESUMO

The mode of action of L-DOPA on excitatory synaptic transmission in second-order neurons of the nucleus tractus solitarius (NTS) was studied using the rat brainstem slices. Superfusion of L-DOPA (10µM) reduced the frequency of miniature excitatory postsynaptic currents (mEPSCs) without any effect on the amplitude. A low concentration (1µM) was ineffective on the mEPSCs, and the highest concentration (100µM) exerted a stronger inhibitory effect. L-DOPA (10µM) decreased the amplitude of EPSCs (eEPSCs) evoked by electrical stimulation of the tractus solitarius and increased the paired-pulse ratio. The inhibitory effects of L-DOPA on mEPSCs and eEPSCs were similar to those of dopamine (100µM). The effects of L-DOPA were blocked by a competitive antagonist, L-DOPA methyl ester (100µM) and also by a D2 receptor antagonist, sulpiride (10µM), while those of dopamine were blocked by the latter but not by the former. In reserpine (5mg/kg, s.c.)-treated rats, the effects of L-DOPA on both mEPSCs and eEPSCs were completely abolished, but those of dopamine remained unchanged. The present results suggest a possibility that L-DOPA may induce the release of dopamine from the axon terminals in the NTS and the released dopamine suppresses the glutamatergic transmission through activation of the presynaptic D2 receptors.


Assuntos
Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Levodopa/farmacologia , Núcleo Solitário/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Animais , Dopamina/metabolismo , Potenciais Pós-Sinápticos Excitadores/fisiologia , Ácido Glutâmico/metabolismo , Masculino , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Terminações Pré-Sinápticas/efeitos dos fármacos , Ratos , Núcleo Solitário/fisiologia , Transmissão Sináptica/fisiologia
20.
Appetite ; 118: 90-96, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28789870

RESUMO

Food preferences have been investigated in Wistar rats utilizing a learned concurrent flavor preference behavioral procedure. Previous studies have demonstrated that the perivagal administration of neurotoxin capsaicin disrupts the learning of preferences induced by intragastric administration of rewarding nutrients (pre-digested milk). The vagus nerve projects almost exclusively towards the nucleus of the solitary tract (NST), a brain medullary gateway for visceral signals. The objective of this study was to investigate the participation of the lateral portion of the dorsomedial region, the gelatinous subnucleus (SolG), in the learning of a concurrent preference task. Results show that unlike neurologically intact animals, which learn this task correctly, animals lesioned in the gelatinous part of NST manifest a disruption of discrimination learning. Thus, intakes of the flavored stimulus paired with predigested liquid diet and of the flavored stimulus paired with physiological saline were virtually identical. However, SolG- and sham-lesioned groups consumed similar total amounts of both flavors. These findings suggest that SolG, as a relay of the vagus nerve, along with its anatomical projection, the external lateral parabrachial subnucleus (LPBe), may constitute an anatomical axis that is important in the induction of concurrent flavor/side preferences. It also appears to be relevant in other behavioral processes that require rapid processing of information from the upper gastrointestinal tract.


Assuntos
Preferências Alimentares/fisiologia , Aprendizagem/fisiologia , Núcleo Solitário/fisiologia , Animais , Peso Corporal , Dieta , Masculino , Ratos , Ratos Wistar , Recompensa , Paladar , Nervo Vago/fisiologia
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