Asunto(s)

RESUMEN

Considering that the retrotrapezoid nucleus/respiratory parafacial region (RTN/pFRG) would be an important center in the central nervous system involved in the maintenance and modulation of respiratory activity, we hypothesized that neurons in this nucleus would also be involved in the postinspiratory phase of the respiratory cycle through a connection with the pontine Kölliker-Fuse (KF) region. Here we performed pharmacogenetic manipulation (AAV-hM3D(Gq)-mCherry or AAV-hM4D(Gi)-mCherry) in VGlut2-cre, Ai6 conscious mice to evaluate breathing parameters through whole body plethysmography under baseline conditions (normoxia: FiO2 = 0.21) or under hypercapnia or hypoxia challenges (FiCO2 = 0.07 or FiO2 = 0.08). Under normoxia, selective stimulation of RTN/pFRG resulted in a smaller increase in VE (1,272 ± 102.5, vs. RTN/pFRG stimulation: 1,878 ± 122.1 ml/kg/min), due to a smaller increase in VT (5.4 ± 0.35, vs. RTN/pFRG stimulation: 7.77 ± 0.21 ml/kg) without changing fR in a condition of KF inhibition. However, inhibition of the VGlut2 neurons in the KF did affect the TE1 produced by selective activation of RTN/pFRG (119.9 ± 2.53, vs. RTN/pFRG stimulation: 104 ± 2.46 ms). Both the hypercapnia and hypoxia ventilatory response were reduced after inhibition of VGlut2-expressing KF neurons. Therefore, consistent with anatomical projections RTN/pFRG neurons regulate lung ventilation by controlling all aspects of breathing, i.e breathing frequency, inspiration, postinspiration and active expiration. All the modulation seems to be dependent on the integrity of the glutamatergic neurons in the KF region.

RESUMEN

Parkinson's disease (PD) involves the degeneration of dopaminergic neurons in the substantia nigra (SNpc) and manifests with both classic and non-classic motor symptoms, including respiratory failure. Our study aims to investigate the involvement of the commissural and intermediate nucleus of the solitary tract (cNTS and iNTS) in the attenuated respiratory response to hypoxia in PD. Using a PD rat model induced by bilateral injection of 6-hydroxydopamine (6-OHDA) into the striatum of male Wistar rats, we explored potential alterations in the population of Phox2b neurons or hypoxia-activated neurons in the NTS projecting to the retrotrapezoid nucleus (RTN). Additionally, we explored neuronal connectivity between SNpc and cNTS. Projections pathways were assessed using unilateral injection of the retrograde tracer Fluorogold (FG) in the cNTS and RTN. Neuronal activation was evaluated by analyzing fos expression in rats exposed to hypoxia. In the PD model, the ventilatory response, measured through whole-body plethysmography, was impaired at both baseline and in response to hypoxia. A reduction in Phox2b-expressing neurons or hypoxia-activated neurons projecting to the RTN was observed. Additionally, we identified an indirect pathway linking the SNpc and cNTS, which passes through the periaqueductal gray (PAG). In conclusion, our findings suggest impairment in the SNpc-PAG-cNTS pathway in the PD model, explaining the loss of Phox2b-expressing neurons or hypoxia-activated neurons in the cNTS and subsequent respiratory impairment during hypoxic stimulation. We propose that the reduced population of Phox2b-expressing neurons in the NTS may include the same neurons activated by hypoxia and projecting to the RTN.

Asunto(s)

RESUMEN

Aging invariably decreases sensory and motor stimuli and affects several neuronal systems and their connectivity to key brain regions, including those involved in breathing. Nevertheless, further investigation is needed to fully comprehend the link between senescence and respiratory function. Here, we investigate whether a mouse model of accelerated senescence could develop central and peripheral respiratory abnormalities. Adult male Senescence Accelerated Mouse Prone 8 (SAMP8) and the control SAMR1 mice (10 months old) were used. Ventilatory parameters were assessed by whole-body plethysmography, and measurements of respiratory input impedance were performed. SAMP8 mice exhibited a reduction in the density of neurokinin-1 receptor immunoreactivity in the entire ventral respiratory column. Physiological experiments showed that SAMP8 mice exhibited a decreased tachypneic response to hypoxia (FiO2 = 0.08; 10 min) or hypercapnia (FiCO2 = 0.07; 10 min). Additionally, the ventilatory response to hypercapnia increased further due to higher tidal volume. Measurements of respiratory mechanics in SAMP8 mice showed decreased static compliance (Cstat), inspiratory capacity (IC), resistance (Rn), and elastance (H) at different ages (3, 6, and 10 months old). SAMP8 mice also have a decrease in contractile response to methacholine compared to SAMR1. In conclusion, our findings indicate that SAMP8 mice display a loss of the NK1-expressing neurons in the respiratory brainstem centers, along with impairments in both central and peripheral respiratory mechanisms. These observations suggest a potential impact on breathing in a senescence animal model.

RESUMEN

OSA is known to increase the risk for SUDEP in persons with epilepsy, but the relationship between these two factors is not clear. Also, there is no study showing the acute responses to obstructive apnea in a chronic epilepsy model. Therefore, this study aimed to characterize cardiorespiratory responses to obstructive apnea and chemoreceptor stimulation in rats. In addition, we analyzed respiratory centers in the brain stem by immunohistochemistry. Epilepsy was induced with pilocarpine. About 30-60 days after the first spontaneous seizure, tracheal and thoracic balloons, and electrodes for recording the electroencephalogram, electromyogram, and electrocardiogram were implanted. Intermittent apneas were made by inflation of the tracheal balloon during wakefulness, NREM sleep, and REM sleep. During apnea, respiratory effort increased, and heart rate fell, especially with apneas made during wakefulness, both in control rats and rats with epilepsy. Latency to awake from apnea was longer with apneas made during REM than NREM, but rats with epilepsy awoke more rapidly than controls with apneas made during REM sleep. Rats with epilepsy also had less REM sleep. Cardiorespiratory responses to stimulation of carotid chemoreceptors with cyanide were similar in rats with epilepsy and controls. Immunohistochemical analysis of Phox2b, tryptophan hydroxylase, and NK1 in brain stem nuclei involved in breathing and sleep (retrotrapezoid nucleus, pre-Bötzinger complex, Bötzinger complex, and caudal raphe nuclei) revealed no differences between control rats and rats with epilepsy. In conclusion, our study showed that rats with epilepsy had a decrease in the latency to awaken from apneas during REM sleep, which may be related to neuroplasticity in some other brain regions related to respiratory control, awakening mechanisms, and autonomic modulation.

Asunto(s)

RESUMEN

BACKGROUND: In response to the COVID-19 pandemic, educational institutions had to swiftly adapt and transition to remote teaching in order to maintain academic activities. However, these changes presented a number of challenges for professors, which could have negative effects on their health. OBJECTIVE: To analyze the association between changes in dietary and sleep habits, physical activity level, and sedentary behavior with the development of non-communicable diseases (NCDs) among Brazilian higher education professors during the pandemic period. METHODS: This is a cross-sectional and retrospective study conducted using an online form. Generalized linear models, adjusted for age, sex, and body mass index, were used to verify the difference between pre-pandemic and pandemic periods. Logistic regression models were used to predict the odds ratio (OR) for the development of NCDs according to physical activity time, sedentary behavior time, dietary and sleep patterns. RESULTS: A total of 936 professors residing across Brazil participated in the survey. The duration of sedentary behavior increased, sleep duration slightly decreased, and meal times shifted to earlier during the pandemic. A total of 22.9%of the participants reported the diagnosis of some NCDs during this period. Physical activity practice was associated with a lower risk of diseases during the pandemic, regardless of the intensity performed. On the other hand, late eating habits and excessive food consumption during the pandemic were associated with a higher risk. CONCLUSION: The results provide data that can help in the development of public policies that promote health actions to minimize the consequences associated with the pandemic period.

Asunto(s)

RESUMEN

Background: Programmed ventricular stimulation (PVS) during electrophysiological study (EPS), is a globally accepted tool for risk stratification of sudden cardiac death (SCD) in some specific clinical situations. The aim of this study was to evaluate the prognosis of ventricular arrhythmia induction in a cohort of patients with syncope of undetermined origin (SUO). Methods: This is a historical cohort study in a population of patients with SUO referred for EPS between the years 2008-2021. In this interval, 575 patients underwent the procedure. Results: Patients with induced ventricular arrhythmias had a higher occurrence of structural heart disease (36.7% vs. 76.5%), ischemic heart disease (28.2 vs. 57.1%), heart failure (15.5% vs. 34.4%), and lower left ventricular ejection fraction (59.16% vs. 47.51%), when compared to the outcome with a negative study. PVS triggered ventricular arrhythmias in 98 patients, 62 monomorphic and 36 polymorphic. During a median follow-up of 37.6 months, 100 deaths occurred. Only the induction of sustained ventricular arrhythmias showed a significant association with the primary outcome (all-cause mortality) with a p value <.001. After the performance of EPS, 142 patients underwent cardioverter-defibrillator (ICD) implantation. At study follow-up, 30 patients had therapies by the device. Only the induction of sustained monomorphic ventricular arrhythmia showed statistically significant association with appropriate therapies by the device (p = .012). Conclusion: In patients with SUO, the induction of sustained monomorphic ventricular arrhythmia after programmed ventricular pacing is related to a worse prognosis, with a higher incidence of mortality and appropriate therapies by the ICD.

RESUMEN

Respiration is regulated by various types of neurons located in the pontine-medullary regions. The Kölliker-Fuse (KF)/A7 noradrenergic neurons play a role in modulating the inspiratory cycle by influencing the respiratory output. These neurons are interconnected and may also project to brainstem and spinal cord, potentially involved in regulating the post-inspiratory phase. In the present study, we hypothesize that the parafacial (pF) neurons, in conjunction with adrenergic mechanisms originating from the KF/A7 region, may provide the neurophysiological basis for breathing modulation. We conducted experiments using urethane-anesthetized, vagotomized, and artificially ventilated male Wistar rats. Injection of L-glutamate into the KF/A7 region resulted in inhibition of inspiratory activity, and a prolonged and high-amplitude genioglossal activity (GGEMG). Blockade of the α1 adrenergic receptors (α1-AR) or the ionotropic glutamatergic receptors in the pF region decrease the activity of the GGEMG without affecting inspiratory cessation. In contrast, blockade of α2-AR in the pF region extended the duration of GG activity. Notably, the inspiratory and GGEMG activities induced by KF/A7 stimulation were completely blocked by bilateral blockade of glutamatergic receptors in the Bötzinger complex (BötC). While our study found a limited role for α1 and α2 adrenergic receptors at the pF level in modulating the breathing response to KF/A7 stimulation, it became evident that BötC neurons are responsible for the respiratory effects induced by KF/A7 stimulation.

Asunto(s)

RESUMEN

Parkinson's Disease (PD) is characterized by classic motor symptoms related to movement, but PD patients can experience symptoms associated with impaired autonomic function, such as respiratory disturbances. Functional respiratory deficits are known to be associated with brainstem neurodegeneration in the mice model of PD induced by 6-hydroxydopamine (6-OHDA). Understanding the causes of neuronal death is essential for identifying specific targets to prevent degeneration. Many mechanisms can explain why neurons die in PD, and neuroinflammation is one of them. To test the influence of inflammation, mediated by microglia and astrocytes cells, in the respiratory disturbances associated with brainstem neurons death, we submitted wild-type (WT) and TNF receptor 1 (TNFR1) knockout male mice to the 6-OHDA model of PD. Also, male C57BL/6 animals were induced using the same PD model and treated with minocycline (45 mg/kg), a tetracycline antibiotic with anti-inflammatory properties. We show that degeneration of brainstem areas such as the retrotrapezoid nucleus (RTN) and the pre-Botzinger Complex (preBotC) were prevented in both protocols. Notably, respiratory disturbances were no longer observed in the animals where inflammation was suppressed. Thus, the data demonstrate that inflammation is responsible for the breathing impairment in the 6-OHDA-induced PD mouse model.

Asunto(s)

RESUMEN

At least four mechanisms have been proposed to elucidate how neurons in the retrotrapezoid (RTN) region sense changes in CO2 /H+ to regulate breathing (i.e., function as respiratory chemosensors). These mechanisms include: (1) intrinsic neuronal sensitivity to H+ mediated by TASK-2 and GPR4; (2) paracrine activation of RTN neurons by CO2 -responsive astrocytes (via a purinergic mechanism); (3) enhanced excitatory synaptic input or disinhibition; and (4) CO2 -induced vascular contraction. Although blood flow can influence tissue CO2 /H+ levels, there is limited understanding of how control of vascular tone in central CO2 chemosensitive regions might contribute to respiratory output. In this review, we focus on recent evidence that CO2 /H+ -induced purinergic-dependent vasoconstriction in the ventral parafacial region near RTN neurons supports respiratory chemoreception. This mechanism appears to be unique to the ventral parafacial region and opposite to other brain regions, including medullary chemosensor regions, where CO2 /H+ elicits vasodilatation. We speculate that this mechanism helps to maintain CO2 /H+ levels in the vicinity of RTN neurons, thereby maintaining the drive to breathe. Important next steps include determining whether disruption of CO2 /H+ vascular reactivity contributes to or can be targeted to improve breathing problems in disease states, such as Parkinson's disease.

RESUMEN

Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra compacta (SNpc). In a mouse model of PD induced by the injection of 6-hydroxydopamine (6-OHDA) into the caudate putamen (CPu) dyspnea events are very common. Neuroanatomical and functional studies show that the number of glutamatergic neurons in the pre-Bötzinger Complex (preBötC) are reduced. We hypothesize that the neuronal loss, and consequently loss of glutamatergic connections in the respiratory network previously investigated, are responsible for the breathing impairment in PD. Here, we tested whether ampakines (CX614), a subgroup of AMPA receptor positive allosteric modulators, could stimulate the respiratory activity in PD-induced animals. CX614 (50 µM) injected intraperitoneally or directly into the preBötC region reduced the irregularity pattern and increased the respiratory rate by 37% or 82%, respectively, in PD-induced animals. CX614 also increased the respiratory frequency in healthy animals. These data suggest that ampakine CX614 could become a tool to restore breathing in PD.

Asunto(s)

RESUMEN

Uncontrolled vasodilation is known to account for hypotension in the advanced stages of sepsis and other systemic inflammatory conditions, but the mechanisms of hypotension in earlier stages of such conditions are not clear. By monitoring hemodynamics with the highest temporal resolution in unanesthetized rats, in combination with ex-vivo assessment of vascular function, we found that early development of hypotension following injection of bacterial lipopolysaccharide is brought about by a fall in vascular resistance when arterioles are still fully responsive to vasoactive agents. This approach further uncovered that the early development of hypotension stabilized blood flow. We thus hypothesized that prioritization of the local mechanisms of blood flow regulation (tissue autoregulation) over the brain-driven mechanisms of pressure regulation (baroreflex) underscored the early development of hypotension in this model. Consistent with this hypothesis, an assessment of squared coherence and partial-directed coherence revealed that, at the onset of hypotension, the flow-pressure relationship was strengthened at frequencies (<0.2 Hz) known to be associated with autoregulation. The autoregulatory escape to phenylephrine-induced vasoconstriction, another proxy of autoregulation, was also strengthened in this phase. The competitive demand that drives prioritization of flow over pressure regulation could be edema-associated hypovolemia, as this became detectable at the onset of hypotension. Accordingly, blood transfusion aimed at preventing hypovolemia brought the autoregulation proxies back to normal and prevented the fall in vascular resistance. This novel hypothesis opens a new avenue of investigation into the mechanisms that can drive hypotension in systemic inflammation.

RESUMEN

Correctional workers form a high-priority group for tuberculosis control measures because of their high exposure and risk. This cross-sectional study conducted in April and May 2022 included 71 criminal police officers from the State Penitentiary of Francisco Beltrão-PR, Brazil. Their sociodemographic and laboratory data were collected. Latent tuberculosis infection (LTBI) was assessed using a QuantiFERON-TB Gold Plus in-tube test kit. Binary logistic regression was applied to calculate the odds ratios (ORs) and 95% confidence intervals (CI) of the LTBI predictors. The prevalence of LTBI was 22.6% (95% CI, 12.8-32.2%). Factors associated with LTBI were age > 43 years (OR, 0.18; 95% CI, 0.04-0.70; p < 0.014) and the use of medications (OR, 5.13; 95% CI, 1.40-18.87; p < 0.014). The prevalence was close to that estimated worldwide for LTBI in correctional workers, reinforcing the need for occupational health control measures consisting of regular screening and treatment of positive cases of latent infection among correctional workers to reduce the risk of illness and spread of infection in the penitentiary system and community.

Asunto(s)

RESUMEN

Parkinson's disease (PD) is a motor disorder resulting from degeneration of dopaminergic neurons of substantia nigra pars compacta (SNpc), with classical and non-classical symptoms such as respiratory instability. An important region for breathing control, the Pedunculopontine Tegmental Nucleus (PPTg), is composed of cholinergic, glutamatergic, and GABAergic neurons. We hypothesize that degenerated PPTg neurons in a PD model contribute to the blunted respiratory activity. Adult mice (40 males and 29 females) that express the fluorescent green protein in cholinergic, glutamatergic or GABAergic cells were used (Chat-cre Ai6, Vglut2-cre Ai6 and Vgat-cre Ai6) and received bilateral intrastriatal injections of vehicle or 6-hydroxydopamine (6-OHDA). Ten days later, the animals were exposed to hypercapnia or hypoxia to activate PPTg neurons. Vglut2-cre Ai6 animals also received retrograde tracer injections (cholera toxin b) into the retrotrapezoid nucleus (RTN) or preBötzinger Complex (preBötC) and anterograde tracer injections (AAV-mCherry) into the SNpc. In 6-OHDA-injected mice, there is a 77% reduction in the number of dopaminergic neurons in SNpc without changing the number of neurons in the PPTg. Hypercapnia activated fewer Vglut2 neurons in PD, and hypoxia did not activate PPTg neurons. PPTg neurons do not input RTN or preBötC regions but receive projections from SNpc. Although our results did not show a reduction in the number of glutamatergic neurons in PPTg, we observed a reduction in the number of neurons activated by hypercapnia in the PD animal model, suggesting that PPTg may participate in the hypercapnia ventilatory response.

Asunto(s)

RESUMEN

INTRODUCTION: The aim of this study was to compare E1-Irrisonic (Helse Ultrasonics, Ocoee, FL) and Irri Black (Helse Ultrasonics), a novel ultrasonic tip with diamondlike carbon treatment, regarding their design, metallurgy, microhardness, bending resistance, and time to fracture under the oscillatory fatigue test. METHODS: A total of 17 E1-Irrisonic and 17 Irri Black new ultrasonic tips were selected. The tip geometry and surface finishing were assessed using scanning electron microscopy. The elemental composition was defined by energy-dispersive X-ray spectroscopy. Hardness Knoop was calculated using a microhardness tester. The maximum load required to displace the instrument in 45° was recorded in gram/force, oscillatory fatigue was measured in seconds at the moment of instrument fracture, and the size of the separate fragments was determined in millimeters. The Student t test was used for statistical comparison (α = 5%). RESULTS: Scanning electron microscopic analyses revealed that E1-Irrisonic had a flat end tip, whereas a noncutting rounded tip was observed in Irri Black. The surface of E1-Irrisonic was smoother than Irri Black, which was irregular. Energy-dispersive X-ray spectroscopic analyses showed that the elemental compositions of the E1-Irrisonic and Irri Black tips were consistent with stainless steel and titanium-aluminum alloys, respectively. Irri Black showed significantly higher bending load resistance, time to fracture under oscillatory motion, and hardness Knoop than the E1-Irrisonic tip (P < .05), whereas the length of fragments was similar (P > .05). CONCLUSION: Diamondlike carbon treatment improved hardness Knoop and reduced the flexibility of the Irri Black ultrasonic tip, improving its time to fracture under oscillatory motion compared with the nontreated E1-Irrisonic tip.

Asunto(s)

RESUMEN

O abandono do tratamento de tuberculose é uma questão relevante e preocu- pante na saúde pública mundial. Mediante uma revisão integrativa, esse estudo busca identificar os possíveis fatores que levam ao abandono do tratamento. Foi realizada pes- quisa em estudos indexados nas bases de dados: Biblioteca Virtual em Saúde (BVS) e Scientific Eletronic Library Online (SciELO), no período de 2017 a 2021, utilizando-se os seguintes descritores (DeCS): tuberculose, agente antituberculose e tuberculose pul- monar. Ao fim, foram selecionados onze estudos, publicados nos idiomas português, es- panhol e inglês. Os resultados mostraram que o abandono está relacionado a fatores de diversas esferas, com destaque para as esferas social, da saúde e a do próprio tratamento. Como perfil das pessoas dos casos de abandono, em geral, observou-se que elas são eco- nomicamente ativas, com faixa etária entre 15 e 49 anos, possuem baixa escolaridade, baixa renda e é comum que os usos abusivos de álcool e drogas sejam apresentados como comorbidades relevantes. Portanto, o trabalho evidenciou os principais fatores associados ao abandono do tratamento de tuberculose e a importância da participação de diferentes atores como forças que somarão para diminuir a ocorrência do problema em questão.

Introduction: Currently, it is understood that bacterial resistance is an ecological event arising from mutations, or selection, occurring as a response to the use of antibiotics and their presence in the environment, causing the change of genes. Objective: To evaluate how the indiscriminate use of antibiotics affects bacterial resistance. Materials and Methods: This is a bibliographical research of the integrative literature review type. Results: The practice and indiscriminate use of medication result from sociocultural factors, economic conditions, access to health services, malpractice in medication prescription and lack of surveillance when purchasing medication. The presence of "home pharmacies" in the study was considered alarming, being a risk factor for the self-medication of antibiotics, such stored drugs show a possible non-completion of a treatment in an adequate period, justified by the absence of pain symptoms, or by individuals who did not consider the drug to be effective. Conclusion: It is necessary to comply with existing legislation in order to regulate the sale of antibiotics and prevent the irrational use of drugs.

Introducción: Actualmente, se entiende que la resistencia bacteriana es un evento ecológico derivado de mutaciones, o selección, que ocurre como respuesta al uso de antibióticos y su presencia en el ambiente, provocando el cambio de genes. Objetivo: Evaluar cómo el uso indiscriminado de antibióticos afecta la resistencia bacteriana. Materiales y Métodos: Se trata de una investigación bibliográfica del tipo revisión integradora de literatura. Resultados: La práctica y uso indiscriminado de medicamentos resultan de factores socioculturales, condiciones económicas, acceso a los servicios de salud, mala práctica en la prescripción de medicamentos y falta de vigilancia en la compra de medicamentos. Se consideró alarmante la presencia de "farmacias domiciliarias" en el estudio, siendo un factor de riesgo para la automedicación de antibióticos, tales medicamentos almacenados evidencian una posible no finalización de un tratamiento en un período adecuado, justificado por la ausencia de síntomas de dolor , o por personas que no consideraron que el fármaco fuera eficaz. Conclusión: Es necesario cumplir con la legislación vigente para regular la venta de antibióticos y prevenir el uso irracional de medicamentos.

RESUMEN

From a previous large epidemiological survey, we randomly selected 474 serum samples (463 horses and 11 mules) distributed among four municipalities of Pará state, Amazon region, Brazil, and from three types: farm animal, urban carthorse, and sport horse. Samples were tested by indirect fluorescence antibody test (IFAT ≥ 64) for antibodies reactive to spotted fever group (SFG) rickettsiae using Rickettsia rickettsii as crude antigens. From the 474 equids tested, 149 (31.4%) had ticks attached during sampling, belonging mostly to the species Dermacentor nitens. The overall seroprevalence for SFG rickettsiae was 31.4% (95% confidence interval: 27.3-35.9%) with 149 seropositive animals out of 474 screened. Notably, 77 equids (16.2%) had high endpoint titers ranging from 512 to 16,384, indicating that they had been exposed to SFG rickettsiae not long before sampling. Animal type affected rickettsial seroprevalence, with significantly higher values among farm horses when compared with urban and sport animals. Presence of dogs and tick infestation were negatively associated with equid seropositivity to R. rickettsii. This is the first report of SFG rickettsiae-reactive antibodies in equids from Pará state, Brazilian Amazon.

Asunto(s)

RESUMEN

Mutations in the transcription factor Phox2b cause congenital central hypoventilation syndrome (CCHS). The syndrome is characterized by hypoventilation and inability to regulate breathing to maintain adequate O2 and CO2 levels. The mechanism by which CCHS impact respiratory control is incompletely understood, and even less is known about the impact of the non-polyalanine repeat expansion mutations (NPARM) form. Our goal was to investigate the extent by which NPARM Phox2b mutation affect (a) respiratory rhythm; (b) ventilatory responses to hypercapnia (HCVR) and hypoxia (HVR); and (c) number of chemosensitive neurons in mice. We used a transgenic mouse line carrying a conditional Phox2bΔ8 mutation (same found in humans with NPARM CCHS). We crossed them with Atoh1cre mice to introduce mutation in regions involved with respiratory function and central chemoreflex control. Ventilation was measured by plethysmograph during neonatal and adult life. In room air, mutation in neonates and adult did not greatly impact basal ventilation. However, Phox2bΔ8, Atoh1cre increased breath irregularity in adults. The HVR and HCVR were impaired in neonates. The HVR, but not HCVR, was still partially compromised in adults. The mutation reduced the number of Phox2b+/TH--expressing neurons as well as the number of fos-activated cells within the ventral parafacial region (also named retrotrapezoid nucleus [RTN] region) induced by hypercapnia. Our data indicates that Phox2bΔ8 mutation in Atoh1-expressing cells impaired RTN neurons, as well as chemoreflex under hypoxia and hypercapnia specially early in life. This study provided new evidence for mechanisms related to NPARM form of CCHS neuropathology.

Asunto(s)

RESUMEN

AIM: Sympathoexcitation and sleep-disordered breathing are common contributors for disease progression. Catecholaminergic neurons from the rostral ventrolateral medulla (RVLM-C1) modulate sympathetic outflow and have anatomical projections to respiratory neurons; however, the contribution of highly selective activation of RVLM-C1 neurons on long-term autonomic and breathing (dys)regulation remains to be understood. METHODS: To explore this relationship, a lentiviral vector carrying the light-sensitive cation channel channelrhodopsin-2 (LVV-PRSX8-ChR2-YFP) was unilaterally injected into the RVLM of healthy rats. On the contralateral side, LVV-PRSX8-ChR2-YFP was co-injected with a specific immunotoxin (DßH-SAP) targeted to eliminate C1 neurons. RESULTS: Intermittent photostimulation of RVLM-C1 in vivo, in unrestrained freely moving rats, elicited long-term facilitation of the sympathetic drive, a rise in blood pressure and sympatho-respiratory coupling. In addition, photoactivation of RVLM-C1 induced long-lasting ventilatory instability, characterized by oscillations in tidal volume and increased breathing variability, but only during non-rapid eye movement sleep. These effects were not observed when photostimulation of the RVLM was performed in the presence of DßH-SAP toxin. CONCLUSIONS: The finding that intermittent activation of RVLM-C1 neurons induces autonomic and breathing dysfunction suggest that episodic stimulation of RVLM-C1 may serve as a pathological substrate for the long-term development of cardiorespiratory disorders.

Asunto(s)