Physical activity (PA) has well-documented cardio-respiratory protective effects in individuals with lung diseases. Whilst most studies examining the relationship between PA, lung function and respiratory symptoms have included self-reported PA data, studies assessing PA objectively using accelerometers are scarce. To explore the association of sedentary behavior (SED) and moderate-and-vigorous PA (MVPA), assessed using accelerometer data, with lung function and respiratory symptoms, and to compare associations in ever-smokers with never-smokers, within a large sample of middle-aged individuals. In the population-based, cross-sectional Swedish CArdioPulmonary BioImage Study (SCAPIS), men and women aged 50 to 64 years were included. PA was assessed from triaxial hip acceleration data processed into PA intensity categories. Time spent in SED and MVPA was used. Dynamic spirometry (FEV1 and FVC) was performed post-bronchodilation and respiratory symptoms were self-reported using a questionnaire. Complete data were obtained from 25,975 individuals (52% females). Lower lung function and presence of respiratory symptoms were both associated with less MVPA, with stronger associations for lung function. An interaction between lung function and smoking status was found, so that each unit of increase in lung function was associated with a greater increase in MVPA among ever-smokers versus never-smokers. Lower lung function and presence of respiratory symptoms were both associated with less MVPA in a general middle-aged Swedish population. In addition, the association between lung function and MVPA were stronger among ever-smokers. Further clinical studies are needed to clarify the role of PA in slowing lung function decline and preventing respiratory diseases.
Severe hypoxemia after generalized convulsive seizures (GCSs) can trigger neural injury and is a potential biomarker for sudden unexpected death in epilepsy (SUDEP). Some degree of variability in interbreath interval is normal, but increased variability may suggest dysfunctional breathing control and may be associated with severe postictal hypoxemia. We evaluated the relationship between interictal breathing variability and severity and duration of hypoxemia after GCS. We prospectively collected video-EEG, respiratory flow and effort, pulse oximetry (SpO2), and ECG from people with epilepsy (PWE). Measures of interictal interbreath interval variability (coefficient of variation, root mean square of successive differences [RMSSD], and long-term [SD-2] variability from Poincaré plots) from interictal asleep and awake periods and other relevant variables were evaluated as covariates for primary outcomes: (1) hypoxemia duration (length of time SpO2 <90%) and (2) severity of hypoxemia (SpO2 nadir), and secondary outcome: occurrence of combined prolonged and pronounced hypoxemia. Univariable and multivariable models were created for primary outcomes, but only univariable analyses were performed for the secondary outcome. Of 2,506 participants enrolled, 257 (141 [∼54%] female; mean age = 37.9 years) had ≥1 GCS, but only 152 GCS in 123 had evaluable respiratory data. Multivariable model for hypoxemia duration showed that SpO2 nadir (mean ratio [MR] = 0.88, 95% CI 0.81-0.96, p = 0.002) and SD-2 of the awake interbreath interval (MR = 1.06, 95% CI 1.01-1.13, p = 0.04) were significantly associated. RMSSD of the non-REM interbreath interval (mean difference = -5.01, 95% CI -8.10 to -1.93, p = 0.002) was the only variable significantly associated with hypoxemia severity after controlling for duration of postictal generalized EEG suppression, SD-2 of the awake interbreath interval, and body mass index. Univariable analyses for combined prolonged and pronounced hypoxemia showed SD-2 of the awake interbreath interval, temporal lobe epilepsy, ictal central apnea, and a shorter tonic phase duration were significantly associated. Measures of interictal respiratory variability are associated with severe and prolonged hypoxemia after GCS. Increased interictal respiratory variability suggests baseline respiratory dysregulation in some PWE and may be a surrogate for SUDEP risk.
Central respiratory chemoreception is a vital homeostatic mechanism maintaining arterial blood gas levels. Central respiratory chemoreceptors in the retrotrapezoid nucleus (RTN) and nucleus tractus solitarius (NTS) form interconnected circuits to regulate respiratory homeostasis. We hypothesized that NTS GABAergic neurons (NTSGABA) modulate hypercapnic ventilatory responses by targeting ventrolateral medulla Phox2b neurons (VLMPhox2b), particularly Phox2b-expressing RTN neurons. Stimulation of NTSGABA neurons significantly attenuated CO2-evoked ventilatory responses, accompanied by a reduction in CO2-activated Phox2b-expressing RTN neurons. Neural tracing revealed that monosynaptic inputs to the VLMPhox2b neurons primarily originate from the ventrolateral and dorsolateral subdivisions of the NTS. Photostimulation of NTSGABA neurons retrogradely labeled from the VLM markedly suppressed respiratory drive, while chemogenetic activation of these neurons induced hypoventilation, increased spontaneous apnea, and attenuated hypercapnic ventilatory response. These findings demonstrate that activation of the NTS-VLM inhibitory circuit diminishes respiratory motor output, offering novel insights into the regulatory mechanisms of respiratory homeostasis.
The Elevation Training Mask 2.0 (ETM) is a respiratory muscle device, designed to simulate altitude training. It works by reducing airflow through a valve system. During exercise, ETM could restore respiratory damage from post-infection phase of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), allowing ventilatory restriction that works as resistance training for respiratory muscles. To comparatively evaluate the spirometry parameters in CrossFit® practitioners training using ETM (EG), compared to a control group (CG). In a single-blind randomized clinical trial, following the Consolidated Standards of Reporting Trials (CONSORT) recommendations, 20 trained male athletes were randomly assigned to an EG and a CG using simulated ETM device. Both groups completed 12 weeks of CrossFit® training after 1 month of finishing SARS-CoV-2 symptoms. Pre- (T1) and post-training (T2) testing included assessment of lung function and respiratory muscle strength. No significant differences (p > 0.05) were observed comparing EG and CG in any of spirometry parameters evaluated. Nevertheless, significant differences (p < 0.05) in behavior were observed throughout the 36 training sessions for maximum voluntary ventilation (MVV) and maximum inspiratory pressure (MIP) with a strong effect (η²p = 0.693). In addition, significant improvements (p < 0.05) were observed in MIP and MVV exclusively in the EG when comparing T1 vs. T2. The findings suggest that the inclusion of ETM in a 12-week CrossFit® training program, in athletes returning to exercise post-SARS-CoV-2 infection, may have modest benefits compared to CG on lung function and respiratory muscle strength. ClinicalTrials.gov, identifier (ID NCT06806124). 25/01/2025 retrospectively registered.
Breathing rhythms bidirectionally modulate affective states, yet the underlying neural pathways remain elusive. Here, we identified an ascending neural circuit that integrates respiratory patterning with affective state in male mice. This circuit originates from glutamatergic neurons in the preBötzinger complex (preBötC), projecting to the paraventricular thalamic nucleus (PVT) and subsequently targeting the central amygdala (CeA). We reveal that photostimulation of the preBötC→PVT circuit significantly alleviates acute restraint stress-induced anxiety-like phenotypes and reduces respiratory frequency variability. Conversely, inhibition of this circuit exacerbates anxiety-like phenotypes and respiratory dysfunction. These effects are significantly abolished by inhibition or ablation of PVT neurons projecting to the CeA. Additionally, this anxiolytic effect is mediated by PVT projections that preferentially excite centrolateral amygdala neurons, thereby inhibiting centromedial amygdala output. Translating these findings, we show that volitional slow breathing reduces anxiety in healthy humans and suppresses anxiety-related beta/high-gamma oscillations in the amygdala of epilepsy patients. This work delineates a conserved respiratory-limbic circuit that mechanistically explains the anxiolytic effect of controlled breathing.
The retrotrapezoid nucleus, located in the parafacial medullary region (RTN/pFRG), is crucial for respiratory activity and central chemoreception. Recent evidence suggests that neuromodulation, including peptidergic signalling, can influence the CO2/H+ sensitivity of RTN neurons. The paraventricular nucleus of the hypothalamus (PVN) projects to the ventral medullary surface, including the RTN, and is considered the primary source of oxytocin to the brainstem. However the physiological significance of oxytocin signalling in RTN neurons has not been determined. To investigate this further we employed neuroanatomical techniques, slice-patch electrophysiology and in vivo pharmacological and optogenetic tools to characterize the effects of oxytocin on breathing. We found that a subset of PVN excitatory neurons (VGlut2-positive) that project to the RTN (Ctb-positive) are also immunoreactive for oxytocin, suggesting the RTN is a downstream target of these neurons. Exogenous application of the selective oxytocin agonist (TGOT) activates RTN chemoreceptors in a dose-dependent manner (EC50 = 3 nm), and this response is blunted by the blockade of KCNQ channels (ML252; 10 µM). In urethane-anaesthetized mice pharmacological (TGOT) or optogenetic activation of oxytocinergic receptors/varicosities in the RTN increases breathing amplitude without changing respiratory frequency. These results identify oxytocin signalling to RTN neurons as a novel regulator of respiratory activity and further demonstrate the importance of KCNQ channels in the modulation of RTN neurons. KEY POINTS: Oxytocin is an important modulator of breathing, including at the level of the retrotrapezoid nucleus (RTN). The paraventricular nucleus of the hypothalamus (PVN), considered as the primary source of oxytocin in the brainstem, projects to the RTN. Selective oxytocin agonist (Thr4,Gly7-oxytocin, TGOT) activates RTN by a mechanism partly dependent on KCNQ channels. In vivo, selective activation of oxytocinergic signalling within the RTN increases breathing amplitude without changing respiratory frequency. Identifying components of the signalling pathway that couples oxytocin receptor activation to changes in chemoreceptor activity may provide new potential therapeutic targets for treating central respiratory disorders.
The heart does not beat like a metronome: varying parasympathetic input to the heart leads to constant heart rate variability. Vagal cardiomotor neuron activity is coupled to the respiratory cycle, leading to respiratory sinus arrhythmia (RSA), a permanent oscillation of heart rate synchronized to respiration. Heart rate also temporarily decelerates in specific conditions such as in freezing due to perceived threat or in anticipation of a salient stimulus. Anticipatory cardiac deceleration (ACD) is observed consistently in anticipation of a stimulus in perceptual tasks, but its relationship with perceptual performance is debated. Previous quantifications of ACD neglect ongoing heart rate oscillations due to RSA, which may have led to inconsistencies in the ACD-related analyses across studies. Here, we suggest a novel approach to estimate trial-averaged RSA amplitude and respiratory phase-independent cardiac deceleration simultaneously and apply it to an EEG-ECG dataset from a visual detection task. While the total ACD was not associated with perception, dissociating RSA-dependent and non-respiratory cardiac modulations revealed that they showed negative and positive correlations with perceptual performance, respectively. Additionally, we found that participants with higher ACD amplitudes also displayed larger Visual Awareness Negativity potentials, further supporting a contribution of ACD to visual perception.
Chronic stress (CS) and hyper-caloric diets promote affective disorders, however pathobiological interactions await definition. Neurobiological and behavioral influences of chronic stress (CS; 2 h/day restraint for 2 wks) were studied in male C57Bl/6 mice fed a control diet (CD; 12% kcal as fat/65% carbohydrate/23% protein) or Western diet (WD; 32% kcal fat/57% carbohydrate/11% protein) for 20 wks. CS induced weight loss and anxiety-like behavior, associated with reduced frontal cortex (FC) brain-derived neurotrophic factor (BDNF) and γ-aminobutyric acid (GABA) vs. elevated glutamate; and mitochondrial dysfunction, including reduced complex I (CI), electron transport system (ETS) and spare respiratory capacities. Hippocampus (HPC) appeared less responsive (CI flux selectively inhibited). Proteomics supports CS disruption of synaptogenesis and mitochondrial pathways, together with “adaptive” changes, including activation of neuroprotective chaperone-mediated autophagy (CMA), reelin and eukaryotic initiation factor 2 (EIF2) paths. The WD alone (inducing weight gain, insulin-resistance and reduced sucrose preference) had no independent effects on FC neurochemistry, FC or HPC respiratory function. Co-morbid CS in WD mice induced anxiety-like behavior and anhedonia, coupled with WD-related reductions in FC GABA and HPC BDNF not evident in un-stressed mice. A co-morbid WD also limited CS-dependent changes in ETS and spare respiratory capacities. Proteomics supports reduced CS activation of reelin and EIF2 pathways, and a switch from CMA activation to suppression, in co-morbid CS + WD mice. Summary: Mild anxiogenic stress disrupts mitochondrial function, glutamate:GABA balance and BDNF/synaptogenesis signaling, primarily in FC vs. HPC. Co-morbid CS + WD exaggerates neurochemical disturbances, and disrupts adaptive pathway responses, in association with anhedonia and anxiety-like behaviors.
Lower respiratory infections (LRIs) remain the world's leading infectious cause of death. This analysis from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023 provides global, regional, and national estimates of LRI incidence, mortality, and disability-adjusted life-years (DALYs), with attribution to 26 pathogens, including 11 newly modelled pathogens, across 204 countries and territories from 1990 to 2023. With new data and revised modelling techniques, these estimates serve as an update and expansion to GBD 2021. Through these estimates, we also aimed to assess progress towards the 2025 Global Action Plan for the Prevention and Control of Pneumonia and Diarrhoea (GAPPD) target for pneumonia mortality in children younger than 5 years. Mortality from LRIs, defined as physician-diagnosed pneumonia or bronchiolitis, was estimated using the Cause of Death Ensemble model with data from vital registration, verbal autopsy, surveillance, and minimally invasive tissue sampling. The Bayesian meta-regression tool DisMod-MR 2.1 was used to model overall morbidity due to LRIs. DALYs were calculated as the sum of years of life lost (YLLs) and years lived with disability (YLDs) for all locations, years, age groups, and sexes. We modelled pathogen-specific case-fatality ratios (CFRs) for each age group and location using splined binomial regression to create internally consistent estimates of incidence and mortality proportions attributable to viral, fungal, parasitic, and bacterial pathogens. Progress was assessed towards the GAPPD target of less than three deaths from pneumonia per 1000 livebirths, which is roughly equivalent to a mortality rate of less than 60 deaths per 100 000 children younger than 5 years. In 2023, LRIs were responsible for 2·50 million (95% uncertainty interval [UI] 2·24-2·81) deaths and 98·7 million (87·7-112) DALYs, with children younger than 5 years and adults aged 70 years and older carrying the highest burden. LRI mortality in children younger than 5 years fell by 33·4% (10·4-47·4) since 2010, with a global mortality rate of 94·8 (75·6-116·4) per 100 000 person-years in 2023. Among adults aged 70 years and older, the burden remained substantial with only marginal declines since 2010. A mortality rate of less than 60 deaths per 100 000 for children younger than 5 years was met by 129 of the 204 modelled countries in 2023. At a super-regional level, sub-Saharan Africa had an aggregate mortality rate in children younger than 5 years (hereafter referred to as under-5 mortality rate) furthest from the GAPPD target. Streptococcus pneumoniae continued to account for the largest number of LRI deaths globally (634 000 [95% UI 565 000-721 000] deaths or 25·3% [24·5-26·1] of all LRI deaths), followed by Staphylococcus aureus (271 000 [243 000-298 000] deaths or 10·9% [10·3-11·3]), and Klebsiella pneumoniae (228 000 [204 000-261 000] deaths or 9·1% [8·8-9·5]). Among pathogens newly modelled in this study, non-tuberculous mycobacteria (responsible for 177 000 [95% UI 155 000-201 000] deaths) and Aspergillus spp (responsible for 67 800 [59 900-75 900] deaths) emerged as important contributors. Altogether, the 11 newly modelled pathogens accounted for approximately 22% of LRI deaths. This comprehensive analysis underscores both the gains achieved through vaccination and the challenges that remain in controlling the LRI burden globally. Furthermore, it demonstrates persistent disparities in disease burden, with the highest mortality rates concentrated in countries in sub-Saharan Africa. Globally, as well as in these high-burden locations, the under-5 LRI mortality rate remains well above the GAPPD target. Progress towards this target requires equitable access to vaccines and preventive therapies-including newer interventions such as respiratory syncytial virus monoclonal antibodies-and health systems capable of early diagnosis and treatment. Expanding surveillance of emerging pathogens, strengthening adult immunisation programmes, and combating vaccine hesitancy are also crucial. As the global population ages, the dual challenge of sustaining gains in child survival while addressing the rising vulnerability in older adults will shape future pneumonia control strategies. Gates Foundation.
Persistent respiratory symptoms in COVID-19 patients have raised concerns about structural remodelling in the lung. We assessed structural changes and their correlation with reduced DLCO, eight months after discharge, in previously hospitalised COVID-19 patients. An exploratory observational study was conducted on 26 male patients (mean age: 60 years, range: 50-69) previously hospitalised for COVID-19. CT scans, performed eight months post-discharge, were analysed using functional respiratory imaging (FRI) to assess lung structure and function. Analyses were made based on diffusion capacity for carbon monoxide (DLCO). Patients with low DLCO (≤75%; n = 9) exhibited a significantly lower proportion of small blood vessels with a cross-sectional area < 5 mm² compared to patients with normal DLCO (>75%; n = 17) (median (IQR) 56 (51-59) % vs. 60 (56-64) %, p = 0.008), as well as a reduced absolute volume of small vessels with a cross-sectional area < 5 mm² (129 (121-151) ml vs. 155 (132-175) ml, p = 0.025). Bronchial dilatation was more evident in the low DLCO group, with a higher ratio of airway volume to lobar volume (siVaw) (149 (138-165) % vs. 117 (93-132) %, p = 0.002). SiVaw showed a significant inverse relationship with DLCO (r = -0.56, p = 0.004, R² = 0.31). Lobar volumes were reduced in both DLCO groups, and more pronounced in the low DLCO group (72 (65-81) % vs. 90 (79-95) %, p = 0.001), as was total lung capacity (TLC) (73 (64-85) % vs. 92 (85-98) % of predicted, p = 0.003). FEV₁/FVC ratios were elevated in both groups, with a potential difference observed between the low and normal DLCO groups (110 (103-118) % vs. 105 (95-113) %, p = 0.074). We demonstrate long-term vascular and airway remodelling detected with FRI in previously hospitalised COVID-19 patients and highlight potential mechanisms underlying persistent pulmonary dysfunction and emphasise the need to investigate the underlying pathophysiology to identify potential individualised treatment strategies for this patient group.
Sudden unexpected death in epilepsy (SUDEP) is the leading cause of premature mortality among people with epilepsy. Evidence from witnessed and monitored SUDEP cases indicates seizure-induced cardiovascular and respiratory failures; yet, the underlying mechanisms remain obscure. SUDEP occurs often during the night and early morning hours, suggesting that sleep or circadian rhythm-induced changes in physiology contribute to the fatal event. Resting-state functional MRI (fMRI) studies have found altered functional connectivity between brain structures involved in cardiorespiratory regulation in later SUDEP cases and in individuals at high risk of SUDEP. However, those connectivity findings have not been related to changes in cardiovascular or respiratory patterns. Here, we compared fMRI patterns of brain connectivity associated with regular and irregular cardiorespiratory rhythms in SUDEP cases with those of living epilepsy patients of varying SUDEP risk and healthy controls. We analysed resting-state fMRI data from 98 patients with epilepsy (9 who subsequently succumbed to SUDEP, 43 categorized as low SUDEP risk (no tonic-clonic seizures (TCS) in the year preceding the fMRI scan), and 46 as high SUDEP risk (>3 TCS in the year preceding the scan)), and 25 healthy controls. The global signal amplitude (GSA), defined as the moving standard deviation of the fMRI global signal, was used to identify periods with regular ("low state") and irregular ("high state") cardiorespiratory rhythms. Correlation maps were derived from seeds in 12 regions with a key role in autonomic or respiratory regulation for the low and high states. Following principal component analysis, component weights were compared between the groups. We found widespread alterations in connectivity of precuneus/posterior cingulate cortex in epilepsy compared with controls in the low state (regular cardiorespiratory activity). In the low state, and to a lesser degree in the high state, reduced anterior insula connectivity (mainly with anterior and posterior cingulate cortex) in epilepsy appeared, relative to healthy controls. For SUDEP cases, the insula connectivity differences were inversely related to the interval between the fMRI scan and death. The findings suggest that anterior insula connectivity measures may provide a biomarker of SUDEP risk. The neural correlates of autonomic brain structural activity associated with different cardiorespiratory rhythms may shed light on the mechanisms underlying the fatal event in SUDEP.
The flow of cerebrospinal fluid (CSF) through the brain is driven by cerebral vasomotion, along with respiratory and cardiac forces. Growing evidence suggests that sleep facilitates this flow, yet the role of homeostatic sleep mechanisms remains largely unknown. In a circadian-controlled sleep and sleep deprivation study in humans, we used accelerated neuroimaging to investigate how sleep pressure and slow-wave-rich sleep affect low-frequency brain pulsations (LFPs; 0.012-0.034 Hz) as well as brain pulsations originating from the respiratory and cardiac cycles. These pulsations cause movement of CSF and brain tissue which may facilitate waste clearance. We also examined the origin of LFPs through pharmacological vasodilation of the cerebral vasculature with the adrenergic antagonist carvedilol in a randomized, cross-over, double-blinded, placebo-controlled design (NCT03576664). We find that sleep deprivation increases LFPs more than nonrapid eye movement (NREM) sleep does, with LFPs during sleep correlating with cognitive measures of sleep pressure. Conversely, NREM sleep (combined stages N2 and N3) enhances brain pulsations driven by the respiration and cardiac cycles, with more pronounced effects in gray and white matter than in the ventricles. The strength of these brain pulsations escalates with sleep depth (N3 > N2) and correlates with EEG delta power, a measure of slow wave activity. Moreover, carvedilol dampens LFPs, supporting that these reflect cerebral vasomotion. In summary, our findings indicate that heightened sleep pressure promotes vasomotion, whereas slow-wave-rich sleep amplifies respiration- and cardiac-driven brain pulsations, possibly indicating increased CSF flow to the brain. Together, this suggests that homeostatic sleep mechanisms are integral to human brain fluid dynamics and potentially also waste clearance.
Humans have long sought to alter their mental states through various cultural practices, with rhythmic sounds emerging as a prominent and enduring method. However, altered states of consciousness induced by rhythmic auditory stimulation have not been comprehensively addressed in academic research, and the associated cognitive and neural underpinnings remain enigmatic. This narrative review synthesizes the behavioral, cognitive, and neural correlates underlying nonordinary experiences elicited by rhythmic sounds. The evidence gathered aligns with the notion that being exposed to these sounds facilitates a state of absorption and relaxation. The findings on the neural activity were diverse, reflecting the use of various methodologies in the reviewed studies. We discussed that altered states induced by rhythmic sounds may be explained by a mechanism involving the entrainment of thalamocortical pathways to low-frequency activity-a physiological state that also characterizes psychotic and psychedelic experiences. This proposal integrates insights from diverse findings, which reflect the variability in methodologies used to address these phenomena.
Sexual dimorphism in lung physiology and disease is well established; yet, the underlying central circuits remain unexplored. Using retrograde trans-synaptic tracing with pseudorabies virus from the lung combined with whole-brain mapping, we uncovered fundamental sex differences in brain-lung connectivity. Male mice exhibited anterior, cognition-associated networks clustering and hemispheric lateralization, whereas female mice displayed posterior, brainstem-predominant circuits specialized for automatic respiratory control, along with more integrated and modular network architectures. These findings reveal a hardwired neural framework for sex-specific respiratory control, with implications for understanding differential susceptibility to respiratory disease between males and females.
This study investigated whether therapists' physiological regulation influences clients' autonomic responses during the first session of couple therapy and whether couples' physiology influences each other's. Drawing on polyvagal, attachment, and interpersonal neurobiology theories, we examined physiological linkages in therapy triads. Thirty-three heterosexual married couples participated in a 50-min session, during which respiratory sinus arrhythmia (RSA), electrodermal activity (EDA), and pre-ejection period (PEP) were recorded from both partners and their therapist. Using dynamic structural equation modeling within an actor-partner interdependence framework, analyses focused on lagged effects across the session's beginning, middle, and end. Results showed clients exhibited strong physiological inertia across all measures, suggesting autonomic rigidity in early therapy. Therapist EDA predicted husbands' EDA early in the session, while wives' EDA predicted husbands' EDA later in the session. No directional effects were found for RSA or PEP. Clinical implications of these subtle therapist and spousal influences on physiological arousal are discussed.
Developing safe and effective pain medications is an ongoing challenge for human health. Agonists for the µ-opioid receptor (MOR) are essential pain medications, but their high intrinsic efficacy also induces adverse side effects, including respiratory depression, constipation, tolerance, dependence, withdrawal and addiction1-7. Strategies to limit adverse effects traditionally include developing MOR agonists that have low intrinsic efficacy or that preferentially activate G-protein signalling over β-arrestin signalling8. Here we identify a novel MOR agonist with supramaximal intrinsic efficacy and a unique pharmacological profile that produced effective analgesia in rodents with minimal adverse effects. N-desethyl-fluornitrazene (DFNZ) was derived from a class of synthetic benzimidazole opioids called nitazenes. DFNZ has impaired brain penetrance, a unique spatiotemporal MOR cellular signalling profile, and diminished efficacy at the MOR-galanin 1 receptor (GAL1) heteromer. DFNZ does not induce respiratory depression, tolerance or MOR downregulation after repeated exposure. Compared with other MOR agonists, DFNZ has limited effects on dopamine neurotransmission in nucleus accumbens and weaker reinforcing effects in the drug self-administration procedure. These results provide novel insights about MOR and nitazene pharmacology, have important implications for pain and addiction treatment, and challenge the prevailing dogma that high-efficacy MOR agonists cannot constitute safe and effective therapeutic agents.
Astrocytes within the preBötzinger complex (preBötC) critically regulate respiratory rhythmogenesis and pattern formation. However, the molecular mechanisms underlying their contributions remain poorly understood. This study aims to investigate whether connexin 43 (Cx43) channels, a prominent subtype of connexin proteins expressed in preBötC astrocytes, are essential for stabilizing breathing patterns. We employed a multidisciplinary approach, integrating whole-body plethysmography, in vivo fiber photometry, phrenic nerve discharge (PND) recordings, photostimulation, RNAscope fluorescence in situ hybridization, and RNA sequencing to elucidate the functional role of Cx43 channels in respiratory regulation. Elevated activation levels of preBötC astrocytes were synchronized with specific respiratory events, including sighs and transiently augmented breathing. RNA-sequencing analysis demonstrated that Gja1 (encoding Cx43) was identified as the predominant connexin transcript in preBötC astrocytes. Photostimulation of preBötC astrocytes significantly increased PND frequency in anesthetized mice, an effect replicated by pharmacological blockade of Cx43 hemichannels. Conditional knockdown of astrocytic Gja1 in the preBötC considerably increased resting breathing frequency and minute ventilation. Blockade of Cx43 hemichannels enhanced astrocytic activation and induced ATP accumulation around somatostatin-expressing preBötC neurons (preBötCSST). Furthermore, Cx43 hemichannel blockade activated preBötCSST neurons, an effect mediated by P2Y1 but not P2X receptors. We identify an astrocyte-to-neuron signaling cascade involving Cx43 hemichannel-dependent ATP release, P2Y1 receptor activation on preBötCSST neurons, and subsequent modulation of respiratory motor output. These findings establish Cx43 hemichannels as critical molecular determinants for stabilizing breathing patterns.
Effective airborne pathogen surveillance is essential for controlling the spread of respiratory infections in public spaces. A simple and effective sampling device, together with the validated sampling scheme and subsequent downstream analysis is needed. We developed and tested wet and dry air sampling concepts to efficiently capture aerosolized model microorganisms. Using Bacillus subtilis and feline infectious peritonitis virus (FIPV, a model for SARS-CoV-2), we evaluated capture efficiency via qPCR-based detection. The dry sampling concept based on the utilization of the intrinsic charge of aerosolized particles demonstrated superior efficiency. After determination of the correct electric field intensity and sampling time, the devices proved their routine applicability by successful sampling in lecture halls and a supermarket, where a higher fluctuation of people was expected. These findings have led to the development of a compact, mobile, and practical air sampling system for real-time pathogen monitoring, offering a valuable tool for epidemiological surveillance and infection control in high-occupancy environments.
Rancid odors can trigger retching and aversion in humans that prevent consumption of spoiled food, and consequently metabolic dysregulation, but the underlying neural mechanisms remain unclear. Here, we show that exposure to 2-methylbutyric acid (2MBA) odor triggers such defensive responses in male mice, mediated by a nose-to-brain axis. 2MBA perception in olfactory epithelium activates neurons in olfactory bulb (OB) projecting to glutamatergic neurons in anterior piriform cortex (aPirGlu), which in turn project to either the mediodorsal thalamic nucleus (MD), which innervates respiratory muscles to drive retching-like behaviors, or project to the nucleus accumbens (NAc) to drive aversion. Artificial inhibition of the nose→OB→aPir→MDGlu→respiratory muscles circuit diminishes retching-like behaviors, but not aversion, while inhibiting the nose→OB→aPir→NAc circuit diminishes aversion, but not retching-like behaviors. These findings thus establish a nose-to-brain axis for rancid odor-triggered retching and aversion in male mice, advancing our understanding of sensory-motor integration and whole-body neural bases of defensive responses to odor.
Spinal muscular atrophy (SMA) is a rare, progressive, neuromuscular disorder that leads to loss of motor and respiratory function, affecting the individual's ability to work and life expectancy. The magnitude of productivity losses due to medical absenteeism and premature death associated with SMA is unknown. We estimated the productivity losses attributable to SMA in a working age population compared with the general working age population in Sweden. This was a population-based, 1:4 matched cohort study of patients with SMA aged ≥ 18 years identified in the Swedish National Patient Registry from 2007 to 2019. Amongst those of working age (18-65 years), morbidity-induced productivity losses compared with a matched-reference cohort were estimated as the difference in the number of workdays lost attributable to SMA, monetised using mean income. Mortality-induced productivity losses were estimated as foregone lifetime earnings due to premature deaths for individuals with SMA compared with matched references, after adjusting for sex, age, and background unemployment. Overall, 172 adult patients with SMA were identified. Amongst those of working age, their average annual medical absenteeism was 100 days (95% confidence interval 61.5-138.1) higher than that of their references, leading to morbidity-induced productivity losses of €31,638 per patient per year alive whilst of productive age, of which €25,650 was directly attributable to SMA. Average mortality-induced productivity losses due to premature death were €108,253 for men and €87,160 for women with SMA. Productivity losses due to medical absenteeism and premature mortality place a significant burden on adult patients with SMA of working age and Swedish society.