Journal of Physiology-London最新文献

A task as simple as holding a cup between your fingers generates complex motor commands to finely regulate the forces applied by muscles. These fine force adjustments ensure the stability and integrity of the object by preventing it from slipping out of grip during manipulation and by reacting to perturbations. To do so, our sensorimotor system constantly monitors tactile and proprioceptive information about the force object exerts on fingertips and the friction of the surfaces to determine the optimal grip force. While the literature describes the transient responses, humans can generate to react to perturbations in load force, it is yet to be determined if humans can also react to abrupt changes in friction while already holding an object. Only recently technology using imperceivable ultrasonic vibrations became available to modulate friction in real time to investigate this question. In this study, we used an object with an integrated friction modulation device suspended in a pulley system controlling the load. With this device, we explored the rapid adaptation of the sensorimotor system to changes in friction alone and in combination with changes in load. When load force and friction changed simultaneously, the grip force response was regulated based on the grip safety requirements. Participants increased their grip force in response to decrease in friction. However, they did not adjust their grip force when the friction increased, which is expected based on our biomechanical model of friction sensing mechanisms. KEY POINTS: Simple tasks like pouring water into a glass mobilize intricate interactions between fingertip sensory inputs and motor commands to account for the weight change and friction. It has been investigated how humans react to force perturbations when holding an object, but very little is known about how frictional changes are sensed and acted upon while holding an object, for example, due to sweating or condensation. We engineered a unique experimental object that utilizes imperceivable ultrasonic vibrations to change the frictional properties of the surface in a few milliseconds. This apparatus enabled us to study how human subjects react to change of friction when gripping or holding an object. We showed that humans adjust the strength of their grasp when forces in the direction of gravity either increase or decrease; however, frictional change evokes adjustments only when friction decreases.

The pericardium plays an important role in mechanical interactions between the right (RV) and left (LV) ventricles, referred to as ventricular interdependence. However, the exact mechanisms of its supportive role remain unknown. The present study aimed to evaluate specifically ventricular interdependence in a model of isolated biventricular working heart of large mammal, which is in absence of neurohormonal influence or series interactions, and to evaluate the impacts of intact pericardium on this phenomenon. Pig hearts were excised with the pericardium intact and connected to a biventricular working mode setup. Low and high ventricular preloads and afterloads were imposed on the hearts by changing independently the left (LA) and right (RA) atrial pressures, or the aortic (Ao) and pulmonary artery (PA) pressures, respectively, in the presence or absence of an intact pericardium. In the presence of the pericardium, increasing atrial pressures mainly impacted the ipsilateral ventricular haemodynamics, including an increase in ventricular outflow and end-diastolic pressures, independent of the contralateral atrial pressure. LV haemodynamics were also mainly altered by the increase in the ipsilateral afterload (Ao pressure). By contrast, RV haemodynamics, including the PA flow, were not only affected by increasing its ipsilateral (PA pressure), but also by its contralateral (Ao pressure) ventricular afterload. The preload but not afterload-dependent effects were abolished after removing the pericardium. Our work indicates that RV haemodynamics are highly impacted by the pericardiectomy. This highlights the requirement of keeping the pericardium intact to explore accurately cardiac haemodynamics, particularly in the RV. KEY POINTS: Pericardium has an important role in maintaining mechanical interventricular interaction, even if it is not essential for life. We used an ex vivo biventricular working pig heart model to explore intrinsic ventricular responses to independent variations of left and right preload and afterload, in the presence and absence of the pericardium. We show that, in the presence of the pericardium, the right ventricular haemodynamics is impacted by the ipsilateral preload as well as the ipsi- and contralateral afterloads, whereas the left ventricular haemodynamics is only impacted by its ipsilateral pre- and afterload. The preload but not afterload-dependent effects are abolished after removing the pericardium. These results demonstrate a critical function of the pericardium in maintaining RV haemodynamics, as well as preload-dependent ventricular interactions.

A fundamental question in sensory neuroscience revolves around how neurons represent complex visual stimuli. In mammalian primary visual cortex (V1), neurons decode intricate visual features to identify objects, with most being selective for edge orientation, but with half of those also developing invariance to edge position within their receptive fields. Position invariance allows cells to continue to code an edge even when it moves around. Combining feature selectivity and invariance is integral to successful object recognition. Considering the marsupial-eutherian divergence 160 million years ago, we explored whether feature selectivity and invariance was similar in marsupials and eutherians. We recovered the spatial filters and non-linear processing characteristics of the receptive fields of neurons in wallaby V1 and compared them with previous results from cat cortex. We stimulated the neurons in V1 with white Gaussian noise and analysed responses using the non-linear input model. Wallabies exhibit the same high percentage of orientation selective neurons as cats. However, in wallabies we observed a notably higher prevalence of neurons with three or more filters compared to cats. We show that having three or more filters substantially increases phase invariance in the V1s of both species, but that wallaby V1 accentuates this feature, suggesting that the species condenses more processing into the earliest cortical stage. These findings suggest that evolution has led to more than one solution to the problem of creating complex visual processing strategies. KEY POINTS: Previous studies have shown that the primary visual cortex (V1) in mammals is essential for processing complex visual stimuli, with neurons displaying selectivity for edge orientation and position. This research explores whether the visual processing mechanisms in marsupials, such as wallabies, are similar to those in eutherian mammals (e.g. cats). The study found that wallabies have a higher prevalence of neurons with multiple spatial filters in V1, indicating more complex visual processing. Using a non-linear input model, we demonstrated that neurons with three or more filters increase phase invariance. These findings suggest that marsupials and eutherian mammals have evolved similar strategies for visual processing, but marsupials have condensed more capacity to build phase invariance into the first step in the cortical pathway.

Preeclampsia (PE) is a hypertensive disorder during human pregnancy. Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor. Exogenous and endogenous AhR ligands can induce hypertension in male rats and mice. Herein, using rats as a model, we tested the hypothesis that over-regulation of endogenous AhR ligands during pregnancy impairs vascular functions by disrupting the transcriptome in the placenta, contributing to the development of PE. Pregnant rats were injected daily with an endogenous AhR ligand, 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), from gestational day (GD) 10 to 19. Maternal mean blood pressure was measured on GD16-20. Proteinuria and uteroplacental blood flow were monitored on GD20. Placentas collected on GD20 were used to determine changes in vascular density and transcriptome. Compared with the vehicle control, ITE elevated maternal mean blood pressure by 22% and 16% on GD16 and 17, respectively. ITE increased proteinuria by 50% and decreased uteroplacental blood flow by 26%. ITE reduced the placental vascular density by 18%. RNA sequencing analysis revealed that ITE induced 1316 and 2020 differentially expressed genes (DEGs) in female and male placentas, respectively. These DEGs were enriched in pathways relevant to heart diseases, vascular functions and inflammation. Bioinformatics analysis also predicted that ITE altered immune cell infiltration in placentas depending on fetal sex. These data suggest that over-regulation of endogenous AhR ligands may lead to PE with impaired vascular functions and disrupted fetal sex-specific transcriptomes and immune cell infiltration in placentas. These AhR ligand-induced DEGs and pathways may represent promising therapeutic targets for PE-induced cardiovascular dysfunctions. KEY POINTS: An endogenous AhR ligand (ITE) elevated maternal blood pressure and proteinuria in pregnant rats, and decreased uteroplacental blood flow and fetal and placental growth, all of which are hallmarks of preeclampsia. ITE reduced vascular density and altered immune cell distribution in rat placentas. ITE dysregulated transcriptomes in rat placentas in a fetal sex-specific manner. These ITE-dysregulated genes and pathways are highly relevant to diseases of heart, vascular functions and inflammatory responses.

Mitochondria adapt to increased energy demands during muscle contraction by acutely altering metabolite fluxes and substrate oxidation. With age, an impaired mitochondrial metabolic response may contribute to reduced exercise tolerance and decreased skeletal muscle mass, specific force, increased overall fatty depositions in the skeletal muscle, frailty and depressed energy maintenance. We hypothesized that elevated energy stress in mitochondria with age alters the capacity of mitochondria to utilize different substrates following muscle contraction. To test this hypothesis, we used in vivo electrical stimulation to simulate high-intensity intervals (HII) or low intensity steady-state (LISS) exercise in young (5-7 months) and aged (27-29 months) male and female mice to characterize effects of age and sex on mitochondrial substrate utilization in skeletal muscle following contraction. Mitochondrial respiration using glutamate decreased in aged males following HII and glutamate oxidation was inhibited following HII in both the contracted and non-stimulated muscle of aged female muscle. Analyses of the muscle metabolome of female mice indicated that changes in metabolic pathways induced by HII and LISS contractions in young muscle are absent in aged muscle. To test improved mitochondrial function on substrate utilization following HII, we treated aged females with elamipretide (ELAM), a mitochondrially-targeted peptide shown to improve mitochondrial bioenergetics and restore redox status in aged muscle. ELAM removed inhibition of glutamate oxidation and showed increased metabolic pathway changes following HII, suggesting rescuing redox status and improving bioenergetic function in mitochondria from aged muscle increases glutamate utilization and enhances the metabolic response to muscle contraction in aged muscle. KEY POINTS: Acute local contraction of gastrocnemius can systemically alter mitochondrial respiration in non-stimulated muscle. Age-related changes in mitochondrial respiration using glutamate or palmitoyl carnitine following contraction are sex-dependent. Respiration using glutamate after high-intensity contraction is inhibited in aged female muscle. Metabolite level and pathway changes following muscle contraction decrease with age in female mice. Treatment with the mitochondrially-targeted peptide elamipretide can partially rescue metabolite response to muscle contraction.

Chronic kidney disease (CKD) is characterized by overactivation of the sympathetic nervous system (SNS) that leads to increased risk of cardiovascular disease. This study was conducted to evaluate the effects of a Mindfulness-Based Stress Reduction (MBSR) programme on SNS activity in CKD patients. Participants with CKD stages III-IV were randomized to the 8 week MBSR programme or Health Enhancement Program (HEP; a structurally parallel, active control group). Intraneural measures of SNS activity directed to muscle [muscle sympathetic nerve activity (MSNA)] via microneurography was recorded at rest and during stress manoeuvres (mental arithmetic, handgrip exercise and cold pressor test). Data analyses were performed based on the intent-to-treat principle. In total, 29 participants (64 ± 9 years; 86% males) completed the intervention with 17 in the MBSR and 12 in the HEP groups. There was a significant Group (MBSR vs. HEP) by Time (baseline vs. post-intervention) interaction in MSNA reactivity to mental stress (P = 0.029), with a significant reduction in the mean ∆MSNA over 3 min of mental arithmetic at post-intervention (10.3 ± 4.2-5.9 ± 5.6 bursts/min, P < 0.001; Hedges' g = -0.858, 95% confidence interval [-1.578, -0.167]), while no change was observed within the HEP group (P = 0.818). Reduced ∆MSNA during handgrip exercise was also observed, while ∆MSNA during the cold pressor test and resting MSNA remained unchanged in both groups from baseline to post-intervention. In this randomized controlled trial, patients with CKD had a reduction of sympathetic reactivity during mental stress and static handgrip exercise following 8 weeks of MBSR but not after HEP. Our findings demonstrate that mindfulness training is feasible and may have clinically beneficial effects on autonomic function in CKD. KEY POINTS: Question: Does the Mindfulness-Based Stress Reduction (MBSR) programme reduce sympathetic activity in patients with chronic kidney disease (CKD)? Finding: In this randomized controlled trial including 29 patients with CKD, 8 weeks of MBSR decreased sympathetic reactivity to mental stress compared to the control Health Enhancement Program (HEP). Meaning: These finding suggest that mindfulness training may have clinically beneficial effects on autonomic function in CKD.