Journal of Physiology-London最新文献

Atrial fibrillation (AF) is associated with reduced cardiac output, which is correlated with increased symptomatic burden and declined quality of life. Predicting haemodynamic effects of AF remains challenging because of the complex interplay of multiple contributing mechanisms. Computational modelling offers a valuable tool for simulating haemodynamics. However, existing models are lacking the capabilities to both replicate beat-to-beat haemodynamic variations during AF at the same time as being well suited for fitting to clinical data. In the present study, we present a computational model comprising: (1) an electrical subsystem that generates unco-ordinated atrial and irregular ventricular activation times characteristic of AF and (2) a mechanical subsystem that simulates haemodynamics using a reduced order model. The model was fitted to replicate individual haemodynamic measurements from 17 patients in the SMURF study during both normal sinus rhythm (NSR) and AF. The fitted model matched a large majority (75%) of blood pressure and intracardiac pressure measurements in both NSR and AF with absolute simulation errors well below 10 mmHg. Furthermore, a large majority of left atrial and left ventricular ejection fraction measurements during NSR were matched with absolute simulation errors well below 10%. The model consistently underestimated right ventricular diastolic pressure during NSR at the same time as overestimating right ventricular systolic and mean left atrial pressures during AF. The presented approach of modelling atrial activity in AF as unco-ordinated atrial contractions, rather than no atrial contraction, achieved lower overall absolute simulation errors when fitting to individual patients. This computationally efficient model provides a platform for future investigations of patient-specific haemodynamics during AF. KEY POINTS: Atrial fibrillation (AF) is linked to the heart pumping less blood, a higher symptomatic burden and a lower quality of life. Although computational models can help us understand the blood circulation in patients with AF, no current models can both replicate beat-to-beat changes during AF and be fitted to individual patients. We developed a computational model that simulates beat-to-beat haemodynamic changes resulting from the unco-ordinated atrial and irregular electrical activation times characteristic of AF. The computational model was fitted to 17 patients and matched a large majority of arterial and intracardiac pressure measurements and ejection fraction measurements well below 10 mmHg and 10%, respectively. This computationally efficient model provides a platform for future investigations of patient-specific haemodynamics during AF.

A hallmark of Alzheimer's disease is reduced cerebral blood flow, which appears to occur early in disease progression and has been associated with amyloid β (Aβ) accumulation. Cerebral artery diameter is regulated by calcium influx via voltage-gated L-type Ca_V1.2 channels, which contribute to arterial myocyte contractility. The potential effects of Aβ on vascular Ca_V1.2 channels remain unclear. To address this knowledge gap, we test the hypothesis that Aβ alters vascular Ca_V1.2 channel spatiotemporal properties. Using freshly dissected cerebral arteries and arterial myocytes from wild-type (WT) mice, super-resolution imaging revealed that Aβ_1-42, but not Aβ_1-40, increased the clustering of Ca_V1.2 channels in male but not female or ovariectomized female arterial myocytes. This Aβ_1-42-associated Ca_V1.2 clustering appears to depend on NADPH oxidases, protein kinase C and protein kinase A signalling. Studies using male arterial myocytes from S1928A knockin mice suggested that Aβ_1-42 effects on Ca_V1.2 clustering require phosphorylation of the α1_C/Ca_V1.2 pore-forming subunit at serine-1928. Single-channel electrophysiology showed increased Ca_V1.2 channel activity and cooperative gating in WT male arterial myocytes exposed to Aβ_1-42, but not in female WT or male S1928A myocytes. In functional studies, WT, but not S1928A, cerebral arteries acutely incubated with Aβ_1-42 demonstrated enhanced constriction in response to the Ca_V1.2 channel agonist BayK8644. These findings provide insight into mechanisms by which Aβ may influence Ca_V1.2 properties and vascular contractility, potentially contributing to vascular changes in Alzheimer's disease. KEY POINTS: Specific amyloid-β peptide (Aβ_1-42) induces α1_C/Ca_V1.2 super-clustering in cerebral vascular smooth muscle, enhancing Ca_V1.2 activity. Aβ_1-42 engages distinct pathways involving NOX-derived ROS-activated PKC and PKA (through unknown mechanisms) to drive α1_C/Ca_V1.2 spatiotemporal reorganization leading to enhance cerebral artery contractile responses to Ca_V1.2 agonists. The Aβ_1-42-mediated PKC- and PKA-dependent effects on α1_C/Ca_V1.2 spatiotemporal remodelling and cerebral artery contractility require phosphorylation of α1_C at S1928, as the effects are lost in S1928A tissue/cells. The molecular and functional changes occur exclusively in male vascular smooth muscle cells, revealing sex-specific vulnerabilities in amyloid β-related cerebrovascular pathology that are independent of sex hormones and establishing a potential mechanism for vascular dysfunction in conditions with elevated Aβ_1-42.

Oxidative stress (OS), defined by an imbalance between reactive oxygen species (ROS) production and antioxidant defences, plays a bivalent and paradoxical role in the male reproductive system. At physiological levels, ROS are indispensable for sperm capacitation, hyperactivation and acrosome reaction, which are crucial for fertilization. However, excessive ROS - stemming from both endogenous sources (e.g. mitochondrial metabolism, enzyme-mediated reactions, seminal leukocytes) and exogenous factors (e.g. environmental pollutants and lifestyle behaviours) - can trigger detrimental OS reactions, including lipid peroxidation, DNA damage and impaired sperm function, contributing to male infertility. This dualistic nature of OS complicates defining the distinction between its physiological and pathological concentrations of ROS. This review comprehensively examines the complex interplay between ROS and OS in male reproduction, delineating how lifestyle factors can contribute to this imbalance and what mechanisms are implicated. Furthermore, we discuss current and emerging non-pharmacological strategies aimed at mitigating pathological OS, including antioxidant supplementation (e.g. resveratrol, vitamins C and E, coenzyme Q10), dietary interventions such as adherence to the Mediterranean diet and lifestyle modifications like regular moderate exercise and stress management techniques. By elucidating these multifaceted aspects, our analysis provides critical insights into maintaining redox homeostasis and advancing clinical interventions for improved male reproductive health.

Incentive motivation is believed to influence various cognitive domains to enhance goal-directed behaviour. For example the association of a reward to a specific location drives attention towards that location and influences the motor programmes involved in achieving that goal. However the interaction between motor and attentional systems in response to reward incentives is still poorly understood. To explore this we administered two Posner-style cueing tasks with varying reward incentives to two monkeys while recording neural activity from the dorsal premotor cortex (PMd), a key area for preparing goal-directed movements. These two cueing tasks differed in terms of motor engagement and visual analysis required: in Experiment 1 the animals manually reported the detection of a target stimulus in each trial, whereas in Experiment 2 the task followed a Go/NoGo paradigm, where the motor response depended on target identification. Behaviour revealed distinct patterns of attentional deployment and motor responses across the two tasks. Interestingly through time-resolved neural decoding we identified a stronger link between the reward incentives, motor activity and attentional shifts in Experiment 2. Overall our results suggest that motivation plays a critical role in modulating the interplay between spatial attention and motor control, with its effects varying based on the cognitive demands of the task. KEY POINTS: Attention and motivation behaviourally interact in tasks requiring complex executive motor control and demanding visual processing. The dorsal premotor cortex (PMd) changes how it responds to rewards based on what the task requires. The PMd encoding of the target location is impaired by invalid cues in a way that depends on both reward and task demands. PMd activity can shape behavioural responses that are usually linked to spatial attention.

Cardiovascular and respiratory responses to sustained hypoxia (SH) in rats and mice are different. To understand the contribution of changes in synaptic transmission in nucleus tractus solitarius (NTS) neurons of C57Bl/6J mice to their responses to SH we evaluated the following: (1) the neuronal excitability and excitatory synaptic transmission in the NTS neurons, (2) in what level of the synapses (pre- and postsynaptic) and also(3) to what extent neuron-astrocyte interaction contribute to these changes. Electrophysiological, immunohistochemical and intracellular Ca²⁺ imaging approaches in NTS slices after normoxia (FIO_2 = 0.21, 24 h) or SH (FIO_2 = 0.10, 24 h) were used. SH increased AMPA and NMDA currents in NTS neurons in response to solitary tract (TS) stimulation, indicating increased glutamatergic excitatory transmission. The number of action potentials after injection of positive current and TS stimulation (10 Hz) was increased by SH. Spontaneous extracellular activity in the NTS also increased, suggesting increased neuronal network activity after SH. The presynaptic mechanisms and the neuron-astrocyte interaction were not affected, but SH increased the amplitude of postsynaptic currents in NTS neurons induced by AMPA and NMDA perfusion. Therefore the enhancement of neuronal excitability and excitatory synaptic transmission in the NTS neurons of mice in response to SH is due to postsynaptic changes rather than changes in presynaptic parameters or in neuron-astrocyte interaction. The findings that the mechanisms underlying the increase in the excitatory synaptic transmission in the NTS of mice and rats are not the same contribute to explain the distinct cardiovascular and respiratory adjustments in mice and rats when exposed to SH. KEY POINTS: Cardiovascular and respiratory responses to sustained hypoxia (SH) in rats and mice are different. The extent to which changes in synaptic transmission in nucleus tractus solitarius (NTS) contribute to these responses is unclear. SH increases excitatory postsynaptic currents in NTS neurons of mice in response to solitary tract (TS) stimulation or to AMPA and NMDA perfusion. SH increases the number of action potentials in NTS neurons in response to injected current and spontaneous extracellular activity evaluated by a multielectrode array. SH did not alter presynaptic parameters, neuron-astrocyte interaction or morphological and electrophysiological properties of astrocytes. Our data show that the overall mechanisms underlying changes in the excitatory synaptic transmission in the NTS neurons of mice in response to SH are different in relation to rats. Although in rats it was documented changes in astrocytic modulation and postsynaptic currents, in mice we are showing that it is restricted to changes in postsynaptic currents.