Journal of Physiology-London最新文献

Given recent declines in North Pacific humpback whale (Megaptera novaeangliae) reproductive output and calf survival, there is additional urgency to better understand how mother-calf pairs allocate energy resources across their migratory cycle. Here, unoccupied aerial system (UAS; or drone) photogrammetry was used to quantify the body size and condition (BC) of humpback whales on their Hawai'i (HI) breeding and Southeast Alaska (SEAK) feeding grounds. Between 2018 and 2022, we collected 2410 measurements of 1659 individuals. Rates of change in body volume (BV) and length (BL) were quantified using 803 repeat measurements of 275 individuals. On average, HI mothers lost 0.106 m³ or 96.84 kg day^-1 while fasting, equivalent to 2641 MJ day^-1 or 830 kg of krill and 424 kg of Pacific herring daily. HI calf BV and BL increased by 0.035 m³ and 2.6 cm day^-1, respectively. In SEAK, maternal BV increased by 0.015 m³ or 14.54 kg day^-1 (367 MJ day^-1), while calf BV and BL increased by 0.039 m³ and 0.93 cm day^-1, respectively. Maternal investment in calf growth correlated with both female BL and BC, with larger females producing larger, faster-growing calves. Finally, using 330 measurements from 156 females, we quantified differences in BC increase over four feeding seasons. Lactating females exhibited an average BC increase of 6.10%, half that of unclassified females (13.51%) and six times lower than pregnant females (37%). These findings represent novel insights into the life history of humpback whales across their migratory cycle, providing key baseline data for bioenergetic models elucidating the effects of anthropogenic disturbance and rapidly changing ocean ecosystems. KEY POINTS: On average, Hawai'i (HI) mothers lost 0.106 m³ or 96.84 kg day^-1, equivalent to 2641 MJ day^-1. Over a 60 day period, this corresponded to an estimated mean energetic cost of 158 GJ, or ≈50 tons of krill or ≈25 tons of Pacific herring, surpassing the total energetic cost of gestation estimated for humpback whales of similar length. In Southeast Alaska (SEAK), maternal body volume (BV) increased by just 0.015 m³ or 14.54 kg day^-1 (367 MJ day^-1). Further, SEAK lactating females showed the slowest rates of growth in body width and condition over a 150 day period compared to non-lactating females. Maternal investment in calf growth correlated with both maternal length and body condition, with larger females producing larger, faster-growing calves. In HI, however, the ratio between maternal BV lost and calf BV gained (conversion efficiency) was relatively low compared to other mammals.

Pregnancy induces significant changes in the maternal cardiovascular system, and insufficient vascular endothelial adaptations to pregnancy contribute to the development of pregnancy complications such as pre-eclampsia. Pre-eclampsia is not only a major cause of maternal morbidity and mortality, but also a significant risk factor for the development of later-life cardiovascular disease. However, the specific mechanisms underlying the pathophysiology of pre-eclampsia, as well as the mechanisms for an increased susceptibility to cardiovascular disease later in life, are not fully characterized. In this review, we discuss the concept that excessive pregnancy-specific dyslipidaemia, particularly hypercholesterolaemia, is a significant risk factor for the development of pre-eclampsia. We further outline novel potential mechanisms (i.e. oxidized low-density lipoprotein receptor 1 and toll-like receptor 4) underlying endothelial dysfunction induced by excessively high cholesterol levels during pregnancy (in the context of pre-eclampsia), in addition to discussing the overall implications of having had a pregnancy complicated by pre-eclampsia on later-life maternal vascular health. Determining the mechanisms by which excessive, pregnancy-specific dyslipidaemia/hypercholesterolaemia impact maternal endothelial health in pregnancy, and later in life, will create a window of opportunity to diagnose and develop targeted therapy for a susceptible population of women, aiming to ultimately reduce the societal burden of cardiovascular disease.

The human cortical inhibitory system is known to play a vital role for normal brain development, function, and plasticity. GABA is the most prominent inhibitory neurotransmitter in the CNS and is a key regulator not only for motor control and motor learning, but also for cognitive processes. With ageing and many neurodegenerative pathologies, a decline in GABAergic function in several cortical regions together with a reduced ability to task-specifically modulate and increase inhibition in the primary motor cortex has been observed. This decline in intracortical inhibition is associated with impaired motor control but also with diminished motor-cognitive (i.e. dual-tasking) and cognitive performance (e.g. executive functions). Furthermore, more general well-being such as sleep quality, stress resistance or non-specific pain perception are also associated with reduced GABA functioning. The current review highlights the interplay between changes in GABAergic function and changes in motor control, motor-cognitive and cognitive performance associated with healthy ageing, as well as in seniors with neurodegenerative diseases such as mild cognitive impairment. Furthermore, recent evidence highlighting the ability to up- or downregulate cortical inhibition by means of physical exercise programs is presented and discussed.

Loss of cardiac physiological function following myocardial infarction (MI) is accompanied by neural adaptations in the baroreflex that are compensatory in the short term, but then become associated with long-term disease progression. One marker of these adaptations is decreased baroreflex sensitivity, a strong predictor of post-MI mortality. The relative contributions of cardiac remodelling and neural adaptation in the sensory, central brainstem and peripheral ganglionic loci to baroreflex sensitivity changes remain underexplored. We used a computational model-based approach that accounts for the short-term dynamics of closed-loop human cardiac control to integrate disparate experimental studies on neural adaptation following MI into a unified quantitative framework. We developed an ensemble of 59 distinct model parameterizations that account for the clinically observed heterogeneity of cardiac control in healthy individuals. We simulated an in silico cohort of 35,400 patients with MI, corresponding to six scenarios of one or more loci of neural adaptation coupled with cardiac remodelling. We evaluated the range of MI-induced shifts in arterial pressure, heart rate and baroreflex curve responses. Our results show that adaptation in any single neural locus coupled with cardiac remodelling is sufficient to account for the MI-induced haemodynamic and autonomic changes observed experimentally. Of the adaptation pathways, we found that individuals with central or peripheral vagal efferent adaptation and preserved baroreceptor gain could maintain high baroreflex sensitivity after ischaemic injury. These results suggest that there are a multitude of adaptive pathways for tuning the baroreflex circuit to shift cardiac control physiology, potentially explaining patient heterogeneity post-MI. KEY POINTS: Baroreflex sensitivity is a strong indicator of post-myocardial ischaemia survival and is variable among individuals. We fine-tuned a computational model ensemble based on physiological observations to develop an in silico patient cohort consistent with the range of baroreflex responses observed experimentally. Simulation and analysis of the in silico cohort show that individuals with a functional afferent pathway and the ability to adapt along the vagal efferent pathway can maintain baroreflex sensitivity post-cardiac ischaemia.

Knee osteoarthritis contributes substantially to worldwide disability. Post-traumatic osteoarthritis (PTOA) develops secondary to joint injury, such as ligament rupture, and there is increasing evidence suggesting a key role for inflammation in the aetiology of PTOA and associated functional deficits. Colony stimulating factor 1 receptor (CSF1-R) has been implicated in the pathogenesis of musculoskeletal degeneration following anterior cruciate ligament (ACL) injury. We sought to assess the efficacy of CSF1-R inhibition to mitigate muscle and joint pathology in a mouse model of PTOA. Four-month-old mice were randomized to receive a CSF1-R inhibitor and studied for 7 or 28 days after joint injury. Additionally, we profiled synovial fluid samples for CSF1-R from patients with injury to their ACL. Transcriptomic analysis of quadriceps muscle and articular cartilage in CSF1-R inhibitor-treated animals at 7 days after injury revealed elevated chondrocyte differentiation within articular cartilage and enhanced metabolic and contractile gene expression within skeletal muscle. At 28 days post-injury, CSF1-R inhibition attenuated PTOA severity and mitigated skeletal muscle atrophy. Patient synovial fluid CSF1-R levels correlated with matrix metalloproteinase 13, a prognostic marker and molecular effector of PTOA. Our findings support an opportunity for CSF1-R targeting to mitigate the severity of PTOA and muscle atrophy after joint injury. KEY POINTS: Posttraumatic osteoarthritis (PTOA) of the knee commonly results from direct injury to the joint, which is characterized by pain, weakness, and disability. Induction of colony stimulating factor one receptor (CSF1-R) is positively associated with knee trauma severity, and the initial acute inflammatory state suppresses muscle recovery and degrades articular cartilage. Skeletal muscle and articular cartilage transcriptomic response following direct joint injury in a murine model of PTOA is rescued by pharmacological inhibition of CSF1-R. CSF1-R inhibition mitigated skeletal muscle atrophy and attenuated PTOA severity and synovitis. Patient synovial fluid CSF1-R levels correlated with matrix metalloproteinase 13, a prognostic marker and molecular effector of PTOA, offering further evidence for CSF1-R as a therapeutic target across musculoskeletal tissues after injury.

The frequent poor functional outcomes after delayed surgical repair of injured human peripheral nerves results in progressive downregulation of growth-associated genes in parallel with reduced neuronal regenerative capacity under each of the experimental conditions of chronic axotomy of neurones that remain without target contact, chronic distal nerve stump denervation, and chronic muscle denervation. Brief (1 h) low-frequency (20 Hz) electrical stimulation (ES) accelerates the outgrowth of regenerating axons across the surgical site of microsurgical repair of a transected nerve. Exercise programmes also promote nerve regeneration with the combination of ES and exercise being the most effective. An ES conditioning lesion of intact nerve (CES) accelerates both axonal outgrowth and regeneration rate after the surgical repair of a more distal injury to the nerve, in contrast to ES of a repaired injury nerve that accelerates only the axon outgrowth. A CES accelerates both axonal outgrowth and regeneration rate after the surgical repair of a more distal injury to the nerve, in contrast to ES of a repaired injury nerve that accelerates only the axon outgrowth. The loss of contractility of permanently denervated muscles in cauda equinae-injured patients with accompanying severe loss of muscle mass, disarray of thick and thin contractile filaments, and disorganization of the sarcoplasmic reticulum that controls calcium delivery to the filaments, is alleviated by a 2-year programme of daily ES of the quadriceps muscle. These findings hold promise for recovery and rehabilitation in patients who suffer injury to the neuromuscular system. KEY POINTS: Poor functional outcomes after delayed surgical repair of injured human peripheral nerves are replicated by chronic neuronal axotomy, Schwann cell denervation in a nerve autograft, and muscle denervation. Exponential decline in expression of growth-associated genes accompanies the same decline in regenerative capacity. Brief (1 h) low-frequency (20 Hz) electrical stimulation (ES) that generates action potential conduction to the neuronal soma accelerates the outgrowth of regenerating axons across the surgical repair site of the transected nerve, even after delayed surgery. The same ES regimen accelerates muscle reinnervation in patients with chronic nerve injury who undergo carpal tunnel syndrome release surgery. A 2-year programme of daily ES of permanently denervated quadriceps muscles in cauda equinae-injured patients reinstated their contractility and organization.

In recent years, evidence supporting non-ionotropic signalling by the NMDA receptor (niNMDAR) has emerged, including roles in long-term depression (LTD). Here, we investigated whether niNMDAR-pannexin-1 (Panx1) contributes to LTD at the CA3-CA1 hippocampal synapse. Using whole-cell, patch clamp electrophysiology in rat hippocampal slices, we show that a low-frequency stimulation (3 Hz) of the Schaffer collaterals produces LTD that is blocked by continuous but not transient application of the NMDAR competitive antagonist, MK-801. After transient MK-801, LTD involved pannexin-1 and sarcoma (Src) kinase. We show that pannexin-1 is not permeable to Ca²⁺, but probably releases ATP to induce LTD via P2X4 purinergic receptors because LTD after transient MK-801 application was prevented by 5-BDBD. Thus, we conclude that niNMDAR activation of Panx1 can link glutamatergic and purinergic pathways to produce LTD following low frequency synaptic stimulation when NMDARs are transiently inhibited. KEY POINTS: Differential effect of short-term D-APV and MK-801 application on long-term depression (LTD) suggests that the NMDA receptor (niNMDAR) contributes to later phases of synaptic depression. niNMDAR LTD involved sarcoma (Src) kinase and pannexin-1 (Panx1), which is a pathway previously identified to be active during excitotoxicity. Panx1 was not calcium permeable but may contribute to late phase LTD via ATP release. Panx1 blockers prevent LTD, and this was rescued with exogenous ATP application. Inhibition of LTD with 5-BDBD suggests the downstream involvement of postsynaptic P2X4 receptors.

Volume-regulated anion channels (VRACs) are heteromeric complexes formed by proteins of the leucine-rich repeat-containing 8 (LRRC8) family. LRRC8A (also known as SWELL1) is the core subunit required for VRAC function, and it must combine with one or more of the other paralogues (i.e. LRRC8B-E) to form functional heteromeric channels. VRACs were discovered in T lymphocytes over 35 years ago and are found in virtually all vertebrate cells. Initially, these anion channels were characterized for their role in Cl^- efflux during the regulatory volume decrease process triggered when cells are subjected to hypotonic challenges. However, substantial evidence suggests that VRACs also transport small molecules under isotonic conditions. These findings have expanded the research on VRACs to explore their functions beyond volume regulation. In innate immune cells, VRACs promote inflammation by modulating the transport of immunomodulatory cyclic dinucleotides, itaconate and ATP. In adaptive immune cells, VRACs suppress their function by taking up cyclic dinucleotides to activate the STING signalling pathway. In this review, we summarize the current understanding of LRRC8 proteins in immunity and discuss recent progress in their structure, function, regulation and mechanisms for channel activation and gating. Finally, we also examine potential immunotherapeutic applications of VRAC modulation.

Volitional respiratory manoeuvres such as sniffing and apnoea play a key role in the active olfactory exploration of the environment. Their impairment by neurodegenerative processes could thus impair olfactory abilities with the ensuing impact on quality of life. Functional brain imaging studies have identified brain networks engaged in sniffing and voluntary apnoea, comprising the primary motor and somatosensory cortices, the insula, the anterior cingulate cortex and the amygdala. The temporal organization and the oscillatory activities of these networks are not known. To elucidate these aspects, we recorded intracranial electroencephalograms in six patients during voluntary sniffs and short apnoeas (12 s). The preparation phase of both manoeuvres involved increased alpha and theta activity in the posterior insula, amygdala and temporal regions, with a specific preparatory activity in the parahippocampus for the short apnoeas and the hippocampus for sniff. Subsequently, it narrowed to the superior and median temporal areas, immediately after the manoeuvres. During short apnoeas, a particular dynamic was observed, consisting of a rapid decline in alpha and theta activity followed by a slow recovery and increase. Volitional respiratory manoeuvres involved in olfactory control involve corticolimbic structures in both a preparatory and executive manner. Further studies are needed to determine whether diseases altering deep brain structures can disrupt these mechanisms and if such disruption contributes to the corresponding olfactory deficits. KEY POINTS: Both sniff manoeuvres and short apnoeas are associated with oscillatory activity predominantly in low-frequency bands (alpha and theta). Preparation of sniff manoeuvres and short apnoeas involve activities in low-frequency bands in the posterior insula and temporal regions that extend to amygdala during the execution of both manoeuvres. During short apnoeas, activities in low-frequency bands initially decline before continuously increasing until the apnoeas end.