The 50 most-cited articles in The Journal of Physiology, 2018

KEY POINTS: Chronic (psychosocial) stress changes gut microbiota composition, as well as inducing behavioural and physiological deficits. The microbial metabolites short-chain fatty acids (SCFAs) have been implicated in gastrointestinal functional, (neuro)immune regulation and host metabolism, but their role in stress-induced behavioural and physiological alterations is poorly understood. Administration of SCFAs to mice undergoing psychosocial stress alleviates enduring alterations in anhedonia and heightened stress-responsiveness, as well as stress-induced increases in intestinal permeability. In contrast, chronic stress-induced alterations in body weight gain, faecal SCFAs and the gene expression of the SCFA receptors FFAR2 and FFAR3 remained unaffected by SCFA supplementation. These results present novel insights into mechanisms underpinning the influence of the gut microbiota on brain homeostasis, behaviour and host metabolism, informing the development of microbiota-targeted therapies for stress-related disorders. ABSTRACT: There is a growing recognition of the involvement of…

KEY POINTS: Activation of the shoulder abductor muscles in the arm opposite a unilateral brain injury causes involuntary increases in elbow, wrist and finger flexion in the same arm, a phenomenon referred to as the flexion synergy. It has been proposed that flexion synergy expression is related to reduced output from ipsilesional motor cortex and corticospinal pathways. In this human subjects study, we provide evidence that the magnitude of flexion synergy expression is instead related to a progressive, task-dependent recruitment of contralesional cortex. We also provide evidence that recruitment of contralesional cortex may induce excessive activation of ipsilateral reticulospinal descending motor pathways that cannot produce discrete movements, leading to flexion synergy expression. We interpret these findings as an adaptive strategy that preserves low-level motor control at the cost of fine motor control. ABSTRACT: A hallmark of hemiparetic stroke is the loss of fine motor control in the contralesional arm and hand and the constraint to a grouped movement pattern known as the…

A tendon transfers force from the contracting muscle to the skeletal system to produce movement and is therefore a crucial component of the entire muscle-tendon complex and its function. However, tendon research has for some time focused on mechanical properties without any major appreciation of potential cellular and molecular changes. At the same time, methodological developments have permitted determination of the mechanical properties of human tendons in vivo, which was previously not possible. Here we review the current understanding of how tendons respond to loading, unloading, ageing and injury from cellular, molecular and mechanical points of view. A mechanistic understanding of tendon tissue adaptation will be vital for development of adequate guidelines in physical training and rehabilitation, as well as for optimal injury treatment.

KEY POINTS: The ability to learn new motor skills is supported by plasticity in the structural and functional organisation of the primary motor cortex in the human brain. Changes inhibitory to signalling by GABA are thought to be crucial in inducing motor cortex plasticity. This study used magnetic resonance spectroscopy (MRS) to quantify the concentration of GABA in human motor cortex during a period of motor learning, as well as during a period of movement and a period at rest. We report evidence for a reduction in the MRS-measured concentration of GABA specific to learning. Further, the GABA concentration early in the learning task was strongly correlated with the magnitude of subsequent learning: higher GABA concentrations were associated with poorer learning. The results provide initial insight into the neurochemical correlates of cortical plasticity associated with motor learning, specifically relevant in therapeutic efforts to induce cortical plasticity during recovery from stroke. ABSTRACT: The ability to learn novel motor skills is a central part of our daily lives and can…

KEY POINTS: The age-related loss of muscle mass is related to the loss of innervating motor neurons and denervation of muscle fibres. Not all denervated muscle fibres are degraded; some may be reinnervated by an adjacent surviving neuron, which expands the innervating motor unit proportional to the numbers of fibres rescued. Enlarged motor units have larger motor unit potentials when measured using electrophysiological techniques. We recorded much larger motor unit potentials in relatively healthy older men compared to young men, but the older men with the smallest muscles (sarcopenia) had smaller motor unit potentials than healthy older men. These findings suggest that healthy older men reinnervate large numbers of muscle fibres to compensate for declining motor neuron numbers, but a failure to do so contributes to muscle loss in sarcopenic men. ABSTRACT: Sarcopenia results from the progressive loss of skeletal muscle mass and reduced function in older age. It is likely to be associated with the well-documented reduction of motor unit numbers innervating limb muscles and the…

We will argue here that there is net lactate transfer from astrocytes to neurons and that this transfer is important for brain function. Following CrossTalk guidelines, we will focus on data published over the last decade.

KEY POINTS: Insulin enters the brain from the blood via a saturable transport system. It is unclear how insulin is transported across the blood-brain barrier (BBB). Using two models of the signalling-related insulin receptor loss or inhibition, we show insulin transport can occur in vivo without the signalling-related insulin receptor. Insulin in the brain has multiple roles including acting as a metabolic regulator and improving memory. Understanding how insulin is transported across the BBB will aid in developing therapeutics to further increase CNS concentrations. ABSTRACT: A saturable system transports insulin from blood across the blood-brain barrier (BBB) and into the central nervous system. Whether or not the classic or signalling-related insulin receptor plays a role in mediating this transport in vivo is controversial. Here, we employed kinetics methods that distinguish between transport across the brain endothelial cell and reversible luminal surface receptor binding. Using a previously established line of mice with endothelial-specific loss of the signalling-related…

Properties of the local internal environment of the adult brain are tightly controlled providing a stable milieu essential for its normal function. The mechanisms involved in this complex control are structural, molecular and physiological (influx and efflux transporters) frequently referred to as the 'blood-brain barrier'. These mechanisms include regulation of ion levels in brain interstitial fluid essential for normal neuronal function, supply of nutrients, removal of metabolic products, and prevention of entry or elimination of toxic agents. A key feature is cerebrospinal fluid secretion and turnover. This is much less during development, allowing greater accumulation of permeating molecules. The overall effect of these mechanisms is to tightly control the exchange of molecules into and out of the brain. This review presents experimental evidence currently available on the status of these mechanisms in developing brain. It has been frequently stated for over nearly a century that the blood-brain barrier is not present or at least is functionally deficient in the embryo, fetus…

KEY POINTS: The spinal alpha motoneuron is the only cell in the human CNS whose discharge can be routinely recorded in humans. We have reengineered motor unit collection and decomposition approaches, originally developed in humans, to measure the neural drive to muscle and estimate muscle force generation in the in vivo cat model. Experimental, computational, and predictive approaches are used to demonstrate the validity of this approach across a wide range of modes to activate the motor pool. The utility of this approach is shown through the ability to track individual motor units across trials, allowing for better predictions of muscle force than the electromyography signal, and providing insights in to the stereotypical discharge characteristics in response to synaptic activation of the motor pool. This approach now allows for a direct link between the intracellular data of single motoneurons, the discharge properties of motoneuron populations, and muscle force generation in the same preparation. ABSTRACT: The discharge of a spinal alpha motoneuron and the resulting contraction…

Over 30 years ago Professor David Barker first proposed the theory that events in early life could explain an individual's risk of non-communicable disease in later life: the developmental origins of health and disease (DOHaD) hypothesis. During the 1990s the validity of the DOHaD hypothesis was extensively tested in a number of human populations and the mechanisms underpinning it characterised in a range of experimental animal models. Over the past decade, researchers have sought to use this mechanistic understanding of DOHaD to develop therapeutic interventions during pregnancy and early life to improve adult health. A variety of animal models have been used to develop and evaluate interventions, each with strengths and limitations. It is becoming apparent that effective translational research requires that the animal paradigm selected mirrors the tempo of human fetal growth and development as closely as possible so that the effect of a perinatal insult and/or therapeutic intervention can be fully assessed. The guinea pig is one such animal model that over the past two decades has…

KEY POINTS: A healthy mitochondrial pool is dependent on the removal of dysfunctional organelles via mitophagy, but little is known about how mitophagy is altered with ageing and chronic exercise. Chronic contractile activity (CCA) is a standardized exercise model that can elicit mitochondrial adaptations in both young and aged muscle, albeit to a lesser degree in the aged group. Assessment of mitophagy flux revealed enhanced targeting of mitochondria for degradation in aged muscle, in contrast to previous theories. Mitophagy flux was significantly reduced as an adaptation to CCA suggesting that an improvement in organelle quality reduces the need for mitochondrial turnover. CCA enhances lysosomal capacity and may ameliorate lysosomal dysfunction in aged muscle. ABSTRACT: Skeletal muscle exhibits deficits in mitochondrial quality with age. Central to the maintenance of a healthy mitochondrial pool is the removal of dysfunctional organelles via mitophagy. Little is known on how mitophagy is altered with ageing and chronic exercise. We assessed mitophagy flux using colchicine…

The development of intestinal-type gastric cancer is preceded by the emergence of metaplastic cell lineages in the gastric mucosa. In particular, intestinal metaplasia and spasmolytic polypeptide-expressing metaplasia (SPEM) have been associated with the pathological progression to intestinal-type gastric cancer. The development of SPEM represents a physiological response to damage that recruits reparative cells to sites of mucosal injury. Metaplastic cell lineages are characterized by mucus secretion, adding a protective barrier to the epithelium. Increasing evidence indicates that the influence of alarmins and cytokines is required to initiate the process of metaplasia development. In particular, IL-33 derived from epithelial cells stimulates IL-13 production by specialized innate immune cells to induce chief cell transdifferentiation into SPEM following the loss of parietal cells from the corpus of the stomach. While SPEM represents a physiological healing response to acute injury, persistent injury and chronic inflammation can perpetuate a recurring pattern of reprogramming and…

Key points Slow periodic activity can propagate with speeds around 0.1 m s −1 and be modulated by weak electric fields. Slow periodic activity in the longitudinal hippocampal slice can propagate without chemical synaptic transmission or gap junctions, but can generate electric fields which in turn activate neighbouring cells. Applying local extracellular electric fields with amplitude in the range of endogenous fields is sufficient to modulate or block the propagation of this activity both in the in silico and in the in vitro models. Results support the hypothesis that endogenous electric fields, previously thought to be too small to trigger neural activity, play a significant role in the self‐propagation of slow periodic activity in the hippocampus. Experiments indicate that a neural network can give rise to sustained self‐propagating waves by ephaptic coupling, suggesting a novel propagation mechanism for neural activity under normal physiological conditions. Abstract Slow oscillations are a standard feature observed in the cortex and the hippocampus during slow wave sleep. Slow…

KEY POINTS: Low-volume high-intensity exercise training promotes muscle mitochondrial adaptations that resemble those associated with high-volume moderate-intensity exercise training. These training-induced mitochondrial adaptations stem from the cumulative effects of transient transcriptional responses to each acute exercise bout. However, whether metabolic stress is a key mediator of the acute molecular responses to high-intensity exercise is still incompletely understood. Here we show that, by comparing different work-matched low-volume high-intensity exercise protocols, more marked metabolic perturbations were associated with enhanced mitochondrial biogenesis-related muscle mRNA responses. Furthermore, when compared with high-volume moderate-intensity exercise, only the low-volume high-intensity exercise eliciting severe metabolic stress compensated for reduced exercise volume in the induction of mitochondrial biogenic mRNA responses. The present results, besides improving our understanding of the mechanisms mediating exercise-induced mitochondrial biogenesis, may have…

KEY POINTS: Motoneuron soma size is a largely plastic property that is altered during amyotrophic lateral sclerosis (ALS) progression. We report evidence of systematic spinal motoneuron soma size plasticity in mutant SOD1-G93A mice at various disease stages and across sexes, spinal regions and motoneuron types. We show that disease-vulnerable motoneurons exhibit early increased soma sizes. We show via computer simulations that the measured changes in soma size have a profound impact on the excitability of disease-vulnerable motoneurons. This study reveals a novel form of plasticity in ALS and suggests a potential target for altering motoneuron function and survival. ABSTRACT: α-Motoneuron soma size is correlated with the cell's excitability and function, and has been posited as a plastic property that changes during cellular maturation, injury and disease. This study examined whether α-motoneuron somas change in size over disease progression in the G93A mouse model of amyotrophic lateral sclerosis (ALS), a disease characterized by progressive motoneuron death. We used 2D- and…

The articular cartilage is exquisitely sensitive to mechanical load. Its structure is largely defined by the mechanical environment and destruction in osteoarthritis is the pathophysiological consequence of abnormal mechanics. It is often overlooked that disuse of joints causes profound loss of volume in the articular cartilage, a clinical observation first described in polio patients and stroke victims. Through the 1980s, the results of studies exploiting experimental joint immobilisation supported this. Importantly, this substantial body of work was also the first to describe metabolic changes that resulted in decreased synthesis of matrix molecules, especially sulfated proteoglycans. The molecular mechanisms that underlie disuse atrophy are poorly understood despite the identification of multiple mechanosensing mechanisms in cartilage. Moreover, there has been a tendency to equate cartilage loss with osteoarthritic degeneration. Here, we review the historic literature and clarify the structural, metabolic and clinical features that clearly distinguish cartilage loss due to disuse…

Pentameric ligand-gated ion channels (pLGICs) mediate fast neurotransmission in the nervous system. Their dysfunction is associated with psychiatric, neurological and neurodegenerative disorders such as schizophrenia, epilepsy and Alzheimer's disease. Understanding their biophysical and pharmacological properties, at both the functional and the structural level, thus holds many therapeutic promises. In addition to their agonist-elicited activation, most pLGICs display another key allosteric property, namely desensitization, in which they enter a shut state refractory to activation upon sustained agonist binding. While the activation mechanisms of several pLGICs have been revealed at near-atomic resolution, the structural foundation of desensitization has long remained elusive. Recent structural and functional data now suggest that the activation and desensitization gates are distinct, and are located at both sides of the ion channel. Such a 'dual gate mechanism' accounts for the marked allosteric effects of channel blockers, a feature illustrated herein by theoretical kinetics…

KEY POINTS: of committed exercise over a lifetime are necessary to preserve 'youthful' vascular compliance, especially of the large central arteries. Casual exercise training of two to three times per week may be sufficient for middle-sized arteries like the carotid to minimize arterial stiffening with ageing. However, there is little effect of exercise training on the small-sized peripheral arteries at any dose. ABSTRACT: Central arterial stiffness increases with sedentary ageing. While near-daily, vigorous lifelong (>25 years) endurance exercise training prevents arterial stiffening with ageing, this rigorous routine of exercise training over a lifetime is impractical for most individuals. The aim was to examine whether a less frequent 'dose' of lifelong exercise training (four to five sessions per week for > 30 min) that is consistent with current physical activity recommendations elicits similar benefits on central arterial stiffening with ageing. A cross-sectional examination of 102 seniors (>60 years old) who had a consistent lifelong exercise history was performed. Subjects…

KEY POINTS: Although the natural decline in walking performance with ageing affects the quality of life of a growing elderly population, its physiological origins remain unknown. By using predictive neuromechanical simulations of human walking with age-related neuro-musculo-skeletal changes, we find evidence that the loss of muscle strength and muscle contraction speed dominantly contribute to the reduced walking economy and speed. The findings imply that focusing on recovering these muscular changes may be the only effective way to improve performance in elderly walking. More generally, the work is of interest for investigating the physiological causes of altered gait due to age, injury and disorders. ABSTRACT: Healthy elderly people walk slower and energetically less efficiently than young adults. This decline in walking performance lowers the quality of life for a growing ageing population, and understanding its physiological origin is critical for devising interventions that can delay or revert it. However, the origin of the decline in walking performance remains unknown, as…

Transforming growth factor-β (TGF-β) is the key player in tissue fibrosis. However, antifibrotic therapy targeting this multifunctional protein may interfere with other physiological processes to cause side effects. Thus, precise therapeutic targets need to be identified by further understanding the underlying mechanisms of TGF-β1 signalling during fibrogenesis. Equilibrium of Smad signalling is crucial for TGF-β-mediated renal fibrosis, where Smad3 is pathogenic but Smad2 and Smad7 are protective. The activation of TGF-β1/Smad signalling triggers extracellular matrix deposition, and local myofibroblast generation and activation. Mechanistic studies have shown that TGF-β/Smad3 transits the microRNA profile from antifibrotic to profibrotic and therefore promotes renal fibrosis via regulating non-coding RNAs at transcriptional levels. More importantly, disease-specific Smad3-dependent long non-coding RNAs have been recently uncovered from mouse kidney disease models and may represent novel precision therapeutic targets for chronic kidney disease. In this review, mechanisms of…

Key points Parkin, an E3 ubiquitin ligase encoded by the Park2 gene, has been implicated in the regulation of mitophagy, a quality control process in which defective mitochondria are degraded. The exact physiological significance of Parkin in regulating mitochondrial function and contractility in skeletal muscle remains largely unexplored. Using Park2 −/− mice, we show that Parkin ablation causes a decrease in muscle specific force, a severe decrease in mitochondrial respiration, mitochondrial uncoupling and an increased susceptibility to opening of the permeability transition pore. These results demonstrate that Parkin plays a protective role in the maintenance of normal mitochondrial and contractile functions in skeletal muscles. Abstract Parkin is an E3 ubiquitin ligase encoded by the Park2 gene. Parkin has been implicated in the regulation of mitophagy, a quality control process in which defective mitochondria are sequestered in autophagosomes and delivered to lysosomes for degradation. Although Parkin has been mainly studied for its implication in neuronal degeneration in…

Good quality sleep of sufficient duration is vital for optimal physiological function and our health. Sleep deprivation is associated with impaired neurocognitive function and emotional control, and increases the risk for cardiometabolic diseases, obesity and cancer. Sleep develops during fetal life with the emergence of a recognisable pattern of sleep states in the preterm fetus associated with the development, maturation and connectivity within neural networks in the brain. Despite the physiological importance of sleep, surprisingly little is known about how sleep develops in individuals born preterm. Globally, an estimated 15 million babies are born preterm (<37 weeks gestation) each year, and these babies are at significant risk of neural injury and impaired brain development. This review discusses how sleep develops during fetal and neonatal life, how preterm birth impacts on sleep development to adulthood, and the factors which may contribute to impaired brain and sleep development, leading to altered neurocognitive, behavioural and motor capabilities in the infant and child.…

Key points While a consensus has now been reached on the effect of motor imagery (MI) – the mental simulation of an action – on motor cortical areas, less is known about its impact on spinal structures. The current study, using H‐reflex conditioning paradigms, examined the effect of a 20 min MI practice on several spinal mechanisms of the plantar flexor muscles. We observed modulations of spinal presynaptic circuitry while imagining, which was even more pronounced following an acute session of MI practice. We suggested that the small cortical output generated during MI may reach specific spinal circuits and that repeating MI may increase the sensitivity of the spinal cord to its effects. The short‐term plasticity induced by MI practice may include spinal network modulation in addition to cortical reorganization. Abstract Kinesthetic motor imagery (MI) is the mental simulation of a movement with its sensory consequences but without its concomitant execution. While the effect of MI practice on cortical areas is well known, its influence on spinal circuitry remains unclear. Here, we…

Key points The mechanisms responsible for the loss in muscle power and increased fatigability with ageing are unresolved. We show that the contractile mechanics of fibres from the vastus lateralis of old men were well‐preserved compared to those of young men, but the selective loss of fast myosin heavy chain II muscle was strongly associated with age‐related decrements in whole‐muscle strength and power. We reveal that the combination of acidosis (H + ) and inorganic phosphate (P i ) is an important mediator of muscle fatigue in humans by inhibiting the low‐ to high‐force state of the cross‐bridge cycle and peak power, but the depressive effects of these ions on cross‐bridge function were similar in fibres from young and old men. These findings suggest that the age‐related loss in muscle power is primarily determined by the atrophy of fast fibres, but the age‐related increased fatigability cannot be explained by an increased sensitivity of the cross‐bridge to H + and P i . Abstract The present study aimed to identify the mechanisms responsible for the loss in muscle power and…

Key points In aged rats, daily muscle stretching increases blood flow to skeletal muscle during exercise. Daily muscle stretching enhanced endothelium‐dependent vasodilatation of skeletal muscle resistance arterioles of aged rats. Angiogenic markers and capillarity increased in response to daily stretching in muscles of aged rats. Muscle stretching performed with a splint could provide a feasible means of improving muscle blood flow and function in elderly patients who cannot perform regular aerobic exercise. Abstract Mechanical stretch stimuli alter the morphology and function of cultured endothelial cells; however, little is known about the effects of daily muscle stretching on adaptations of endothelial function and muscle blood flow. The present study aimed to determine the effects of daily muscle stretching on endothelium‐dependent vasodilatation and muscle blood flow in aged rats. The lower hindlimb muscles of aged Fischer rats were passively stretched by placing an ankle dorsiflexion splint for 30 min day –1 , 5 days week –1 , for 4 weeks. Blood flow to the stretched limb and…

KEY POINTS: Increased activation of the renin-angiotensin-aldosterone system (RAAS) and elevated growth factor production are of crucial importance in the development of renal fibrosis leading to diabetic kidney disease. The aim of this study was to provide evidence for the antifibrotic potential of RAAS inhibitor (RAASi) treatment and to explore the exact mechanism of this protective effect. We found that RAASi ameliorate diabetes-induced renal interstitial fibrosis and decrease profibrotic growth factor production. RAASi prevents fibrosis by acting directly on proximal tubular cells, and inhibits hyperglycaemia-induced growth factor production and thereby fibroblast activation. These results suggest a novel therapeutic indication and potential of RAASi in the treatment of renal fibrosis. ABSTRACT: In diabetic kidney disease (DKD) increased activation of renin-angiotensin-aldosterone system (RAAS) contributes to renal fibrosis. Although RAAS inhibitors (RAASi) are the gold standard therapy in DKD, the mechanism of their antifibrotic effect is not yet clarified. Here we tested the…

Key points The recent development of exogenous ketone supplements allows direct testing of the metabolic effects of elevated blood ketones without the confounding influence of widespread changes experienced with ketogenic diets or prolonged fasting. In the present study, we determined the effect of (R)‐3‐hydroxybutyl (R)‐3‐hydroxybutyrate ketone monoester on the glycaemic response and insulin sensitivity index during a 2 h oral glucose tolerance test (OGTT) in humans. The results obtained show that consuming a ketone monoester supplement 30 min prior to an OGTT reduced the glycaemic response and markers of insulin sensitivity without affecting insulin secretion. The findings of the present study provides evidence that ketone supplements could have therapeutic potential for future application as a glucose‐lowering nutritional supplement. Abstract The main objectives of the present study were: (i) to determine whether acute ingestion of ketone monoester (Kme); (R)‐3‐hydroxybutyl (R)‐3‐hydroxybutyrate impacts plasma glucose levels during a standardized oral glucose tolerance test…

The maintenance of skeletal muscle mass and strength throughout life is a key determinant of human health and well-being. There is a gradual loss of both skeletal muscle mass and strength with ageing (a process termed sarcopenia) that increases the risk of functional dependence, morbidity and mortality. Understanding the factors that regulate the size of human muscle mass, particularly during the later years of life, has therefore become an area of intense scientific inquiry. The amount of muscle mass is determined by coordinated changes in muscle protein synthesis (MPS) and muscle protein breakdown (MPB). In this review, we assess both classical and contemporary work that has examined how resistance exercise and nutrition impact on MPS and MPB. Special consideration is given to the role of different sources of dietary protein (food vs. supplements) and non-protein nutrients such as omega-3 fatty acids in regulating MPS. We also critically evaluate recent studies that have employed novel 'omic' technologies such as dynamic protein profiling to probe for changes in rates of MPS and…

KEY POINTS: During long-term missions, some astronauts experience structural and functional changes of the eyes and brain which resemble signs/symptoms experienced by patients with intracranial hypertension. Weightlessness prevents the normal cerebral volume and pressure 'unloading' associated with upright postures on Earth, which may be part of the cerebral and ocular pathophysiology. By placing the lower body in a negative pressure device (LBNP) that pulls fluid away from cranial compartments, we simulated effects of gravity and significantly lowered pressure within the brain parenchyma and ventricle compartments. Application of incremental LBNP demonstrated a non-linear dose-response curve, suggesting 20 mmHg LBNP as the optimal level for reducing pressure in the brain without impairing cerebral perfusion pressure. This non-invasive method of reducing pressure in the brain holds potential as a countermeasure in space as well as having treatment potential for patients on Earth with traumatic brain injury or other pathology leading to intracranial hypertension. ABSTRACT: Patients…

Key points Animal preparations have revealed that moderate synaptic release of serotonin (5‐HT) onto motoneurones enhances motor activity via activation of 5‐HT 2 receptors, whereas intense release of 5‐HT causes spillover of 5‐HT to extrasynaptic 5‐HT 1A receptors on the axon initial segment to reduce motoneurone activity. We explored if increasing extracellular concentrations of endogenously released 5‐HT (via the selective serotonin reuptake inhibitor paroxetine) influences the ability to perform unfatigued and fatigued maximal voluntary contractions in humans. Following the ingestion of paroxetine, voluntary muscle activation and torque generation increased during brief unfatigued maximal contractions. In contrast, the ability to generate maximal torque with increased 5‐HT availability was compromised under fatigued conditions, which was consistent with paroxetine‐induced reductions in motoneurone excitability and voluntary muscle activation. This is the first in vivo human study to provide evidence that 5‐HT released onto the motoneurones could play a role in central fatigue.…

KEY POINTS: A ketogenic diet is known to lead to weight loss and is considered metabolically healthy; however there are conflicting reports on its effect on hepatic insulin sensitivity. KD fed animals appear metabolically healthy in the fasted state after 3 days of dietary challenge, whereas obesogenic high-fat diet (HFD) fed animals show elevated insulin levels. A glucose challenge reveals that both KD and HFD fed animals are glucose intolerant. Glucose intolerance correlates with increased lipid oxidation and lower respiratory exchange ratio (RER); however, all animals respond to glucose injection with an increase in RER. Hyperinsulinaemic-euglycaemic clamps with double tracer show that the effect of KD is a result of hepatic insulin resistance and increased glucose output but not impaired glucose clearance or tissue glucose uptake in other tissues. ABSTRACT: Despite being a relevant healthcare issue and heavily investigated, the aetiology of type 2 diabetes (T2D) is still incompletely understood. It is well established that increased endogenous glucose production (EGP) leads to a…

KEY POINTS: Chronic mountain sickness (CMS) is a maladaptation syndrome encountered at high altitude (HA) characterised by severe hypoxaemia that carries a higher risk of stroke and migraine and is associated with increased morbidity and mortality. We examined if exaggerated oxidative-inflammatory-nitrosative stress (OXINOS) and corresponding decrease in vascular nitric oxide bioavailability in patients with CMS (CMS+) is associated with impaired cerebrovascular function and adverse neurological outcome. Systemic OXINOS was markedly elevated in CMS+ compared to healthy HA (CMS-) and low-altitude controls. OXINOS was associated with blunted cerebral perfusion and vasoreactivity to hypercapnia, impaired cognition and, in CMS+, symptoms of depression. These findings are the first to suggest that a physiological continuum exists for hypoxaemia-induced systemic OXINOS in HA dwellers that when excessive is associated with accelerated cognitive decline and depression, helping identify those in need of more specialist neurological assessment and targeted support. ABSTRACT: Chronic mountain…

KEY POINTS: Maternal high-fat diet consumption predisposes to metabolic dysfunction in male and female offspring at young adulthood. Maternal obesity programs non-alcoholic fatty liver disease (NAFLD) in a sex-dependent manner. We demonstrate sex-dependent liver transcriptome profiles in rat offspring of obese mothers. In this study, we focused on pathways related to insulin, glucose and lipid signalling. These results improve understanding of the mechanisms by which a maternal high-fat diet affects the offspring. ABSTRACT: Maternal obesity (MO) predisposes offspring (F1) to obesity, insulin resistance (IR) and non-alcoholic fatty liver disease (NAFLD). MO's effects on the F1 liver transcriptome are poorly understood. We used RNA-seq to determine the liver transcriptome of male and female F1 of MO and control-fed mothers. We hypothesized that MO-F1 are predisposed to sex-dependent adult liver dysfunction. Female Wistar rat mothers ate a control (C) or obesogenic (MO) diet from the time they were weaned through breeding at postnatal day (PND) 120, delivery and lactation. After…

Caesarean section and instrumental delivery rates are increasing in many parts of the world for a range of cultural and medical reasons, with limited consideration as to how 'mode of delivery' may impact on childhood and long-term health. However, babies born particularly by pre-labour caesarean section appear to have a subtly different physiology from those born by normal vaginal delivery, with both acute and chronic complications such as respiratory and cardio-metabolic morbidities being apparent. It has been hypothesized that inherent mechanisms within the process of labour and vaginal delivery, far from being a passive mechanical process by which the fetus and placenta are expelled from the birth canal, may trigger certain protective developmental processes permissive for normal immunological and physiological development of the fetus postnatally. Traditionally the primary candidate mechanism has been the hormonal surges or stress response associated with labour and vaginal delivery, but there is increasing awareness that transfer of the maternal microbiome to the infant during…

In 1993, Dringen et al. concluded that 'glycogen in astrocytes can be considered as a store for lactate rather than for glucose', and suggested that lactate derived from the breakdown of glycogen in astrocytes may serve the energetic needs of neighbouring cells. The following year, Pellerin and Magistretti (1994) published their now famed astrocyte-to-neuron lactate shuttle hypothesis in which the transfer of lactate from astrocytes to neurons, in this case derived from extracellular glucose rather than glycogen, is coupled to uptake of neurotransmitter glutamate (i.e. neuronal activity). According to this hypothesis, glycolysis and lactate production are astrocytic phenomena while oxidative metabolism of lactate takes place in neurons. The astrocyte-to-neuron lactate shuttle hypothesis as proposed by Pellerin and Magistretti (1994) has gained widespread acceptance, and its popularity is not surprising due to its conceptually simple and compelling idea of an activity-based coupling between neuronal synaptic activity and astrocyte metabolism. We will argue that the biochemical and…

Key Points This study investigated the influence of group III/IV muscle afferents on corticospinal excitability during cycling exercise and focused on GABAB neuron‐mediated inhibition as a potential underlying mechanism. The study provides novel evidence to demonstrate that group III/IV muscle afferent feedback facilitates inhibitory intracortical neurons during whole body exercise. Firing of these interneurons probably contributes to the development of central fatigue during physical activity. Abstract We investigated the influence of group III/IV muscle afferents in determining corticospinal excitability during cycling exercise and focused on GABAB neuron‐mediated inhibition as a potential underlying mechanism. Both under control conditions (CTRL) and with lumbar intrathecal fentanyl (FENT) impairing feedback from group III/IV leg muscle afferents, subjects (n = 11) cycled at a comparable vastus‐lateralis EMG signal (∼0.26 mV) before (PRE; 100 W) and immediately after (POST; 90 ± 2 W) fatiguing constant‐load cycling exercise (80% Wpeak; 221 ± 10 W; ∼8 min). During, PRE and POST…

KEY POINTS: An ex vivo preparation was developed to record from single sensory fibres innervating the glabrous skin of the mouse forepaw. The density of mechanoreceptor innervation of the forepaw glabrous skin was found to be three times higher than that of hindpaw glabrous skin. Rapidly adapting mechanoreceptors that innervate Meissner's corpuscles were severalfold more responsive to slowly moving stimuli in the forepaw compared to those innervating hindpaw skin. We found a distinct group of small hairs in the centre of the mouse hindpaw glabrous skin that were exclusively innervated by directionally sensitive D-hair receptors. The directional sensitivity, but not the end-organ anatomy, were the opposite to D-hair receptors in the hairy skin. Glabrous skin hairs in the hindpaw are not ubiquitous in rodents, but occur in African and North American species that diverged more than 65 million years ago. ABSTRACT: Rodents use their forepaws to actively interact with their tactile environment. Studies on the physiology and anatomy of glabrous skin that makes up the majority of the…

KEY POINTS: The central nucleus of the amygdala (CeA) encompasses the main output pathways of the amygdala, a temporal lobe structure essential in affective and cognitive dimensions of pain. A major population of neurons in the CeA send projections to the periaqueductal gray (PAG), a key midbrain structure that mediates coping strategies in response to threat or stress. CeA-PAG neurons are topographically organized based on their targeted subregion within the PAG. PAG-projecting neurons in the central medial (CeM) and central lateral (CeL) regions of CeA are intrinsically distinct. CeL-PAG neurons are a homogeneous population of intrinsically distinct neurons while CeM-PAG neurons are intrinsically heterogeneous. Membrane properties of distinct CeM-PAG subtypes are altered in the complete Freund's adjuvant model of inflammatory pain. ABSTRACT: A major population of neurons in the central nucleus of amygdala (CeA) send projections to the periaqueductal gray (PAG), a key midbrain structure that mediates coping strategies in response to threat or stress. While the CeA-PAG pathway has…

Key points The fluctuations in force during a steady isometric contraction (force steadiness) are associated with oscillations in common synaptic input to the involved motor neurons. Decreases in force steadiness are associated with increases in pegboard times in older adults, although a mechanism for this link has not been established. We used a state‐space model to estimate the variability in common synaptic input to motor neurons during steady, isometric contractions. The estimate of common synaptic input was derived from the discharge times of motor units as recorded with high‐density surface electrodes. We found that the variability in common synaptic input to motor neurons modulates force steadiness for young and older adults, as well as pegboard time for older adults. Abstract We investigated the associations between grooved pegboard times, force steadiness (coefficient of variation for force) and variability in an estimate of the common synaptic input to motor neurons innervating the wrist extensor muscles during steady contractions performed by young and older adults. The…

Key points Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells are required to eliminate cancer cells. We analysed the Ca 2+ dependence of CTL and NK cell cytotoxicity and found that in particular CTLs have a very low optimum of [Ca 2+ ] i (between 122 and 334 n m ) and [Ca 2+ ] o (between 23 and 625 μ m ) for efficient cancer cell elimination, well below blood plasma Ca 2+ levels. As predicted from these results, partial down‐regulation of the Ca 2+ channel Orai1 in CTLs paradoxically increases perforin‐dependent cancer cell killing. Lytic granule release at the immune synapse between CTLs and cancer cells has a Ca 2+ optimum compatible with this low Ca 2+ optimum for efficient cancer cell killing, whereas the Ca 2+ optimum for CTL migration is slightly higher and proliferation increases monotonously with increasing [Ca 2+ ] o . We propose that a partial inhibition of Ca 2+ signals by specific Orai1 blockers at submaximal concentrations could contribute to tumour elimination. Abstract Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells are required to protect the…

Key points The blood–brain barrier (BBB) is an important and dynamic structure which contributes to homeostasis in the central nervous system. BBB permeability changes occur in health and disease but measurement of BBB permeability in humans is not straightforward. Dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) can be used to model the movement of gadolinium contrast into the brain, expressed as the influx constant K i . Here evidence is provided that K i as measured by DCE‐MRI behaves as expected for a marker of overall BBB leakage. These results support the use of DCE‐MRI for in vivo studies of human BBB permeability in health and disease. Abstract Blood–brain barrier (BBB) leakage can be measured using dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) as the influx constant K i . To validate this method we compared measured K i with biological expectations, namely (1) higher K i in healthy individual grey matter (GM) versus white matter (WM), (2) GM/WM cerebral blood volume (CBV) ratio close to the histologically established GM/WM vascular density…

The fetus is consistently exposed to repeated periods of impaired oxygen (hypoxaemia) and nutrient supply in labour. This is balanced by the healthy fetus's remarkable anaerobic tolerance and impressive ability to mount protective adaptations to hypoxaemia. The most important mediator of fetal adaptations to brief repeated hypoxaemia is the peripheral chemoreflex, a rapid reflex response to acute falls in arterial oxygen tension. The overwhelming majority of fetuses are able to respond to repeated uterine contractions without developing hypotension or hypoxic-ischaemic injury. In contrast, fetuses who are either exposed to severe hypoxaemia, for example during uterine hyperstimulation, or enter labour with reduced anaerobic reserve (e.g. as shown by severe fetal growth restriction) are at increased risk of developing intermittent hypotension and cerebral hypoperfusion. It is remarkable to note that when fetuses develop hypotension during such repeated severe hypoxaemia, it is not mediated by impaired reflex adaptation, but by failure to maintain combined ventricular output, likely…

KEY POINTS: Wild-type mice and mice with hepatocyte-specific or whole-body deletions of perilipin-2 (Plin2) were used to define hepatocyte and extra-hepatocyte effects of altered cellular lipid storage on obesity and non-alcoholic fatty liver disease (NAFLD) pathophysiology in a Western-diet (WD) model of these disorders. Extra-hepatocyte actions of Plin2 are responsible for obesity, adipose inflammation and glucose clearance abnormalities in WD-fed mice. Hepatocyte and extra-hepatic actions of Plin2 mediate fatty liver formation in WD-fed mice through distinct mechanisms. Hepatocyte-specific actions of Plin2 are primary mediators of immune cell infiltration and fibrotic injury in livers of obese mice. ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) is an obesity- and insulin resistance-related metabolic disorder with progressive pathology. Perilipin-2 (Plin2), a ubiquitously expressed cytoplasmic lipid droplet scaffolding protein, is hypothesized to contribute to NAFLD in humans and rodent models through effects on cellular lipid metabolism. In this study, we delineate…

Abstract Hypoxia‐inducible factors mediate adaptive responses to reduced O2 availability. In patients with obstructive sleep apnoea, repeated episodes of hypoxaemia and reoxygenation (intermittent hypoxia) are sensed by the carotid body (CB). The ensuing CB chemosensory reflex activates the sympathetic nervous system and increased secretion of catecholamines by the adrenal medulla, resulting in hypertension and breathing abnormalities. In the CB, intermittent hypoxia induces the formation of reactive oxygen species (ROS) and increased intracellular Ca2+ levels, which drive increased expression of hypoxia‐inducible factor (HIF) 1α and a decrease in the levels of HIF‐2α. Intermittent hypoxia increases HIF‐1α‐dependent expression of Nox2, encoding the pro‐oxidant enzyme NADPH oxidase 2, and decreased HIF‐2α‐dependent expression of Sod2, encoding the anti‐oxidant enzyme superoxide dismutase 2. These changes in gene expression drive persistently elevated ROS levels in the CB, brainstem, and adrenal medulla that are required for the development of hypertension and breathing abnormalities.…

Abstract Mammalian ether‐à‐go‐go (EAG) channels are voltage‐gated K + channels. They are encoded by the KCNH gene family and divided into three subfamilies, eag (Kv10), erg (eag‐related gene; Kv11) and elk (eag‐like; Kv12). All EAG channel subtypes are expressed in the brain where they effectively modulate neuronal excitability. This Topical Review describes the biophysical properties of each of the EAG channel subtypes, their function in neurons and the neurological diseases induced by EAG channel mutations. In contrast to the function of erg currents in the heart, where they contribute to repolarization of the cardiac action potential, erg currents in neurons are involved in the maintenance of the resting potential, setting of action potential threshold and frequency accommodation. They can even support high frequency firing by preventing a depolarization‐induced Na + channel block. EAG channels are modulated differentially, e.g. eag channels by intracellular Ca 2+ , erg channels by extracellular K + and GPCRs, and elk channels by changes in pH. So far, only currents mediated by…

The pulmonary epithelial and vascular endothelial cell layers provide two sequential physical and immunological barriers that together form a semi-permeable interface and prevent alveolar and interstitial oedema formation. In this review, we focus specifically on the continuous endothelium of the pulmonary microvascular bed that warrants strict control of the exchange of gases, fluid, solutes and circulating cells between the plasma and the interstitial space. The present review provides an overview of emerging molecular mechanisms that permit constant transcellular exchange between the vascular and interstitial compartment, and cause, prevent or reverse lung endothelial barrier failure under experimental conditions, yet with a clinical perspective. Based on recent findings and at times seemingly conflicting results we discuss emerging paradigms of permeability regulation by altered ion transport as well as shifts in the homeostasis of sphingolipids, angiopoietins and prostaglandins.

Key points In rodents, including mice, the superior colliculus is the major target of the retina, but its visual response is not well characterized. In the present study, extracellular recordings from single nerve cells in the superficial layers of the superior colliculus were made in awake, head‐restrained mice, and their responses to visual stimuli were measured. It was found that these neurons show brisk, highly sensitive and short latency visual responses, a preference for black over white stimuli, and diverse responses to moving patterns. At least five broad classes can be defined by variation in functional properties among units. The results of the present study demonstrate that eye movements have a measurable impact on visual responses in awake animals and show how they may be mitigated in analyses. Abstract The mouse is an increasingly important animal model of visual function in health and disease. In mice, most retinal signals are routed through the superficial layers of the midbrain superior colliculus, and it is well established that much of the visual behaviour of mice…

KEY POINTS: This is the first study to demonstrate an altered circadian phase shifting response in a circadian rhythm sleep disorder. Patients with delayed sleep-wake phase disorder (DSWPD) demonstrate greater sensitivity of the circadian system to the phase-delaying effects of light. Increased circadian sensitivity to light is associated with later circadian timing within both control and DSWPD groups. DSWPD patients had a greater sustained pupil response after light exposure. Treatments for DSWPD should consider sensitivity of the circadian system to light as a potential underlying vulnerability, making patients susceptible to relapse. ABSTRACT: Patients with delayed sleep-wake phase disorder (DSWPD) exhibit delayed sleep-wake behaviour relative to desired bedtime, often leading to chronic sleep restriction and daytime dysfunction. The majority of DSWPD patients also display delayed circadian timing in the melatonin rhythm. Hypersensitivity of the circadian system to phase-delaying light is a plausible physiological basis for DSWPD vulnerability. We compared the phase shifting…

Abstract Rising atmospheric oxygen (O 2 ) levels provided a selective pressure for the evolution of O 2 ‐dependent micro‐organisms that began with the autotrophic eukaryotes. Since these primordial times, the respiring mammalian cell has become entirely dependent on the constancy of electron flow, with molecular O 2 serving as the terminal electron acceptor in mitochondrial oxidative phosphorylation. Indeed, the ability to ‘sense’ O 2 and maintain homeostasis is considered one of the most important roles of the central nervous system (CNS) and probably represented a major driving force in the evolution of the human brain. Today, modern humans have evolved with an oversized brain committed to a continually active state and, as a consequence, paradoxically vulnerable to failure if the O 2 supply is interrupted. However, our pre‐occupation with O 2 , the elixir of life, obscures the fact that it is a gas with a Janus face, capable of sustaining life in physiologically controlled amounts yet paradoxically deadly to the CNS when in excess. A closer look at its quantum structure reveals…

Disrupted in schizophrenia 1 (DISC1) is an important hub protein, forming multimeric complexes by self-association and interacting with a large number of synaptic and cytoskeletal molecules. The synaptic location of DISC1 in the adult brain suggests a role in synaptic plasticity, and indeed, a number of studies have discovered synaptic plasticity impairments in a variety of different DISC1 mutants. This review explores the possibility that DISC1 is an important molecule for organizing proteins involved in synaptic plasticity and examines why mutations in DISC1 impair plasticity. It concentrates on DISC1's role in interacting with synaptic proteins, controlling dendritic structure and cellular trafficking of mRNA, synaptic vesicles and mitochondria. N-terminal directed mutations appear to impair synaptic plasticity through interactions with phosphodiesterase 4B (PDE4B) and hence protein kinase A (PKA)/GluA1 and PKA/cAMP response element-binding protein (CREB) signalling pathways, and affect spine structure through interactions with kalirin 7 (Kal-7) and Rac1. C-terminal directed…