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Congratulations are in order for Dr Lukas Krone who is one of just five University of Oxford researchers selected to attend the Global Young Scientists Summit 2021.
Iron bioavailability and cardiopulmonary function during ascent to very high altitude.
Intravenous iron supplementation at sea level is associated with enhanced stroke volume and higher SpO2 on ascent to very high altitude (5100 m). These effects appear to result from reduced pulmonary vascular resistance and improved right heart function. https://bit.ly/2VQX5fR
Metabolic cost of external work: a novel CPET parameter optimises characterisation of exercise performance in obese individuals.
PURPOSE: Both obesity and cardiorespiratory fitness are crucial determinants of symptoms and prognosis. However, interpreting the gold-standard cardiopulmonary exercise test (CPET) is complicated by increasing body size and varying body composition. We hypothesised that the 'metabolic cost of external work' (or oxygen uptake (ml/min)/workload (Watts); V̇O2/W), a body weight-independent determinant of endurance capacity, would reflect metabolic health more accurately than V̇O2 alone. METHODS: A test cohort of 160 fit individuals underwent anthropomorphic and metabolic assessment, maximal bicycle ergometer CPET, and six-minute walk test (6MWT). V̇O2/W was calculated at VT1 and peak. The performance of V̇O2/W was validated in 62 older, less fit individuals, undergoing the same protocol. 24 obese volunteers were assigned a weight loss intervention, and the impact on V̇O2/W examined. RESULTS: In both test and validation cohort, V̇O2/W at VT1 and peak correlated with 6MWT distance, more strongly than standard CPET parameters. Including V̇O2/W improved the accuracy of predicting 6MWT distance. V̇O2/W correlated with BMI, insulin sensitivity and waist-to-hip ratio. Metabolic cost falls with weight loss, in parallel to metabolic and functional improvements, in contrast to other CPET parameters. CONCLUSION: Metabolic cost is strongly associated with functional capacity and metabolic health across a range of body weight and fitness, outperforming standard CPET metrics. It is a simple measure which may improve our assessment of the extent to which exertional symptoms are determined by metabolic factors in an individual, and thereby target the most appropriate intervention to those who will benefit most.
Cardiopulmonary exercise testing excludes significant disease in patients recovering from COVID-19.
OBJECTIVE: Post-COVID-19 syndrome presents a health and economic challenge affecting ~10% of patients recovering from COVID-19. Accurate assessment of patients with post-COVID-19 syndrome is complicated by health anxiety and coincident symptomatic autonomic dysfunction. We sought to determine whether either symptoms or objective cardiopulmonary exercise testing could predict clinically significant findings. METHODS: 113 consecutive military patients were assessed in a comprehensive clinical pathway. This included symptom reporting, history, examination, spirometry, echocardiography and cardiopulmonary exercise testing (CPET) in all, with chest CT, dual-energy CT pulmonary angiography and cardiac MRI where indicated. Symptoms, CPET findings and presence/absence of significant pathology were reviewed. Data were analysed to identify diagnostic strategies that may be used to exclude significant disease. RESULTS: 7/113 (6%) patients had clinically significant disease adjudicated by cardiothoracic multidisciplinary team (MDT). These patients had reduced fitness (V̇O2 26.7 (±5.1) vs 34.6 (±7.0) mL/kg/min; p=0.002) and functional capacity (peak power 200 (±36) vs 247 (±55) W; p=0.026) compared with those without significant disease. Simple CPET criteria (oxygen uptake (V̇O2) >100% predicted and minute ventilation (VE)/carbon dioxide elimination (V̇CO2) slope <30.0 or VE/V̇CO2 slope <35.0 in isolation) excluded significant disease with sensitivity and specificity of 86% and 83%, respectively (area under the receiver operating characteristic curve (AUC) 0.89). The addition of capillary blood gases to estimate alveolar-arterial gradient improved diagnostic performance to 100% sensitivity and 78% specificity (AUC 0.92). Symptoms and spirometry did not discriminate significant disease. CONCLUSIONS: In a population recovering from SARS-CoV-2, there is reassuringly little organ pathology. CPET and functional capacity testing, but not reported symptoms, permit the exclusion of clinically significant disease.
Defence Medical Rehabilitation Centre (DMRC) COVID-19 Recovery Service.
Coronavirus disease 2019 (COVID-19) causes significant mortality and morbidity, with an unknown impact in the medium to long term. Evidence from previous coronavirus epidemics indicates that there is likely to be a substantial burden of disease, potentially even in those with a mild acute illness. The clinical and occupational effects of COVID-19 are likely to impact on the operational effectiveness of the Armed Forces. Collaboration between Defence Primary Healthcare, Defence Secondary Healthcare, Defence Rehabilitation and Defence Occupational Medicine resulted in the Defence Medical Rehabilitation Centre COVID-19 Recovery Service (DCRS). This integrated clinical and occupational pathway uses cardiopulmonary assessment as a cornerstone to identify, diagnose and manage post-COVID-19 pathology.
Incubation of cocaine craving coincides with changes in dopamine terminal neurotransmission.
Relapse to drug use is one of the major challenges in treating substance use disorders. Exposure to drug-related cues and contexts triggers drug craving, which drives cocaine seeking, and increases the probability of relapse. Clinical and animal studies have shown a progressive intensification of cocaine seeking and craving that develops over the course of abstinence, a phenomenon commonly referred to as incubation of cocaine craving. Although the neurobiology underlying incubation of cocaine craving has been examined - particularly within the context of glutamate plasticity- the extent to which increased cocaine craving engenders mesolimbic dopamine (DA) changes has received relatively little attention. To assess whether incubation of cocaine craving is associated with alterations in DA terminal neurotransmission in the nucleus accumbens core (NAc), we used ex vivo fast scan cyclic voltammetry in female and male rats to assess DA dynamics following short access, long access, or intermittent access to cocaine self-administration followed by 28 days of abstinence. Results indicated that both long access and intermittent access to cocaine produced robust incubation of cocaine craving, which was associated with increases in cocaine potency. In addition, intermittent access self-administration also produced a robust increase in DA uptake rate at baseline. In contrast, short access to cocaine did not engender incubation of cocaine craving, nor produce changes in DA neurotransmission. Together these observations indicate that incubation of cocaine craving coincides with changes in DA transmission, suggesting that underlying changes in mesolimbic DA signaling may contribute to the progressive intensification of drug craving that occurs across periods of abstinence.
Individual differences in dopamine uptake in the dorsomedial striatum prior to cocaine exposure predict motivation for cocaine in male rats.
A major theme of addiction research has focused on the neural substrates of individual differences in the risk for addiction; however, little is known about how vulnerable populations differ from those that are relatively protected. Here, we prospectively measured dopamine (DA) neurotransmission prior to cocaine exposure to predict the onset and course of cocaine use. Using in vivo voltammetry, we first generated baseline profiles of DA release and uptake in the dorsomedial striatum (DMS) and nucleus accumbens of drug-naïve male rats prior to exposing them to cocaine using conditioned place preference (CPP) or operant self-administration. We found that the innate rate of DA uptake in the DMS strongly predicted motivation for cocaine and drug-primed reinstatement, but not CPP, responding when "price" was low, or extinction. We then assessed the impact of baseline variations in DA uptake on cocaine potency in the DMS using ex vivo voltammetry in naïve rats and in rats with DA transporter (DAT) knockdown. DA uptake in the DMS of naïve rats predicted the neurochemical response to cocaine, such that rats with innately faster rates of DA uptake demonstrated higher cocaine potency at the DAT and rats with DAT knockdown displayed reduced potency compared to controls. Together, these data demonstrate that inherent variability in DA uptake in the DMS predicts the behavioral response to cocaine, potentially by altering the apparent potency of cocaine.
Screening for drugs to reduce zebrafish aggression identifies caffeine and sildenafil.
Although aggression is a common symptom of psychiatric disorders the drugs available to treat it are non-specific and can have unwanted side effects. In this study we have used a behavioural platform in a phenotypic screen to identify drugs that can reduce zebrafish aggression without affecting locomotion. In a three tier screen of ninety-four drugs we discovered that caffeine and sildenafil can selectively reduce aggression. Caffeine also decreased attention and increased impulsivity in the 5-choice serial reaction time task whereas sildenafil showed the opposite effect. Imaging studies revealed that both caffeine and sildenafil are active in the zebrafish brain, with prominent activation of the thalamus and cerebellum evident. They also interact with 5-HT neurotransmitter signalling. In summary, we have demonstrated that juvenile zebrafish are a suitable model to screen for novel drugs to reduce aggression, with the potential to uncover the neural circuits and signalling pathways that mediate such behavioural effects.
Inhibition of striatal dopamine release by the L-type calcium channel inhibitor isradipine co-varies with risk factors for Parkinson's.
Ca2+ entry into nigrostriatal dopamine (DA) neurons and axons via L-type voltage-gated Ca2+ channels (LTCCs) contributes, respectively, to pacemaker activity and DA release and has long been thought to contribute to vulnerability to degeneration in Parkinson's disease. LTCC function is greater in DA axons and neurons from substantia nigra pars compacta than from ventral tegmental area, but this is not explained by channel expression level. We tested the hypothesis that LTCC control of DA release is governed rather by local mechanisms, focussing on candidate biological factors known to operate differently between types of DA neurons and/or be associated with their differing vulnerability to parkinsonism, including biological sex, α-synuclein, DA transporters (DATs) and calbindin-D28k (Calb1). We detected evoked DA release ex vivo in mouse striatal slices using fast-scan cyclic voltammetry and assessed LTCC support of DA release by detecting the inhibition of DA release by the LTCC inhibitors isradipine or CP8. Using genetic knockouts or pharmacological manipulations, we identified that striatal LTCC support of DA release depended on multiple intersecting factors, in a regionally and sexually divergent manner. LTCC function was promoted by factors associated with Parkinsonian risk, including male sex, α-synuclein, DAT and a dorsolateral co-ordinate, but limited by factors associated with protection, that is, female sex, glucocerebrosidase activity, Calb1 and ventromedial co-ordinate. Together, these data show that LTCC function in DA axons and isradipine effect are locally governed and suggest they vary in a manner that in turn might impact on, or reflect, the cellular stress that leads to parkinsonian degeneration.
NEAT1-mediated regulation of proteostasis and mRNA localization impacts autophagy dysregulation in Rett syndrome
Abstract Rett syndrome (RTT) is a severe neurodevelopmental disorder primarily caused by loss-of-function mutations in the MECP2 gene, resulting in diverse cellular dysfunctions. Here, we investigated the role of the long noncoding RNA (lncRNA) NEAT1 in the context of MeCP2 deficiency using human neural cells and RTT patient samples. Through single-cell RNA sequencing and molecular analyses, we found that NEAT1 is markedly downregulated in MECP2 knockout (KO) cells at various stages of neural differentiation. NEAT1 downregulation correlated with aberrant activation of the mTOR pathway, abnormal protein metabolism, and dysregulated autophagy, contributing to the accumulation of protein aggregates and impaired mitochondrial function. Reactivation of NEAT1 in MECP2-KO cells rescued these phenotypes, indicating its critical role downstream of MECP2. Furthermore, direct RNA–RNA interaction was revealed as the key process for NEAT1 influence on autophagy genes, leading to altered subcellular localization of specific autophagy-related messenger RNAs and impaired biogenesis of autophagic complexes. Importantly, NEAT1 restoration rescued the morphological defects observed in MECP2-KO neurons, highlighting its crucial role in neuronal maturation. Overall, our findings elucidate lncRNA NEAT1 as a key mediator of MeCP2 function, regulating essential pathways involved in protein metabolism, autophagy, and neuronal morphology.
Dopaminergic systems create reward seeking despite adverse consequences.
Resource-seeking behaviours are ordinarily constrained by physiological needs and threats of danger, and the loss of these controls is associated with pathological reward seeking1. Although dysfunction of the dopaminergic valuation system of the brain is known to contribute towards unconstrained reward seeking2,3, the underlying reasons for this behaviour are unclear. Here we describe dopaminergic neural mechanisms that produce reward seeking despite adverse consequences in Drosophila melanogaster. Odours paired with optogenetic activation of a defined subset of reward-encoding dopaminergic neurons become cues that starved flies seek while neglecting food and enduring electric shock punishment. Unconstrained seeking of reward is not observed after learning with sugar or synthetic engagement of other dopaminergic neuron populations. Antagonism between reward-encoding and punishment-encoding dopaminergic neurons accounts for the perseverance of reward seeking despite punishment, whereas synthetic engagement of the reward-encoding dopaminergic neurons also impairs the ordinary need-dependent dopaminergic valuation of available food. Connectome analyses reveal that the population of reward-encoding dopaminergic neurons receives highly heterogeneous input, consistent with parallel representation of diverse rewards, and recordings demonstrate state-specific gating and satiety-related signals. We propose that a similar dopaminergic valuation system dysfunction is likely to contribute to maladaptive seeking of rewards by mammals.
Compensatory enhancement of input maintains aversive dopaminergic reinforcement in hungry Drosophila.
Hungry animals need compensatory mechanisms to maintain flexible brain function, while modulation reconfigures circuits to prioritize resource seeking. In Drosophila, hunger inhibits aversively reinforcing dopaminergic neurons (DANs) to permit the expression of food-seeking memories. Multitasking the reinforcement system for motivation potentially undermines aversive learning. We find that chronic hunger mildly enhances aversive learning and that satiated-baseline and hunger-enhanced learning require endocrine adipokinetic hormone (AKH) signaling. Circulating AKH influences aversive learning via its receptor in four neurons in the ventral brain, two of which are octopaminergic. Connectomics revealed AKH receptor-expressing neurons to be upstream of several classes of ascending neurons, many of which are presynaptic to aversively reinforcing DANs. Octopaminergic modulation of and output from at least one of these ascending pathways is required for shock- and bitter-taste-reinforced aversive learning. We propose that coordinated enhancement of input compensates for hunger-directed inhibition of aversive DANs to preserve reinforcement when required.
New insights into axonal regulators of dopamine transmission in health and disease.
Dopamine release in the striatum is credited with being critical to the selection and learning of motivated actions and outcomes. Dysregulation of striatal dopamine release underlies multiple disorders of action selection and reward-processing, such as Parkinson's disease, schizophrenia and addiction disorders, and is a major target for therapeutic interventions. The axonal molecular and circuit mechanisms governing dopamine exocytosis are incompletely resolved, but accumulating evidence suggests some key points of divergence from canonical neurotransmitter synapses. In this review, we bring together recent insights into mechanisms shaping dopamine transmission in the striatum, spanning the molecular machinery regulating exocytosis, striatal modulators locally governing release probability, and the mechanisms regulating dopamine vesicle endocytosis. Together, these findings continue to support points of divergence from canonical presynaptic mechanisms, they inform principles of axonal neuromodulation, and point to potential contributions to the susceptibility to neurodegeneration in Parkinson's disease.