Search

Long COVID, die lang anhaltende Krankheit und Erschöpfung, die bei einem kleinen Teil der SARS-CoV-2-Infizierten auftritt, stellt eine zunehmende Belastung für die Betroffenen und die Gesellschaft dar. Eine virtuelle Tagung der Physiological Society im Februar 2022 brachte Kliniker und Forscher zusammen, um das aktuelle Verständnis der Mechanismen, Risikofaktoren und Genesung nach Long COVID zu erörtern. In dieser Übersichtsarbeit werden die Themen behandelt, die sich aus dieser Tagung ergeben haben. Die Übersichtsarbeit befasst sich mit der Natur von Long COVID, untersucht den Zusammenhang mit anderen postviralen Erkrankungen wie der myalgischen Enzephalomyelitis/dem chronischen Erschöpfungssyndrom und zeigt auf, wie die Forschung zu Long COVID helfen kann, Patienten mit allen möglichen postviralen Syndromen besser zu unterstützen. Die Forschung zu Long COVID hat besonders rasche Fortschritte bei Bevölkerungsgruppen gemacht, die ihre körperliche Leistungsfähigkeit routinemäßig überwachen, insbesondere beim Militär und bei Leistungssportlern. In der Übersichtsarbeit wird hervorgehoben, inwiefern das hohe Niveau von Diagnose, Intervention und Erfolgskontrolle in diesen aktiven Bevölkerungsgruppen Informationen über Managementstrategien für die Allgemeinbevölkerung liefern kann. Anschließend wird untersucht, wie eine Schlüsselkomponente der Leistungsüberwachung bei diesen aktiven Bevölkerungsgruppen, das kardiopulmonale Training, Long-COVID-bedingte Veränderungen in der Physiologie aufdeckt – einschließlich Veränderungen der peripheren Muskelfunktion, der ventilatorischen Ineffizienz und der autonomen Dysfunktion. Das Wesen und die Auswirkungen der Dysautonomie werden im Zusammenhang mit dem posturalen orthostatischen Tachykardiesyndrom, der Fatigue und den Behandlungsstrategien, die darauf abzielen, der Überaktivierung des Sympathikus durch Stimulation des Vagusnervs entgegenzuwirken, erörtert. Anschließend untersuchen wir die Mechanismen, die den Symptomen von Long COVID zugrunde liegen. Dabei konzentrieren wir uns auf die gestörte Sauerstoffversorgung durch Mikrokoagulation und die Störung des zellulären Energiestoffwechsels, bevor wir Behandlungsstrategien betrachten, die direkt oder indirekt auf diese Mechanismen abzielen. Dazu gehören ein fernbetreutes Atemmuskeltraining und integrierte Versorgungspfade, die Rehabilitation und medikamentöse Interventionen mit der Erforschung des Zugangs zur Long-COVID-Versorgung in verschiedenen Bevölkerungsgruppen kombinieren. Insgesamt zeigt diese Übersichtsarbeit, wie im Rahmen der physiologischen Forschung die bei Long COVID auftretenden Veränderungen aufgedeckt werden und wie verschiedene therapeutische Strategien zur Bekämpfung dieser Erkrankung entwickelt und getestet werden.

Animals must quickly adapt food-seeking strategies to locate nutrient sources in dy-namically changing environments. Learned associations between food and environ-mental cues that predict its availability promote food-seeking behaviors. However,when such cues cease to predict food availability, animals undergo “extinction” learn-ing, resulting in the inhibition of food-seeking responses. Repeatedly activated setsof neurons, or “neuronal ensembles,” in the dorsal medial prefrontal cortex (dmPFC)are recruited following appetitive conditioning and undergo physiological adapta-tions thought to encode cue-reward associations. However, little is known about howthe recruitment and intrinsic excitability of such dmPFC ensembles are modulated byextinction learning. Here, we used in vivo 2-Photon imaging in male Fos-GFP micethat express green fluorescent protein (GFP) in recently behaviorally activated neu-rons to determine the recruitment of activated pyramidal and GABAergic interneu-ron dmPFC ensembles during extinction. During extinction, we revealed a persistentactivation of a subset of interneurons which emerged from a wider population of in-terneurons activated during the initial extinction session. This activation pattern wasnot observed in pyramidal cells, and extinction learning did not modulate the excit-ability properties of activated pyramidal cells. Moreover, extinction learning reducedthe likelihood of reactivation of pyramidal cells activated during the initial extinction ession. Our findings illuminate novel neuronal activation patterns in the dmPFCunderlying extinction of food-seeking, and in particular, highlight an important rolefor interneuron ensembles in this inhibitory form of learning.

Following the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in PR China in late 2019 a number of variants have emerged, with two of these – alpha and delta – subsequently growing to global prevalence. One characteristic of these variants are changes within the spike protein, in particular the receptor-binding domain (RBD). From a public health perspective, these changes have important implications for increased transmissibility and immune escape; however, their presence could also modify the intrinsic host range of the virus. Using viral pseudotyping, we examined whether the variants of concern (VOCs) alpha, beta, gamma and delta have differing host angiotensin-converting enzyme 2 (ACE2) receptor usage patterns, focusing on a range of relevant mammalian ACE2 proteins. All four VOCs were able to overcome a previous restriction for mouse ACE2, with demonstrable differences also seen for individual VOCs with rat, ferret or civet ACE2 receptors, changes that we subsequently attributed to N501Y and E484K substitutions within the spike RBD.

Following the emergence of SARS-CoV-2 in China in late 2019 a number of variants have emerged, with two of these – Alpha and Delta – subsequently growing to global prevalence. One characteristic of these variants are changes within the Spike protein, in particular the receptor binding domain (RBD). From a public health perspective these changes have important implications for increased transmissibility and immune escape; however, their presence could also modify the intrinsic host-range of the virus. Using viral pseudotyping we examined whether the variants of concern (VOCs) Alpha, Beta, Gamma and Delta have differing host ACE2 receptor usage patterns, focusing on a range of relevant mammalian ACE2 proteins. All four VOCs were able to overcome a previous restriction for mouse ACE2, with demonstrable differences also seen for individual VOCs with rat, ferret or civet ACE2 receptors, changes which we subsequently attribute to N501Y and E484K substitutions within the Spike RBD.

Animals selectively respond to environmental cues associated with food reward to optimize nutrient intake. Such appetitive conditioned stimulus–unconditioned stimulus (CS-US) associations are thought to be encoded in select, stable neuronal populations or neuronal ensembles, which undergo physiological modifications during appetitive conditioning. These ensembles in the medial prefrontal cortex (mPFC) control well-established, cue-evoked food seeking, but the mechanisms involved in the genesis of these ensembles are unclear. Here, we used maleFos-GFPmice that express green fluorescent protein (GFP) in recently behaviorally activated neurons, to reveal how dorsal mPFC neurons are recruited and modified to encode CS-US memory representations using an appetitive conditioning task. In the initial conditioning session, animals did not exhibit discriminated, cue-selective food seeking, but did so in later sessions indicating that a CS-US association was established. Using microprism-basedin vivo2-Photon imaging, we revealed that only a minority of neurons activated during the initial session was consistently activated throughout subsequent conditioning sessions and during cue-evoked memory recall. Notably, usingex vivoelectrophysiology, we found that neurons activated following the initial session exhibited transient hyperexcitability. Chemogenetically enhancing the excitability of these neurons throughout subsequent conditioning sessions interfered with the development of reliable cue-selective food seeking, indicated by persistent, nondiscriminated performance. We demonstrate how appetitive learning consistently activates a subset of neurons to form a stable neuronal ensemble during the formation of a CS-US association. This ensemble may arise from a pool of hyperexcitable neurons activated during the initial conditioning session.SIGNIFICANCE STATEMENTAppetitive conditioning endows cues associated with food with the ability to guide food-seeking, through the formation of a food-cue association. Neuronal ensembles in the mPFC control established cue-evoked food-seeking. However, how neurons undergo physiological modifications and become part of an ensemble during conditioning remain unclear. We found that only a minority of dorsal mPFC neurons activated on the initial conditioning session became consistently activated during conditioning and memory recall. These initially activated neurons were also transiently hyperexcitable. We demonstrate the following: (1) how stable neuronal ensemble formation in the dorsal mPFC underlies appetitive conditioning; and (2) how this ensemble may arise from hyperexcitable neurons activated before the establishment of cue-evoked food seeking.

The hippocampus is essential for spatial and episodic memory but is damaged early in Alzheimer's disease and is very sensitive to hypoxia. Understanding how it regulates its oxygen supply is therefore key for designing interventions to preserve its function. However, studies of neurovascular function in the hippocampus in vivo have been limited by its relative inaccessibility. Here we compared hippocampal and visual cortical neurovascular function in awake mice, using two photon imaging of individual neurons and vessels and measures of regional blood flow and haemoglobin oxygenation. We show that blood flow, blood oxygenation and neurovascular coupling were decreased in the hippocampus compared to neocortex, because of differences in both the vascular network and pericyte and endothelial cell function. Modelling oxygen diffusion indicates that these features of the hippocampal vasculature may restrict oxygen availability and could explain its sensitivity to damage during neurological conditions, including Alzheimer's disease, where the brain's energy supply is decreased.

Vascular dysfunction is an early feature of late onset Alzheimer’s disease (AD), preceding classic AD pathology such as beta amyloid accumulation and formation of hyperphosphorylated tau. Such vascular dysfunction may promote classic AD pathology by decreasing blood flow, impairing brain oxygenation and clearance of molecules such as beta amyloid. The main genetic risk factor for AD is the e4 allele of APOE, which has been found to increase blood brain barrier permeability and decrease vascular density, as well as decrease blood flow and functional hyperaemia in anaesthetised mice undergoing acute surgery. These results suggest that APOE4 may confer AD risk via its effects on the vasculature. However, the responses of neurons and individual vessels have not been studied, so neurovascular relationships are unknown, and no previous studies have looked at awake mice. We therefore measured neurovascular responses at rest and in response to visual stimulation using 2 photon imaging of awake APOE3 and APOE4 targeted-replacement (APOE TR) mice that expressed the calcium indicator GCaMP6f in excitatory neurons, while labelling the vascular lumen with Texas Red dextran. In parallel, we measured cerebral blood flow, blood oxygenation and cerebral blood volume using combined laser Doppler flowmetry and haemoglobin spectrometry. Measurements were performed in mice aged between 3-4 months to 12-13 months. We found a milder vascular deficit in awake mice than previous studies that used an acute surgical preparation: capillary responses to visual stimulation were the same in APOE3 and APOE4 TR mice, leading to unimpaired functional hyperaemia. However, neuronal calcium signals during visual stimulation were significantly enhanced in APOE4 mice, while there was a marked decrease in pial arteriole responsiveness and vasomotion. This pattern of results was unaffected by age, suggesting that APOE4 expression creates a stable, but mildly altered neurovascular state that does not itself cause degeneration. However, these changes likely make the system more sensitive to subsequent insults; for example, weaker vasomotion could impair clearance of beta amyloid as it starts to accumulate, and therefore may help explain how APOE4 expression increases risk of developing AD.

The hippocampus is essential for spatial and episodic memory but is damaged early in Alzheimer’s disease and is very sensitive to hypoxia. Understanding how it regulates its oxygen supply is therefore key for designing interventions to preserve its function. However, studies of neurovascular function in the hippocampus in vivo have been limited by its relative inaccessibility. Here we compared hippocampal and visual cortical neurovascular function in awake mice, using two photon imaging of individual neurons and vessels and measures of regional blood flow and haemoglobin oxygenation. We show that blood flow, blood oxygenation and neurovascular coupling were decreased in the hippocampus compared to neocortex, because of differences in both the vascular network and pericyte and endothelial cell function. Modelling oxygen diffusion indicates that these features of the hippocampal vasculature may restrict oxygen availability and could explain its sensitivity to damage during neurological conditions, including Alzheimer’s disease, where the brain’s energy supply is decreased., The hippocampus is particularly sensitive to hypoxia but it has been difficult to study blood flow in this region. Here the authors compare the neurovascular function of the hippocampus and cortex and in awake mice, and find differences associated with microvascular structure.

The brain's high energy requirements drive the need for close coupling of local neuronal activity to blood supply. Capillaries have been shown to dilate before arterioles in response to sensory stimulation, pointing to a key role for microvascular pericytes in mediating cerebrovascular dynamics. However, many aspects of these cells' function remain unknown and even controversial, from their identification, to the mechanism and regulation of their contractility in physiology and disease. Investigating how pericytes regulate vascular diameter is therefore likely to be the subject of many future experiments. Here we provide protocols for three different techniques (ex vivo slice imaging, in vivo imaging, and immunohistochemistry) that are highly valuable for performing such experiments.

The brain's high energy requirements drive the need for close coupling of local neuronal activity to blood supply. Capillaries have been shown to dilate before arterioles in response to sensory stimulation, pointing to a key role for microvascular pericytes in mediating cerebrovascular dynamics. However, many aspects of these cells' function remain unknown and even controversial, from their identification, to the mechanism and regulation of their contractility in physiology and disease. Investigating how pericytes regulate vascular diameter is therefore likely to be the subject of many future experiments. Here we provide protocols for three different techniques (ex vivo slice imaging, in vivo imaging, and immunohistochemistry) that are highly valuable for performing such experiments.

The brain’s inability to store nutrients for more than a few seconds makes it one of the most tightly regulated systems in the body. Driven by metabolic demand, cerebral autoregulation (CA) ensures a constant cerebral blood flow (CBF) over a ±50% change in arterial blood pressure (ABP) from baseline. Recent evidence suggests that pericytes, contractile cells in the capillary bed, play a previously-ignored regulatory role. To elucidate the CA phenomenon, the role of oxygen metabolism, pericyte activity and neural signaling in CBF modulation were quantified. Driven by nutrient metabolism in the tissue and pressure sensitivity in the vasculature, the model introduced here successfully replicates CA. To highlight the role of different vessel sizes, vessels with a diameter above 1 mm were represented using a lumped parameter model while the microvasculature was illustrated as a branching tree network model. This novel approach elucidated the relationship between the microvasculature’s nutrient supply and arterial regulation. Capillary responses to local increases in neuronal activity were experimentally determined, showing that pericytes can increase the diameter of the adjacent vessel by 2.5% in approximately 1 s. Their response was quantified and included in the computational model as an active component of the capillary bed. To compare the efficacy model presented here to existing ones, four feedback mechanisms were tested. To simulate dynamic CBF regulation a 10% increase in ABP was imposed. This resulted in a 23.79%–34.33% peak increase in CBF, depending on the nature of the feedback mechanism of the model. The four feedback mechanisms that were studied significantly differ in the response time, ultimately highlighting that capillaries play a fundamental role in the rapid regulation of CBF. Conclusively, this study indicates that while pericytes do not greatly alter the peak CBF change, they play a fundamental role in the speed of regulation.

Functional neuroimaging using MRI relies on measurements of blood oxygen level-dependent (BOLD) signals from which inferences are made about the underlying neuronal activity. This is possible because neuronal activity elicits increases in blood flow via neurovascular coupling, which gives rise to the BOLD signal. Hence, an accurate interpretation of what BOLD signals mean in terms of neural activity depends on a full understanding of the mechanisms that underlie the measured signal, including neurovascular and neurometabolic coupling, the contribution of different cell types to local signalling, and regional differences in these mechanisms. Furthermore, the contributions of systemic functions to cerebral blood flow may vary with ageing, disease and arousal states, with regard to both neuronal and vascular function. In addition, recent developments in non-invasive imaging technology, such as high-field fMRI, and comparative inter-species analysis, allow connections between non-invasive data and mechanistic knowledge gained from invasive cellular-level studies. Considered together, these factors have immense potential to improve BOLD signal interpretation and bring us closer to the ultimate purpose of decoding the mechanisms of human cognition. This theme issue covers a range of recent advances in these topics, providing a multidisciplinary scientific and technical framework for future work in the neurovascular and cognitive sciences. This article is part of the theme issue ‘Key relationships between non-invasive functional neuroimaging and the underlying neuronal activity'.

Functional neuroimaging techniques are widely applied to investigations of human cognition and disease. The most commonly used among these is blood oxygen level-dependent (BOLD) functional magnetic resonance imaging. The BOLD signal occurs because neural activity induces an increase in local blood supply to support the increased metabolism that occurs during activity. This supply usually outmatches demand, resulting in an increase in oxygenated blood in an active brain region, and a corresponding decrease in deoxygenated blood, which generates the BOLD signal. Hence, the BOLD response is shaped by an integration of local oxygen use, through metabolism, and supply, in the blood. To understand what information is carried in BOLD signals, we must understand how several cell types in the brain—local excitatory neurons, inhibitory neurons, astrocytes and vascular cells (pericytes, vascular smooth muscle and endothelial cells), and their modulation by ascending projection neurons—contribute to both metabolism and haemodynamic changes. Here, we review the contributions of each cell type to the regulation of cerebral blood flow and metabolism, and discuss situations where a simplified interpretation of the BOLD response as reporting local excitatory activity may misrepresent important biological phenomena, for example with regards to arousal states, ageing and neurological disease. This article is part of the theme issue ‘Key relationships between non-invasive functional neuroimaging and the underlying neuronal activity’.

Pathological tau disrupts the association between nitric oxide (NO) synthase and PSD95, impairing NO signaling and neurovascular coupling before causing neurodegeneration. Stopping production of pathological tau rescues NO signaling, neurovascular coupling and neuronal function, but doesn’t remove tangles, suggesting that (like amyloid-β) soluble tau is an important driver of early neurovascular dysfunction and subsequent neuronal damage.

Assessment of outcome in preclinical studies of vascular cognitive impairment (VCI) is heterogenous. Through an ARUK Scottish Network supported questionnaire and workshop (mostly UK-based researchers), we aimed to determine underlying variability and what could be implemented to overcome identified challenges. Twelve UK VCI research centres were identified and invited to complete a questionnaire and attend a one-day workshop. Questionnaire responses demonstrated agreement that outcome assessments in VCI preclinical research vary by group and even those common across groups, may be performed differently. From the workshop, six themes were discussed: issues with preclinical models, reasons for choosing functional assessments, issues in interpretation of functional assessments, describing and reporting functional outcome assessments, sharing resources and expertise, and standardization of outcomes. Eight consensus points emerged demonstrating broadly that the chosen assessment should reflect the deficit being measured, and therefore that one assessment does not suit all models; guidance/standardisation on recording VCI outcome reporting is needed and that uniformity would be aided by a platform to share expertise, material, protocols and procedures thus reducing heterogeneity and so increasing potential for collaboration, comparison and replication. As a result of the workshop, UK wide consensus statements were agreed and future priorities for preclinical research identified.

Over the past decade, historians, journals, conferences, and even job advertisements have devoted attention to a new field of inquiry, “Britain and the world.” This emergent category is far from coherent but, despite a variety of approaches, shares a common assumption that Britain's interactions with the world beyond its shores enable us to better understand the histories of both Britain and the globe. Writing the history of Britain from a comparative, imperial, or transnational perspective is not wholly new. British historians have long worked comparatively in a predominantly European frame, while historians of empire and internationalism have also highlighted the importance of transnational and global frameworks. What, then, is signified by the articulation of “Britain and the world” as a new field? What do historians of Britain, and indeed historians of its empire and the world, stand to gain or lose from the promotion of Britain and the world as a field? What new skills, methodologies, and archives are required to become a historian of Britain and the world? We invited historians from different generations and national academies as well as with different ways of approaching the history of Britain in an extranational frame. Our hope is that these essays will open up debate and stimulate broader discussions about the changing nature of the field and our work as historians of Britain.

Jane Lydon's new book is a wonderfully lucid account of the interconnections between the ending of slavery in the British Caribbean and the development of the new settler colonies that were to beco...

The hippocampus is essential for spatial and episodic memory but is damaged early in Alzheimer’s disease and is very sensitive to hypoxia. Understanding how it regulates its oxygen supply is therefore key for designing interventions to preserve its function. However, studies of neurovascular function in the hippocampus in vivo have been limited by its relative inaccessibility. Here we compared hippocampal and visual cortical neurovascular function in awake mice, using two photon imaging of individual neurons and vessels and measures of regional blood flow and haemoglobin oxygenation. We show that blood flow, blood oxygenation and neurovascular coupling were decreased in the hippocampus compared to neocortex, because of differences in both the vascular network and pericyte and endothelial cell function. Modelling oxygen diffusion indicates that these features of the hippocampal vasculature could explain its sensitivity to damage during neurological conditions, including Alzheimer’s disease, where the brain’s energy supply is decreased.

This article uses the database created by the Legacies of British Slave-ownership project (www.ucl.ac.uk/lbs) which documents the recipients of the twenty million pounds paid in compensation to the slave-owners at the time of abolition, as a starting point from which to explore some of the implications of the flow of human and financial capital to Australia in the 1830s and 1840s. Once the Caribbean was no longer a place to make a fortune, descendants of slave-owners chose this new colony of white settlement as the next frontier of empire. Colonial officials, sheep farmers and writers were amongst those who attempted to make a new life, carrying with them attitudes to racial difference which inflected their understanding of Aboriginal peoples.

Jack Greene is well known for his extensive writings over decades on the constitutional and political histories of the North American colonies and their contested and negotiated relationships with ...

Pericytes, spatially isolated contractile cells on capillaries, have been reported to control cerebral blood flow physiologically, and to limit blood flow after ischaemia by constricting capillaries and then dying. Paradoxically, a recent paper dismisses the idea of pericytes controlling cerebral blood flow, despite confirming earlier data showing a role for pericytes. We show that these discrepancies are apparent rather than real, and depend on the new paper defining pericytes differently from previous reports. An objective definition of different sub-classes of pericyte along the capillary bed is needed to develop novel therapeutic approaches for stroke and disorders caused by pericyte malfunction.

Cerebral small vessel disease (SVD) is a major health challenge. Therapeutic approaches remain limited, hampered by the lack of mechanistic understanding and identification of therapeutic targets. Relevant animal models could provide a cornerstone to basic scientific studies of disease mechanisms and pre-clinical studies of potential therapies, but there is a critical need to improve the current translational gap that exists between pre-clinical research and treatments in patients. The Medical Research Council Dementias Platform UK (MRC DPUK) Vascular Experimental Medicine Theme identified that a comprehensive assessment of the latest developments in animal models and of their contribution to understanding of cerebral microvascular disease would reduce the translational gap. In response to this, a two day workshop took place in late January 2017 at the British Heart Foundation Centre of Research Excellence in Glasgow, Scotland in conjunction with MRC DPUK and brought together experts from several disciplines in cerebrovascular disease, dementia and cardiovascular biology, to highlight current advances in these fields, explore synergies and scope for development. There were presentations from UK and international researchers and a specific focus on animal models of cerebral microvascular disease and dementia, considering vascular biology, neurogliovascular coupling, blood-brain barrier function, neuroinflammation, cerebral drainage pathways, and methodological and translational challenges (see Figure 1 for the general organisation of the meeting including the key topics and themes discussed). This overview provides a summary of the key talks, with a particular focus on mechanisms of cerebral vascular disease (see Figure 2) and improving translation. These talks were followed by related themed discussion groups on the gaps in knowledge and requirements to advance knowledge, the outcomes of which are highlighted in Table 1. Additional related articles are published in the Special Edition of Clinical Science (http://www.portlandpresspublishing.com/cc/small-vessels).

The cerebral circulation is highly specialized, both structurally and functionally, and it provides a fine-tuned supply of oxygen and nutrients to active regions of the brain. Our understanding of blood flow regulation by cerebral arterioles has evolved rapidly. Recent work has opened new avenues in microvascular research; for example, it has been demonstrated that contractile pericytes found on capillary walls induce capillary diameter changes in response to neurotransmitters, suggesting that pericytes could have a role in neurovascular coupling. This concept is at odds with traditional models of brain blood flow regulation, which assume that only arterioles control cerebral blood flow. The investigation of mechanisms underlying neurovascular coupling at the capillary level requires a range of approaches, which involve unique technical challenges. Here we provide detailed protocols for the successful physiological and immunohistochemical study of pericytes and capillaries in brain slices and isolated retinae, allowing investigators to probe the role of capillaries in neurovascular coupling. This protocol can be completed within 6-8 h; however, immunohistochemical experiments may take 3-6 d.

Cognitive neuroscience depends on the use of blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) to probe brain function. Although commonly used as a surrogate measure of neuronal activity, BOLD signals actually reflect changes in brain blood oxygenation. Understanding the mechanisms linking neuronal activity to vascular perfusion is, therefore, critical in interpreting BOLD. Advances in cellular neuroscience demonstrating differences in this neurovascular relationship in different brain regions, conditions or pathologies are often not accounted for when interpreting BOLD. Meanwhile, within cognitive neuroscience, the increasing use of high magnetic field strengths and the development of model-based tasks and analyses have broadened the capability of BOLD signals to inform us about the underlying neuronal activity, but these methods are less well understood by cellular neuroscientists. In 2016, a Royal Society Theo Murphy Meeting brought scientists from the two communities together to discuss these issues. Here, we consolidate the main conclusions arising from that meeting. We discuss areas of consensus about what BOLD fMRI can tell us about underlying neuronal activity, and how advanced modelling techniques have improved our ability to use and interpret BOLD. We also highlight areas of controversy in understanding BOLD and suggest research directions required to resolve these issues. This article is part of the themed issue ‘Interpreting BOLD: a dialogue between cognitive and cellular neuroscience’.

Neural activity has been suggested to initially trigger ATP production by glycolysis, rather than oxidative phosphorylation, for three reasons: glycolytic enzymes are associated with ion pumps; neurons may increase their energy supply by activating glycolysis in astrocytes to generate lactate; and activity increases glucose uptake more than O₂ uptake. In rat hippocampal slices, neuronal activity rapidly decreased the levels of extracellular O₂ and intracellular NADH (reduced nicotinamide adenine dinucleotide), even with lactate dehydrogenase blocked to prevent lactate generation, or with only 20% superfused O₂ to mimic physiological O₂ levels. Pharmacological analysis revealed an energy budget in which 11% of O₂ use was on presynaptic action potentials, 17% was on presynaptic Ca²⁺ entry and transmitter release, 46% was on postsynaptic glutamate receptors, and 26% was on postsynaptic action potentials, in approximate accord with theoretical brain energy budgets. Thus, the major mechanisms mediating brain information processing are all initially powered by oxidative phosphorylation, and an astrocyte-neuron lactate shuttle is not needed for this to occur.

��� It is a pleasure to be here on this occasion, to celebrate Gareth Stedman Jones’s work together with the festschrift edited by David Feldman and Jon Lawrence that is being launched in his honour, and to take this opportunity to think with others about the state of modern British history. 1 I am very aware of the varied routes that historians have taken in these decades, the proliferation of sub-disciplines and the scale of professionalization, much of it driven by the exigencies of higher education. It is quite impossible to ‘know’ the full field of modern British history but I do know the particularity of the routes that I have taken. My reflections are necessarily partial and cannot do justice to the range of work represented in the book, which provide a very welcome sign of the diverse approaches being actively pursued by modern British historians. I first met Gareth in a garden in Richmond in 1963 when he was playing cricket – not an occasion which I imagine he would remember but etched on my memory – a hot summer’s day and a group of young men, scions of the New Left, taking their game quite as seriously as their politics. Gareth and I are the same generation – shaped by the politics of the early 1960s, the beginnings of the disintegration of the Cold War blocs, the emergence of new social movements, the events of 1968, the development of the women’s movement, the failures of both socialism and labourism. We have shared a broadly similar political and intellectual project – reacting both to the narrow political and constitutional history that dominated the professional agenda in the 1960s and to the group of British Marxist historians who were so formative for us. We share the view that history matters, that it is never confined to the academy, that the historical imagination flourishes in diverse spaces, that history writing is always theoretically informed, and that the task of the historian is to bring the past into the present – finding ways, as Gareth has put it, ‘of challenging greed, exploitation and misery’. 2 One of the early fruits of that political moment was History Workshop – both the journal and the movement that was connected with it. The historical vision it celebrated was an opening up of the subject, not

Low nanomolar concentrations of nitric oxide activate guanylyl cyclase to produce cGMP, which has diverse physiological effects. Higher concentrations inhibit mitochondrial respiration at cytochrome c oxidase and this has been proposed to be important physiologically, increasing oxygen permeation into tissue (by reducing the oxygen use of cells near blood vessels), activating AMP kinase, and regulating the relationship between cerebral blood flow and oxygen use. It is unclear, however, whether nitric oxide can accumulate physiologically to concentrations at which inhibition of respiration occurs. In rat cerebellar slices, we activated nitric oxide production from each isoform of nitric oxide synthase. Only activation of inducible nitric oxide synthase, which is expressed pathologically, caused any significant inhibition of respiration. Modelling oxygen and nitric oxide concentrations predicted that, in vivo, physiological nitric oxide levels are too low to affect respiration. Even pathologically, the nitric oxide concentration may only rise to 2.5 nm, producing a 1.5% inhibition of respiration. Thus, under physiological conditions, nitric oxide signals do not inhibit respiration but are well-tuned to the dynamic range of guanylyl cyclase activation.

Nitric oxide (NO) functions as an intercellular messenger throughout the brain. For this role to be performed efficiently, there must be a mechanism for neutralizing NO, but whether an active biological process exists, or whether NO is lost mainly through diffusion is unclear. To investigate this issue, rat cerebellar slices were exposed to constant levels of NO and the cGMP generated within the slice used as an indicator of NO concentrations therein. NO was about 1000-fold less potent in slices (EC50, 1 μm) than in separated cells from the same tissue (EC50, 1.6 nm), consistent with access of NO to the slice interior being greatly hindered by inactivation. Supporting this interpretation, immunohistochemical analysis indicated a marked concentration gradient of cGMP across the thickness of slices exposed to subsaturating NO concentrations, signifying a marked NO gradient. Several known NO-degrading processes, including reaction with lipid peroxyl radicals, erythrocytes and superoxide ions, were eliminated as contributing factors, indicating a novel mechanism. A diffusion–inactivation model was used to estimate the kinetics of NO consumption by the slices. The best fits to experimental data indicated a Michaelis-Menten-type reaction having a Vmax of 1–2 μm s−1 and a Km of around 10 nm. The rates predict that inactivation would impose a very short half-life (

Mechanisms which inactivate NO (nitric oxide) are probably important in governing the physiological and pathological effects of this ubiquitous signalling molecule. Cells isolated from the cerebellum, a brain region rich in the NO signalling pathway, consume NO avidly. This property was preserved in brain homogenates and required both particulate and supernatant fractions. A purified fraction of the particulate component was rich in phospholipids, and NO consumption was inhibited by procedures that inhibited lipid peroxidation, namely a transition metal chelator, the vitamin E analogue Trolox and ascorbate oxidase. The requirement for the supernatant was accounted for by its content of ascorbate which catalyses metal-dependent lipid peroxidation. The NO-degrading activity of the homogenate was mimicked by a representative mixture of brain lipids together with ascorbate and, under these conditions, the lipids underwent peroxidation. In a suspension of cerebellar cells, there was a continuous low level of lipid peroxidation, and consumption of NO by the cells was decreased by approx. 50% by lipid-peroxidation inhibitors. Lipid peroxidation was also abolished when NO was supplied at a continuously low rate (∼100 nM/min), which explains why NO consumption by this process is saturable. Part of the activity remaining after the inhibition of lipid peroxidation was accounted for by contaminating red blood cells, but there was also another component whose activity was greatly enhanced when the cells were maintained under air-equilibrated conditions. A similar NO-consuming process was present in cerebellar glial cells grown in tissue culture but not in blood platelets or leucocytes, suggesting a specialized mechanism.

This article uses the World Anti-Slavery Convention of 1840, and the way in which it was represented in Benjamin Robert Haydon's painting of it, to reflect on the ways in which Britons thought of themselves as an 'imperial people', 'lords of humankind', fit to rule over others. The Whig reforms of the 1830s had brought the enfranchisement of large numbers of middle-class men, and the emancipation of the enslaved across the British Empire. Excavating the assumptions of the abolitionists who gathered at the Convention allows us to see how new hierarchies of difference were encoded by 1840, placing freed black men, middle-class women and Irish Catholics on the margins of the new body politic. © School of Oriental and African Studies.

First, let me thank the three commentators for taking the time and trouble to read and discuss Civilising Subjects. Critical and constructive responses are what all authors want, and I am grateful that these scholars, whose work I greatly admire, have given my book their attention. To have the chance to reply is, of course, even better! The central argument of Civilising Subjects is that being a colonizer was part of the construction of Englishness in the nineteenth century. Given my location as a white English woman formed through socialist and feminist politics, my task as an historian, as I defined it at the end of the 1980s, was to explore Englishness as a racial formation. The complex ‘‘race’’ politics of postcolonial Britain with its multicultural population posed a challenge to the national story, the ‘‘island story’’ of the homogeneity of the English-British nation. What were the possible chains of connection in racial thinking between imperial and postimperial times? I wanted to understand what difference it made to the English-British sense of self in the nineteenth century that Britain was at the heart of an empire. In the United States race was understood as an issue within from the moment of the inception of the nation: the Native American and AfricanAmerican presence ensured this. Race was not present in the same way in British society, for empire was always at a distance and people of color had a relatively small presence in the metropole. Prior to decolonization and the arrival of large numbers of erstwhile imperial subjects in the metropole, issues of race were commonly conceptualized as belonging to the empire, outside of the nation. It was only in the wake of the migrations of the late 1940s and 1950s that race came to be seen as a problem of the ‘‘inside’’ rather than the ‘‘outside.’’ Yet if, as Frantz Fanon argued, colonialism shaped the colonizers as much as the colonized then how was this expressed in everyday culture? How was it lived ‘‘at home’’ as well as in the empire? How did Englishmen and women become colonizers, and what kind of racialized and gendered selves were these? And if particular kinds of racial thinking were embedded in what it meant to be English, then what were the implications of this for postcolonial times? I aimed to explore the construction of the colonizer and to break the binary of inside-outside through two case studies, one of Jamaica, the other of England. I focused on a relatively short period—between 1830 and 1867—in an effort to understand the shift in English racial thinking

Increases in brain blood flow, evoked by neuronal activity, power neural computation and form the basis of BOLD (blood-oxygen-level-dependent) functional imaging. Whether blood flow is controlled solely by arteriole smooth muscle, or also by capillary pericytes, is controversial. We demonstrate that neuronal activity and the neurotransmitter glutamate evoke the release of messengers that dilate capillaries by actively relaxing pericytes. Dilation is mediated by prostaglandin E2, but requires nitric oxide release to suppress vasoconstricting 20-HETE synthesis. In vivo, when sensory input increases blood flow, capillaries dilate before arterioles and are estimated to produce 84% of the blood flow increase. In pathology, ischaemia evokes capillary constriction by pericytes. We show that this is followed by pericyte death in rigor, which may irreversibly constrict capillaries and damage the blood-brain barrier. Thus, pericytes are major regulators of cerebral blood flow and initiators of functional imaging signals. Prevention of pericyte constriction and death may reduce the long-lasting blood flow decrease that damages neurons after stroke.

Because regional blood flow increases in association with the increased metabolic demand generated by localised increases in neural activity, functional imaging researchers often assume that changes in blood flow are an accurate read-out of changes in underlying neural activity. An understanding of the mechanisms that link changes in neural activity to changes in blood flow is crucial for assessing the validity of this assumption, and for understanding the processes that can go wrong during disease states such as ischaemic stroke. Many studies have investigated the mechanisms of neurovascular regulation in arterioles but other evidence suggests that blood flow regulation can also occur in capillaries, because of the presence of contractile cells, pericytes, on the capillary wall. Here we review the evidence that pericytes can modulate capillary diameter in response to neuronal activity and assess the likely importance of neurovascular regulation at the capillary level for functional imaging experiments. We also discuss evidence suggesting that pericytes are particularly sensitive to damage during pathological insults such as ischaemia, Alzheimer’s disease and diabetic retinopathy, and consider the potential impact that pericyte dysfunction might have on the development of therapeutic interventions and on the interpretation of functional imaging data in these disorders.

Clarity about the nitric oxide (NO) concentrations existing physiologically is essential for developing a quantitative understanding of NO signalling, for performing experiments with NO that emulate reality, and for knowing whether or not NO concentrations become abnormal in disease states. A decade ago, a value of about 1 microM seemed reasonable based on early electrode measurements and a provisional estimate of the potency of NO for its guanylyl cyclase-coupled receptors, which mediate physiological NO signal transduction. Since then, numerous efforts to measure NO concentrations directly using electrodes in cells and tissues have yielded an irreconcilably large spread of values. In compensation, data from several alternative approaches have now converged to provide a more coherent picture. These approaches include the quantitative analysis of NO-activated guanylyl cyclase, computer modelling based on the type, activity and amount of NO synthase enzyme contained in cells, the use of novel biosensors to monitor NO release from single endothelial cells and neurones, and the use of guanylyl cyclase as an endogenous NO biosensor in tissue subjected to a variety of challenges. All these independent lines of evidence suggest the physiological NO concentration range to be 100 pM (or below) up to approximately 5 nM, orders of magnitude lower than was once thought.

Low nanomolar concentrations of nitric oxide activate guanylyl cyclase to produce cGMP, which has diverse physiological effects. Higher concentrations inhibit mitochondrial respiration at cytochrome c oxidase and this has been proposed to be important physiologically, increasing oxygen permeation into tissue (by reducing the oxygen use of cells near blood vessels), activating AMP kinase, and regulating the relationship between cerebral blood flow and oxygen use. It is unclear, however, whether nitric oxide can accumulate physiologically to concentrations at which inhibition of respiration occurs. In rat cerebellar slices, we activated nitric oxide production from each isoform of nitric oxide synthase. Only activation of inducible nitric oxide synthase, which is expressed pathologically, caused any significant inhibition of respiration. Modelling oxygen and nitric oxide concentrations predicted that, in vivo, physiological nitric oxide levels are too low to affect respiration. Even pathologically, the nitric oxide concentration may only rise to 2.5 nm, producing a 1.5% inhibition of respiration. Thus, under physiological conditions, nitric oxide signals do not inhibit respiration but are well-tuned to the dynamic range of guanylyl cyclase activation.

The location, identity and functional properties of the primary molecular components of the NO/cGMP pathway have now been well-characterised. These components are widespread, but not ubiquitous, across the brain, and the downstream effects of activation of this pathway are diverse and often incompletely understood. It is now important to consider the identity of these later stages of the transduction pathway and the way in which different dynamic patterns of NO and cGMP signalling induce such a variety of change in the long- and short-term function of neuronal circuitry. Future studies need to concentrate on the effects of endogenously-released NO and on the application of concentrations of exogenous NO that are physiologically relevant, in order to dissect out the downstream targets of NO signalling that relate to normal function.

The Lone Protestor: A. M. Fernando in Australia and Europe . By Fiona Paisley. Canberra: Aboriginal Studies Press, 2012. Pp. 256. A$34.95 paper. The Lone Protestor is an evocative account of the ex...