A lesson for us all: the Hodgkin-Keynes long pore model of ion flux.

In this article we analyze the classic Hodgkin and Keynes 1955 paper describing investigations of the independence principle, with the expectation that there is much students and educators can learn from such exercises, most notably how the authors applied their diverse skill set to tackling the numerous obstacles that the study presented. The paper encompasses three of the physiology core concepts, cell membranes, flow down gradients, and scientific reasoning, which were recently assigned to the classes The Biological World, The Physical World, and Ways of Looking at the World, respectively. Thus, analysis of such a paper illuminates the relationships that exist between distinct concepts and encourages a holistic approach to understanding physiology.

Sieyès's Constitutional Jury, the Pennsylvania Council of Censors, and the Debate on the Conservative Power in the French Revolution.

Emmanuel-Joseph Sieyès's 1795 proposal for a Constitutional Jury is usually portrayed as the first proposal for an institution to control the constitutionality of laws, and thus the ancestor of the modern constitutional court. Challenging this view, this article resituates the Constitutional Jury in a broader transatlantic tradition concerned with creating a conservative power, a non-judicial and explicitly political constitutional guardian, and demonstrates the influence of the 1776 Pennsylvania Council of Censors on Sieyès's Constitutional Jury. Drawing upon the insights provided by this tradition, it then reevaluates the history of constitutionalism and the contemporary crisis of constitutional guardianship.

Resilience of compound action potential peaks to high-frequency firing in the mouse optic nerve.

Action potential conduction in axons triggers trans-membrane ion movements, where Na enters and K leaves axons, leading to disruptions in resting trans-membrane ion gradients that must be restored for optimal axon conduction, an energy dependent process. The higher the stimulus frequency, the greater the ion movements and the resulting energy demand. In the mouse optic nerve (MON), the stimulus evoked compound action potential (CAP) displays a triple peaked profile, consistent with subpopulations of axons classified by size producing the distinct peaks.

Activity-Dependent Fluctuations in Interstitial [K]: Investigations Using Ion-Sensitive Microelectrodes.

In the course of action potential firing, all axons and neurons release K from the intra- cellular compartment into the interstitial space to counteract the depolarizing effect of Na influx, which restores the resting membrane potential. This efflux of K from axons results in K accumulation in the interstitial space, causing depolarization of the K reversal potential (E), which can prevent subsequent action potentials. To ensure optimal neuronal function, the K is buffered by astrocytes, an energy-dependent process, which acts as a sink for interstitial K, absorbing it at regions of high concentration and distributing it through the syncytium for release in distant regions.

A color-coded graphical guide to the Hodgkin and Huxley papers.

The five papers published by Hodgkin and Huxley in 1952 are seminal works in the field of physiology, earning their authors the Nobel Prize in 1963 and ushering in the era of membrane biophysics. The papers present a considerable challenge to the novice student, but this has been partly allayed by recent publications that have updated the reporting of current and voltage to reflect the modern convention and two books that describe the contents of the papers in detail. A disadvantage is that these guides contain hundreds of pages, requiring considerable time and energy on behalf of the reader.

Energy Metabolism in Mouse Sciatic Nerve A Fibres during Increased Energy Demand.

The ability of sciatic nerve A fibres to conduct action potentials relies on an adequate supply of energy substrate, usually glucose, to maintain necessary ion gradients. Under our ex vivo experimental conditions, the absence of exogenously applied glucose triggers Schwann cell glycogen metabolism to lactate, which is transported to axons to fuel metabolism, with loss of the compound action potential (CAP) signalling glycogen exhaustion. The CAP failure is accelerated if tissue energy demand is increased by high-frequency stimulation (HFS) or by blocking lactate uptake into axons using cinnemate (CIN).

The Nernst equation: using physico-chemical laws to steer novel experimental design.

The application of physico-chemical principles has been routinely used to explain various physiological concepts. The Nernst equation is one example of this, used to predict the potential difference created by the transmembrane ion gradient resulting from uneven ion distribution within cellular compartments and the interstitial space. This relationship remains of fundamental importance to the understanding of electrical signaling in the brain, which relies on current flow across cell membranes.

Trends in referrals to liaison psychiatry teams from UK emergency departments for patients over 65.

Introduction: The number of people over the age of 65 attending Emergency Departments (ED) in the United Kingdom (UK) is increasing. Those who attend with a mental health related problem may be referred to liaison psychiatry for assessment. Improving responsiveness and integration of liaison psychiatry in general hospital settings is a national priority.

A classic experiment revisited: membrane permeability changes during the action potential.

The ability to understand the relationship between the reversal potential and the membrane potential is a fundamental skill that must be mastered by students studying membrane excitability. To clarify this relationship, we have reframed a classic experiment carried out by Hodgkin and Katz, where we compare graphically the membrane potential at three phases of the action potential (resting potential, action potential peak, and afterhyperpolarization) to reversal potential for K (), reversal potential for Na (), and membrane potential () (calculated by the Goldman Hodgkin Katz equation) to illustrate that the membrane potential approaches the reversal potential of the ion to which it is most permeable at that instant.

Universal Glia to Neurone Lactate Transfer in the Nervous System: Physiological Functions and Pathological Consequences.

Whilst it is universally accepted that the energy support of the brain is glucose, the form in which the glucose is taken up by neurones is the topic of intense debate. In the last few decades, the concept of lactate shuttling between glial elements and neural elements has emerged in which the glial cells glycolytically metabolise glucose/glycogen to lactate, which is shuttled to the neural elements via the extracellular fluid. The process occurs during periods of compromised glucose availability where glycogen stored in astrocytes provides lactate to the neurones, and is an integral part of the formation of learning and memory where the energy intensive process of learning requires neuronal lactate uptake provided by astrocytes.

Calbindin Deficits May Underlie Dissociable Effects of 5-HT and mGlu Antagonists on Glutamate and Cognition in a Dual-Hit Neurodevelopmental Model for Schizophrenia.

Despite several compounds entering clinical trials for the negative and cognitive symptoms of schizophrenia, few have progressed beyond phase III. This is partly attributed to a need for improved preclinical models, to understand disease and enable predictive evaluation of novel therapeutics. To this end, one recent approach incorporates "dual-hit" neurodevelopmental insults like neonatal phencyclidine plus isolation rearing (PCP-Iso).

A method for reducing animal use whilst maintaining statistical power in electrophysiological recordings from rodent nerves.

The stimulus evoked compound action potential, recorded from nerve trunks such as the rodent optic and sciatic nerve, is a popular model system used to study aspects of nervous system metabolism. This includes (1) the role of glycogen in supporting axon conduction, (2) the injury mechanisms resulting from metabolic insults, and (3) to test putative benefits of clinically relevant neuroprotective strategies. We demonstrate the benefit of simultaneously recording from pairs of nerves in the same superfusion chamber compared with conventional recordings from single nerves.

The Role of Brain Glycogen in Supporting Physiological Function.

Glycogen is present in the mammalian brain but occurs at concentrations so low it is unlikely to act as a conventional energy reserve. Glycogen has the intriguing feature of being located exclusively in astrocytes, but its presence benefits neurones, suggesting that glycogen is metabolized to a conduit that is transported between the glia and neural elements. In the rodent optic nerve model glycogen supports axon conduction in the form of lactate to supplement axonal metabolism during aglycemia, hypoglycemia and during periods of increased energy demand under normoglycemic conditions.

Metabolism of Glycogen in Brain White Matter.

Brain glycogen is a specialized energy buffer, rather than a conventional reserve. In the rodent optic nerve, a central white matter tract, it is located in astrocytes, where it is converted to lactate, which is then shuttled intercellularly from the astrocyte to the axon. This basic pathway was elucidated from non-physiological experiments in which the nerve was deprived of exogenous glucose.

Hypothermic neuroprotection during reperfusion following exposure to aglycemia in central white matter is mediated by acidification.

Hypoglycemia is a common iatrogenic consequence of type 1 diabetes therapy that can lead to central nervous system injury and even death if untreated. In the absence of clinically effective neuroprotective drugs we sought to quantify the putative neuroprotective effects of imposing hypothermia during the reperfusion phase following aglycemic exposure to central white matter. Mouse optic nerves (MONs), central white matter tracts, were superfused with oxygenated artificial cerebrospinal fluid (aCSF) containing 10 mmol/L glucose at 37°C.

Fibre sub-type specific conduction reveals metabolic function in mouse sciatic nerve.

Key Points: We have developed an improved method that enables simultaneous recording of stimulus evoked compound action potentials from large myelinated A fibres and small unmyelinated C fibres in mouse sciatic nerves. Investigations into the ability of fructose to support conduction in sciatic nerve revealed a novel glia-to-axon metabolic pathway in which fructose is converted in Schwann cells to lactate for subsequent shuttling to A fibres. The C fibres most likely directly take up and metabolise fructose.

Glia in brain energy metabolism: A perspective.

Early views of glia as relatively inert, housekeeping cells have evolved, and glia are now recognized as dynamic cells that not only respond to neuronal activity but also sense metabolic changes and regulate neuronal metabolism. This evolution has been aided in part by technical advances permitting progressively better spatial and temporal resolution. Recent advances in cell-type specific genetic manipulation and sub-cellular metabolic probes promise to further this evolution by enabling study of metabolic interactions between intertwined fine neuronal and glial processes in vivo.

Current technical approaches to brain energy metabolism.

Neuroscience is a technology-driven discipline and brain energy metabolism is no exception. Once satisfied with mapping metabolic pathways at organ level, we are now looking to learn what it is exactly that metabolic enzymes and transporters do and when, where do they reside, how are they regulated, and how do they relate to the specific functions of neurons, glial cells, and their subcellular domains and organelles, in different areas of the brain. Moreover, we aim to quantify the fluxes of metabolites within and between cells.

Acute Effect of Pore-Forming ε-Toxin on Compound Action Potentials of Optic Nerve of Mouse.

ε-Toxin is a pore forming toxin produced by types B and D. It is synthesized as a less active prototoxin form that becomes fully active upon proteolytic activation. The toxin produces highly lethal enterotoxaemia in ruminants, has the ability to cross the blood-brain barrier (BBB) and specifically binds to myelinated fibers.