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The endocrinology of the brain

Gareth Leng

Endocrine Connections  Volume 7 Issie 12 R275-285


The brain hosts a vast and diverse repertoire of neuropeptides, a class of signalling molecules often described as neurotransmitters. Here I argue that this description entails a catalogue of misperceptions, misperceptions that feed into a narrative in which information processing in the brain can be understood only through mapping neuronal connectivity and by studying the transmission of electrically conducted signals through chemical synapses. I argue that neuropeptide signalling in the brain involves primarily autocrine, paracrine and neurohormonal mechanisms that do not depend on synaptic connectivity and that it is not solely dependent on electrical activity but on mechanisms analogous to secretion from classical endocrine cells. As in classical endocrine systems, to understand the role of neuropeptides in the brain, we must understand not only how their release is regulated, but also how their synthesis is regulated and how the sensitivity of their targets is regulated. We must also understand the full diversity of effects of neuropeptides on those targets, including their effects on gene expression.


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Models in neuroendocrinology

Gareth Leng, Duncan J. MacGregor

Mathematical Biosciences 305 (2018) 29–41

The neuroendocrine systems of the hypothalamus are critical for survival and reproduction, and are highly
conserved throughout vertebrate evolution. Their roles in controlling body metabolism, growth and body
composition, stress, electrolyte balance and reproduction have been intensively studied, and have yielded a rich
crop of original and challenging insights into neuronal function, insights that circumscribe a vision of the brain
that is quite different from conventional views. Despite the diverse physiological roles of pituitary hormones,
most are secreted in a pulsatile pattern, but arising through a variety of mechanisms. An important exception is
vasopressin which uses bursting neural activity, but produces a graded secretion response to osmotic pressure, a
sustained robust linear response constructed from noisy, nonlinear components. Neuroendocrine systems have
many features such as multiple temporal scales and nonlinearity that make their underlying mechanisms hard to
understand without mathematical modelling. The models presented here cover the wide range of temporal scales
involved in these systems, including models of single cell electrical activity and calcium dynamics, receptor
signalling, gene expression, coordinated activity of neuronal networks, whole-organism hormone dynamics and
feedback loops, and the menstrual cycle. Many interesting theoretical approaches have been applied to these
systems, but important problems remain, at the core the question of what is the true advantage of pulsatility.


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The Heart of the Brain: The Hypothalamus and Its Hormones

A new book by our project co-ordinator Gareth Leng.  Published by MIT Press

How hormonal signals in one small structure of the brain—the hypothalamus—govern our physiology and behavior.

As human beings, we prefer to think of ourselves as reasonable. But how much of what we do is really governed by reason? In this book, Gareth Leng considers the extent to which one small structure of the neuroendocrine brain—the hypothalamus—influences what we do, how we love, and who we are.

The hypothalamus contains a large variety of neurons. These communicate not only through neurotransmitters, but also through peptide signals that act as hormones within the brain. While neurotransmitter signals tend to be ephemeral and confined by anatomical connectivity, the hormone signals that hypothalamic neurons generate are potent, wide-reaching, and long-lasting. Leng explores the evolutionary origins of these remarkable neurons, and where the receptors for their hormone signals are found in the brain. By asking how the hypothalamic neurons and their receptors are regulated, he explores how the hypothalamus links our passions with our reason. The Heart of the Brain shows in an accessible way how this very small structure is very much at the heart of what makes us human.


Gareth book

Food and drug addictions: Similarities and differences

Peter J Rogers

Pharnacology, Biochemistry and Behaviour  153 (2017) 182-190

This review examines the merits of ‘food addiction’ as an explanation of excessive eating (i.e., eating in excess of
what is required to maintain a healthy body weight). It describes various apparent similarities in appetites for foods and drugs. For example, conditioned environmental cues can arouse food and drug-seeking behaviour, ‘craving’ is an experience reported to precede eating and drug taking, ‘bingeing’ is associated with both eating and drug use, and conditioned and unconditioned tolerance occurs to food and drug ingestion. This is to be ex- pected, as addictive drugs tap into the same processes and systems that evolved to motivate and control adaptive behaviours, including eating. The evidence, however, shows that drugs of abuse have more potent effects than foods, particularly in respect of their neuroadaptive effects that make them ‘wanted.’ While binge eating has been conceptualised as form of addictive behaviour, it is not a major cause of excessive eating, because binge eating has a far lower prevalence than obesity. Rather, it is proposed that obesity results from recurrent overconsumption of energy dense foods. Such foods are, relatedly, both attractive and (calorie for calorie) weakly satiating. Limiting their availability could partially decrease
excessive eating and consequently decrease obesity. Arguably, persuading policy makers that these foods are addictive could support such action. However, blaming excessive eating on food addiction could be counterproductive, because it risks trivialising serious addictions, and because the attribution of excessive eating to food addiction implies an inability to control one's eating. Therefore, attributing everyday excessive eating to food addiction may neither explain nor significantly help reduce this problem.

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Oxytocin – The Sweet Hormone?

Gareth Leng and Nancy Sabatier

Trends in Endocrinology and Metabolism   May 2017, Vol 28, no 5, pp 365-376

Mammalian neurons that produce oxytocin and vasopressin apparently evolved from an ancient cell type with both sensory and neurosecretoryproperties that probably linked reproductive functions to energy status and feeding behavior. Oxytocin in modern mammals is anautocrine/paracrine regulator of cell function,asystemic hormone,a neuromodulator released from axon terminals within the brain,and a ‘neurohormone’ that acts at receptors distant from its site of release.In the periphery oxytocin is involved in electrolyte homeostasis, gastric motility, glucose homeostasis, adipogenesis, and osteo-genesis, and within the brain it is involved in food reward,food choice,and satiety. Oxytocin preferentially suppresses intake of sweet-tasting carbohydrates while improving glucose tolerance and supporting bone remodeling,making it an enticing translational target.

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The determinants of food choice - Nudge-it review

Gareth Leng, Roger A.H. Adan,  Michele Belot, Jeffrey M. Brunstrom, Kees de Graaf, Suzanne L Dickson, Todd Hare, Silvia Maier, John Menzies, Hubert Preissl, Lucia A. Reisch, Peter J. Rogers, Paul A.M. Smeets,

Preprint: in press, Proceedings of the Nutrition Society, accepted 18th October 2016

Health nudge interventions to steer people into healthier lifestyles are increasingly applied by governments worldwide. ‘Nudges’ are approaches to law and policy that maintain freedom of choice, but which steer people in certain directions  they consist of small yet relevant behavioral stimuli such as simplification of information and choices, framing and priming of messages, feedback to one’s behavior, defaults and reminders and similar behavioral cues. Much of the health burden is caused by modifiable behaviors such as smoking, unhealthy food consumption, and sedentary lifestyles, but neither decades of health information and education, nor attempts at hard regulation (such as fat taxes or sugar taxes), nor voluntary self-regulation of industry have markedly promoted healthier lifestyles or helped to stop the rise of non-communicable diseases. At the same time, there is increasing evidence that the purposeful design of the living and consumption environments – the “choice architecture” – is key to changing nutritional and activity patterns  and to maintaining healthier lifestyles. There is mounting evidence for the usefulness of World Health Organization’s motto: “make the healthier choice the easy choice”, through easier access, availability, priming and framing. More than 150 governments now use behavioral science, with an emphasis on nudges. In these countries, “nudging for health” is regarded as an attractive option to make health policies more effective and efficient; a recent poll in six European countries found that health nudges are overwhelmingly “approved” by the people. This is the backcloth against which we set out to test nudging tools that might be useful add-ons to traditional health policies.

However, to produce policy recommendations that are likely to be effective, we need to be able to make valid, non-trivial predictions about the consequences of particular behaviors and interventions. For this, we need a better understanding of the determinants of food choice. These determinants include dietary components (e.g. highly palatable foods and alcohol), but also diverse cultural and social pressures, cognitive-affective factors (perceived stress, health attitude, anxiety and depression), and familial, genetic and epigenetic influences on personality characteristics. Our choices are influenced by how foods are marketed and labelled and by economic factors, and they reflect both habits and goals, moderated, albeit imperfectly, by an individual understanding of what constitutes ‘healthy eating’. In addition, our choices are influenced by physiological mechanisms, including signals to the brain from the gastrointestinal tract and adipose tissue which affect not only our hunger and satiety but also our motivation to eat particular nutrients, and the reward we experience from eating.

To develop the evidence base necessary for effective policies, we need to build bridges across different levels of knowledge and understanding. This requires experimental models that can fill in the gaps in our understanding that are needed to inform policy, translational models that connect mechanistic understanding from laboratory studies to the real life human condition, and formal models that encapsulate scientific knowledge from diverse disciplines, and which embed understanding in a way that enables policy-relevant predictions to be made.

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Computational Neuroendocrinology

Computational Neuroendocrinology

Neuroendocrinology with its well defined functions, inputs, and outputs, is one of the most fertile grounds for computational modeling in neuroscience. But modeling is often seen as something of a dark art. This book aims to display the power of modeling approaches in neuroendocrinology, and to showcase its potential for understanding these complex systems.

A recurring theme in neuroendocrinology is rhythms. How are rhythms generated, and what purpose do they serve? Are these two questions inextricably intertwined?

This book is written for innocents, presuming no math beyond high school or computing beyond calculators. It seeks to lead the curious into the thinking of the modeler, providing the tools to the reader to understand models, and even develop their own, giving life to paper diagrams. The diverse chapters, from ion channels to networks, systems, and hormonal rhythms, each tell the story of a model serving to join the hard won dots of experimentation, mapping a new understanding, and revealing hidden knowledge.

• Written by a team of internationally renowned researchers
• Both print and enhanced e-book versions are available
• Illustrated in full colour throughout

available to purchase from Wiley

The Economics of Nudge

Economics of Nudge
Proponents of ‘nudge theory’ argue that, because of our human susceptibility to an array of biases, we often make subprime choices and decisions that make us poorer, less healthy, and more miserable than we might otherwise be. However, using behavioural economics—and insights from other disciplines—they suggest that apparently small and subtle solutions (or ‘nudges’) can lead to disproportionately beneficial outcomes without unduly restricting our freedom of choice. Indeed, the apparently virtuous—and cost-effective—possibilities of nudge theory has led to its enthusiastic adoption by adherents in the highest echelons of government and business, and ‘nudge units’ (such as the Behavioural Insights Team in the British Cabinet Office) have been established in the UK, the United States, and Australia.

While far from uncontroversial (some critics have questioned its ethical implications and dismissed many of its practical applications as short-term, politically motivated initiatives based on flimsy evidence), in recent years there has been an astonishing growth in scholarly output about and around the economics of nudge. And now, while the hybrid field continues to flourish, Routledge announces a new four-volume collection to provide users with a much-needed compendium of foundational and the very best cutting-edge scholarship.

The collection is co-edited by Cass R. Sunstein (Robert Walmsley University Professor at Harvard), the co-author (with Richard Thaler) of the pioneering Nudge: Improving Decisions About Health, Wealth, and Happiness (2008), and Lucia Reisch of the Copenhagen Business School. The Economics of Nudge is fully indexed and has a comprehensive introduction, newly written by the editors, which places the collected material in its historical and intellectual context. It is an essential work of reference and is destined to be valued by scholars, students, and policymakers as a vital resource.

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Neuroendocrinology of Appetite


Neuroendocrinology of Appetite

This cutting-edge, interdisciplinary volume  describes established and state of the art approaches for exploring the pathways that influence and control appetite, including: behavioural, electrophysiological, neuroanatomical, gene knockout and pharmacological techniques.   The book presents key peptide and neurotransmitter systems, together with newly emerging concepts of metabolic signalling and hypothalamic inflammation.  The impact of early life experience on neuroendocrine appetite circuits is also looked at, including early programming of these circuits by circulating hormones.  Finally, new emerging therapeutic approaches to appetite suppression are discussed, including those linked to bariatric (weight loss) surgery.

Neuroendocrinology of Appetite is especially focused on established and emerging technologies and approaches for investigating appetite control.  It is written so as to provide an overview of sufficient depth for an undergraduate or new scientist in the field to come up to speed in the complementary approaches used by researchers in this field. Taking an interdisciplinary approach, the book aims to appeal to all those with a basic, clinical or therapeutic interest in research into obesity and eating disorders

aviailable to purchase from Wiley

Measuring oxytocin and vasopressin: bioassays, immunoassays and random numbers

Gareth Leng and Nancy Sabatier

Journal of Neuroendocrinology, 2016, 28

In this review, we consider the ways in which vasopressin and oxytocin have been measured since their first discovery. Two different ways of measuring oxytocin in widespread use currently give values in human plasma that differ by two orders of magnitude, and the values measured by these two methods in the same samples show no correlation. The notion that we should accept this seems absurd. Either one (or both) methods is not measuring oxytocin, or, by ‘oxytocin’, the scientists that use these different methods mean something very different. If these communities are to
talk to each other, it is important to validate one method and invalidate the other, or else to establish exactly what each community understands by ‘oxytocin’. A similar issue concerns vasopressin: again, different ways of measuring vasopressin give values in human plasma that differ by two orders of magnitude, and it appears that the same explanation for discrepant oxytocin measurements applies to discrepant vasopressin measurements. The first assays for oxytocin and vasopressin measured biological activity directly. When immunoassays were introduced, they
encountered problems: high molecular weight factors in raw plasma interfered with the binding of antibodies to the hormones, leading to high and erroneous readings. When these interfering factors were removed by extraction of plasma samples, immunoassays gave measurements consistent with bioassays, with measures of turnover and with the sensitivity of target tissues to exogenous hormone. However, many recent papers use an enzyme-linked immunoassay to measure plasma levels without extracting the samples. Like the first radioimmunassays of unextracted plasma, this generates impossibly high and wholly erroneous measurements.


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