Handbook of Neuroendocrinology

Table of Contents

Cover Image

Front Matter

Copyright

List of How Do We Know? Boxes

Preface

About the Editors

List of Contributors

Notes on Nomenclature

Chapter 1. An Introduction to Neuroendocrine Systems

Chapter 2. Neuroendocrine GPCR Signaling

Chapter 3. Neuroendocrine Feedback Control Systems

Chapter 4. Evolution of Reproductive Neurohormones

Chapter 5. Neural Control of the Anterior Lobe of the Pituitary Gland (Pars Distalis)

Chapter 6. Neural Control of the Posterior Pituitary Gland (Neurohypophysis)

Chapter 7. Neural Control of the Intermediate Lobe of the Pituitary Gland (Pars Intermedia) and Proopiomelanocortin

Chapter 8. The Hypothalamic–Pituitary–Adrenal Axis and Neuroendocrine Responses to Stress

Chapter 9. Neuroendocrine Control of Reproduction

Chapter 10. Lifetime Regulation of Growth Hormone (GH) Secretion

Chapter 11. Neuroendocrine Regulation of Development, Growth and Metabolism – Thyroid

Chapter 12. Circadian Rhythms in Neuroendocrine Systems

Chapter 13. Cardiovascular Neuroendocrinology

Chapter 14. Neuroendocrine Regulation of Food Intake

Chapter 15. Neuropeptide Regulation of Stress-Induced Behavior

Chapter 16. Neuroendocrine Regulation of Body Water and Electrolytes

Chapter 17. Sexual Differentiation of Brain and Behavior

Chapter 18. Corticosteroid Actions on Neurotransmission

Chapter 19. Neuroendocrine Mechanism of Puberty

Chapter 20. Sexual Behaviors

Chapter 21. Stress and Brain Function

Chapter 22. Neuroendocrinology of Aggression

Chapter 23. Chronic Social Stress

Chapter 24. Estrogen and Cognitive Aging in Women

Chapter 25. Hormones, Mood and Affect

Chapter 26. Hormones and the Aging Brain

Chapter 27. Kallmann Syndrome and Other Causes of Hypothalamic Hypogonadism and Related Development Disorders

Chapter 28. Parental Behavior and the Perinatal Programming of Infant Development

Chapter 29. Disorders of the Hypothalamic–Pituitary–Adrenocortical System

Chapter 30. Disorders of the Hypothalamic–Pituitary–Gonadal Axis

Chapter 31. Disorders of the Hypothalamic–Pituitary–Thyroid Axis

Chapter 32. Neuroendocrine Growth Disorders – Dwarfism, Gigantism

Chapter 33. Neuroendocrine Inherited or Induced Aromatase Enzyme Deficits

Chapter 34. Pituitary Adenomas

Chapter 35. Neuroendocrine Tumors

Chapter 36. Psychoneuroendocrinology

Subject Index

Author Index

Front Matter

Handbook of Neuroendocrinology

Edited by

George Fink

Donald W. Pfaff

Jon E. Levine

AMSTERDAM • BOSTON • HEIDELBERG • LONDON NEW YORK • OXFORD • PARIS • SAN DIEGO SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO

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12 13 14 15 16 10 9 8 7 6 5 4 3 2 1

List of How Do We Know? Boxes

Chapter 3

Box 3.1 How do we know the validity of the concept of the set point?

George Fink

Chapter 4

Box 4.1 How do we know that GnRH and its receptor are essential for reproduction?

Graeme J. Roch, Ellen R. Busby and Nancy M. Sherwood

Box 4.2 How do we know about establishing a new GnRH receptor and its signaling path?

Graeme J. Roch, Ellen R. Busby and Nancy M. Sherwood

Box 4.3 How do we know about the structure of neuropeptides and receptors beyond mammals?

Graeme J. Roch, Ellen R. Busby and Nancy M. Sherwood

Chapter 5

Box 5.1 How do we know that anterior pituitary hormone secretion is under neurohumoral control?

George Fink

Box 5.2 How do we know about the teleological advantages of neurohormonal control?

George Fink

Box 5.3 How do we know about the apparent paradox of negative–positive feedback?

George Fink

Box 5.4 How do we know that somatostatin 1-28 is a physiological neurohormone?

George Fink

Chapter 6

Box 6.1 How do we know that oxytocin and vasopressin are released from dendrites?

Gareth Leng, Mike Ludwig and Alison J. Douglas

Chapter 7

Box 7.1 How do we know the role of IL MSH in background-adapted skin pigmentation of amphibians?

Malcolm J. Low

Box 7.2 How do we know about regulation of POMC transgenes in mouse IL?

Malcolm J. Low

Box 7.3 How do we know about neuroanatomic mapping of the hypothalamic innervation of IL melanotropes?

Malcolm J. Low

Chapter 8

Box 8.1 How do we know the hypothalamic–pituitary–adrenal axis is a major mediator of the stress response?

Greti Aguilera

Box 8.2 How do we know CRH and VP controlling ACTH secretion are produced by the paraventricular nucleus of the hypothalamus?

Greti Aguilera

Box 8.3 How do we know CRH and VP act by interacting with plasma membrane receptors in the target tissue?

Greti Aguilera

Chapter 9

Box 9.1 How do we know that the GnRH-1 neurons come from the nose?

Iain J. Clarke, Rebecca Campbell, Jeremy T. Smith, Vincent Prevot, and Susan Wray

Box 9.2 How do we know that GnRH cells are interconnected and receive input through their dendrites?

Iain J. Clarke, Rebecca Campbell, Jeremy T. Smith, Vincent Prevot, and Susan Wray

Box 9.3 How do we know that there is plasticity within the median eminence that influences GnRH secretion?

Iain J. Clarke, Rebecca Campbell, Jeremy T. Smith, Vincent Prevot, and Susan Wray

Box 9.4 How do we know that the secretion of FSH does not require the pulsatile input of GnRH to the pituitary gland?

Iain J. Clarke, Rebecca Campbell, Jeremy T. Smith, Vincent Prevot, and Susan Wray

Box 9.5 How do we know that kisspeptin relays negative and positive feedback effects of estrogen to GnRH neurons?

Iain J. Clarke, Rebecca Campbell, Jeremy T. Smith, Vincent Prevot, and Susan Wray

Box 9.6 How do we know GnIH is a peptide that negatively regulates the GnRH/gonadotropin axis in mammals?

Iain J. Clarke, Rebecca Campbell, Jeremy T. Smith, Vincent Prevot, and Susan Wray

Chapter 10

Box 10.1 How do we know there is lifetime regulation of growth hormone (GH) secretion?

Johannes D. Veldhuis, Ali Iranmanesh, Dana Erickson, Ferdinand Roelfsema, and Cyril Y. Bowers

Chapter 11

Box 11.1 How do we know that thyroid hormone receptor regulates gene expression in the absence of T3?

R. Thomas Zoeller

Box 11.2 How do we know that thyroid hormone from the mother acts on the fetal brain?

R. Thomas Zoeller

Chapter 12

Box 12.1 How do we know about the Clock gene?

Deanna M. Arble, Georges Copinschi, Martha H. Vitaterna, Eve Van Cauter, and Fred W. Turek

Chapter 13

Box 13.1 How do we know that the hypothalamic paraventricular nucleus links to brainstem and spinal cord neurons controlling cardiovascular function?

Gina L.C. Yosten and Willis K. Samson

Box 13.2 How do we know that brain-derived angiotensin peptides control cardiovascular function?

Gina L.C. Yosten and Willis K. Samson

Box 13.3 How do we know how to prove the physiologic relevance of a neuropeptide when gene knockout is lethal?

Gina L.C. Yosten and Willis K. Samson

Chapter 14

Box 14.1 How do we know how animals eat? The structured meal as the unit of feeding behavior

Alan G. Watts

Box 14.2 How do we know that leptin acts in the brain to control metabolism?

Alan G. Watts

Chapter 15

Box 15.1 How do we know the genetic approach for intracerebroventricular delivery?

Yehezkel Sztainberg and Alon Chen

Chapter 16

Box 16.1 How do we know about water intake and VP secretion in response to hypovolemia in rats?

Edward M. Stricker and Joseph G. Verbalis

Box 16.2 How do we know about salt appetite in response to hypovolemia in rats?

Edward M. Stricker and Joseph G. Verbalis

Chapter 17

Box 17.1 How do we know about prostaglandins and the developing preoptic area?

Margaret M. McCarthy

Chapter 18

Box 18.1 How do we know that corticosteroid hormones rapidly change neurotransmitter release?

Marian Joëls, E. Ronald de Kloet, and Henk Karst

Box 18.2 How do we know that corticosteroid hormones slowly change the response of identified neurons to a particular neurotransmitter?

Marian Joëls, E. Ronald de Kloet, and Henk Karst

Box 18.3 How do we know the effects of early life stress on brain function?

Marian Joëls, E. Ronald de Kloet, and Henk Karst

Chapter 19

Box 19.1 How do we know that, in humans and non-human primates, a juvenile hiatus in LH secretion is controlled by a mechanism that is independent of gonadal influence?

Ei Terasawa and Joseph R. Kurian

Box 19.2 How do we know that a shift in balance of excitatory versus inhibitory neurotransmitters occurs at puberty and may be responsible for the pubertal acceleration of hypothalamic GnRH release?

Ei Terasawa and Joseph R. Kurian

Chapter 20

Box 20.1 How do we know about male sexual behavior?

Marilyn Y. McGinnis and Donald W. Pfaff

Box 20.2 How do we know how hormones activate female sexual behavior?

Marilyn Y. McGinnis and Donald W. Pfaff

Box 20.3 How do we know about the role of androgen receptors in modulating sexual behavior?

Marilyn Y. McGinnis and Donald W. Pfaff

Chapter 21

Box 21.1 How do we know that stress affects hippocampal neurogenesis?

Ilia N. Karatsoreos and Bruce S. McEwen

Box 21.2 How do we know that sleep and circadian disruption may be a potential stressor?

Ilia N. Karatsoreos and Bruce S. McEwen

Chapter 22

Box 22.1 How do we know about establishing neuroendocrine–behavior interactions?

Brian C. Trainor and Randy J. Nelson

Box 22.2 How do we know how to identify neurosteroids in brain tissue?

Brian C. Trainor and Randy J. Nelson

Chapter 23

Box 23.1 How do we know that subordinate rats are stressed?

Karen A. Scott, Kellie L. K. Tamashiro, Randall R. Sakai

Chapter 24

Box 24.1 How do we know that the effect of estrogen treatment (ET) on cognition in women depends on the timing of the initiation of therapy?

Barbara B. Sherwin

Chapter 25

Box 25.1 How do we know that the human brain is sexually dimorphic?

Sarah L. Berga, and Yolanda R. Smith

Box 25.2 How do we know that the synthetic hormones used in oral contraceptives modulate the neural circuitry of emotion of women?

Sarah L. Berga, and Yolanda R. Smith

Box 25.3 How do we know that estradiol and progesterone have independent effects upon key neurotransmitter systems that mediate affect and emotion

Sarah L. Berga, and Yolanda R. Smith

Box 25.4 How do we know that the postmenopausal use of exogenous hormones alters brain metabolism?

Sarah L. Berga, and Yolanda R. Smith

Chapter 26

Box 26.1 How do we know that some hormones protect the nervous system from aging-associated deterioration?

Iñigo Azcoitia and Luis M. Garcia-Segura

Chapter 27

Box 27.1 How do we know about oligogenicity – a new concept in the genetic basis of isolated GnRH deficiency?

TS Han and PMG Bouloux

Chapter 28

Box 28.1 How do we know that hormones increase maternal responsivity?

Frances A. Champagne and James P. Curley

Box 28.2 How do we know that prolactin receptors are involved in maternal behavior?

Frances A. Champagne and James P. Curley

Box 28.3 How do we know that infants activate reward pathways in the brain of parents?

Frances A. Champagne and James P. Curley

Box 28.4 How do we know that 11-β HSD in the placenta is involved in prenatal programming of the stress response?

Frances A. Champagne and James P. Curley

Box 28.5 How do we know that maternal care influences DNA methylation during postnatal development?

Frances A. Champagne and James P. Curley

Chapter 29

Box 29.1 How do we know about familial or sporadic generalized glucocorticoid resistance syndrome or Chrousos' syndrome?

Tomoshige Kino, Evangelia Charmandari, and George P. Chrousos

Chapter 30

Box 30.1 How do we know if FSH is necessary for androgen production?

Lawrence C. Layman

Chapter 31

Box 31.1 How do we know about the pathogenesis of RTH and the function of thyroid hormone receptors?

Aniket R. Sidhaye and Frederic E. Wondisford

Chapter 32

Box 32.1 How do we know about d3GH receptor polymorphism and responsiveness to GH therapy?

Roberto Salvatori

Chapter 33

Box 33.1 How do we know about androgen specificity of aromatase?

Wah Chin Boon and Evan R Simpson

Box 33.2 How do we know about sexual behavior in male ArKO mice

Wah Chin Boon and Evan R Simpson

Box 33.3 How do we know about in situ apoptosis?

Wah Chin Boon and Evan R Simpson

Box 33.4 How do we know about learning and memory in rodents?

Wah Chin Boon and Evan R Simpson

Chapter 34

Box 34.1 How do we know there may be an intrinsic cell defect in the origin of pituitary adenomas?

Ines Donangelo and Shlomo Melmed

Box 34.2 How do we know? Diagnostic approach to elevated prolactin

Ines Donangelo and Shlomo Melmed

Box 34.3 How do we know? Diagnostic and therapeutic approaches to acromegaly

Ines Donangelo and Shlomo Melmed

Box 34.4 How do we know? Diagnostic approach to Cushing’s syndrome

Ines Donangelo and Shlomo Melmed

Box 34.5 How do we know novel genes are involved in pituitary pathogenesis?

Ines Donangelo and Shlomo Melmed

Chapter 35

Box 35.1 How do we know about somatostatin receptors, key targets for diagnosis and treatment of neuroendocrine tumors?

Richard A. Feelders, Leo J. Hofland, Dik J. Kwekkeboom, Steven W. Lamberts, and Wouter W. De Herder

Chapter 36

Box 36.1 How do we know that endocrine function affects behavioral and mood disturbances?

David R. Rubinow, Virginia L. Crowder, Peter J. Schmidt, and Katya B. Rubinow

Preface

Reproduction, growth, stress, aggression, metabolism, birth, feeding and drinking, and blood pressure are some of the bodily functions that are triggered and controlled by neuroendocrine systems. Neuroendocrinology is the discipline concerned with the study of how the nervous system controls hormonal secretion by endocrine glands and, in turn, the ways in which hormones control the brain. The neural–endocrine nexus facilitates appropriate hormonal responses to (1) outside (so called exteroreceptive) influences such as day-length, stressful challenges, suckling and temperature, and (2) internal (interoreceptive) influences such as hunger, thirst, plasma osmolality, emotions, and afferent impulses from the uterus in parturition.

The main neuroendocrine nexus in vertebrates is at the base of the brain, where the pituitary gland is connected to the hypothalamus by way of the pituitary stalk – the hypothalamic–pituitary system. The hypothalamus is connected by way of major nerve pathways with the rest of the forebrain and hindbrain, and with the peripheral and autonomic nervous systems through the spinal cord.

The human pituitary gland weighs no more than 1 gram, but nonetheless controls all the major endocrine systems and is indispensable for life. The gland is comprised of the neural and anterior lobes. Derived embryologically from a neural downgrowth, the neural lobe (neurohypophysis) is comprised of axons that project from perikarya in the hypothalamus to terminate on capillaries of the inferior pituitary artery. This is the site at which the neurohormones vasopressin and oxytocin are released into the systemic circulation, by means of which they are transported to their target organs – the kidneys, blood vessels, uterus and breast. Synthesized in hypothalamic nuclei, vasopressin controls the volume of body water, whereas oxytocin triggers milk ejection in response to suckling, or contraction of the uterus during parturition.

Derived from an outgrowth of the embryonic roof of the mouth, the anterior pituitary gland controls the adrenal and thyroid glands, the gonads, body growth and metabolism, and development of the breast and lactation. Anterior pituitary hormone secretion is under central nervous control, and is modulated by the feedback of hormones secreted by the pituitary target organs – i.e., the adrenal and thyroid glands, the gonads, and fat tissue. Neural control of anterior pituitary hormones is mediated by hypothalamic–pituitary regulatory neurohormones that are released from nerve terminals in the hypothalamus into the hypophysial portal vessels. This set of small vessels (portal veins), in the pituitary stalk, transports the neurohormones to the anterior pituitary gland, where they either stimulate or inhibit the synthesis and release of the anterior pituitary hormones.

In addition to the hypothalamic–pituitary system, neurovascular organs (e.g., the pineal gland) that comprise neurohemal junctions surround the cerebral ventricles (the circumventricular organs) and also satisfy the criteria of neuroendocrine systems in that they facilitate the transmission of chemical signals between soma and brain. The term neuroendocrine is also applied to junctional zones between nerve and endocrine cells in the periphery and especially the viscera, of which the adrenal medulla (the main source of the body’s epinephrine) and the gastrointestinal system and its appendages are the most prominent.

Neuroendocrinology is pivotal to physiology and medicine in that this discipline has disclosed and underpins numerous fundamental molecular biological and genetic principles. Thus, for example, much of our knowledge of gene regulation, gene transcription and post-translational protein processing derives from neuroendocrine models. Similarly, much of our knowledge of the mechanisms of neurochemical transmitter synthesis, release (exocytosis) and stimulus–secretion coupling derives from studies of the neural lobe of the pituitary gland and the adrenal medulla.

Neuroendocrine systems have played a seminal role in enabling us to understand biological control, and especially positive and negative feedback mechanisms and biological rhythms (e.g., circhoral, circadian, seasonal, and reproductive rhythms such as estrous and menstrual cycles). Neuroendocrine mechanisms subserve many key functions of the body, and are pivotal to the body’s ability to cope with stress. Consequently, neuroendocrine dysfunction due to genetic or other deficits leads to disorders such as infertility, impotence, precocious or delayed puberty, defective or excessive growth (dwarfism and acromegaly, respectively), obesity and anorexia, Cushing’s syndrome, Addison’s disease, hypertension, and hypothyroidism and hyperthyroidism. Neuroendocrine tumors are relatively common, and in turn neuroendocrine strategies are being used as adjunct therapy to control tumor growth.

Hormones exert powerful effects on brain and behavior. In birds and mammals, for example, development of the male brain (sexual differentiation of the brain) depends, at least in part, on exposure to androgens secreted by the testes. Central nervous development also depends on the secretion of normal amounts of thyroid hormone in the fetus and early postnatal period. Absence of thyroid hormone during this critical period results in cretinism, due to failure of nerve cells to develop normal dendritic trees and synaptic connections. This defective brain development can be rectified by thyroid hormone administration before the end of the critical postnatal period (about 6 months of age in man).

Hormones exert powerful appetitive drives with respect to sex, water, food, brooding and nest-building, and parenting. Closely related to the need to find optimal conditions for reproduction and care of the young offspring, day-length dependent neuroendocrine mechanisms drive migration – perhaps seen most dramatically in birds, but also readily observed in other phyla. Aggression is a key behavior driven by hormones. In stags, for example, changes in day-length result in massive neuroendocrine changes that are manifested by androgen-induced growth of antlers in preparation for rutting – the annual fight for mating rights – that is also driven by androgen, and occurs each autumn. Similarly, changes in day-length switch the female into estrus, a state in which she is receptive to sexual advances of the male.

The stress response is closely related to aggressive behavior and the need to compete for territory, food, water, and appropriate mates. Orchestrated by neuroendocrine mechanisms that involve the forebrain, hypothalamus, pituitary gland, adrenal gland and autonomic nervous system, the stress response enables the individual to fight or flee, and to reset the metabolic and cardiovascular feedback control set-points to levels optimum for particular environmental situations or challenges.

This handbook is aimed at a level suitable for senior undergraduate students, graduate students, post-doctoral fellows and faculty in neuroscience, medicine, clinical psychology, neuropsychology, endocrinology and/or hormones and behavior. The handbook is also relevant for students and researchers in cognate disciplines such as psychiatry or neuropharmacology. In addition to covering neuroendocrine science, the handbook addresses clinically and socially topical areas of research, such as obesity, diabetes and the metabolic syndrome, stress and aggression, endocrine disrupters, sexual behavior and gender assignment, and neuroendocrine pathology.

We were fortunate to be able to attract internationally acknowledged experts in the field to prepare up-to-date reviews in most major areas of the field, and thereby satisfy what we believe to be a current unmet need in the discipline of neuroendocrinology. Key points have been underscored by the inclusion of How do we know? callout sections that highlight and demonstrate the experimental or technical foundation for a major concept, principle or methodological advance (both classic and modern). These callout sections will add to the educative value of this handbook for neuroscience and medicine.

We thank Mica Haley (Elsevier’s Senior Neuroscience Editor) for her enthusiasm and encouragement, and invaluable assistance that enabled us to complete this work.

George Fink

Donald W. Pfaff

Jon E. Levine

About the Editors

George Fink

George Fink is a neuroendocrinologist and neuropharmacologist with a special interest in reproduction, stress and the pathogenesis of mental disorders. Currently, Fink is Honorary Professor in the University of Melbourne and Professorial Research Fellow of the Mental Health Research Institute, Australia, of which he was formerly Director (2004 – 2006). Following an appointment as senior lecturer in Anatomy at Monash University, Australia (1968–1971), Fink moved to Oxford University to serve as University Lecturer in Human Anatomy and Official Fellow and Tutor (Brasenose College) in Physiology and Medicine (1971 – 1980). This was followed by nearly 20 years as Director of the MRC Brain Metabolism Unit (BMU) Edinburgh. Under Fink's Directorship the BMU became renowned for integrated molecular and clinical neuroendocrinology and psychopharmacology. Between 1999 and 2003, Fink served as Vice President Research, Pharmos Corporation, an Israeli/USA biotechnology company focused on neuroinflammatory disorders.

Fink graduated MB BS (Hons and Prosector in Anatomy) and MD (awarded for a selection of his published neuroendocrine papers) from the University of Melbourne, Australia. An Oxford DPhil was gained under tenure of a Nuffield Dominions Demonstratorship in the laboratory of Geoffrey Harris FRS. Fink's recent research, focused on sex steroid control of central neurotransmission, is relevant to our understanding of gender differences in disorders of mood and mental state. His earlier research discoveries include (i) characterization of neurohormone release into hypophysial portal blood, (ii) the mechanism by which estrogen positive feedback triggers the ovulatory gonadotropin surge, (iii) the self-priming effect of gonadotropin releasing hormone, and (iv) aspects of adrenal and gonadal steroid control of pituitary hormone secretion by way of feedback and servomechanisms. Fink's research contributions are reported in more than 360 scientific publications including Elsevier's Encyclopedia of Stress of which Fink was founding Editor and which was awarded the 2001 BMA Medical Book Commendation in Mental Health.

Fink has served on numerous editorial boards and scientific committees including Chair of the Brain Research Panel of the EU Biomedical Programs 3 and 4, the Mental Health Panel of the Wellcome Trust, Council of the European Neuroscience Association and President of the European Neuroendocrine Association.

His distinctions include Fellow of the Royal Society of Edinburgh (elected 1989), Fellow of the Royal College of Physicians of Edinburgh (elected 1998), Honorary Professor in the University of Edinburgh (appointed 1984), Lifetime Achievement Award of the International Society of Psychoneuroendocrinology (2000), Honorary Member of the British Society for Neuroendocrinology (2005) and Distinguished Scholar of Melbourne High School (2000). Fink has given numerous invited lectures including the inaugural Geoffrey Harris Prize Lecture of the British Physiological Society and the Wolfson Lecture. His other appointments include: Visiting Professor at the Rockefeller University (Neurobiology and Behavior Laboratory) New York; Visiting Professor in Neurobiology, the Mayo Clinic, Rochester Minnesota; Arthur Fishberg Professor, Mount Sinai Medical Center, New York; Walter Cottman Visiting Professor at Monash University; Royal Society-Israel Academy Exchange Fellow at the Weizmann Institute, Rehovot, Israel.

Donald W. Pfaff

Donald W. Pfaff, Ph.D., professor and head of the Laboratory of Neurobiology and Behavior at The Rockefeller University, is a brain scientist who uses neuroanatomical, neurochemical and neurophysiological methods to study the cellular mechanisms by which the brain controls behavior. His laboratory's research has proceeded to demonstrate how steroid hormone effects on nerve cells can direct natural, instinctive behaviors.

In 2003, Pfaff received an NIH MERIT Award for the study of generalized arousal, responsible for activating all behavioral responses. His team formulated the first operational definition of nervous system arousal, enabling scientists to measure arousal quantitatively in laboratory animals, as well as in human beings. In humans, deficits in arousal contribute to such cognitive problems as attention deficit hyperactivity disorder, autism and Alzheimer's disease.

Pfaff has made fundamental contributions to our understanding of how the administration of sex hormones can affect health. Pfaff's lab recently showed that giving hormone doses in pulses, rather than as a steady exposure, may maximize the benefits and limit the side effects now associated with hormone therapies. By giving estrogen replacement to the rats, the scientists studied the actions of the hormone at the level of the brain cell's protective outer membrane, and inside the nucleus where the cell's DNA is housed. They found that both the membrane and the DNA pathways are crucial, with one facilitating the other, in triggering hormone-dependent gene expression and female mating behavior. By limiting the estrogen exposure of to short pulses, the total dose can be kept much smaller than with steady delivery, and therefore some of the negative effects will be reduced.

Born in Rochester, N.Y., on December 9, 1939, he received the A.B. degree magna cum laude from Harvard College in 1961 and a Ph.D. from the Massachusetts Institute of Technology in 1965. He held a National Merit Scholarship, Harvard National Scholarship, Woodrow Wilson Fellowship, MIT President's Award Fellowship, National Institutes of Health Predoctoral Fellowship and National Science Foundation Postdoctoral Fellowship.

Pfaff joined The Rockefeller University in 1966 as a postdoctoral fellow. He was named assistant professor in 1969, associate professor in 1971, granted tenure in 1973 and promoted to full professor in 1978. He is a member of the U.S. National Academy of Sciences and a fellow of the American Academy of Arts and Sciences. He also is a member of several scientific organizations related to studies of the central nervous system.

He is the author of Estrogens and Brain Function (Springer, 1980); Drive: Neurobiological and Molecular Mechanisms of Sexual Motivation (MIT Press, 1999); and Brain Arousal and Information Theory (Harvard University Press, 2005). He has edited ‘The Physiological Bases of Motivation’ (1982), ‘Ethical Questions in Brain and Behavior’ (1984), ‘Genetic Influences on the Nervous System’ (CRC Press, 1999) and ‘Hormones, Brain and Behavior’ (5 volumes, Academic Press, 2002, 2009). He also is on the editorial boards of several scientific journals.

Jon E. Levine

Dr. Jon E. Levine, Ph.D. completed his B.A. at Oberlin College in Oberlin, Ohio, and his Ph.D. from the University of Illinois, Champaign-Urbana. Dr. Levine completed postdoctoral training at the Oregon National Primate Research Center & Oregon Health Sciences University. Levine joined the faculty at Northwestern University in Evanston, Illinois in 1984, and remained there as Professor in the Department of Neurobiology and Physiology until 2010. While on the faculty at Northwestern, Dr. Levine served as Director of the Program in Biological Sciences (1999–2006), and as Director of a NIH-sponsored Training Program in Reproductive Biology (1991–2010). He is currently the Director of the Wisconsin National Primate Research Center and Professor in the Department of Neuroscience at the University of Wisconsin-Madison. For the past 30 years Dr. Levine has studied the neuroendocrine regulation of gonadotropin releasing hormone (GnRH) neurons. Dr. Levine's research has also focused on the molecular and cellular mechanisms by which ovarian steroids exert their physiological and behavioral effects in the brain, including the negative feedback mechanisms that maintain homeostatic control within the reproductive axis, as well as the positive feedback actions of steroids that trigger preovulatory gonadotropin surges. His recent work has made use of newly developed mutant mice to analyze the cell signaling mechanisms that mediate negative and positive feedback actions of estradiol, as well as the effects of estrogens on energy homeostasis and body weight. Dr. Levine is currently Editor-in-Chief of the journal Frontiers in Neuroendocrinology, and is a member of the Steering Council for the Office of Research on Women's Health at the NIH. He is an active member of numerous professional societies including the Endocrine Society, Society for Neuroscience, Society for the Study of Reproduction, American Neuroendocrine Society, and the Society for Behavioral Neuroendocrinology.

List of Contributors

Greti Aguilera

Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver Institute of Child Health and Human Development, NIH, Bethesda, Maryland, USA

Deanna M. Arble

Center for Sleep and Circadian Biology, Department of Neurobiology and Physiology, Northwestern University, Evanston, IL, USA

Iñigo Azcoitia

Departamento de Biología Celular, Facultad de Biología, Universidad Complutense de Madrid, Madrid, Spain

Sarah L. Berga

Division of Reproductive Endocrinology and Infertility, Departments of Gynecology and Obstetrics and Psychiatry, Emory University School of Medicine, Atlanta, GA, USA

Wah Chin Boon

Florey Neuroscience Institutes, Centre for Neuroscience, University of Melbourne, and Department of Anatomy and Development, Monash University, Melbourne, Australia

Pierre M.G. Bouloux

Centre for Neuroendocrinology, University College London Medical School, Royal Free Hospital, Hampstead, London, UK

Cyril Y. Bowers

Division of Endocrinology, Department of Internal Medicine, Tulane University Health Sciences Center, New Orleans, LA, USA

Ellen R. Busby

University of Victoria, Department of Biology, Victoria, BC, Canada

Rebecca Campbell

Department of Physiology, School of Medical Science, University of Otago, Dunedin, New Zealand

Frances A. Champagne

Department of Psychology, Columbia University, New York, NY, USA

Evangelia Charmandari

First Department of Pediatrics, University of Athens Medical School, Aghia Sophia Children's Hospital, Athens, Greece; and Division of Endocrinology and Metabolism, Biomedical Research Foundation of the Academy of Athens, Athens, Greece

Alon Chen

Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel

George P. Chrousos

First Department of Pediatrics, University of Athens Medical School, Aghia Sophia Children's Hospital, Athens, Greece; and ³Division of Endocrinology and Metabolism, Biomedical Research Foundation of the Academy of Athens, Athens, Greece

Iain J. Clarke

Department of Physiology, Monash University, Clayton, Victoria, Australia

Georges Copinschi

Laboratory of Physiology, School of Medicine, Université Libre de Bruxelles, Brussels, Belgium

Virginia L. Crowder

Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

James P. Curley

Department of Psychology, Columbia University, New York, NY, USA

Wouter W. de Herder

Department of Internal Medicine, Section of Endocrinology, Erasmus Medical Center, Rotterdam, The Netherlands

E. Ronald de Kloet

LACDR, Leiden University, Leiden, The Netherlands

Ines Donangelo

Pituitary Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA

Alison J. Douglas

Centre for Integrative Physiology, University of Edinburgh, Edinburgh, UK

Dana Erickson

Endocrine Research Unit, Mayo School of Graduate Medical Education, Clinical Translational Science Center, Mayo Clinic, Rochester, MN, USA

Richard A. Feelders

Department of Internal Medicine, Section of Endocrinology, Erasmus Medical Center, Rotterdam, The Netherlands

George Fink

Mental Health Research Institute, University of Melbourne, Melbourne, Victoria, Australia

Luis M. Garcia-Segura

Instituto Cajal, Consejo Superior de Investigaciones Científicas, Madrid, Spain

Thang S. Han

Centre for Neuroendocrinology, University College London Medical School, Royal Free Hospital, Hampstead, London, UK

Leo J. Hofland

Department of Internal Medicine, Section of Endocrinology, Erasmus Medical Center, Rotterdam, The Netherlands

Ali Iranmanesh

Endocrine Service, Medical Section, Salem Veterans Affairs Medical Center, Salem, VA, USA

Marian Joëls

Rudolf Magnus Institute, UMC Utrecht, Utrecht, The Netherlands

Ilia N. Karatsoreos

Harold and Margaret Milliken Hatch, Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY, USA

Henk Karst

Rudolf Magnus Institute, UMC Utrecht, Utrecht, The Netherlands

Tomoshige Kino

Unit on Molecular Hormone Action, Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA

Joseph R. Kurian

Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI, USA

Dik J. Kwekkeboom

Department of Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands

Steven W. Lamberts

Department of Internal Medicine, Section of Endocrinology, Erasmus Medical Center, Rotterdam, The Netherlands

Lawrence C. Layman

Section of Reproductive Endocrinology, Infertility, & Genetics, Dept Obstetrics and Gynecology, Developmental Neurobiology Program, Institute of Molecular Medicine and Genetics, Neuroscience Program, Georgia Health Sciences University, Augusta, GA, USA

Gareth Leng

Centre for Integrative Physiology, University of Edinburgh, Edinburgh, UK

Jon E. Levine

Wisconsin National Primate Research Center, and Department of Neuroscience University of Wisconsin, Madison, WI, USA

Malcolm J. Low

Department of Molecular & Integrative Physiology, Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, and Brehm Center for Diabetes Research, University of Michigan Medical School, Ann Arbor, MI, USA

Mike Ludwig

Centre for Integrative Physiology, University of Edinburgh, Edinburgh, UK

Margaret M. McCarthy

Departments of Physiology and Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA

Bruce S. McEwen

Harold and Margaret Milliken Hatch, Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY, USA

Marilyn Y. McGinnis

Department of Pharmacology and Center for Biomedical Neuroscience, University of Texas Health Sciences Center at San Antonio, San Antonio, TX, USA

Shlomo Melmed

Pituitary Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA

Robert P. Millar

Centre for Integrative Physiology, University of Edinburgh, School of Biomedical Sciences, Hugh Robson Building, Edinburgh, UK; UCT/MRC Group for Receptor Biology, University of Cape Town, Cape Town, South Africa; Mammal Research Institute, University of Pretoria, Hatfield, Pretoria, South Africa

Ali Mohamadi

Division of Endocrinology, Johns Hopkins School of Medicine, Baltimore, MD, USA

Randy J. Nelson

Departments of Neuroscience and Psychology, Ohio State University, Columbus, OH, USA

Claire L. Newton

Centre for Integrative Physiology, University of Edinburgh, School of Biomedical Sciences, Hugh Robson Building, Edinburgh, UK

Donald W. Pfaff

Neurobiology and Behavior, The Rockefeller University, New York, NY, USA

Vincent Prevot

Inserm, Jean-Pierre Aubert Research Center, U837, Development and Plasticity of the Postnatal Brain, Lille, France; Université Nord de France, Lille, France; UDSL, Laboratory of Anatomy, School of Medicine, Place de Verdun, Lille, France; CHRU Lille, Department of Neurosurgery, Hôpital Roger Salengro, Lille, France

Graeme J. Roch

University of Victoria, Department of Biology, Victoria, BC, Canada

Ferdinand Roelfsema

Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, The Netherlands

Antonia K. Roseweir

Centre for Integrative Physiology, University of Edinburgh, School of Biomedical Sciences, Hugh Robson Building, Edinburgh, UK

David R. Rubinow

Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Katya B. Rubinow

Division of Endocrinology in the Department of Medicine, University of Washington School of Medicine; Seattle, WA, USA

Randall R. Sakai

University of Cincinnati College of Medicine, Department of Psychiatry and Behavioral Neurosciences, Cincinnati, OH, USA

Roberto Salvatori

Division of Endocrinology, Johns Hopkins School of Medicine, Baltimore, MD, USA

Willis K. Samson

Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St Louis, MO, USA

Peter J. Schmidt

Section on Behavioral Endocrinology, NIMH, Bethesda, MD, USA

Karen A. Scott

University of Cincinnati College of Medicine, Department of Psychiatry and Behavioral Neurosciences, Cincinnati, OH, USA

Barbara B. Sherwin

Department of Psychology, McGill University, Montreal, Quebec, Canada

Nancy M. Sherwood

University of Victoria, Department of Biology, Victoria, BC, Canada

Aniket R. Sidhaye

Division of Metabolism, Departments of Pediatrics and Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

Evan R. Simpson

Prince Henry's Institute, Melbourne, Australia

Jeremy T. Smith

Department of Physiology, Monash University, Clayton, Victoria, Australia

Yolanda R. Smith

Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Michigan School of Medicine, Ann Arbor, MI, USA

Edward M. Stricker

Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA

Yehezkel Sztainberg

Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel

Kellie L.K. Tamashiro

The Johns Hopkins University School of Medicine, Department of Psychiatry and Behavioral Sciences, Baltimore, MD, USA

Ei Terasawa

Wisconsin National Primate Research Center, and Department of Pediatrics, University of Wisconsin, Madison, WI, USA

Brian C. Trainor

Department of Psychology, University of California, Davis, CA, USA

Fred W. Turek

Center for Sleep and Circadian Biology, Department of Neurobiology and Physiology, Northwestern University, Evanston, IL, USA

Eve Van Cauter

Sleep, Metabolism and Health Center Department of Medicine, University of Chicago Pritzker School of Medicine, Chicago, IL, USA

Johannes D. Veldhuis

Endocrine Research Unit, Mayo School of Graduate Medical Education, Clinical Translational Science Center, Mayo Clinic, Rochester, MN, USA

Joseph G. Verbalis

Department of Medicine, Georgetown University Medical Center, Washington, DC, USA

Martha H. Vitaterna

Center for Sleep and Circadian Biology, Department of Neurobiology and Physiology, Northwestern University, Evanston, IL, USA

Alan G. Watts

Department of Biological Sciences, USC College of Letters, Arts, and Sciences, University of Southern California, Los Angeles, CA, USA

Fredric E. Wondisford

Division of Metabolism, Departments of Pediatrics and Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

Susan Wray

Cellular and Developmental Neurobiology Section, NINDS, NIH, Bethesda, Maryland, USA

Gina L.C. Yosten

Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St Louis, MO, USA

R. Thomas Zoeller

Biology Department, University of Massachusetts, Amherst, MA, USA

Notes on Nomenclature

Catecholamines

Adrenaline and noradrenaline are catecholamines that play a pivotal role in the stress and other neuroendocrine responses. These terms are synonymous with epinephrine and norepinephrine, respectively. Both sets of terms are used interchangeably in the endocrine and neuroendocrine literature, and this principle has been adopted for the Handbook. Style has depended on author preference.

Corticotropin-Releasing Factor/Hormone

The central nervous regulation of the anterior pituitary gland is mediated by substances, mainly peptides, synthesized in the hypothalamus and transported to the gland by the hypophysial portal vessels. Because these compounds are transported in the blood stream, the term neurohormone gained acceptance in the neuroendocrine literature. This convention, endorsed by the Endocrine Society (USA), has been applied without dissension to all hypothalamic peptide neurohormones with the exception of the 41-amino acid residue corticotropin-releasing factor (CRF). Hauger and colleagues, ¹ in liaison with the International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification, argue that the CRF's function extends well beyond the biology of a hormone, and that therefore it should be termed corticotropin-releasing factor (CRF) rather than hormone. Since the terminology of CRF versus CRH has yet to be resolved, the two terms and abbreviations are here used interchangeably, depending on author preference.

Gonadotropin-Releasing Hormone (GnRH)/LHRH

The anterior pituitary gland secretes two gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). At the start of research into the nature of hypothalamic pituitary releasing (subsequently regulatory) factors it was assumed that neural control of LH and FSH would be mediated by distinct LH-releasing and FSH-releasing factors. However, despite extensive studies over the past 55 years, current evidence points to the fact that neural control of the synthesis and release of both gonadotropins is mediated by one and the same decapeptide. This was at first termed LH-releasing factor (LRF), then LH-releasing hormone (LHRH), and then finally, because it mediates neural control of both gonadotropins, gonadotropin-releasing hormone (GnRH). The latter, adopted as the standard term and abbreviation by the Endocrine Society, is used by most authors in this Handbook. However, readers should be aware that GnRH, LHRH and LRF are synonymous.

Reference

1. Hauger, R.L.; Grigoriadis, D.E.; Dallman, M.F.; Plotsky, P.M.; Vale, W.W.; Dautzenberg, F.M., International Union of Pharmacology. XXXVI. Current status of the nomenclature for receptors for corticotropin-releasing factor and their ligands, Pharmacol Rev. 55 (1) (2003) 21–26.

Chapter 1. An Introduction to Neuroendocrine Systems

Jon E. Levine

Wisconsin National Primate Research Center, and Department of Neuroscience, University of Wisconsin, Madison, WI, USA

Outline

Neuroendocrinology Defined3

Neurosecretion4

The Basic Anatomy of Neuroendocrine Systems4

The Hypothalamus4

The Pituitary Gland6

The Hypothalamo-hypophysial Portal Vessel System7

Neurosecretory Cells7

Neuroendocrine Transduction and Neuroendocrine Systems8

Basic Aspects of Neuroendocrine Integration9

Neuroendocrine Reflexes Mediated by Neurohypophysial Systems9

The Basic Elements of Homeostatic Neuroendocrine Systems10

Homeostatic Systems: Hypothalamic–Pituitary–End-Organ Axes11

Homeostatic Neuroendocrine Systems Controlling Motivated Behaviors13

Experimental Characterization of Homeostatic Neuroendocrine Systems14

Environmental Stimuli, Homeostatic Settings and Allostasis14

Cellular Mechanisms of Neuroendocrine Integration15

Clinical Neuroendocrinology16

The Study of Neuroendocrinology17

Summary18

Summary

The field of neuroendocrinology is concerned with the inter-relationships between the neural and endocrine systems, and addresses regulatory mechanisms of two basic types: the neural control of hormone secretions, and the actions of peripheral hormones on neurophysiological processes and behavior. In most cases, neuroendocrine systems of both types are linked together in broader bidirectional control mechanisms which govern vitally important processes that include growth, reproduction, metabolism and energy homeostasis, electrolyte and water balance, and responses to stress. The editors and authors of this volume of work have endeavored to provide a comprehensive presentation of the state-of-the-science of neuroendocrinology, presented in a format that will be accessible for both generalist and specialist students and researchers who seek a current understanding of neuroendocrine systems. Chapter 1 introduces the basic anatomical and physiological components of neuroendocrine systems, and defines and describes their fundamental operating characteristics.

Neuroendocrinology Defined

Neuroendocrinology is a relatively new science that emerged in the mid-20th century as a branch of endocrinology, propelled in part by the realization that the brain produces neurohormones and thereby functions as an endocrine organ. During the same period, fundamental observations were made in the relatively new field of behavioral neuroscience, revealing effects of peripheral hormones on brain function, neural development, and behavior. We now consider that both processes – control of hormone secretions by the brain and effects of hormones on brain function – together define the scope of modern neuroendocrine science. Neuroendocrine systems can be defined as the sets of neurons, glands and non-endocrine tissues, and the neurochemicals, hormones, and humoral signals they produce and receive, that function in an integrated manner to collectively regulate a physiological or behavioral state. Neuroendocrine integration is the process by which neuroendocrine systems register, transduce, and interpret important signals from the internal and external environment, and thereafter direct adaptive changes in prevailing physiological and behavioral states. In this introductory chapter, we define and describe different types of neuroendocrine systems, and review the basic integrative mechanisms that each employ to operate under normal physiological circumstances.

Neurosecretion

By the 1920s, the existence of the major hormones of the pituitary gland, and their effects on the gonads, adrenal glands and growth, had been established. In the years following, there was greater awareness that the functions of the pituitary gland are largely governed by neural influences. The concept of neurosecretion – the production and secretion of neurohormones by neurons, and the actions of these hormones at target tissues – was proposed by Ernst and Berta Scharrer¹ based on their work in fish, and subsequently confirmed in a variety of species in the succeeding decades. This seminal advance is regarded as the launching point for the study of neuroendocrine systems, and perhaps as the start of the field of neuroendocrinology as a whole. Recognition that specialized neurosecretory cells can release hormones at neurovascular junctions provided the conceptual framework for understanding the two major neuroendocrine systems that govern pituitary function. In one, neurosecretion of neurohormones (vasopressin and oxytocin) occurs at neurovascular junctions in the posterior pituitary gland, directly into the systemic circulation to act at distant target tissues. In the other, hypothalamic neurohormones that were later identified as hypothalamic releasing and inhibiting factors,². and ³. are released from neurovascular junctions in the median eminence of the hypothalamus, into a hypothalamo-hypophysial portal vessel system that conveys these factors to their target cells in the anterior pituitary gland. The basic structural and physiological features of these neuroendocrine systems are described below.

The Basic Anatomy of Neuroendocrine Systems

The Hypothalamus

In 1859, the celebrated French physiologist Claude Bernard noted that the constancy of the internal milieu is essential for the survival and perpetuation of warm-blooded animals. The regulation of the internal state in the face of changing external and internal conditions is homeostasis – a process that requires coordinated control over endocrine, behavioral and autonomic nervous system responses to the environment. It is clear that the hypothalamus – and the neuroendocrine neuronal systems that reside in it – has evolved to assume a critically important role as a major integrative center for mediating these homeostatic functions. It is located at the base of the forebrain, where it can direct the endocrine functions of the pituitary gland, while also receiving hormonal signals from the periphery. The hypothalamus is also adjacent to – and highly interconnected with – limbic and cortical structures and brainstem autonomic centers. The hypothalamus is uniquely positioned to send and receive endocrine signals, as well as neural signals from sensory systems, emotion- and memory-processing circuitries, and autonomic centers. Neural and endocrine information is continuously transduced, integrated and interpreted in hypothalamic neurons, and appropriate homeostatic signals are conveyed back to these endocrine, autonomic and behavioral control systems to affect coordinated changes, when necessary, in hormone secretions, autonomic outflow and behavioral state. The hypothalamus is thus responsible for monitoring the internal and external environment and coordinating adaptive physiological responses among several systems.

The hypothalamus is defined anatomically as an area of gray matter that is located in the basal forebrain, consisting of two symmetrical halves divided medially by the third ventricle. It emerges in the developing diencephalon to be bounded rostrally by the optic chiasm, caudally by the mammillary bodies, laterally by the optic tracts, and dorsally by the thalamus. The preoptic area (POA) lies rostrally to the hypothalamus, and although it is considered telencephalic in origin, it is often regarded as a functional hypothalamic tissue. Groups of neuronal cell bodies and their neuropils constitute bilaterally symmetrical hypothalamic nuclei, as schematically depicted in Fig. 1.1. Although there are species differences in the topography of the major hypothalamic nuclei as well as the less distinct hypothalamic areas, in general the anterior region of the hypothalamus contains the supraoptic nucleus (SON), paraventricular nucleus (PVN), suprachiasmatic nucleus (SCN) and anterior hypothalamic area (AHA), and a periventricular nucleus that continues caudally; the middle region of the hypothalamus includes the arcuate nucleus (AN), ventromedial nucleus (VMN), dorsomedial nucleus (DMN) and lateral hypothalamic area (LHA); and within the posterior region of the hypothalamus lie the posterior hypothalamic nucleus (PHN) and the premammillary nucleus (PMN).

Classical studies utilized lesion and electrical stimulation techniques to ascribe integrative functions to specific nuclei as centers for the control of functions such as feeding, drinking, sexual behavior, stress responses, and electrolyte and water balance. The center concept has been somewhat outmoded with the recognition that these regulatory systems are distributed throughout many interconnected neuronal populations within and beyond the hypothalamus. Nevertheless, several of the hypothalamic nuclei do contain well-characterized neurohormone and neurotransmitter-producing cell groups that clearly serve specific integrative and effector functions that are essential components of these systems (Table 1.1). The PVN and SON, for example, are critically important in the regulation of electrolyte and water balance by virtue of the fact that magnocellular neurons within these nuclei produce the antidiuretic neurohypophysial hormone vasopressin, as described below; parvocellular neurons within the PVN express corticotropin-releasing hormone (CRH) and thereby regulate neural and hormonal responses to stress; the POA similarly contains neurons that produce the central neurohormonal effector of the reproductive axis, gonadotropin-releasing hormone (GnRH), and is therefore essential for the maintenance of gonadal function in rodents; the AN includes neuronal groups that express orexigenic and anorexigenic peptides, as well as receptors for peripheral metabolic hormones, and is thus integrally important in the regulation of food intake and energy expenditure; and subsets of neurons in the VMN express receptors for ovarian hormones, estrogens and progestins, and mediate many of the actions of these hormones on female sexual behavior. The concept of a neural center might be best retained for the case of the SCN, which contains neurons that exhibit circadian pacemaking activity and hence function as a 24-hour clock that controls circadian rhythms in physiology and behavior. The roles played by all of the foregoing cell groups, and the nuclei within which they reside, are described in the context of each of the major neuroendocrine systems characterized in subsequent sections in this and succeeding chapters.

The homeostatic functions of the hypothalamus require that afferent neural signals, derived from brain regions concerned with sensory processing, memory and emotion, are processed and integrated with humoral signals; efferent neural signals that produce appropriate alterations in neurohormone secretions and transmission through efferent pathways are consequently initiated. Not surprisingly, the hypothalamus is known to receive and send neural signals through efferent and afferent pathways that connect it with a ring of subcortical limbic structures known to be critically important in emotional status, such as the amygdala; in learning and memory, such as the hippocampus; and in autonomic nervous system control, such as the lower brainstem nuclei. For example, the major connections between the amygdala and the hypothalamus include the stria terminalis and a direct amygdalohypothalamic tract; the hippocampus connects with the POA, AN and mammillary bodies via the fornix; the medial forebrain bundle connects the hypothalamus to the more anterior septal area of the basal forebrain; the hypothalamus is highly interconnected with the midbrain and lower brainstem nuclei via the dorsal longitudinal fasciculus, mammillotegmental tract and mammillopeduncular tract; and the epithalamus (dorsal posterior segment of the diencephalon that includes the habenula and pineal gland) provides afferents to the POA via the stria medullaris.

Within the hypothalamus, well-characterized fiber tracts consist of bundles of axons that extend from the soma of neurosecretory cells, and terminate at sites of neurosecretion. Prominent paraventricular hypophsyial tracts and supraoptic hypophysial tracts project from the paraventricular and supraoptic nuclei, respectfully, to the posterior lobe. These projections consist of axons of the magnocellular neurons that transport vasopressin and oxytocin to their release sites at neurovascular junctions in the pars nervosa. Tuberoinfundibular tracts likewise extend from parvocellular (smaller soma) neurons that produce the hypothalamic releasing and inhibiting factors, to terminate in the median eminence where they release these neurosecretory products into the primary plexus of the hypothalamo-hypophysial portal vasculature.

The median eminence is one of several specialized structures that are located at sites about the cerebroventricular system, and are therefore called circumventricular organs. These structures lack the blood–brain barrier, in which the endothelium of brain capillaries normally restricts movement of compounds from blood to brain or brain to blood. The endothelia of these organs are typically fenestrated, revealing a morphological basis for the diffusion of substances secreted by neurosecretory neurons into the systemic or portal circulation. Conversely, some of the circumventricular organs clearly serve as targets of circulating factors that may activate neural circuitries. The area postrema, located in the caudal extremity of the fourth ventricle, monitors substances present in the circulation, and serves to trigger emesis as an appropriate response to certain blood-borne stimuli.

The Pituitary Gland

The pituitary gland was at one time considered the master endocrine gland of vertebrates, since it was known to control the activity of other major endocrine glands, such as the thyroid, adrenals and gonads. It is now known to be primarily controlled by hormonal stimuli delivered from the hypothalamus and other glands. The pituitary gland, also known as the hypophysis, is comprised of the adenohypophysis, alternatively referred to as the anterior lobe, and the neurohypophysis, also called the posterior lobe. The adenohypophysis is primarily glandular tissue, while the neurohypophysis consists of neuronal processes that originate from the soma of neurosecretory neurons in the PVN and SON. These axons pass through the median eminence, the mediobasal extremity of the hypothalamus that is continuous with the infundibulum, or pituitary stalk, and ultimately end in the posterior lobe, or pars nervosa.

The embryologic origins of the two lobes of the pituitary are distinct. The neural lobe arises from the neural ectoderm of the floor of the developing forebrain, while the anterior lobe is derived from an inward invagination of the primitive mouth cavity (oral ectoderm) known as Rathke’s pouch. Cells of the anterior wall of Rathke’s pouch develop into the pars distalis, containing the majority of the hormone-producing cells of the adenohypophysis. The hormone-secreting cell types and their corresponding hormonal products include the corticotropes (adrenocorticotropic hormone; ACTH), somatotropes (growth hormone; GH), lactotropes (prolactin; PRL), gonadotropes (luteinizing hormone; LH, and follicle-stimulating hormone; FSH) and thyrotropes (thyroid-stimulating hormone; TSH). Dorsal extensions of the anterior lobe constitute a pars tuberalis, a non-secretory tissue that wraps around the infundibular stalk. An intermediate lobe develops between the two lobes that can vary greatly in size among different species; in humans, this regresses and disappears in adults. In many vertebrates the intermediate lobe produces hormones that include melanotropins, such as melanocyte-stimulating hormone (MSH). The anatomical components of the pituitary gland are given in Fig. 1.2.

The Hypothalamo-hypophysial Portal Vessel System

The hypophysial vasculature was initially studied in detail in the 1930s, when it was first demonstrated that blood flows downward in the hypophsyial portal vessels, rather than upward from pituitary to brain. ⁴ Detailed studies thereafter revealed that the superior hypophysial artery provides blood supply to the median eminence and pituitary stalk, from where blood passes via capillary loops through the long portal vessels to the sinusoids of the pars distalis. ⁵ These findings provided the conceptual basis for Harris’ proposal that the hypothalamus exerts a neurohumoral control over anterior pituitary hormone secretions. ⁶ The pituitary transplantation studies of Harris (described in Chapter 5 of this volume), as well as elegant electrical stimulation experiments by Markee, Sawyer and Hollinshead, as well as Harris,⁷. and ⁸. confirmed this hypothesis, and in turn revealed the existence of hypothalamic releasing factors that are conveyed by the hypothalamo-hypophysial portal vessel system to control release of anterior pituitary hormones. Two research groups, headed by Roger Guillemin and Andrew Schally, respectively, simultaneously determined the structure of thyrotropin-releasing hormone (TRH), as well as GnRH (or as it was known, LRF or LHRH) and somatostatin (SST), for which these two neuroendocrinologists were awarded the Nobel Prize in Physiology and Medicine in 1977.². and ³. Major releasing factors discovered, in the years following, included corticotropin-releasing hormone (CRH) in 1981, ⁹ and growth hormone-releasing hormone (GHRH) in 1982 (Fig. 1.3).¹⁰. and ¹¹.

Neurosecretory Cells

The major groups of neurosecretory cells in the hypothalamus include those in the neurohypophysial and the tuberoinfundibular systems. Neurons in both groups are predominantly peptidergic, although some may co-produce non-peptide products. An exception is the short-axon tuberoinfundibular dopaminergic (TIDA) neurons that primarily secrete the catecholamine, dopamine, into the portal vasculature. In most regards, neurosecretory neurons are similar in structure and function to neurons elsewhere in the brain. They have dendrites, perikarya and axons that resemble those in most central neurons. Furthermore, they exhibit relatively normal resting potentials, action potentials and synaptic potentials, and can display a normal range of intrinsic and synaptically-driven activity patterns that are relatively common among other brain cell types, regardless of their neurotransmitter phenotype. However, the morphology of some neurosecretory neurons, such as the magnocellular vasopressinergic and oxytocinergic neurons, differs in some respects due to the specialized neurosecretory functions. Because they release neurohormones that are delivered via the portal or peripheral circulation to distant target tissues, these neurosecretory cells are required to make copious amounts of neuropeptide hormone in their soma. Thus, these neurons have characteristics of active peptide-producing cells, including abundant rough endoplasmic reticulum, Golgi, and membrane bound granules.

Like other proteins, neuropeptide hormones are synthesized by a ribosomal mechanism. The process of neurohormone gene expression – the transcription of a neurohormone gene and translation of the corresponding mRNA – culminates in the ribosomal synthesis of a pre-prohormone protein that is longer, but inclusive of the specific neurohormone amino acid sequence. It is longer because it contains an amino terminal, hydrophobic signal peptide sequence that functions to permit movement of the protein across the ER membrane into the Golgi apparatus. There, enzymatic removal of the signal sequence, which yields the prohormone, is typically followed by the actions of proteolytic processing enzymes that additionally attack dibasic amino acid cleavage sites. This releases the mature protein hormone sequence from the remaining prohormone precursor molecule, and other peptide sequences with or without biological functions may be produced by these cleavages – for example, the neurophysins in magnocellular neurons. Within the Golgi elements the hormone may additionally be altered by processing enzymes that conjugate carbohydrate, C-terminal amide or other moieties, or create covalent linkages between two sulfur-containing cysteine residues, termed disulfide bridges. These modifications typically endow the molecule with secondary or tertiary structures that are required for biological activity. Vesicles containing the mature neurohormone are pinched off at the terminal cisternae of the Golgi apparatus, and undergo axonal transport to neurovascular terminals. Release of the neurohormone from the neurosecretory cell thereafter occurs through calcium-dependent exocytosis, a process that involves fusion of the secretory vesicle with the plasma membrane and diffusion of its contents into the extracellular space within the neurovascular junction. The neurohormone diffuses through fenestrated capillary walls into the blood.

Neuroendocrine Transduction and Neuroendocrine Systems

The transformation of neural signals into the release of hormones is called neuroendocrine transduction. In general, secretion of neurohormones is a regulated process that reflects neuroendocrine transduction in its simplest form. Both synaptic and hormonal excitation of the neurosecretory cell body initiates action potentials that propagate along the axon and invade the axon terminal. The depolarization of the axon terminal, in turn, triggers an elevation of intracellular Ca²+, which prompts vesicular fusion with the plasma membrane and exocytosis of the granule contents. The amplitude of neurohormone secretion is generally determined by the frequency of action potentials that depolarize the neurosecretory cell terminal. Notably, this stereotyped stimulus-secretion coupling process was first characterized by Douglas and Poisner¹² in their classical experiments on isolated posterior pituitary tissues.

Neuroendocrine transduction can take place