Barr's The Human Nervous System PDF

BARR’S The Human Nervous System An Anatomical Viewpoint Te n t h E d i t i o n BARR’S The Human Nervous System An Anatomical Viewpoint Te n t h E d i t i o n John A. Kiernan, MB, ChB, PhD, DSc Professor Emeritus Department of Anatomy and Cell Biology The University of Western Ontario London, Ca...

BARR’S The Human Nervous System An Anatomical Viewpoint Te n t h E d i t i o n BARR’S The Human Nervous System An Anatomical Viewpoint Te n t h E d i t i o n John A. Kiernan, MB, ChB, PhD, DSc Professor Emeritus Department of Anatomy and Cell Biology The University of Western Ontario London, Canada and Nagalingam Rajakumar, MB, BS, PhD Associate Professor Departments of Psychiatry and Anatomy and Cell Biology The University of Western Ontario London, Canada Acquisitions Editor: Crystal Taylor Product Manager: Jenn Verbiar Marketing Manager: Joy Fisher-Williams Vendor Manager: Bridgett Dougherty Manufacturing Coordinator: Margie Orzech Creative Director: Doug Smock Compositor: Integra Software Services Pvt. Ltd. Tenth Edition Copyright © 2014 Lippincott Williams & Wilkins, a Wolters Kluwer business 351 West Camden Street Two Commerce Square Baltimore, MD 21201 2001 Market Street Philadelphia, PA 19103 Printed in China All rights reserved. This book is protected by copyright. No part of this book may be reproduced or transmitted in any form or by any means, including as photocopies or scanned-in or other electronic copies, or utilized by any information storage and retrieval system without written permission from the copyright owner, except for brief quotations embodied in critical articles and reviews. Materials appearing in this book prepared by individuals as part of their official duties as U.S. government employees are not covered by the above-mentioned copyright. To request permission, please contact Lippincott Williams & Wilkins at 530 Walnut Street, Philadelphia, PA 19106, via email at [email protected], or via Web site at lww.com (products and services). 9 8 7 6 5 4 3 2 1 Library of Congress Cataloging-in-Publication Data Kiernan, J. A. (John Alan) Barr’s the human nervous system: an anatomical viewpoint/John A. Kiernan, MB, ChB, PhD, DSc, professor, Department of Anatomy and Cell Biology, The University of Western Ontario, London, Canada, and Nagalingam Rajakumar, MB, BS, PhD, associate professor, Departments of Psychiatry and Anatomy and Cell Biology, The University of Western Ontario, London, Canada.—Tenth edition. pages cm Includes bibliographical references and index. ISBN 978-1-4511-7327-7 1. Neuroanatomy. I. Barr, Murray Llewellyn, 1908-1995. II. Rajakumar, Nagalingam, 1957- III. Title. IV. Title: Human nervous system. QM451.B27 2014 611'.8—dc23 2012041508 DISCLAIMER Care has been taken to confirm the accuracy of the information present and to describe generally accepted practices. The authors, editors, and publisher, however, are not responsible for errors or omissions or for any consequences from application of the information in this book and make no warranty, expressed or implied, with respect to the currency, completeness, or accuracy of the contents of the publication. 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Lippincott Williams & Wilkins customer service representatives are available from 8:30 am to 6:00 pm, EST.  Preface Murray Llewellyn Barr (1908 to 1995) obtained New to the Edition his medical degree in 1933 from the Univer- sity of Western Ontario in London, Canada, In this Tenth Edition, the improvement and and after a few years in practice, he entered the changing of illustrations has continued, and Department of Anatomy at the same institution. nearly all are now colored. The text and recom- He studied and taught neuroanatomy there until mended readings have also been updated. R ­ eaders 1978. This period of service was interrupted of this edition have access to the publisher’s by the Second World War, when he served in Web site—www.lww.thepoint.com—which the Medical Branch of the Royal Canadian Air includes a variety of additional materials. These Force. In 1949, the direction of Barr’s research include labeled and unlabeled versions of all the changed abruptly from neurohistology to cyto- illustrations for instructors, sample exam questions genetics. With Ewart G. (“Mike”) Bertram, who and clinical cases, an extended glossary, and bio- was then a graduate student, he had observed graphical information about researchers and phy- an intranuclear inclusion in neurons of female sicians whose names are associated with anatomy, animals. This was the sex chromatin, now widely physiology, and diseases of the nervous system. known as the Barr body; its discovery was an early landmark in the science of human cytogenetics. Acknowledgments For this and his later work in the field, Murray Barr received more than 30 awards and honors, An important feature in the production of the including the Kennedy Foundation International Tenth Edition has been the publisher’s extensive Award in Mental Retardation, Fellowship of the use of external reviewers. The book is undoubtedly Royal Society of London, the Order of Canada, improved as a result of their recommendations and and 7 honorary doctorates. comments, for which we thank them. It is a plea- Although Barr’s research career was largely con- sure to acknowledge also the helpful advice given cerned with the cytological diagnosis of inherited by present and former colleagues during the writ- diseases, he continued to teach neuroanatomy. The ing of this and the five preceding editions: Drs. J. first edition of this book, published in 1972, was Ronald Doucette, ­Jonathan Hore, Kost ­Elisevich, one of the first medium-sized texts in its field. It Brian A. ­Flumerfelt, Elias B. Gammal, Alan W. was written to make life easier for those approach- ­Hrycyshyn, Arthur J. Hudson, Peeyush K. Lala, ing neuroscience for the first time, especially Peter Merrifield, D.G. Montemurro, David M. medical students and those in the allied health sci- Pelz, David Ramsay, A. Jon Stoessl, Shannon ences. This objective has not changed, although a Venance, Tutis Vilis, and Chris Watling. We greater variety of students now study the subject. appreciate also the numerous insightful comments Advances in the science necessitated much revi- of Professor Ronan O’Rahilly (Villars-sur-Glâne, sion over the years, and the book became larger Switzerland), especially on matters of embryology with successive editions. With the Eighth and and terminology. Ninth Editions, this trend was reversed, result- The artwork for the first seven editions of ing in a somewhat smaller book. The illustrations the book was prepared by local artists (Margaret were enhanced, however, with more extensive use Corrin, Louise Gadbois, Jeannie Ross, and ­ of colors. Nancy Somerville) supervised by the authors. v vi Preface For this and the previous edition, all the illus- Tenth Edition, and Jennifer Verbiar and Bridgett trations were prepared in electronic form by the Dougherty, including Gordon Hammy Matchado publisher’s art department, Jennifer Clements from Integra Software Services presided over pro- and artist Kim Battista, working from older art- duction of the book. We thank all of them for work and from our sketches. Among other staff their contributions. at Lippincott Williams & Wilkins, Crystal Taylor J. A. KIERNAN arranged the reviewing and the contract for the N. rajakumar London, Canada  Contents Preface v PART I: Introduction and Neurohistology 1  evelopment, Composition, and Evolution D of the Nervous System 3 2 Cells of the Nervous System 13 3 Peripheral Nervous System 35 4 Imaging Techniques and Neuroanatomical Research Methods 49 PART II: Regional Anatomy of the Central Nervous System 5 Spinal Cord 63 6 Brain Stem: External Anatomy 81 7 Brain Stem: Nuclei and Tracts 89 8 Cranial Nerves 115 9 Reticular Formation 143 10 Cerebellum 159 11 Diencephalon 175 12 Corpus Striatum 201 13 Topography of the Cerebral Hemispheres 213 14 Histology of the Cerebral Cortex 221 15 Functional Localization in the Cerebral Cortex 229 16 Cerebral White Matter and Lateral Ventricles 247 17 Olfactory System 261 18 Limbic System: The Hippocampus and the Amygdala 269 PART III: REVIEW OF THE MAJOR SYSTEMS 19 General Sensory Systems 285 20 Visual System 305 vii viii Contents 21 Auditory System 321 22 Vestibular System 333 23 Motor Systems 341 24 Visceral Innervation 357 PART IV: BLOOD SUPPLY AND THE MENINGES 25 Blood Supply of the Central Nervous System 371 26 Meninges and Cerebrospinal Fluid 387 Glossary of Neuroanatomical and Related Terms  399 Index 413 Part I Introduction and Neurohistology Chapter 1 Development, Composition, and Evolution of the Nervous System an animal’s body to another. All the neurons of Important Facts an organism, together with their supporting cells, constitute a nervous system. The nervous system is derived from the ecto- To carry out its communicative function, a derm of the embryo. neuron exhibits two different but coupled activi- The central nervous system is formed from ties. They are conduction of a signal from one part the neural tube, and the peripheral nervous of the cell to another and synaptic ­transmission, system is formed from the neural crest. which is communication between adjacent cells. The first cells to differentiate in the nervous An impulse, also called an action potential, is system are neurons, which are specialized for a wave of electrical depolarization that is propa- communication. They are followed by sup- gated within the surface membrane of the neuron. porting cells known as neuroglia (or simply A stimulus applied to one part of the neuron initi- glia). ates an impulse that travels to all other parts of the Abnormal development of the brain or spinal cell. Neurons commonly have long cytoplasmic cord can result from faulty closure of the processes, known as neurites, that end in close neural tube or failed development of the apposition to the surfaces of other cells. The ends overlying bone and skin. of the neurites are called synaptic terminals, and Obstruction of the flow of cerebrospinal the cell-to-cell contacts they make are known as fluid within or out of the cavities of the brain synapses. The neurites in higher animals usually results in fluid accumulation known as hydro- are specialized to form d ­ endrites and axons, which cephalus. typically conduct signals toward and away from the The major divisions of the central nervous sys- cell body, respectively. Most axons are ensheathed tem are present from the 4th week after fer- tilization. They are the spinal cord, medulla, in myelin, which is a lipid-rich material composed pons, midbrain, diencephalon, and cerebral of tightly packed membranous layers. The arrival hemispheres. The cerebellum appears later, as of an impulse at a terminal triggers synaptic trans- an outgrowth of the brain stem. mission. This event normally involves the release Within normal limits, the size of the brain of a chemical compound from the neuronal cyto- does not correlate with intelligence. plasm, which evokes some type of response in the postsynaptic cell. At some synapses, the two cells are ­electrically coupled. Another type of neuron All living organisms respond to chemical and exists that discharges its chemical products into physical stimuli. The response may be a move- the circulating blood, thereby influencing dis- ment, or it may be the expulsion of biosynthetic tant parts of the body. Neurons of the latter type, products from cells. These receptive, motor, and known as ­ neurosecretory cells, are functionally secretory functions are combined in a single cell in related to endocrine gland cells. both unicellular organisms and the simplest mul- The central nervous system (CNS) consists ticellular animals, the sponges. In all other groups of the brain and spinal cord and is protected by of animals, cells are able to communicate, so that the cranium and the vertebral column. Bundles the reception of a stimulus by one cell may result of axons called nerves connect the CNS with all in motile or secretory activity of other cells. Spe- parts of the body. Nerves are the most conspicu- cialized cells known as neurons or nerve cells exist ous components of the peripheral nervous sys- to transfer information rapidly from one part of tem. The cell bodies of neurons in the CNS are in 3 4 Part I: Introduction and Neurohistology regions known as gray matter. A compact aggre- Neural gation of gray matter is called a nucleus, not to fold be confused with the nucleus of a cell. Regions of Neural Rostral CNS tissue that contain axons but not neuronal neuropore groove cell bodies are called white matter. In the periph- eral nervous system, neuronal cell bodies occur in nodular structures called ganglia (singular: gan- glion). This word is also used (commonly but Neural wrongly) for certain nuclei in the CNS. tube Development of the Nervous System Caudal The neurons and other cells of the nervous sys- neuropore tem develop from the dorsal ectoderm of the early embryo. The ectoderm is the layer that also becomes the epidermis, which covers the surface of the body. The first indication of the future ner- FIGURE 1-1 Dorsal view of a human embryo about vous system is the neuroectoderm, consisting of 22 days after fertilization. Closure of the neural tube is in progress. the neural plate, which appears in the dorsal mid- line of the embryo at the 16th day after fertiliza- tion. The cells of the neural plate become taller about the 24th and 27th days, respectively (stages than those of the ordinary ectoderm. This change 11 and 12). The neural tube is the forerunner of is induced by the underlying mesodermal cells. the brain and spinal cord. The cells lining the The neural plate grows rapidly, and in 2 days, it tube constitute the neuroepithelium, which will becomes a neural groove with a neural fold along give rise to all the neurons and most of the other each side. cells in the CNS. A note on times and ages. In clinical practice, Cells that originate at the junction between the pregnancy is timed from the 1st day of the last neural plate and ectodermal cells that will give rise menstrual period, about 14 days before fertiliza- to the epidermis of the skin are not incorporated tion. The age of an embryo is stated from the into the neural tube. These cells come together in known or estimated time of fertilization. When the midline to form the neural crest, dorsal to the it is 8 weeks old and all the organs are formed, tube. Cells from the neural crests migrate laterally an embryo is renamed a fetus. For exact descrip- and ventrally, eventually forming the dorsal root tion, the embryonic period is divided into 23 ganglia of spinal nerves, some of the neurons in Carnegie stages, based on studies of anatomical sensory ganglia of cranial nerves, autonomic gan- development in the large collection of embryos of glia, the nonneuronal cells (neuroglia) of periph- the Carnegie Institution for Science. The neural eral nerves, and secretory cells of the adrenal folds appear at stage 8, when the embryo is 1.0 to medulla. Many neural crest cells differentiate into 1.5 mm long. nonneural elements, including the melanocytes of the skin; the calcitonin-secreting cells of the thy- Neural Tube, Crest, and Placodes roid gland; chemosensory cells in the carotid and By the end of the 3rd week (stage 10), the neu- aortic bodies; odontoblasts of teeth; and some of ral folds have begun to fuse with one another, the bones, muscles, and other structures of mesen- thereby converting the neural groove into a neu- chymal origin in the head. The connective tissue ral tube (Figs. 1-1 and 1-2). This transformation cells in nerves and ganglia are, however, derived begins in the middle (in what will eventually be from the local mesoderm. the cervical segments of the spinal cord) and pro- Some of the neurons and other cells in the ceeds rostrally and caudally. The openings at each peripheral sense organs and ganglia are derived end (the rostral and caudal neuropores) close at from placodes, which are thickened regions of  Chapter 1: Development, Composition, and Evolution of the Nervous System 5 1 Ectoderm Neural plate 2 Epidermis Neural crest Epidermis 3 Neural groove Roof plate Neuron in alar plate Epidermis Neuron in spinal 4 ganglion Sulcus limitans Neural tube Neuron in basal plate Floor plate Axon of a descending tract entering spinal gray matter Dorsal horn Sensory axons in dorsal root 5 Spinal ganglion Ventral horn Axons in ventral root Axon from Alar plate and derived gray matter contralateral dorsal Basal plat and derived gray matter horn will join an ascending tract Neural crest and derivatives White matter FIGURE 1-2 Diagrammatic transverse sections of embryos (1–4) at a level that will become the spinal cord, showing closure of the neural tube, formation of the alar and basal laminae, and the origin of spinal ganglia from the neural crest. Some neuronal connections are indicated for the embryonic (4) and adult (5) spinal cord. (Modified from Lemire RJ, Loeser JD, Leech RW, Alvord EC. Normal and Abnormal Development of the Human Nervous System. Hagerstown, MD: Harper & Row; 1975:16.) the ectoderm of the embryonic head. Thus, the formed, they do not divide again.) Most of the olfactory neurosensory cells, the sensory cells neurons are produced between the 4th and 20th and associated ganglia of the inner ear, and some weeks. The young neurons migrate, grow cyto- of the neurons in the sensory ganglia of cranial plasmic processes, and form synaptic connections nerves are derived from placodes. Some cells of with other neurons. the olfactory placode migrate into the rostral end The number of neurons formed in the neural of the neural tube and become intrinsic neurons tube exceeds the number in the adult brain and and neuroglial cells of the CNS (see Chapters 11 spinal cord. Large numbers of neurons die in the and 17). normal course of development. This occurrence, known as cell death or apoptosis, is seen in many embryonic systems throughout the animal king- Production of Neurons and dom. In invertebrates, the cell death is genetically Neuroglia programmed. Experimental studies carried out The first populations of cells produced in the neu- by Viktor Hamburger in the 1930s showed that ral tube are neurons. (The old term neuroblasts is in vertebrates, the cells that died were those that inappropriate for these cells because after they are failed to make synaptic connections. 6 Part I: Introduction and Neurohistology In some animals, including rodents, new neu- neuropore. The vesicles are derived from the cau- rons are generated throughout life in some parts of dal eminence, a mass of pluripotent cells located the brain, from pluripotent precursor cells. Quan- dorsal to the developing coccyx. titative histochemical studies indicate little or no As described conventionally, three major divi- such activity in the corresponding regions of the sions of the brain appear at the end of the 4th week: adult human brain. the prosencephalon (forebrain), mesencephalon The neurons in sensory ganglia derived from (midbrain), and rhombencephalon (hindbrain). the neural crest send neurites into peripheral During the 5th week, secondary swellings develop nerves and into the neural tube. By the 8th week in the prosencephalon and rhombencephalon, so of intrauterine life, the centrally directed neurites that the number of major parts becomes five: the have extensive synaptic connections with neurons telencephalon, diencephalon, mesencephalon, in the spinal cord. The number and complexity of metencephalon, and myelencephalon (Fig. 1-3). synapses continue to increase until well after birth, The same words are used for the corresponding as does the generation of neuroglial cells. parts of the adult human brain. (In the chick Neuroglia, more commonly called glia, com- embryo, a favorite subject for embryological inves- prises the cells of the nervous system that are not tigation, the swellings in the embryonic brain are neurons. The structures and functions of different known as “brain vesicles,” a term that should not glial cell types are dealt with in Chapter 2. be used in human anatomy.) The early embryonic The first glial cells, known as radial glia, develop CNS is also divisible longitudinally into smaller alongside the first neurons, having cytoplasmic segments known as neuromeres. The neuromeres processes that extend from the lumen to the outside become indistinguishable as the complex structure surface of the neural tube. The processes of radial of the brain develops, but segmental organization glia guide the migration of the young neurons. of the spinal cord persists throughout life. Most astrocytes and oligodendrocytes, however, As cellular proliferation and differentiation are generated from the neuroepithelium during the proceed in the neural tube, a longitudinal groove fetal period. Mature glial cells are visible with clas- called the sulcus limitans appears along the inner sical staining methods by 19 weeks, but some can aspect of each lateral wall. The sulcus demarcates be detected by immunohistochemical techniques as a dorsal alar plate from a ventral basal plate; they early as 7 weeks. Microglial cells arise from hemo- acquire afferent and efferent connections, respec- poietic tissue and enter the brain and spinal cord by tively, and are present from the rostral end of the passing through the walls of blood vessels. mesencephalon to the caudal end of the spinal In the peripheral nervous system, neurons (in cord. Responding to an inductive effect of the sensory and autonomic ganglia) and glial cells nearby notochord (which marks the position of (satellite cells in ganglia and Schwann cells in future vertebrae), the basal plates of the left and nerves) are derived from the neural crest. right sides become separated by a thin floor plate (Fig. 1-2). Some of the basal plate cells differenti- Formation of the Brain and ate into motor neurons, with axons that grow out Spinal Cord into the developing muscles. The growing axons of neurons of the sensory ganglia enter the alar plate. Even before the closure of the neural folds, the neural plate is conspicuously larger at the rostral Further Development of the end of the embryo, and irregularities correspond- Brain ing to the major divisions of the developing brain are already visible. The remainder of the neural As the parts of the brain differentiate and grow, some tube becomes the spinal cord. The site of closure of the formal Greek-derived names are replaced by of the caudal neuropore corresponds to the upper others for common usage (Table 1-1). The myelen- lumbar segments of the cord. Further caudally, the cephalon becomes the medulla oblongata, and the spinal cord is formed by secondary neurulation, metencephalon develops into the pons and cerebel- which is the coalescence of a chain of vesicles that lum. The mesencephalon of the mature brain usu- becomes continuous with the lumen of the neural ally is called the midbrain. The names diencephalon tube about 3 weeks after the closure of the caudal and telencephalon are retained because of the diverse  Chapter 1: Development, Composition, and Evolution of the Nervous System 7 7&8 10&11 9 5 Ot R6 R4 R3 R2 R1 R8 R7 Is. M2 M1 D2 1 mm Op D1 T M Cx Cb R 5 D In 8 7 T E 1 mm FIGURE 1-3 Major parts of the brain in human embryo at 4 weeks (above, a midline section) and at 8 weeks (below, reconstructed from serial sections). Color scheme: telencephalon (forebrain), yellow; diencephalon, blue; mesen- cephalon (midbrain), orange; rhombencephalon (hindbrain, composed of medulla, pons, and cerebellum), gray. In the embryo, some neuromeres are indicated for the telencephalon (T), diencephalon (D1, D2), mesencephalon (M1, M2), isthmus (Is), and rhombencephalon (R1 to R8). The levels of the optic (Op) and otic (Ot) vesicles, which are lateral to the neural tube, are indicated. (These vesicles will become the lens and inner ear, respectively.) In the fetus: Cb, cerebellum; Cx, cerebral cortex; D, diencephalon; E, eye; In, insula; M, mesencephalon; R, rhombencephalon; T, trigeminal ganglion; 5, sensory root of trigeminal nerve; 7, 8, rootlets of facial and vestibulocochlear nerves. (Modi- fied from O’Rahilly R, Müller F. The Embryonic Human Brain. An Atlas of Developmental Stages. 3rd ed. Hoboken, NJ: Wiley-Liss; 2006.) 8 Part I: Introduction and Neurohistology Table 1-1 Development of the Brain Embryonic Brain Major Division Adult Brain Major Subdivision Rhombencephalon Myelencephalon Medulla oblongata Metencephalon Pons and cerebellum Mesencephalon Mesencephalon Midbrain, consisting of tectum and cerebral peduncles Prosencephalon Diencephalon Thalamus, epithalamus, hypothalamus, and subthalamus Telencephalon Cerebral hemispheres, each containing olfactory system, corpus striatum, cerebral cortex, and white matter nature of their derivatives. A large mass of gray mat- matter with motor functions), an extensive surface ter, the thalamus, develops in the diencephalon. layer of gray matter known as the cortex or pallium, Adjacent regions are known as the epithalamus, and a medullary center of white matter. hypothalamus, and subthalamus, each with dis- The lumen of the neural tube becomes the ven- tinctive structural and functional characteristics. tricular system. A lateral ventricle develops in The left and right halves of the telencephalon are each cerebral hemisphere. The third ventricle is known as the cerebral hemispheres. These undergo in the diencephalon, and the fourth ventricle is the greatest development in the human brain, in bounded by the medulla, pons, and cerebellum. respect both to other regions and to the brains of The third and fourth ventricles are connected by a other animals. The telencephalon includes the olfac- narrow channel, the cerebral aqueduct, through tory system, the corpus striatum (a mass of gray the midbrain. The lumen also remains narrow in Mesencephalic Cervical M Cb Me Di P Pontine T FIGURE 1-4 Embryonic brain at 7 weeks (stage 20) showing the three flexures in the approximate form of the let- ter M. The major divisions of the brain are colored: telencephalon (T), yellow; diencephalon (Di), blue; midbrain (M), orange; rhombencephalon, gray, comprising medulla (Me), pons (P), and cerebellum (Cb). (Modified from O’Rahilly R, Müller F. The Embryonic Human Brain. An Atlas of Developmental Stages. 3rd ed. Hoboken, NJ: Wiley-Liss; 2006:221.)  Chapter 1: Development, Composition, and Evolution of the Nervous System 9 the caudal part of the medulla and throughout the the cranial cavity and spinal canal. The subarach- spinal cord, where it becomes the central canal. noid space, which contains cerebrospinal fluid Flexures in the neural tube help to accommodate (CSF), is between the inner two meningeal layers. the initially cylindrical brain in what will eventually be a round head. The first to form are the cervical Summary of Main Regions of flexure at the junction of the rhombencephalon the Central Nervous System with the spinal cord and the mesencephalic flexure Certain features of the main regions are now briefly at the level of the midbrain. The pontine flexure in reviewed, by way of introduction and to provide the metencephalon soon follows. These flexures in a first acquaintance with some neuroanatomical the brain (Fig. 1-4) ensure that the optical axes of the terms. Before proceeding to later chapters, the eyes (which connect with the prosencephalon) are student should know the meanings of all the at right angles to the axis of the vertebral column. words used in the following eight paragraphs. This necessary feature of the erect posture of humans There is a glossary at the end of the book. The major contrasts with the posture of quadrupedal animals, divisions of the adult brain are shown in Figure 1-5. in which there is no abrupt bend at the junction of the midbrain with the forebrain. Spinal Cord Development of the Meninges The spinal cord is the least differentiated component of the CNS. The segmental nature of the spinal cord The membranous coverings of the brain and spinal is reflected in a series of paired spinal nerves, each of cord first appear in the 4th week as a single meso- which is attached to the cord by a dorsal sensory root dermally derived primary (or primitive) meninx. and a ventral motor root. The central gray matter, in Fluid-filled spaces appear within the primary meninx which neuronal cell bodies are located, has a roughly 1 week later, and subsequent differentiation leads H-shaped outline in transverse section. White mat- to the formation of three layers that constitute the ter, which consists of myelinated axons running lon- meninges: the pia mater, closest to the nervous tis- gitudinally, occupies the periphery of the cord. The sue; the arachnoid; and the dura mater, which lines spinal gray matter includes neuronal connections Cerebral hemisphere Midbrain Cerebellum Pons Diencephalon Spinal cord Medulla oblongata FIGURE 1-5 Regions of the mature central nervous system, as seen in sagittal section. 10 Part I: Introduction and Neurohistology that provide for spinal reflexes. The white matter shared with the rest of the brain stem. There- contains axons that convey sensory data to the brain fore, it includes ascending and descending and others that conduct impulses, typically of motor tracts, together with some nuclei of cranial significance, from the brain to the spinal cord. nerves. The ventral portion or basal pons is special to this part of the brain stem. Its func- Medulla Oblongata tion is to provide for extensive connections The fiber tracts of the spinal cord are continued in between the cortex of a cerebral hemisphere the medulla, which also contains clusters of neu- and that of the contralateral cerebellar hemi- rons called nuclei. The most prominent of these, sphere. These connections contribute to max- the inferior olivary nuclei, sends fibers to the cer- imal efficiency of motor activities. A pair of ebellum through the inferior cerebellar peduncles, middle cerebellar peduncles attaches the cer- which attach the cerebellum to the medulla oblon- ebellum to the pons. gata. Of the smaller nuclei, some are components of cranial nerves. Midbrain Similar to other parts of the brain stem, the mid- Pons brain contains ascending and descending path- The pons consists of two distinct parts. The ways, together with nuclei for two cranial nerves. dorsal portion or tegmentum has features A dorsal region, the roof or tectum, is concerned Abnormal Development of the Clinical Notes Nervous System Anencephaly and Spina Bifida the lump at the surface is a meningocele, a cyst Congenital malformations of the CNS include containing CSF. These types of spina bifida can those that result from failure of the neural be corrected surgically, but permanent paralysis tube to close normally. Developmental failure or weakness of the lower limbs often persists. occurs also in associated bone and skin. In Spina bifida occulta is a common condition in anencephaly, the neural folds do not fuse at which the dura and skin remain intact but one the rostral end of the developing neural tube, or more bony vertebral arches fail to develop. so that the forebrain, cranial vault, and much Usually there are no symptoms other than of the scalp are missing. The abnormal brain a dimple, a tuft of hair, or some other minor (the brain stem and, sometimes, the dienceph- irregularity of the overlying skin. alon) is exposed to the exterior. Anencephaly occurs in about 1 out of 1,000 births and is Hydrocephalus incompatible with sustained life. The equiva- CSF accumulates in the ventricles of the brain if lent condition at the caudal end of the CNS is its normal flow is obstructed (see Chapter 26). myeloschisis (cleft spinal cord), in which there Nervous tissue is destroyed by the pressure, is extensive exposure of nonfunctional nervous and the head can become greatly enlarged. tissue in the lumbosacral region. Sometimes Causes include stenosis of the cerebral these two conditions coexist in the same baby. aqueduct in the midbrain and Chiari mal- Myeloschisis is the severest form of spina formation, in which the medulla and part of bifida. In less severe types, the spinal cord and the cerebellum are located in the upper cervi- its adjacent connective tissue ensheathment (the cal spinal canal rather than in the skull. This leptomeninges; see Chapter 26) are intact, but abnormal anatomy can obstruct the flow of the overlying mesodermal derivatives are not. In CSF out of the ventricular system, resulting in meningomyelocele, the dura mater, vertebral internal hydrocephalus. Spina bifida is also arches, and skin are missing, and a visible pro- present in many infants with Chiari malfor- trusion contains either the caudal part of the mation. Internal hydrocephalus is treated by spinal cord or its associated nerve roots. If the installing an alternative pathway for drainage neural elements remain in the vertebral canal, of the ventricular system of the brain.  Chapter 1: Development, Composition, and Evolution of the Nervous System 11 principally with the visual and auditory systems. gonadotrophin-releasing hormone. They migrate The midbrain also includes two prominent nuclei, along the terminal nerve into the forebrain. The the red nucleus and the substantia nigra, which terminal nerve is a tiny cranial nerve (sometimes are concerned with motor control. The cerebellum given number zero) rostral to the olfactory nerves. is attached to the midbrain by the superior cer- The subthalamus includes sensory tracts that ebellar peduncles. proceed to the thalamus, axons that originate in the cerebellum and corpus striatum, and the sub- Cerebellum thalamic nucleus, which has motor functions. The retina is a derivative of the diencephalon; The cerebellum is especially large in the human therefore, the optic nerve and the visual system are brain. Receiving data from most of the sensory intimately related to this part of the brain. systems and the cerebral cortex, the cerebellum eventually influences motor neurons that supply Telencephalon (Cerebral the skeletal musculature. The functions of the cer- Hemispheres) ebellum are to produce changes in muscle tone in relation to equilibrium, locomotion, and posture The telencephalon includes the cerebral cortex, and to coordinate the timing, force, and extent corpus striatum, and cerebral white matter. The of contraction of muscles being used for skilled cerebral cortex is much folded, with ridges (gyri) movements. The cerebellum operates at a subcon- separated by grooves (sulci). Major sulci sepa- scious level. rate the frontal, parietal, occipital, and tempo- ral lobes of the cerebral hemisphere, which are Diencephalon named after the overlying bones of the skull. Dif- ferent modalities of sensation and motor functions The diencephalon forms the central core of the are represented in distinct areas of the cortex, and cerebrum. The largest component of the dien- there are also large expanses of association cor- cephalon, the thalamus, consists of several regions tex, in which the highest levels of neural function or nuclei, some of which receive data from sensory take place, including those inherent in intellectual systems and project to sensory areas of the cere- activity. bral cortex. Part of the thalamus has connections The corpus striatum is a large mass of gray with cortical areas that are concerned with com- matter with motor functions situated near the plex mental processes. Other regions participate in base of each hemisphere. It consists of the caudate neural circuits related to emotions, and certain tha- and lentiform nuclei, which are parts of a system lamic nuclei are incorporated into pathways from known as the basal ganglia, discussed in Chapters the cerebellum and corpus striatum to motor areas 12 and 23. The cerebral white matter (medul- of the cerebral cortex. The epithalamus includes lary center) consists of fibers that connect cortical small tracts and nuclei, together with the pineal areas of the same hemisphere, fibers that cross the gland, an endocrine organ. The hypothalamus midline (most are in a large commissure known as has an important controlling influence over the the corpus callosum) to connect cortical areas of sympathetic and parasympathetic systems, which the two hemispheres, and fibers that pass in both supply internal organs, exocrine glands, and blood directions between the cortex and subcortical parts vessels. In addition, neurosecretory cells in the of the CNS. Fibers of the last category converge to hypothalamus synthesize hormones that enter the form the compact internal capsule in the region bloodstream. Some act on the kidneys and other of the thalamus and corpus striatum. organs; others influence the hormonal output of the anterior lobe of the pituitary gland through a Size of the Human Brain special portal system of blood vessels. Some of the neurosecretory cells in the hypothalamus and in At birth, the average brain weighs about 400 g. the immediately adjacent part of the telencepha- Further increase in size is attributable to con- lon are derived from the olfactory placode, not tinuing formation of synaptic connections, pro- from the epithelium of the neural tube. These neu- duction of neuroglial cells, and thickening of the rons contain and secrete a polypeptide known as myelin sheaths around axons. The most rapid 12 Part I: Introduction and Neurohistology growth of the brain occurs in utero and during Konstantinidou AD, Silos-Santiago I, Flaris N, et al. Develop- ment of the primary afferent projection in human spinal the first 20 postnatal weeks. By age 3 years, the cord. J Comp Neurol. 1995;354:1-12. average weight (1,200 g) of the brain is almost Lemire RJ, Loeser JD, Leech RW, et al. Normal and Abnormal that of an adult, although slow growth contin- Development of the Human Nervous System. Hagerstown, MD: Harper & Row; 1975. ues until age 18 years. After age 50 years, there is Miller RH. Oligodendrocyte origins. Trends Neurosci. a slow decline in brain size. This decrease in size 1996;19:92-96. does not lead to intellectual deterioration unless Müller F, O’Rahilly R. The timing and sequence of appearance of neuromeres and their derivatives in staged human em- there is considerable atrophy caused by disease. bryos. Acta Anat. 1997;158:83-99. The weight of the mature brain varies with age Müller F, O’Rahilly R. The initial appearance of the cranial and stature. The normal range in adult men is 1,100 nerves and related neuronal migration in staged human embryos. Cells Tissues Organs. 2011;193:215-238. to 1,700 g (mean 1,360 g). The lower figures for O’Rahilly R, Müller F. Developmental Stages in Humans. Carn- adult women (1,050–1,550 g; mean 1,275 g) are egie Institute of Washington, Publication 637; 1987. mainly attributable to the smaller stature of women O’Rahilly R, Müller F. Minireview: initial development of the human nervous system. Teratology. 1999;60:39-41. compared with men. There is no evidence of a rela- O’Rahilly R, Müller F. Two sites of fusion of the neural folds tion between brain weight, within normal limits, and the two neuropores in the human embryo. Teratology. and a person’s level of intelligence. 2002;65:162-170. O’Rahilly R, Müller F. The Embryonic Human Brain. An Atlas of Developmental Stages. 3rd ed. New York, NY: Wiley-Liss; 2006. Suggested Reading O’Rahilly R, Müller F. Significant features in the early pre- natal development of the human brain. Ann Anat. 2008;190:105-118. Campbell K, Gotz M. Radial glia: multi-purpose cells for verte- Sierra A, Encinas JM, Maletic-Savatic M. Adult human neuro- brate brain development. Trends Neurosci. 2002;25:235-238. genesis: from microscopy to magnetic resonance imaging. Del Bigio MR. Proliferative status of cells in the human den- Front Neurosci. 2011;5:1-18. Article 47. tate gyrus. Microsc Res Tech. 1999;45:353-368. Webb JF, Noden DM. Ectodermal placodes: contributions Doucette R. Transitional zone of the first cranial nerve. J Comp to the development of the vertebrate head. Am Zool. Neurol. 1991;312:451-466. 1993;33:434-447. Hill M. UNSW embryology. Ver. 6.1. An educational Weiss S, Dunne C, Hewson J, et al. Multipotent CNS stem resource for learning concepts in embryological develop- cells are present in the adult mammalian spinal cord and ment. http://embryology.med.unsw.edu.au. Accessed 12th ventricular neuraxis. J Neurosci. 1996;16:7599-7609. ­December 2012 Zecevic N, Chen Y, Filipovic R. Contributions of cortical sub- Jessen KR, Richardson WD, eds. Glial Cell Development: Basic ventricular zone to the development of the human cerebral Principles and Clinical Relevance. 2nd ed. Oxford: Oxford cortex. J Comp Neurol. 2005;491:109-122. University Press; 2001. Chapter 2 Cells of the Nervous System Proteins and other substances are transported Important Facts within axons at different speeds and in both directions. Neurons are cells specialized for rapid commu- Much of the cytoplasm of a neuron is nication. Most of the cytoplasm of a neuron is removed when the axon is transected. The in long processes, the neurites (dendrites and segment that has been isolated from the cell axon, which conduct signals toward and away body degenerates together with its myelin from the cell body, respectively). sheath, and the fragments are eventually In the central nervous system (CNS), neuronal phagocytosed. cell bodies and dendrites occur in gray mat- The neuronal cell body initially reacts to ter. White matter consists largely of axons, axotomy with increased protein synthesis, most of which have myelin sheaths that serve accompanied by structural changes known to increase the velocity of conduction. as the axon reaction, or chromatolysis. In the A neuronal surface membrane has a resting absence of axonal regeneration, the cell body potential of −70 mV, maintained by the sodium may later shrink or die. Axons severed in the pump. This is reversed to +40 mV in an axon peripheral nervous system can regrow and during the passage of an action potential. reinnervate their targets. The fastest signals, known as impulses or In mammals, axons transected within the action potentials, are carried in the surface CNS fail to regenerate effectively. Synaptic membrane of the axon. There is rapid (salta- rearrangements, however, can occur in partly tory) conduction in myelinated axons because denervated regions of gray matter, and some the ion channels in the axolemma are con- recovery of function occurs as a result of fined to the nodes. recruitment of alternative neuronal circuitry. The surface membrane of the perikaryon The neuroglial cells of the normal CNS are and dendrites does not conduct impulses. astrocytes, oligodendrocytes, ependymal cells Potential changes move more slowly and are (derived from neural tube ectoderm), and graded. An action potential is initiated when microglia (derived from mesoderm). Astro- the region of the axonal hillock is depolarized cytes occur throughout the brain and spinal to a threshold level. cord. Oligodendrocytes produce myelin and Neurons communicate with one another at are also found next to the cell bodies of some synapses. Chemical transmitters released neurons. Microglial cells become phagocytes by axonal terminals evoke changes in the when local injury or inflammation is present. membrane of the postsynaptic cell, which The neuroglial cells of the peripheral nervous may be either stimulated or inhibited. The system are Schwann cells in nerves and satel- effect depends on the transmitter and the lite cells in ganglia. type of receptor molecule in the postsynaptic membrane. Local reductions of membrane potential Two classes of cells are present in the nervous (excitatory postsynaptic potentials or depolar- system in addition to the usual cells found in izations) add together and may result in ini- blood vessel walls. Neurons, or nerve cells, are tiation of action potentials. Hyperpolarization specialized for nerve impulse conduction and for (inhibitory postsynaptic potentials) reduces the likelihood of initiation of an impulse. exchanging signals with other neurons. They are, therefore, responsible for most of the functional 13 14 Part I: Introduction and Neurohistology characteristics of nervous tissue. Neuroglial cells, lack of cytoplasmic continuity between neurons collectively known as the neuroglia or simply as at synapses was conclusively demonstrated in the glia, have important ancillary functions. 1950s when it became possible to obtain electron The central nervous system (CNS) consists micrographs with sufficient resolution to show the of gray matter and white matter. Gray matter structures of intimately apposed cell membranes. contains the cell bodies of neurons, each with a nucleus, embedded in a neuropil made up pre- Different Shapes and Sizes of dominantly of delicate neuronal and glial pro- Neurons cesses. White matter, on the other hand, consists Although all neurons conform to the general prin- mainly of long processes of neurons, the majority ciples already outlined, a wide range of structural being surrounded by myelin sheaths; nerve cell diversity exists. The size of the cell body varies bodies are lacking. Both the gray and the white from 5 μm across for the smallest cells in complex matter contain large numbers of neuroglial cells circuits to 135 μm for the largest motor neurons. and a network of blood capillaries. Dendritic morphology, especially the pattern of branching, varies greatly and is distinctive for neu- Neurons rons that constitute a particular group of cells. The axon of a local circuit neuron may be as short as Neurons are cells specialized for sending and 100 μm, less than 1 μm in diameter, and devoid receiving chemically mediated electrical signals. of a myelin covering. On the other hand, the axon The part of the cell that includes the nucleus is of a motor neuron that supplies a muscle in the called the cell body, and its cytoplasm is known foot is nearly 1 m long, up to 10 μm in diameter, as the perikaryon. Dendrites are typically short and encased in a myelin sheath up to 5 μm thick. branching processes that receive signals from other (Much longer axons are present in large animals neurons. Most neurons of the CNS have several such as giraffes and whales.) dendrites and are, therefore, multipolar in shape. Neurons occur in ganglia in the peripheral By reaching out in various directions, dendrites nervous system and in either laminae (layers) or increase the ability of a neuron to receive input groups called nuclei in the CNS. The large neu- from diverse sources. Each cell has a single axon. rons of a nucleus or comparable region are called This process, which varies greatly in length from principal cells; their axons carry the encoded one type of neuron to another, typically conducts output of information from the region containing impulses away from the cell body. Some neurons their cell bodies to other parts of the nervous sys- have no axons, and their dendrites conduct signals tem. The dendrites of a principal cell are contacted in both directions. Axons of efferent neurons in by axonal terminals of several other neurons. These the spinal cord and brain are included in spinal neurons include principal cells of other areas and and cranial nerves. They end on striated muscle nearby small neurons. The latter are known vari- fibers or on nerve cells of autonomic ganglia. The ously as internuncial, or local circuit neurons, or, term neurite refers to any neuronal process: axon more simply, as interneurons. In many parts of or dendrite. the brain, these neurons greatly outnumber the The fact that each neuron is a structural and principal cells. functional unit is known as the neuron doctrine, Examples of large and small neurons are shown proposed in the latter part of the 19th century in in Figure 2-1, which shows the cells as they might opposition to the then-prevailing view that nerve appear in specimens stained by the Golgi method. cells formed a continuous reticulum or syncytium. The unitary concept, conforming to the cell theory, Neurohistological Techniques was advanced by His on the basis of embryological studies, by Forel on the basis of the responses of Structural features of neurons and neuroglial nerve cells to injury, and by Ramón y Cajal from cells are not well shown in sections prepared by his histological observations. The neuron doc- general purpose staining methods such as the trine was given wide distribution in a review by alum-hematoxylin-eosin beloved by patholo- Waldeyer of the individuality of nerve cells. The gists. Specialized staining methods are preferred  Chapter 2: Cells of the Nervous System 15 Primary sensory neuron Principal neuron of spinal ganglion Motor neuron of sympathetic (has no true dendrites) of spinal cord ganglion Amacrine cell of retina (has no axon) Golgi type ll Tract cell of interneuron spinal gray matter FIGURE 2-1 Examples of neurons, showing variations in size, shape, and branching of processes. for light microscopy. Additional information is Therefore, these stains demonstrate the nuclei obtained with the electron microscope and from of all cells and the cytoplasmic Nissl substance studies in which functionally significant chemical (RNA of rough endoplasmic reticulum) of neu- compounds are histochemically localized in the rons (Fig. 2-2). cells and parts of cells in which they are synthe- Reduced silver methods produce dark sized or stored. deposits of colloidal silver in various structures, Cationic dyes, called “Nissl stains,” when applied notably the proteinaceous filaments inside to nervous tissue bind to DNA and RNA. axons (Fig. 2-3). Other silver methods are 16 Part I: Introduction and Neurohistology FIGURE 2-2 Motor neuron in the spinal cord, stained with cresyl violet to show the Nissl bodies and a prominent nucleolus (×800). available for demonstration of different types of The Golgi method, which has many variants, neuroglial cells. is valuable for the study of neuronal morphology, Stains for myelin rely on the affinities of cer- especially of dendrites. Insoluble salts of silver or tain dyes for hydrophobic proteins and protein- mercury are precipitated within the cells in blocks bound phospholipids. They reveal the major of tissue that are then cut into thick sections. tracts of fibers. Some of the photographs in this Some neurons, including the finest branches of book (e.g., in Chapter 7) are of sections stained their dendrites, stand out in black against a clear by Weigert’s method for myelin. background (Fig. 2-4). Occasional neuroglial cells FIGURE 2-3 Cell body of a neuron in the brain, surrounded by axons. In addition, the nucleolus and a small accessory body of Cajal are seen in the nucleus. (Stained by one of Cajal’s silver nitrate methods; ×1,000.)  Chapter 2: Cells of the Nervous System 17 contained in specific populations of neurons. These substances include putative neurotransmit- ters and enzymes involved in their synthesis or degradation. Several previously unrecognized sys- tems of neurons have been identified by the use of these methods. With immunohistochemistry, substances in tissues are detected by the binding of specific antibodies. Immunohistochemical meth- ods for cell-specific proteins have largely replaced the traditional silver methods for staining axons and glial cells. Electron microscopy reveals the detailed inter- nal structure of neurons and the specializations that exist at synaptic junctions. The necessity of using very thin sections makes it difficult to recon- struct in three dimensions. Electron microscopy may be combined with staining by Golgi methods or with immunohistochemical procedures. Confocal microscopy allows the examination of thin optical sections within thicker specimens prepared for light (usually fluorescence) micros- copy. Resolution is enhanced, and images can be superimposed digitally to make pictures that are in focus for the whole depth of the specimen. In con- focal images, immunohistochemical localizations FIGURE 2-4 Pyramidal cell of the cerebral cortex, can be combined with tracing based on filling or stained by the Golgi technique. The cell body is in the axonal transport. lower one third of the picture, and dendrites extend up toward the cortical surface. The axon is not visible. (×90; courtesy of Dr. E. G. Bertram.) Neuron Cytology The parts of a generalized multipolar neuron are are similarly displayed, but axons (especially if shown in Figure 2-5. myelinated) are typically unstained. An important feature of these methods is the random staining Cell Surface of only a small proportion of the cells, enabling The surface or limiting membrane of the neuron the resolution of structural details of the dendritic assumes special importance because of its role in trees of individual neurons. the initiation and transmission of signals. The Filling techniques provide pictures similar plasma membrane, or plasmalemma, is a double to those obtained by the Golgi method but for layer of phospholipid molecules whose hydropho- individual neurons that have been studied physi- bic hydrocarbon chains are all directed toward ologically. A histochemically demonstrable ion or the middle of the membrane. Embedded in this enzyme or a fluorescent dye is injected into the structure are protein molecules, many of which neuron through a micropipette that has been used pass through the whole thickness. Some trans- for intracellular electrical recording. Some lipo- membrane proteins provide hydrophilic channels philic fluorescent dyes move laterally within cell through which inorganic ions may enter and leave membranes. These can be applied to fresh or even the cell by diffusion. Each of the common ions fixed tissue and used to trace neuronal connec- (Na+, K+, Ca2+, Cl−) has its own specific type of tions over distances up to 5 mm. molecular channel, and there are also mixed ion Histochemical and immunohistochemical channels that allow passage of multiple ions such methods are available for localizing substances as Na+ and K+ or Na+, K+, and Ca2+. Some channels 18 Part I: Introduction and Neurohistology Axoaxonic synapse Microtubules in dendrites Rough endoplasmic reticulum Golgi apparatus Lysosome Mitochondria Axosomatic Polysomes synapse Nucleolus Axodendritic synapse Nucleus Nuclear pore Dendritic spine Axon hillock Neurofilaments in axon FIGURE 2-5 Components of a neuron, traced from an electron micrograph. Mitochondria are colored green and presynaptic terminals from other neurons yellow. (Modified from Heimer L. The Human Brain and Spinal Cord. 2nd ed. New York, NY: Springer-Verlag; 1995.) are voltage gated, which means that they open and binding to specific receptors. Nerve impulses are close in response to changes in the electrical poten- propagated (conducted) along the cell membrane tial across the membrane. Other channels open of the neuronal surface. Pumps are protein mol- in response to ligand, such as neurotransmitters, ecules of the cell membrane that consume energy  Chapter 2: Cells of the Nervous System 19 (from adenosine triphosphate [ATP]) as they small neurons, the chromatin is in coarse clumps. move ions against concentration gradients. A Typically, there is a prominent nucleolus. The single pump, known as Na/K-ATPase, transports sex chromatin (see Fig. 2-5), present only in potassium ions into and sodium ions out of the females, was first described in the large nuclei of cell, resulting in a net negative charge within the motor neurons. cell and contributing to the membrane potential. The cytoplasm of the cell body (Fig. 2-6) is Receptors are protein molecules that respond to dominated by the organelles of protein synthe- specific chemical stimuli, typically by causing the sis (rough endoplasmic reticulum and polyribo- opening of associated channels. somes) and cellular respiration (mitochondria). Also present is a well-developed Golgi apparatus, Signaling in neurons where carbohydrate side chains are added to pro- The most abundant ions in extracellular fluid are tein molecules packaged into membrane-bound sodium (Na+) and chloride (Cl−). Inside the cell, vesicles destined to enter or pass through the sur- potassium (K+) is the main positive ion; it is neu- face membrane of the cell. In light microscopy, tralized by organic anions of amino acids and pro- the rough endoplasmic reticulum is conspicuous teins. Both the extracellular fluid and the cytoplasm as striated bodies of Nissl substance (see Fig. 2-2). are electrically neutral, and each has the same total Filamentous organelles are most prominent osmotic pressure. A consequence of these condi- in the neurites. Neurofilaments (diameter 7.5 tions is that there is a potential difference across the to 10 nm) are made of structural proteins similar membrane: The inside is negative (−70 mV) with to those of the intermediate filaments of other respect to the outside when the neuron is not con- types of cells. When gathered into bundles, ducting a signal. This resting membrane potential they form the neurofibrils of light microscopy. opposes the outward diffusion of K+ and the inward Microtubules (external diameter 25 nm) are diffusion of Cl− because unlike charges attract and involved in the rapid transport of protein mole- like charges repel one another. The membrane is cules and small particles in both directions along much less permeable to Na+ because the voltage- axons and dendrites. Microfilaments (4 nm) are gated channels for this cation are closed as a con- molecules of the contractile protein actin. They sequence of the resting membrane potential. The are present on the inside of the plasmalemma cytoplasmic anions are too large to pass through and are particularly numerous in the tips of the membrane. The ionic concentrations are main- growing neurites. tained by the activity of the sodium pump. Neuronal cytoplasm also contains small num- The signals carried by a neuron are changes bers of membrane-bound vesicles called lyso- in the potential difference across the plasma- somes, which contain enzymes that catalyze the lemma. At rest, the cytoplasm is negative (about breakdown of unwanted large molecules. Neurons −70 mV) with respect to the extracellular fluid. may also contain two types of pigment granules. This difference is reversed to about +40 mV Lipofuscin is a yellow-brown pigment formed inside when an axon is sufficiently stimulated. from lysosomes that accumulates with aging. The reversal, known as an impulse or action Neuromelanin is a black pigment seen only in potential, propagates along the axon. An action neurons that use catecholamines (dopamine or potential is an all-or-none phenomenon. In con- noradrenaline) as neurotransmitters. trast, the dendrites and the cell body respond to stimuli with graded potential changes. Lowering Neurites of the membrane potential to a threshold level of Dendrites taper from the cell body and branch −55 mV at the initial segment of the axon trig- in its immediate environs. In some neurons, the gers an action potential. smaller branches bear large numbers of minute projections, called dendritic spines, which par- Nucleus and Cytoplasm ticipate in synapses. The surface of the cell body is The nucleus of a neuron is usually in the center also included in the receptive field of the neuron. of the cell body. In large neurons, it is vesicular The single axon has a uniform diameter (with finely dispersed chromatin), but in most throughout its length. In interneurons, it is 20 Part I: Introduction and Neurohistology PM M Memb N FIGURE 2-6 Electron micrograph of part of the cell body of a neuron in the preoptic area of a rabbit’s brain. The series of membranes, together with the free polyribosomes between the membranes, constitute the Nissl material of light microscopy. M, mitochondria; Memb, membranes of endoplasmic reticulum; PM, plasma membrane at surface of cell. (×36,000; courtesy of Dr. R. Clattenburg.) short and branches terminally to establish syn- they typically end as synaptic terminals (also aptic contact with adjacent neurons. Some inter- known as boutons terminaux) in contact with neurons have no axon, so they can conduct only other cells. The cytoplasm of the axon is called graded changes of membrane potential. In prin- axoplasm, and the surface membrane is known cipal cells, the diameter of the axon increases as the axolemma. The axoplasm includes neu- in proportion to its length. Collateral branches rofilaments, microtubules, scattered mitochon- may be given off at right angles to the axon. The dria, and fragments of smooth endoplasmic terminal branches are known as telodendria; reticulum.  Chapter 2: Cells of the Nervous System 21 Myelin saltatory conduction in which the action poten- tial jumps electrically from one node to the next, so The axon of a principal cell is usually surrounded that signaling is much faster in a myelinated than by a myelin sheath, which begins near the origin of in an unmyelinated axon. A nerve fiber consists of the axon and ends short of its terminal branching. the axon and the surrounding myelin sheath or of Myelin is laid down by neuroglial cells—Schwann the axon only in the case of an unmyelinated fiber. cells in the peripheral nervous system and oligoden- The greater the diameter of a nerve fiber, the faster drocytes in the CNS. The sheath consists of closely is the conduction of the nerve impulse. apposed layers of glial plasma membranes. Inter- Myelin sheaths are laid down during the later ruptions called nodes of Ranvier indicate junc- part of fetal development and during the early tions between regions formed by different Schwann postnatal period in the manner shown, for a cells or oligodendrocytes. The ion movements of peripheral fiber, in Figure 2-7. The ultrastructure impulse conduction in a myelinated axon are con- of the sheath is seen in Figure 2-8. A Schwann cell fined to the nodes. This arrangement provides for myelinates only one axon, but in the CNS, each A B C D E F FIGURE 2-7 (A) The myelin sheath and Schwann cell as they are seen (ideally) by light microscopy. (B–D) Successive stages in the development of the myelin sheath from the plasma membrane of a Schwann cell. (E) Ultrastructure of a node of Ranvier sectioned longitudinally. (F) Relation of a Schwann cell to several unmyelinated axons. 22 Part I: Introduction and Neurohistology E M A FIGURE 2-8 Ultrastructure of the myelin sheath (M) in a peripheral nerve. The dense and less dense layers alternate, and the latter includes a thin intraperiod line. A, axoplasm; E, endoneurium, with collagen fibers. (Electron micrograph, ×107,500; courtesy of Dr. R. C. Buck.) process of a single oligodendrocyte contributes to a conjunction or connection, was introduced by the myelination of a different axon (Fig. 2-9). Sherrington in 1897. An action potential can be Experiments with peripheral nerves of animals propagated in either direction along the surface show that all Schwann cells have the potential to of an axon. The direction it follows under physi- make myelin sheaths and that each neuron deter- ological conditions is determined by a consistent mines whether the glial cells around its axon will polarity at most synapses, where transmission is or will not produce a myelin sheath. from the axon of one neuron to a dendrite or the perikaryon of another neuron. Consequently, Saltatory Conduction in Myelinated Axons Nerve Fibers A nerve fiber is an axon together with a myelin sheath, if present, and the ensheathing glial cells. The velocity of conduction of an impulse along a nerve fiber increases with the diameter. The largest Myelin sheath axons have the thickest myelin sheaths and, there- fore, the greatest external diameters. The axonal Oligodendrocyte diameter is approximately two thirds of the total external diameter of the fiber. The thinnest, most slowly conducting axons are unmyelinated. Peripheral nerve fibers are classified into groups Axon according to external diameter and conduction velocity (Table 2-1). Axons in the CNS are not as easy to classify; their diameters vary greatly. Node of Ranvier Conduction Velocity and the Compound Action Potential FIGURE 2-9 An oligodendrocyte with cytoplasmic ex- tensions forming the myelin sheaths of axons in the cen- Synapses tral nervous system. (Modified from Bunge MB, Bunge RP, Ris H. Ultrastructural study of remyelinization in an A neuron influences other neurons at junctional experimental lesion in adult cat spinal cord. J Biophys points, or synapses. The term synapse, meaning Biochem Cytol. 1961;10:67-94.)  Chapter 2: Cells of the Nervous System 23 Table 2-1 Size and Conduction Velocity of Nerve Fibers Name and Function of External Diameter Conduction Velocity Type of Fibera (μm) (m/sec) Myelinated fibers Aα or IA 12–20 70–120 Motor to skeletal muscle; sensory from muscle spindle proprioceptive endings (phasic, annulospiral type) Aβ or IB 10–15 60–80 Sensory from tendons (tension); also Ruffini endings in skin Aβ or II 5–15 30–80 Sensory from Meissner’s and Pacinian corpuscles and similar endings in skin and connective tissue; from large hair follicles and tonic proprioceptive endings (flower- spray type) of muscle spindles Aγ 3–8 15–40 Motor to intrafusal fibers of muscle spindles Aδ or III 3–8 10–30 Sensory from small hair follicles and from free nerve endings for temperature and pain sensations B 1–3 5–15 Preganglionic autonomic (white rami and cranial nerves 3, 7, 9, and 10) Unmyelinated fibers C or IV 0.2–1.5 0.5–2.5 Pain and temperature; olfaction; postganglionic autonomic a Letters are used for any nerve; Roman numerals are used for sensory fibers in dorsal spinal roots. action potentials are initiated at the axonal hill- is boutons terminaux. This French term recalls ock and are propagated away from the cell body. the appearance in light microscopy). A synaptic terminal contains numerous mitochondria and a Chemical Synapses cluster of synaptic vesicles. The latter are mem- A point of functional contact between two neu- brane-bound organelles 40 to 150 nm in diameter rons, or between a neuron and an effector cell, is (Fig. 2-10), which contain chemical neurotrans- a synapse. The structural details of synapses can mitters. The vesicles may be spherical (in Gray’s be resolved only by electron microscopy. Most type 1 synapses, which are generally excitatory) or synapses in vertebrate animals are chemical syn- ellipsoidal (in Gray’s type 2 synapses, which use apses. The surface membranes of the two cells are the inhibitory transmitter gamma-aminobutyric thickened by deposition of proteins (receptors and acid [GABA]). Type 1 synapses are asymmetric, ion channels) on their cytoplasmic surfaces. The with deposits of fibrillary material that are con- intervening synaptic cleft contains an electron- spicuously thicker on the postsynaptic than on the dense glycoprotein that is absent from the general presynaptic membrane. extracellular space. The postsynaptic structure is typically a den- The presynaptic neurite, which is most often a drite. Often, it bears a pedunculated projection, branch of an axon, is known as a synaptic terminal a dendritic spine, that invaginates the presyn- or bouton terminal (“terminal button”; the plural aptic neurite. Commonly, synapses are grouped 24 Part I: Introduction and Neurohistology M SV Pre Post D FIGURE 2-10 Electron micrograph of an axodendritic Gray’s type I (asymmetrical) synapse in a rabbit’s hypothala- mus. D, dendrite; M, mitochondria; Pre, presynaptic membrane; Post, postsynaptic membrane; SV synaptic vesicles. (×82,000; courtesy of Dr. R. Clattenburg.) together on a dendrite or an axonal terminal to of other synaptic terminals. Dendrodendritic syn- form a larger structure, known as a synaptic com- apses can modify a neuron’s responses to input at plex or glomerulus. In the CNS, the cytoplasmic other synapses and occurs via gap junctions. processes of protoplasmic astrocytes intimately When the membrane potential of a presynaptic invest synaptic complexes, restricting diffusion neurite is reversed by the arrival of an action poten- in the intercellular spaces of released transmitters tial (or, in the case of a dendrodendritic synapse, and inorganic ions such as calcium and potassium. ­adequately reduced by a graded fluctuation), calcium These small molecules and ions are absorbed into channels are opened and Ca2+ ions diffuse into the the cytoplasm of astrocytes and can then diffuse, cell because they are present at a much higher con- by way of gap junctions, to adjacent astrocytes. centration in the extracellular fluid than in the cyto- Some different types of chemical synapses are plasm. Entry of calcium triggers the fusion of s­ ynaptic shown in Figure 2-11. The most common arrange- vesicles to the terminal plasmalemma, thereby ments for transferring signals from one neuron to releasing neurotransmitters and neuromodulators another are axodendritic and axosomatic synapses. into the synaptic cleft. A classical n ­ eurotransmitter Axoaxonal synapses are strategically placed to inter- either stimulates or inhibits the postsynaptic cell. fere either with the initiation of impulses at the ini- A neuromodulator has other actions, including tial segments of other axons or with the activities modifying the responsiveness to transmitters.  Chapter 2: Cells of the Nervous System 25 Axodendritic synapse Dendrodendritic synapse (Gray's type I) (Gray's type I) D Axodendritic synapse Axodendritic synapse en passant A (Gray's type II) (Gray's type II) D A A A A D D Axoaxonal synapse (Gray's type I) Axodendritic synapse with Electrical synapse dendritic spine (Gray's type I) (dendrodendritic) FIGURE 2-11 Ultrastructure of various types of synapses. The green areas represent the cytoplasmic processes of astrocytes. Neuronal cytoplasm is yellow. A, axons; D, dendrites. Having crossed the synaptic cleft, the trans- responses in the receptive field of a neuron deter- mitter molecules combine with receptors on the mines whether, at any given moment, an impulse postsynaptic cell. If the transmitter–receptor inter- will be sent along the axon. action is one that results in excitation, nonspecific Some neurotransmitters act rapidly (within cation channels are opened, allowing entry of Na+ milliseconds) by binding to ionotropic receptors, + and Ca2+ and efflux of K at postsynaptic sites. which are also the ion channels in the membrane. Inhibition, on the other hand, primarily involves Other substances, notably the peptides, have more the opening of chloride channels in the postsyn- protracted actions (within seconds, minutes, or aptic membrane, which is transiently hyperpolar- hours). Slowly acting transmitters or modulators – ized as a consequence of the diffusion of Cl ions bind to metabotropic receptors associated with into the cytoplasm. Some inhibition results from G proteins. The latter substances bind guanosine + + the opening of K channels, which allows K to triphosphate and participate in intracellular second- leave the cell, thereby resulting in a net negative messenger systems in the cytoplasm of the postsyn- charge inside the neuron, similar to the effect of aptic cell. The inhibitory transmitter GABA acts on – the entry of Cl ions. These changes in the mem- ionotropic receptors associated with chloride chan- brane potential are additive over the whole recep- nels and on G protein–associated receptors that tive surface of the postsynaptic neuron. If the net induce opening of potassium channels. Glutamate, electrical change reaches a threshold level of depo- the most abundant excitatory transmitter