Fundamental Neuroscience for Basic

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Duane E. Haines
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FUNDAMENTAL
NEUROSCIENCE
for Basic and Clinical Applications

As seen in this unretouched photograph of a small myelinated axon, mitochondria may

­assume a variety of sizes, shapes, and orientations.
This page intentionally left blank

     
 FIFTH EDITION

FUNDAMENTAL
NEUROSCIENCE
for Basic and Clinical Applications

Duane E. Haines, PhD, FAAAS, FAAA

Professor, Department of Neurobiology and Anatomy,
and Professor of Neurology,
Wake Forest School of Medicine
Winston-Salem, North Carolina;
Professor Emeritus (and Former Chairman)
Neurobiology and Anatomical Sciences
Professor, Departments of Neurology and Neurosurgery
The University of Mississippi Medical Center
Jackson, Mississippi

Gregory A. Mihailoff, PhD

Professor Emeritus
Department of Anatomy
Arizona College of Osteopathic Medicine
Midwestern University
Glendale, Arizona

Medical Illustrators:
W.K. Cunningham, BA, MSMI, and M.P. Schenk, BS,
MSMI, CMI, FAMI

Photographer:
G.W. Armstrong, RBP

Computer Graphics:
C.P. Runyan
1600 John F. Kennedy Blvd.
Ste 1800
Philadelphia, PA 19103-2899

FUNDAMENTAL NEUROSCIENCE FOR BASIC AND CLINICAL

APPLICATIONS, FIFTH EDITION ISBN: 978-0-323-39632-5

Copyright © 2018 by Elsevier, Inc. All rights reserved.

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Spanish Translation (2003) of the Second English (2002)

Spanish Translation (2014) of the Fourth English (2013)
Previous editions copyrighted 2013, 2006, 2002, and 1997.

Library of Congress Cataloging-in-Publication Data

Names: Haines, Duane E., editor. | Mihailoff, Gregory A., editor.

Title: Fundamental neuroscience for basic and clinical applications / [edited
by] Duane E. Haines, Gregory A. Mihailoff ; medical illustrator, W.K.
Cunningham and M.P. Schenk ; photographer, G.W. Armstrong ; computer
graphics, C.P. Runyan.
Description: Fifth edition. | Philadelphia, PA : Elsevier, [2018] | Includes
bibliographical references and index.
Identifiers: LCCN 2017024153 | ISBN 9780323396325 (hardcover : alk. paper)
Subjects: | MESH: Central Nervous System--physiology | Neurons |
Neuroimaging--methods
Classification: LCC QP355.2 | NLM WL 300 | DDC 612.8/22--dc23 LC record
available at https://lccn.loc.gov/2017024153

Content Strategist: Marybeth Thiel

Senior Content Development Specialist: Rae Robertson
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Printed in China

Last digit is the print number: 9 8 7 6 5 4 3 2 1

Contributors
NORMAN F. CAPRA, MS, PhD
Professor Emeritus, Department of Neural and Pain Sciences,
University of Maryland, Baltimore, Baltimore, Maryland
The Somatosensory System I: Tactile Discrimination and Position Sense;
The Somatosensory System II: Nociception, Thermal Sense, and Touch
JIAN CHEN, MD, PhD
Department of Neurology, The University of Mississippi
­Medical Center, Jackson, Mississippi
The Visual System; The Neurologic Examination
JAMES J. CORBETT, MD
Professor Emeritus (and Former Chairman), Department of
Neurology, Professor of Ophthalmology, The University of
Mississippi Medical Center, Jackson, Mississippi
The Ventricles, Choroid Plexus, and Cerebrospinal Fluid; The Visual
System; Visual Motor Systems; The Neurologic Examination
J. DAVID DICKMAN, PhD
Professor, Department of Neuroscience, Baylor College of
Medicine; Adjunct Professor, Department of Biosciences &
Psychology, Rice University, Houston, Texas
The Vestibular System
TERRY M. DWYER, MD, PhD
Professor Emeritus, Department of Physiology and Biophysics,
Division of Pulmonary and Critical Care Medicine, Depart-
ment of Medicine, The University of Mississippi Medical
Center, Jackson, Mississippi
The Electrochemical Basis of Nerve Function; Chemical Signaling in
the Nervous System
HOWARD L. GEYER, MD, PhD
Assistant Professor, The Saul R. Korey Department of Neurology,
Albert Einstein College of Medicine; Director, Division of Move-
ment Disorders, Montefiore Medical Group, Bronx, New York
The Basal Nuclei
WADE A. GROW, PhD
Professor and Chair, Department of Anatomy, Arizona College
of Osteopathic Medicine, Midwestern University, Glendale,
Arizona
Development of the Nervous System; The Cerebral Cortex
DUANE E. HAINES, PhD, FAAAS, FAAA
Professor, Department of Neurobiology and Anatomy, and
Professor of Neurology, Wake Forest School of Medicine,
Winston-Salem, North Carolina; Professor Emeritus (and
Former Chairman), Neurobiology and Anatomical Sciences,
Professor, Departments of Neurology and Neurosurgery, The
University of Mississippi Medical Center, Jackson, Mississippi
Orientation to the Structure and Imaging of the Central Nervous
System; The Cell Biology of Neurons and Glia; The Ventricles, Cho-
roid Plexus, and Cerebrospinal Fluid; The Meninges; A Survey of
the Cerebrovascular System; The Spinal Cord; An Overview of the
Brainstem; The Medulla Oblongata; The Pons and Cerebellum; The
Midbrain; A Synopsis of Cranial Nerves of the Brainstem; The Dien-
cephalon; The Telencephalon; Motor System I: Peripheral Sensory,
Brainstem, and Spinal Influence on Anterior Horn Neurons; Motor
System II: Corticofugal Systems and the Control of Movement; The
Cerebellum; The Limbic System
CRAIG K. HENKEL, PhD
Professor, Department of Neurobiology and Anatomy, Wake
Forest School of Medicine, Winston-Salem, North Carolina
The Auditory System
T. BUCKY JONES, PhD
Associate Professor, Department of Anatomy, Arizona College
of Osteopathic Medicine, Midwestern University, Glendale,
Arizona
Viscerosensory Pathways; Visceral Motor Pathways
JASON A. KAUFMAN, PhD
Associate Professor, Department of Anatomy, Arizona College
of Osteopathic Medicine, Midwestern University, Glendale,
Arizona
Viscerosensory Pathways; Visceral Motor Pathways
TERENCE P. MA, PhD
Assistant Dean for Educational Information Resources,
Office of Medical Education, Professor of Clinical Anatomy
and Structural Biology, Department of Anatomy and
Structural Biology, Albert Einstein College of Medicine,
Bronx, New York
The Basal Nuclei
PAUL J. MAY, PhD
Professor, Neurobiology & Anatomical Sciences, Assistant
Professor, Department of Neurology and Department of
Ophthalmology, The University of Mississippi Medical Center,
Jackson, Mississippi
The Midbrain; Visual Motor Systems
GREGORY A. MIHAILOFF, PhD
Professor Emeritus, Department of Anatomy, Arizona College
of Osteopathic Medicine, Midwestern University, Glendale,
Arizona
The Cell Biology of Neurons and Glia; The Spinal Cord; An Overview
of the Brainstem; The Medulla Oblongata; The Pons and Cerebel-
lum; The Midbrain; A Synopsis of Cranial Nerves of the Brainstem;
The Diencephalon; The Telencephalon; Motor System I: Periph-
eral Sensory, Brainstem, and Spinal Influence on Anterior Horn
Neurons; Motor System II: Corticofugal Systems and the Control of
Movement; The Cerebellum
ANDREW D. PARENT, MD
Professor of Neurosurgery, The University of Mississippi Medi-
cal Center, Jackson, Mississippi
The Hypothalamus
EDDIE PERKINS, PhD
Associate Professor, Department of Neurosurgery, Neurology,
Neurobiology, and Anatomical Sciences, The University of
Mississippi Medical Center, Jackson, Mississippi
The Hypothalamus
KIMBERLY L. SIMPSON, PhD
Associate Professor, Department of Neurobiology and Anatomi-
cal Sciences, The University of Mississippi Medical Center,
Jackson, Mississippi
Olfaction and Taste
v
vi Contributors

ALLEN C. TERRELL, MS, RT(R) (MR), FASRT MARY ALISSA WILLIS, MD

Operations Manager, Central Mississippi Diagnostics, LLC,
Flowood, Mississippi
Orientation to the Structure and Imaging of the Central Nervous
System
SUSAN WARREN, PhD
Professor, Department of Neurobiology and Anatomical
Sciences, The University of Mississippi Medical Center,
Jackson, Mississippi
The Somatosensory System I: Tactile Discrimination and Position
Sense; The Somatosensory System II: Nociception, Thermal Sense,
and Touch
Assistant Professor, Neurological Institute,
Cleveland Clinic, Cleveland, Ohio
The Limbic System
ROBERT P. YEZIERSKI, PhD
College of Dentistry, Department of Orthodontics, Pain
Research and Intervention Center of Excellence, University
of Florida, Gainesville, Florida
The Spinal Cord; The Somatosensory System I: Tactile Discrimination
and Position Sense; The Somatosensory System II: Nociception,
Thermal Sense, and Touch
Preface
The significant changes in the fifth edition of Fundamental
Neuroscience for Basic and Clinical Applications take into
consideration (1) new discoveries in the basic neurosciences, (2)
how these may be applied to educating students in the clinical
setting, (3) new observations in the clinical neurosciences, and of
particular importance (4) how this information may be used to
understand and diagnose the neurologically compromised patient.
These concepts recognize two important points essential to medical
education. First, the contemporary approach allows educators
to integrate basic and clinical science information, rather than
to just teach anatomy or connections within the nervous system
for their own sake. The clinical observation is a springboard for
students to understand and apply basic science concepts to a
neurologically compromised patient. Second, accrediting and
licensing bodies that govern the various branches of medicine,
dentistry, and allied health have clearly indicated that the inte-
gration of basic science and clinical information is an integral part
of the contemporary educational experience.
The significant changes and additions to Fundamental Neuro-
science (both great and small) emphasize the intimate interaction
between the basic and clinical neurosciences. The main goals are
to introduce additional and relevant clinical information, to inte-
grate clinical and basic science information in a seamless fashion,
and to introduce new anatomic information when it enhances the
understanding of clinical concepts. The emphasis is clearly shifted
to an even more clinically oriented approach. Of particular note is
the fact that of the approximate 598 illustrations in this new edi-
tion, about 48%, are new/revised (artwork, CT, MRI): labels have
been changed, artwork was modified, and many drawings were
recast so as to now appear in color.
In addition, about 275 general Review Questions with explana-
tory answers are available online on the Student Consult website
(www.studentconsult.com) for review, practice, or assessment.
It is not possible to describe each individual change, modifica-
tion, or addition; only the more significant are mentioned here.
First, key words, phrases, and concepts appear in boldface.
This expedites quick and easy access.
Second, the presentation, or availability, of anatomic informa-
tion in a “clinical orientation” is an essential feature of contem-
porary neuroscience education; it prepares the student for the
significant realities of the clinical environment where viewing the
central nervous system in MRI and CT in a “clinical orientation”
is the established standard. This is especially true for images such
as stained sections or artwork of the spinal cord or brainstem,
when they are presented in an axial plane. For example, in an axial
MRI of the midbrain, its dorsal aspect (the colliculi) is “down” in
the image, and its ventral portion (the crus and interpeduncular
fossa) is “up” in the image. This is opposite the “anatomic
orientation.” Because the MRI/clinical orientation is opposite
the anatomic orientation (commonly used in the instructional
setting), a method is incorporated into this edition that allows
the reader to easily flip selected images from the anatomic orien-
tation to the clinical orientation and thereby view the anatomy as
it is presented in MRI and CT. Images that are identified by a flip
symbol in the figure description within the book can be viewed
in either anatomic or clinical orientation with online resources at
www.studentconsult.com. The availability of this feature accom-
modates a wide variety of educational approaches and review
opportunities but especially prepares the user for the expecta-
tions and requirements of the clinical experience.
Third, the relevance of clinical information and its integration
with basic neuroscience concepts is an absolutely essential com-
ponent of the contemporary educational process. To this end, all
clinical information, including reflexes, appears in a light blue
highlight throughout the book. This approach allows the clinical
correlations to remain in their proper textual context within
the natural flow of structural and functional information. At the
same time, it also allows the reader to immediately identify what
text on any given page is clinical in nature.
Fourth, new clinical and anatomic terminology is introduced
that reflects a contemporary, and more correct, usage of classic
terms. This also has allowed existing concepts and interpreta-
tions to be clarified and corrected.
Fifth, new clinical information in the form of MRI and CT,
clinical examples, line drawings, and related information is intro-
duced. A special effort has been made to fully integrate this
information with existing text and new basic neuroscience data.
Sixth, throughout the book, a significant number of anatomic
and clinical drawings are corrected; modified to increase their
clarity; replaced with new artwork; correlated with clinical
images such as MRI, CT, and angiograms; or otherwise improved.
This edition follows the official international list of anatomic
terms for neuroanatomy (Terminologia Anatomica, Thieme,
1998) or draws on recent publications that provide particular
clarity. We have made a concerted effort to include the most cur-
rent and most correct terminology; if some terms have eluded us,
these will be corrected in future printings.
To further improve this work, the editor and contributors wel-
come comments, corrections, and suggestions from students, our
colleagues, and any other readers of this book.
vii
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Acknowledgments
This fifth edition of Fundamental Neuroscience for Basic and
Clinical Applications is the result of helpful input from many
individuals. We express our sincere thanks to our students
for their probing interest and insightful comments that have
allowed us to better address their present, and future, educa-
tional needs.
A special thanks is extended to those many colleagues who
have provided valuable input to this, and earlier, editions,
including Drs. V.K. Anand, D.E. Angelaki, R.H. Baisden, M.
Behari, A.J. (Tony) Castro, S.C. Crawford, J.L. Culberson,
E. Dietrichs, J.T. Ericksen, W.C. Hall, R. Hoffman, J.S.
King, W.M. King, S. Ledoux, G.R. Leichnetz, G.F. Martin,
I.J. Miller, E. Mugnaini, R. Nieuwenhuys, R.S. Nowakowski,
D.F. Peeler, A. Peters, J.D. Porter, J.A. Rafols, W.A. Roy,
L.F. Schweitzer, D.L. Tolbert, and M.L. Woodruff. The MRI
of nasal polyps in Chapter 23 was generously provided by
Dr. Vinod Anand, Baptist Medical Center, Jackson, MS. The
photographs of Golgi-stained material in Chapters 26 and 27
are from the Clement A. Fox Collection at Wayne State Univer-
sity and through the courtesy of Dr. Rafols. The photograph of
the unipolar brush cell in Chapter 27 was generously provided
by Dr. Enrico Mugnaini, Northwestern University Institute
for Neuroscience, and Dr. Madhuri Behari, All India Institute
of Medical Sciences, generously supplied the MRI image of a
Wilson patient in Chapter 26. Dr. Richard Miller, The Univer-
sity of Mississippi Medical Center (UMMC), kindly provided
the images of congenital megacolon in Chapters 5 and 29. The
photograph on the half-title page was provided by Drs. Ross
Kosinski and Greg Mihailoff.
We especially wish to thank our colleagues for their
willingness to assume authorship, or co-authorship, of several
chapters in this fifth edition: Dr. Terry Dwyer (Chapters 3 and 4),
Dr. Wade Grow (Chapters 5 and 32), Dr. Bucky Jones and
Dr. Jason Kaufman (Chapters 19 and 29), and Dr. Jian Chen
(Chapter 33). In addition, Dr. Quang Vu, Wake Forest, Depart-
ment of Neurology; and Dr. Jian Chen, UMMC, Department
of Neurology, have generously given of their time to collect
MRI and CT images for this edition. We greatly appreciate
their help.
We also extend our sincere thanks to Professor Roy R.
Weller, University of Southampton, School of Medicine, for
his review of new material included in this edition on an alter-
nate route for the return of CSF to the venous system. This
particular system has important clinical implications, and we
appreciate his insights and suggestions.
The Review Questions that are available on Student Consult
for Chapters 1-2 and 5-33 are from a book written by D.E.
Haines and J.A. Lancon, Review of Neuroscience ©2003, and
questions for Chapters 3 and 4 were prepared by Dr. Terry
M. Dwyer.
Our colleagues at UMMC have been most cooperative in
the giving of their time and energy as the fifth edition was in prep-
aration. We want to thank all my colleagues in the Department
of Neurobiology and Anatomical Sciences, particularly
Drs. Ard, Lin, Lynch, May, Moore, Naftel, Simpson, and Warren;
in the Department of Neurology, especially Drs. Auchus,
Corbett, Herndon, Uschmann, and Wolf; and the residents,
particularly Drs. Ali, Bradley, Hussaini, Sinclair, Sapkota, and
Willis; in the Department of Neurosurgery, particularly Drs.
Gaspard, Harkey, Luzardo, Marks, and Parent; and the resi-
dents, particularly Drs. Johnson, Orozco, and Rey-Dios; and
in the Department of Radiology, especially Drs. Buciuc, Kahn,
and McCowan.
The following individuals have participated in past editions
of this work: Drs. March Ard, Jim Bloedel, Paul Brown, Robert
Chronister, Owen (Bev) Evans, Jonathan Fratkin, Patrick Hardy,
James Hutchins, John Lancon, James Lynch, John Naftel,
Frank Raila, Rob Rockhold, Maria Santiago, and Robert
Sweazey. Most are not participating due to life changes
such as retirement. Their participation was most gratefully
acknowledged.
All the artwork and photography (but not including
specifically acknowledged photographs) were provided in the
Department of Biomedical Illustration Services at UMMC. The
authors are indebted to Mr. Michael P. Schenk (former Director
of the Department, now retired) and his colleagues, Mr. W.K.
Cunningham, Mr. G.W. Armstrong, and Mr. C.P. Runyan,
for their exemplary efforts. All photography was undertaken
by Mr. Armstrong; Mr. Runyan scanned images and cleaned
those as needed. We are enormously appreciative of their
patience and cooperation in getting the best quality artwork
and photographs.
For this fifth edition the vast majority of the artwork (cor-
rections, new images, revising for color, labeling, and many
other essential tasks) was completed by Mr. W.K. (Kyle) Cun-
ningham, who now works as a freelance medical illustrator.
His high-quality work, excellent cooperation, insights into
what qualifies as an excellent result, and numerous sugges-
tions were absolutely essential to the completion of the fifth
edition. We are very grateful for his outstanding cooperation
and participation.
Production of this finely done and visually appealing book
would not have been accomplished without Elsevier. We are
very grateful to Ms. Lauren Willis (Associate Content Strat-
egist) and Ms. Marybeth Thiel (Content Strategist) for their
excellent cooperation and help, and for ensuring that everything
went smoothly, Ms. Melissa Darling (Marketing Manager),
Ms. Kristine Feeherty (Book Production Specialist), and
Mr. Ryan Cook (Book Designer). We are especially indebted to
Ms. Rae Robertson (Senior Content Development Specialist)
for her wonderful cooperation and patience with us, in her
ability to upload the manuscript, her deliberate review of every
page, and her attention to the details that resulted in a finished
book. D.E.H. expresses a special thanks to his wife, Gretchen
(now Nana Gretchen, times 6); she was an absolutely essential
element in getting everything done.
ix
x Acknowledgments
Dr. Robert Chronister (August 24, 1942–October 25, 2009)
was a good friend of ours for many years and a fellow traveler
along the neuroscience highway. Bob was enthusiastic about
all things neuro, gracious and genuinely friendly, and always
had a smile and a robust greeting when we saw each other at
meetings. He was always interested in or had an opinion on
almost any neuro topic that would come up in a conversation.
For Editions 1, 2, and 3, Bob was senior author of The Limbic
System and co-author of The Hypothalamus. We greatly appreci-
ated his contributions and valued his friendship. He is missed.
Contents

SECTION I SECTION III

ESSENTIAL CONCEPTS SYSTEMS NEUROBIOLOGY

1 Orientation to the Structure and Imaging of the 17 The Somatosensory System I: Tactile Discrimination
Central Nervous System   3 and Position Sense   243
D.E. Haines and A.C. Terrell S. Warren, N.F. Capra, and R.P. Yezierski

2 The Cell Biology of Neurons and Glia   15
G.A. Mihailoff and D.E. Haines
3 The Electrochemical Basis of Nerve
Function  34
T.M. Dwyer
18 The Somatosensory System II: Nociception,
Thermal Sense, and Touch   258
S. Warren, R.P. Yezierski, and N.F. Capra
19 
Viscerosensory Pathways  278
J.A. Kaufman and T.B. Jones

4 Chemical Signaling in the Nervous System   54 20 The Visual System   286

T.M. Dwyer J.J. Corbett and J. Chen

5 Development of the Nervous System   72 21 The Auditory System   306

W.A. Grow C.K. Henkel
22 The Vestibular System   320
J.D. Dickman
SECTION II
REGIONAL NEUROBIOLOGY 23 Olfaction and Taste   334
K.L. Simpson
6 The Ventricles, Choroid Plexus, and Cerebrospinal 24 Motor System I: Peripheral Sensory, Brainstem, and
Fluid  93 Spinal Influence on Anterior Horn Neurons   346
J.J. Corbett and D.E. Haines G.A. Mihailoff and D.E. Haines
7 
The Meninges  107 25 Motor System II: Corticofugal Systems and the
D.E. Haines
­Control of Movement   360
8 A Survey of the Cerebrovascular G.A. Mihailoff and D.E. Haines
System  122 26 The Basal Nuclei   377
D.E. Haines T.P. Ma and H.L. Geyer
9 The Spinal Cord   138 27 
The Cerebellum  394
D.E. Haines, G.A. Mihailoff, and R.P. Yezierski D.E. Haines and G.A. Mihailoff
10 An Overview of the Brainstem   152 28 Visual Motor Systems   413
D.E. Haines and G.A. Mihailoff P.J. May and J.J. Corbett
11 The Medulla Oblongata   160 29 Visceral Motor Pathways   430
D.E. Haines and G.A. Mihailoff T.B. Jones and J.A. Kaufman
12 The Pons and Cerebellum   172 30 
The Hypothalamus  442
G.A. Mihailoff and D.E. Haines A.D. Parent and E. Perkins
13 
The Midbrain  183 31 The Limbic System   457
G.A. Mihailoff, D.E. Haines, and P.J. May M.A. Willis and D.E. Haines
14 A Synopsis of Cranial Nerves of the 32 The Cerebral Cortex   468
Brainstem  195
­ W.A. Grow
D.E. Haines and G.A. Mihailoff
33 The Neurologic Examination   480
15 
The Diencephalon  212 J.J. Corbett and J. Chen
G.A. Mihailoff and D.E. Haines
Illustration Credits  494
16 
The Telencephalon  225
D.E. Haines and G.A. Mihailoff Index  496

xi
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 Section I

ESSENTIAL CONCEPTS

1-5
This page intentionally left blank

     

Orientation to the Structure and Imaging of the
Central Nervous System
Overview-3
Central, Peripheral, and Visceromotor Nervous
Systems-3
Neurons-3
Reflexes and Pathways-4
Regions of the Central Nervous System-4
Spinal Cord-4
Medulla Oblongata-5
Pons and Cerebellum-5
Midbrain-5
Thalamus-5
Cerebral Hemispheres-6
Functional Systems and Regions-6
Localizing Signs and Localization-7
Concept of Afferent and Efferent-7
Posterior (Dorsal), Anterior (Ventral), and Other
Directions in the Central Nervous System-8
Symptom or Sign?-8
Symptom-8
Sign-8
Clinical Images of the Brain and Skull-8
Computed Tomography-9
Magnetic Resonance Imaging-10
Image Density and Intensity-11
Imaging of the Brain and Skull-11
Our nervous system makes us what we are. Personality, outlook,
intellect, coordination, and the many other characteristics are the
result of complex interactions within our nervous system. Infor-
mation is received from the environment and transmitted into
the brain or spinal cord. Once this sensory information is pro-
cessed and integrated, an appropriate motor response is initiated.
The nervous system can be viewed as a scale of structural com-
plexity. At the microscopic level, the individual structural and
functional unit of the nervous system is the neuron (the cell body
and its processes), or nerve cell. Interspersed among the neurons
of the central nervous system are supportive elements called glial
cells. At the macroscopic end of the scale are the large divisions (or
parts) of the nervous system that can be handled and studied with-
out magnification. These two extremes are not independent but
form a continuum; functionally related neurons aggregate to form
small structures that combine to form larger structures. Commu-
nication takes place at many different levels, the end result being a
wide range of productive or life-sustaining nervous activities.
OVERVIEW
Central, Peripheral, and Visceromotor Nervous
Systems
The human nervous system is divided into the central nervous
system (CNS) and the peripheral nervous system (PNS) (Fig.
1.1A). The CNS consists of the brain and spinal cord. Because
Chapter 1
D.E. Haines and A.C. Terrell
of their locations in the skull and vertebral column, these struc-
tures are the most protected in the body. The PNS is made up
of nerves that connect the brain and spinal cord with periph-
eral structures. These nerves innervate muscle (skeletal, cardiac,
smooth) and glandular epithelium and contain a variety of sen-
sory fibers. These sensory fibers enter the spinal cord through
the posterior (dorsal) root, and motor fibers exit through the
anterior (ventral) root. The spinal nerve is formed by the joining
of posterior (sensory) and anterior (motor) roots and is, conse-
quently, a mixed nerve (Fig. 1.1B). In the case of mixed cranial
nerves, the sensory and motor fibers are combined into a single
root.
The visceromotor nervous system (also called visceral motor)
is a functional division of the nervous system that has parts in
both the CNS and the PNS (Fig. 1.1). It is made up of neu-
rons that innervate smooth muscle, cardiac muscle, or glandular
epithelium or combinations of these tissues. These individual
visceral tissues, when combined, make up visceral organs such
as the stomach and intestines. The visceromotor nervous system
is also called the autonomic nervous system because it regulates
visceral motor responses normally outside the realm of conscious
control.
Neurons
At the histologic level, the nervous system is composed of neu-
rons and glial cells. As the basic structural and functional units
of the nervous system, neurons are specialized to receive infor-
mation, to transmit electrical impulses, and to influence other
neurons or effector tissues. In many areas of the nervous system,
neurons are structurally modified to serve particular functions.
At this point, we consider the neuron only as a general concept
(see Chapter 2).
A neuron consists of a cell body (perikaryon or soma) and
the processes that emanate from the cell body (Fig. 1.2A). Col-
lectively, neuronal cell bodies constitute the gray matter of the
CNS. Named and usually function-specific clusters of cell bod-
ies in the CNS are called nuclei (singular, nucleus). Typically,
dendrites are those processes that ramify in the vicinity of the
cell body, whereas a single, longer process called the axon carries
impulses to a more remote destination. The white matter of the
CNS consists of bundles of axons that are wrapped in a sheath of
insulating lipoprotein called myelin.
In general, there is a direct relationship between (1) the diam-
eter of the axon, (2) the thickness of the myelin sheath, (3) the
distance between the nodes of the myelin sheath (nodes of Ran-
vier), and (4) the conduction velocity of the nerve fiber. Axons
with a large diameter have thick myelin sheaths with longer inter-
nodal distances and therefore exhibit faster conduction veloci-
ties. Likewise, axons with a thin diameter that have thin myelin
sheaths with shorter internodal distances have slower conduction
velocities. The axon terminates at specialized structures called
synapses or, if they innervate muscles, motor end plates (neuro-
muscular junctions), which function much like synapses.
The generalized synapse (Fig. 1.2A) is the most common type
seen in the CNS and is sometimes called an electrochemical syn-
apse. It consists of a presynaptic element, which is part of an
3
4 Essential Concepts

brief example, we see that (1) the neuron is structurally special-

ized to receive and propagate electrical signals, (2) this propaga-
tion is accomplished by a combination of electrical and chemical
B events, and (3) the transmission of signals across the synapse is in
r
a one direction (unidirectional), that is, from the presynaptic neu-
i ron to the postsynaptic neuron. There are a number of neurologic
n disorders, such as myasthenia gravis, Lambert-Eaton syndrome,
or botulism, that represent a failure of neurotransmitter action
Hypothalamus
at the presynaptic membrane, synapse, or at the receptors on the
postsynaptic membrane.

C S Reflexes and Pathways

N p
S i
n between neurons. Fig. 1.2B illustrates one of the simplest types
P
a N
l S
c
o is involved. In this example, the peripheral end of a sensory fiber
r responds to a particular type of input. The resulting action poten-
d
A tary responses to a particular bit of sensory input. For example,
Sympathetic
Nerves to
chain ganglion
Anterior root viscera
Spinal nerve
Posterior root ganglion
Posterior root ganglion
B ing tract on the contralateral side. In the forebrain, these signals
Fig. 1.1 A, General relationships of central (CNS), peripheral (PNS), and vis-
ceromotor nervous systems. Visceromotor regions of CNS and PNS are shown
in red. B, A representation of the thoracic spinal cord in a clinical orientation
showing the relationships of efferent (outgoing, motor) and afferent (incoming,
sensory) fibers to spinal nerves and roots. Motor fibers are visceral efferent (vis-
ceromotor; red) and somatic efferent (green); sensory fibers are somatic afferent
(blue) and visceral afferent (black).
axon, a gap called the synaptic cleft, and the postsynaptic region
of the innervated neuron or effector structure. Communica-
tion across this synapse is accomplished as follows. An electrical
impulse (the action potential) causes the release of a neuroactive
substance (a neurotransmitter, neuromodulator, or neuromedia-
tor) from the presynaptic element into the synaptic cleft. This
substance is stored in synaptic vesicles in the presynaptic ele-
ment and is released into the synaptic space by the fusion of
these vesicles with the presynaptic membrane (Fig. 1.2A).
The neurotransmitter diffuses rapidly across the synaptic space
and binds to receptor sites on the postsynaptic membrane. On
the basis of the action of the neurotransmitter at receptor sites,
the postsynaptic neuron may be excited (lead to generation of
an action potential) or inhibited (prevent generation of an action
potential). Neurotransmitter residues in the synaptic cleft are
rapidly inactivated by other chemicals found in this space. In this
The function of the nervous system is based on the interactions
of neuronal circuits, a reflex arc composed of only two neurons.
This is called a monosynaptic reflex arc because only one synapse
tial is conducted by the sensory fiber into the spinal cord, where
it influences a motor neuron. The axon of the motor neuron con-
ducts a signal from the spinal cord to the appropriate skeletal
muscle, which responds by contracting. This is an example of
a muscle stretch reflex, which is actually one of the more com-
monly tested reflexes in clinical medicine. Reflexes are involun-
the physician taps on the patellar tendon, and the leg quickly
extends at the knee without the patient consciously controlling
the movement. The lack of a reflex (areflexia), an obviously
weakened reflex (hyporeflexia), or an excessively active reflex
(hyperreflexia) is usually indicative of a neurologic disorder.
By building on these summaries of the neuron and of the basic
reflex arc, we shall briefly consider what neuronal elements con-
stitute a neural pathway. If the patient bumps his or her knee
and not only hits the patellar tendon but also damages the skin
over the tendon, two things happen (Fig. 1.2C). First, impulses
from receptors in the muscle stretched by the tendon travel
through a reflex arc that causes the leg to extend (knee jerk, or
patellar reflex). The synapse for this reflex arc is located in the
lumbosacral spinal cord. Second, impulses from pain receptors
in the damaged skin are transmitted in the lumbosacral cord to
a second set of neurons that convey them via ascending axons
to the forebrain (Fig. 1.2C). As can be seen in Fig. 1.2C, these
axons cross the midline of the spinal cord and form an ascend-
are passed to a third group of neurons that distribute them to a
region of the cerebral cortex specialized to interpret them as pain
from the knee.
This three-neuron chain constitutes a pathway, a series of neu-
rons designed to carry a specific type of information from one
site to another (Fig. 1.2C). Some pathways carry information to
a level of conscious perception (we not only recognize pain but
know that it is coming from the knee), and others convey infor-
mation that does not reach the conscious level. It is common to
refer to all the neurons comprising a pathway and conducting a
specific type of information as a system. For example, the antero-
lateral system conducts pain and thermal information, whereas
the posterior column–medial lemniscus system conducts body
position and vibratory sense, and the corticospinal system con-
ducts descending information from the cerebral cortex to spinal
cord motor neurons.
REGIONS OF THE CENTRAL NERVOUS SYSTEM
Spinal Cord
The spinal cord is located inside the vertebral canal and is ros-
trally continuous with the medulla oblongata of the brain (Fig.
1.3). An essential link between the PNS and the brain, it conveys
sensory information originating from the body wall, extremities,
 Orientation to the Structure and Imaging of the Central Nervous System
Neurons & Synapse – A Simple Reflex – B
Dendrites
Cell body
Sensory
neuron
Axon
Motor
neuron
Synapse
Presynaptic
Synaptic element
cleft Postsynaptic
element
Fig. 1.2 A representative neuron and synapse (A), a simple (monosynaptic) reflex (B), and a pathway
(C). Many pathways share the feature of being crossed (a decussation or commissure) at some point in
their trajectory.
and gut and distributes motor impulses to these areas. Impulses
enter and leave the spinal cord through the 31 pairs of spinal
nerves (Fig. 1.1; see also Fig. 9.2). The spinal cord contains sen-
sory fibers and motor neurons involved in reflex activity and
ascending and descending pathways or tracts that link spinal cen-
ters with other parts of the CNS. Ascending pathways convey
sensory information to higher centers, whereas descending path-
ways influence neurons in the spinal cord or brainstem.
Medulla Oblongata
At the level of the foramen magnum, the spinal cord is continu-
ous with the most caudal part of the brain, the medulla oblon-
gata, commonly called the medulla (Fig. 1.3). The medulla
consists of (1) neurons that perform functions associated with
the medulla and (2) ascending (generally sensory) and descend-
ing (generally motor) tracts that pass through the medulla on
their way from or to the spinal cord. Some of the neuronal cell
bodies of the medulla are organized into nuclei associated with
specific cranial nerves. The medulla contains the nuclei for the
glossopharyngeal (cranial nerve IX), vagus (X), and hypoglossal
(XII) nerves as well as portions of the nuclei for the trigemi-
nal (V) and vestibulocochlear (VIII) nerves; the nucleus of the
accessory nerve (XI) is located in cervical levels of the spinal
cord. It also contains important relay centers and nuclei that are
essential to the regulation of respiration, heart rate, and various
visceral functions.
Pons and Cerebellum
The pons and cerebellum originate embryologically from the
same segment of the developing neural tube. However, in the
adult, the pons forms part of the brainstem (the other parts
being the midbrain and medulla) and the cerebellum is a supra-
segmental structure because it is located posterior (dorsal) to the
brainstem (Fig. 1.3).
Like the medulla, the pons contains many neuronal cell
bodies, some of which are organized into cranial nerve nuclei,
5
Pathway – C
Sensory
cortex
Relay in
forebrain
Sensory
receptor
Tract
neuron
Motor
ending
Relay in
spinal cord
Midline
Pain receptors Sensory neuron
and it is traversed by ascending and descending tracts. The
pons contains the nuclei of the abducens (VI) and facial (VII)
nerves and portions of the nuclei for the trigeminal (V) and
vestibulocochlear (VIII) nerves. The anterior (ventral) part
of the pons contains large populations of neurons (pontine
nuclei) that form a relay station between the cerebral cortex
and cerebellum and descending motor fibers that travel to all
spinal levels.
The cerebellum is connected with diverse regions of the CNS
and is considered part of the motor system. It serves to coordi-
nate the activity of individual muscle groups to produce smooth,
purposeful, synergistic movements.
Midbrain
Rostrally, the pons is continuous with the midbrain (Fig. 1.3).
This part of the brain is, quite literally, the link between the
brainstem and the forebrain. Ascending or descending pathways
to or from the forebrain must traverse the midbrain. The nuclei
for the oculomotor (III) and trochlear (IV) cranial nerves as well
as part of the trigeminal (V) complex are found in the midbrain.
Other midbrain centers are concerned with visual and auditory
reflex pathways, motor function, transmission of pain, and vis-
ceral functions.
Thalamus
The forebrain consists of the cerebral hemispheres, large groups
of neurons that comprise the basal nuclei, and the thalamus (Fig.
1.3). We shall see later that the thalamus actually consists of sev-
eral regions—for example, the hypothalamus, subthalamus, epi-
thalamus, and dorsal thalamus. The thalamus is also commonly
called the diencephalon, a term that reflects its embryologic
origin.
The thalamus is rostral to the midbrain and almost completely
surrounded by elements of the cerebral hemisphere. Individual
parts of the thalamus can be seen in detail only when the brain is
cut in coronal or axial planes.
6 Essential Concepts

Cerebral hemisphere Cerebral Hemispheres

The largest and most obvious parts of the human brain are the
two cerebral hemispheres. Each hemisphere is composed of three
major subdivisions. First, the cerebral cortex is a layer of neuro-
nal cell bodies about 0.5 cm thick that covers the entire surface
of the hemisphere. This layer of cells is thrown into elevations
or peaks called gyri (singular, gyrus) separated by valleys called
sulci (singular, sulcus).
The second major part of the hemisphere is the subcortical
white matter, which is made up of myelinated axons that carry
information to or from the cerebral cortex. The largest and most
Thalamus
organized part of the white matter is the internal capsule. This
Midbrain bundle contains fibers passing to and from the cerebral cortex,
Pons such as corticospinal and thalamocortical fibers.
Medulla oblongata Cerebellum The third major component of the hemisphere is a prominent
Foramen magnum Skull
group of neuronal cell bodies collectively called the basal nuclei.
These prominent forebrain centers are involved in motor func-
tion. Parkinson disease, a neurologic disorder associated with
Cervical the basal nuclei, is characterized by a progressive impairment of
movements and in many cases eventual dementia.
The gyri and sulci that make up the cerebral cortex are
named, and many are associated with particular functions.
Some gyri receive sensory input from thalamic relay nuclei,
whereas descending fibers from these gyri may influence cen-
ters in the brainstem or spinal cord. The cerebral cortex also
includes association areas that are essential for analysis and cog-
nitive thought.

Thoracic
Spinal cord
Lumbar
Sacral
Coccygeal
Fig. 1.3 The basic divisions of the central nervous system.
With the exception of olfaction (sense of smell), all sensory
information that eventually reaches the cerebral cortex must syn-
apse in the thalamus. One function of the thalamus, therefore,
is to receive sensory information of many sorts and to distribute
it to the specific regions in the cerebral cortex that are special-
ized to decode it. Other areas of the thalamus receive input from
pathways conveying information on, for example, position sense
or the tension in a tendon or muscle. This input is relayed to
areas of the cerebral cortex that function to generate smooth,
purposeful movements.
Although it is small, the hypothalamus functions in sexual
behavior, feeding, hormonal output of the pituitary gland, body
temperature regulation, and a wide range of visceromotor func-
tions. Through descending connections, the hypothalamus influ-
ences visceral centers in the brainstem and spinal cord.
FUNCTIONAL SYSTEMS AND REGIONS
A functional system is a set of neurons linked together to convey
a particular block of information or to accomplish a particular
task. In this respect, systems and pathways, in some cases, may
be similar, and their meanings may frequently overlap.
Anatomic parts of the CNS, such as the medulla and pons, are
commonly called regions. The study of their structure and func-
tion, called regional neurobiology, is the focus of the second
section of this book. Systems and pathways, however, generally
traverse more than one region. The system of neurons and axons
that allows you to feel the edge of this page, for example, crosses
every region of the nervous system between your fingers and the
somatosensory cortex of the cerebral hemisphere. The study of
functional systems, called systems neurobiology, is the focus of
the third section of this text. It is important to remember that the
functional characteristics of regions coexist with those of systems.
Let us consider an example of how the interrelation of systems
and regions can be important clinically. The signals that influence
movements of the hand originate in the cerebral cortex. Neurons
in the hand area of the motor cortex send their axons to cervi-
cal levels of the spinal cord, where they influence spinal motor
neurons that innervate the muscles of the upper extremity. These
are called corticospinal fibers because their cell bodies are in the
cerebral cortex (cortico-) and their axons end in the spinal cord
(-spinal). These fibers pass through the subcortical white matter,
the entire brainstem, and the upper levels of the cervical spinal
cord. En route, they pass near nuclei and fiber tracts that are
specific to that particular region (Fig. 1.4). In the midbrain, for
example, they pass near fibers of the oculomotor nerve, which
originate in the midbrain and control certain extraocular muscles.
In the medulla, they pass near fibers that originate in the medulla
and innervate the musculature of the tongue. An injury to the
midbrain could therefore cause motor problems in the hand (sys-
tems damage) combined with partial paralysis of eye movement
(regional damage). In similar fashion, an injury to the medulla
could cause the same hand problem but now in association with
partial paralysis of the tongue rather than of eye movements.
Successful diagnosis of patients with neurologic disorders will
 Orientation to the Structure and Imaging of the Central Nervous System
Hand area of
Corticospinal motor cortex
fibers
Eye
muscles
Midbrain
Tongue muscles
Medulla
oblongata
Cervical
spinal cord
Muscles that
move the hand
Fig. 1.4 An example of the relation of systems to regions. Fibers of the motor
system that control hand movement descend from the motor cortex to the cer-
vical spinal cord. In the cord, these fibers influence motor neurons that control
hand and forearm muscles. Injury at any point along the way can damage fibers
of the system and structures specific to the region. For example, injury to the
midbrain could damage both fibers to the hand and fibers to the eye muscles,
whereas injury to the medulla could damage both fibers to the hand and fibers
to the tongue musculature. In cases of damage to a long tract (motor or sensory)
and to a cranial nerve (root or nucleus), the cranial nerve deficits are usually the
best localizing signs.
depend on, among other things, a good understanding of both
regional and systems neurobiology.
Localizing Signs and Localization
The example (Fig. 1.4) of corticospinal fibers that innervate
spinal motor neurons serving the hand coupled with neuron cell
bodies in the midbrain that innervate eye muscles via the ocu-
lomotor nerve also illustrates the concept of localizing signs.
Brain injury that results in only a weakness or paralysis of the
upper extremity generally localizes the lesion only to one cere-
bral hemisphere or perhaps to one side of the brainstem. The
clinical examination does not tell us which region of the brain
is injured (internal capsule, midbrain, pons, or medulla) or, for
that matter, even whether the lesion is in the upper portions of
the cervical spinal cord. However, if the paralysis of the upper
extremity is coupled with a partial paralysis of eye movement,
the lesion can be specifically localized to the midbrain. In this
example, the lesion in the midbrain damages the fibers of the
oculomotor nerve that are specific to this level, whereas the
corticospinal fibers are injured as they traverse the midbrain
(Fig. 1.4). In general, cranial nerve signs are more helpful than
long tract signs in localizing the lesion; that is, they are better
localizing signs.
Another general concept of localization states that certain
combinations of neurologic deficits may indicate involvement
7
Nucleus A
Axon/fiber/tract
Nucleus B
Axon/fiber/tract
Nucleus C
Fig. 1.5 Diagrammatic representation of the use of the terms afferent and effer-
ent to describe information conducted toward or away from a particular refer-
ence point.
of one of three general locations of the CNS. First, deficits
(motor or sensory) located on the same side of the head and
body frequently signify lesions in the cerebral hemisphere.
Second, deficits on one side of the head and on the opposite
side of the body generally indicate a lesion in the brainstem.
Such deficits are called crossed (alternating, or alternate)
deficits. Third, deficits of the body only usually suggest a
lesion in the spinal cord. Although there are exceptions to
these general rules, we shall see that they hold true in many
clinical situations.
CONCEPT OF AFFERENT AND EFFERENT
The terms afferent and efferent are used to describe a variety of
structures in the human body, such as nerve fibers, small vessels,
and lymphatics. Afferent refers to conduction (of an impulse on
a nerve or fluid in a vessel) toward a structure; this is an incom-
ing bit of information. Efferent refers to conduction (of an
impulse or fluid) away from a structure; this is an outgoing bit of
information.
In this respect, the posterior root of the spinal nerve is
afferent because it conducts sensory impulses toward the
spinal cord, whereas the anterior root is efferent because it
conducts motor impulses away from the spinal cord (Figs. 1.1
and 1.2). This has given rise to the widely held but incorrect
view that afferent nerve fibers are always sensory and efferent
nerve fibers are always motor. Although this may be true for
the restricted examples of spinal and cranial nerves, the terms
afferent and efferent can also be used to designate bundles of
fibers (axons) traveling toward or away from a specific nucleus
(Fig. 1.5).
Whether a bundle of axons is afferent or efferent, in rela-
tion to a specific nucleus, depends on what reference point
is selected to define the bundle and its relationships. For
example, the neuron cell body in nucleus A in Fig. 1.5 gives
rise to an axon that is an efferent of nucleus A (conducting
away from), but at the same time, this axon is an afferent of
nucleus B (coming toward). If nucleus B is chosen as the ref-
erence point, it would be described as receiving afferent input
from nucleus A and sending efferent impulses to nucleus C
(Fig. 1.5). The use of these terms is commonplace in describ-
ing connections within the nervous system. For example, as
described in the previous section, corticospinal fibers are
efferents of the cerebral cortex and, at the same time, affer-
ents to the spinal cord.
8 Essential Concepts
POSTERIOR (DORSAL), ANTERIOR (VENTRAL),
AND OTHER DIRECTIONS IN THE CENTRAL
NERVOUS SYSTEM
By convention, directions in the human CNS—such as posterior
(dorsal) and anterior (ventral), medial (toward or at the mid-
line) and lateral (away from the midline), rostral (or rostrad, a
direction toward the nose), and caudal (or caudad, a direction
toward the tail)—are absolute with respect to the central axis
of the brain and spinal cord. In a similar manner, the anatomic
orientation of the body in space is related to its central axis. For
example, if the patient is lying on his or her stomach, the pos-
terior surface of the trunk is up and its anterior surface is down
(Fig. 1.6). If the patient rolls over, the back remains the posterior
surface of the patient’s body even though it now faces down.
As shown in Fig. 1.7, the spinal cord and the brainstem
(medulla, pons, and midbrain) form a nearly straight line that is
roughly parallel with the superoinferior axis of the body. There-
fore anatomic directions in these regions of the CNS coincide
roughly with those of the body as a whole.
During embryonic development, the forebrain rotates (at the
cephalic flexure) relative to the midbrain until its rostrocau-
dal axis corresponds to a line drawn from the forehead to the
occiput (from the frontal to the occipital poles of the cerebral
hemispheres). This rotation creates a sharp angle in the long axis
of the CNS at the midbrain-thalamus junction. Consequently,
the long axis of the CNS bends at the midbrain-thalamus junc-
tion, and the directions posterior and anterior follow accordingly
(Fig. 1.7).
In the cerebral hemisphere (forebrain), posterior (dorsal)
is toward the top of the brain, anterior (ventral) is toward the
base of the brain, rostral is toward the frontal pole, and caudal
is toward the occipital pole. Anatomic directions in the forebrain
relate to its long axis; therefore the posterior side of the forebrain
structures faces the vertex of the head, and the anterior aspect of
the forebrain faces the base of the skull (Fig. 1.7). Posterior and
dorsal and anterior and ventral are considered synonymous and
are commonly and frequently used interchangeably.
These directional terms are extremely valuable in the descrip-
tion of the relative position of a structure within the brain or
spinal cord or the relative positions of two structures to each
other. For example, the midbrain is rostral to the pons but cau-
dal to the thalamus (Fig. 1.3). The midbrain is selected as the
reference point and adjacent structures are described in relation
to it. Also, directional terms, such as posterior and lateral, can
be combined to describe a structure that occupies an intermedi-
ate position. For example, the nuclei in the spinal cord transmit-
ting sensory information can be described as posterolateral to the
central canal.
SYMPTOM OR SIGN?
These terms are used literally every day in countless clinical set-
tings and serve to form an essential and important part of the
physician-patient relationship—that is, the communication of
Po s r
t e r io
A n t e r i or
Anterior
Po s t e r i o r
Fig. 1.6 The anatomic directions of the body are absolute with respect to the
axes of the body, not with respect to the position of the body in space.
information that will result in proper and successful medical
treatment. It is useful to establish what constitutes a symptom
versus a sign at this point. These concepts and definitions are
revisited throughout subsequent chapters.
Symptom
A symptom is a departure from any normal state of structure
or function that is experienced by the patient. In other words,
something is wrong and the patient knows it. Symptoms may
develop slowly, almost imperceptibly, as in a slow-growing tumor
or as part of the aging process, or appear suddenly, as in hemor-
rhage or trauma. A symptom such as pain may be clear to the
patient (a symptom) but difficult for the attending physician to
evaluate. A symptom is a subjective indicator of a presumably
abnormal process.
Sign
A sign is a departure from any normal state of structure or func-
tion that is discovered, observed, and evaluated by a health care
professional on examination of the patient. In this situation, the
clinical problem (be it great or small) is seen and can be evaluated
by the physician. It is possible that a patient may have signs of
a disease process, seen during the examination, that he or she is
unaware of; the patient has signs but no symptoms. A sign is an
objective indicator of a presumably abnormal process.
CLINICAL IMAGES OF THE BRAIN AND SKULL
The most routinely used methods to image the brain and skull
are computed tomography (CT) and magnetic resonance imaging
(MRI) (Fig. 1.8). As we shall see, CT is especially useful in visu-
alizing the skull and the brain in the early stages of subarachnoid
hemorrhage. On the other hand, MRI, by use of T1-weighted or
T2-weighted techniques, shows brain anatomy in elegant detail,
Rostral Caudal
Frontal pole
P P
A A
p
a
p
a
Occipital
pole
Posteri
Rostra
Anterio
r o
l
r
Cauda
P, p = Posterior (dorsal)
A, a = Anterior (ventral)
l
Fig. 1.7 The central axis and anatomic directions of the central nervous system
(CNS). The dashed line shows the long (rostrocaudal) axis of the CNS. The long
axis of the spinal cord and brainstem forms a sharp angle with the long axis of the
forebrain. Posterior (dorsal) and anterior (ventral) orientations are also shown.
 Orientation to the Structure and Imaging of the Central Nervous System 9

cisternal relationships, cranial nerves, and a wide variety of clini-
cal abnormalities.
Magnetic resonance angiography (MRA) visualizes arteries
and veins by measuring the velocity of flow in these structures
(Fig. 1.9A). The resultant images show detail of vascular struc-
tures that, in some situations, may be superior to that seen on
angiograms. Arterial structures may be selectively imaged, or
combinations of arterial and venous structures or only venous
structures can be visualized. Clinicians refer to these images of
venous structures as MRVs (magnetic resonance venograms).
Computed tomography angiography (CTA, Fig. 1.9B) visual-
izes arteries with use of an injectable radiopaque substance (such
as ioversol, Optiray 300) that can be infused through superficial
veins on the upper extremity. When x-rays are passed through
the patient, the infused vessels appear clearly more white than
the surrounding brain (they are hyperdense). As with MRA, arte-
rial and venous structures may be imaged in great detail, and in
certain clinical situations, CTA offers advantages over standard
angiography.
Computed Tomography
CT is an x-ray imaging technique that measures the effects that
tissue density and the various types of atoms in the tissue have
on x-rays passing through that tissue (Table 1.1; see also Fig.
1.8A, B). Changes in the emerging x-ray beam are measured by
detectors.
The higher the atomic number, the greater the ability of
the atom to attenuate, or stop, x-rays. These attenuation
transmission intensities emerging from the tissue are trans-
formed by a computer into numbers that represent values
found in all the points located in the volume of the tissue
slice. These values are expressed in Hounsfield units (HUs).
HU values, also known as CT numbers, are used in an arbi-
trary scale in which bone is specified as +1000 (and is
very white; Fig. 1.8A, B), water as zero, and air as −1000
(and is very black). With use of this scale, the HU values,
or CT numbers, represent specific shades of gray for each
of the various points located in the slice (Table 1.1; see also
Fig. 1.8A, B).

Blood

A B

C D
Fig. 1.8 CT scans (A and B) of a 2-month-old infant who was a victim of the shaken baby syndrome and
MR images (C and D) of a normal 20-year-old woman. On the CT study, note that brain detail is less than
on the MR images but that the presence of blood (A, in the interhemispheric fissure between the hemi-
sphere and in the brain substance) is obvious. In the same patient, the bone window (B) clearly illustrates
the outline of the skull but also clearly shows skull fractures (arrows in A and B). In this infant, the ven-
tricles on the left are largely compressed, and the gyri have largely disappeared because of pressure from
bleeding into the hemisphere. This is evidence of increased intracranial pressure, potential compromised
brain function, and possible brain herniation. The pressure results in the effacement of the sulci and gyri
on the left side. In the T2-weighted image (C), cerebrospinal fluid is white, internal brain structures are
seen in excellent detail, and vessels are obvious. In the T1-weighted image (D), cerebrospinal fluid is dark
and internal structures of the brain are somewhat less obvious.
10 Essential Concepts

Present-generation CT scanners, known as helical (spiral)
scanners, image a continuous spiral slice through a preselected
body region very quickly. Computer software converts this
information into contiguous slices of a chosen thickness. This
technique eliminates movement artifacts and enables recon-
struction of soft tissues, bone, or contrast medium–enhanced
vessels into three-dimensional images that can be manipulated
in any plane.
CT is a fast and accurate method of detecting recent sub-
arachnoid hemorrhage (Table 1.2; see also Fig. 1.8A). An acute
subarachnoid hemorrhage in a noncontrast CT scan appears
hyperdense (white) in contrast to the subarachnoid spaces and
cisterns, which normally are hypodense (dark).
Enhanced CT is a technique using an iodinated contrast mate-
rial injected intravenously followed by CT examination. Iodine
has a large atomic number and attenuates x-rays. As a result,
Anterior cerebral arteries
Anterior communicating
artery
Middle cerebral artery
Posterior cerebral artery
Carotid artery
Basilar artery
A Vertebral artery
Posterior cerebral artery
(P1)
Superior cerebellar
artery
Basilar artery
Vertebral arteries
B of the emitted radio waves from all the specific points in that
Fig. 1.9 A, MR angiography (MRA) of portions of the internal carotid artery and
vertebrobasilar system. B, CT angiography (CTA) of a corresponding view of the
vertebrobasilar system. Note that in the CTA image, the initial segment of the
posterior cerebral artery (P1) is constricted in this patient.
vasculature is visualized as hyperdense (white) structures. This
contrast material may also enhance neoplasms or areas of inflam-
mation because the contrast agent leaks from the vessels into
the cellular spaces owing to a breakdown of the blood-brain bar-
rier. Imaged in this way, the tumor, inflamed meninges, or brain
parenchyma will show varying degrees of enhancement or hyper-
density (varying degrees of whiteness).
Magnetic Resonance Imaging
Protons (hydrogen) constitute a large proportion of body tissue.
These atoms have a nucleus and a shell of electrons and a north
and a south pole, and they spin around an angulated axis like
small planets. As the electrons move with the spinning atom, they
induce an electrical current that creates a magnetic field. These
atoms function somewhat like little spinning bar magnets. They
are aligned randomly because of the changing magnetic effects on
each other. When these protons are exposed to a powerful mag-
net, they stop pointing randomly and align themselves parallel
to the external magnetic field but at different energy levels. The
stronger the external magnetic field, the faster the frequency of
the spin at that angle. When undergoing an MRI examination, the
patient becomes a magnet, with all the protons aligning along the
external magnetic field and spinning at an angle with a certain
frequency.
A radio wave is an electromagnetic wave. When a radio wave is
sent as a short burst into the magnet containing the patient, it is
known as a radiofrequency (RF) pulse. This RF pulse can vary in
frequency strength. Only when the frequency strength of the RF
pulse matches the frequency strength of the angulated spinning
proton will the proton absorb energy from the radio wave. This
phenomenon is called resonance and is the “resonance” in “mag-
netic resonance imaging.” This results in a twofold effect: it can-
cels out the magnetic effects of certain protons, and it raises the
energy levels and magnetic effects of another group of protons.
When the radio wave is turned off, the canceled-out protons grad-
ually return to their original state and strength of magnetization,
which is called relaxation and is described by a time constant
known as T1 (Fig. 1.8D). The protons that aligned themselves
at a higher energy level and magnetization also start to lose their
energy (relaxation), and this time constant is known as T2 (Fig.
1.8C). The T1 relaxation time is longer than the T2 relaxation
time. The “de-excited” or relaxed protons release their energy
as an “echo” of radio waves. A receiver coil (antenna) absorbs
this information, and a computer determines the characteristics
section of the body. The MR image is then constructed and trans-
ferred to a computer monitor or recorded on film. T1-weighted
or T2-weighted images can be obtained by use of varying times to
receive the echoes (TE).

Table 1.1 Appearance of Tissues Imaged by CT and MRI

Tissue
WHITE
MODALITY BONE CSF GRAY MATTER MATTER FAT AIR MUSCLE
CT* ↑↑↑ ↓↓ ↓ ↓↓ ↓ ↓↓↓ ↑↑
MRI/T1† ↓↓↓ ↓↓↓ ↓↓ ↓ ↑↑ ↓↓↓ ↓↓
MRI/T2† ↓↓↓ ↑↑↑ ↓↓ ↓↓↓ ↑ ↓↓↓ ↓↓–↓↓↓

*Measures tissue density.

†Measures tissue signal.

↑↑↑–↑ represents very white to light gray:

↓–↓↓↓ represents light gray to very black:

CSF, cerebrospinal fluid; CT, computed tomography; MRI, magnetic resonance imaging.
  
 Orientation to the Structure and Imaging of the Central Nervous System 11

Conventional spin-echo sequences generate images that may of bone and is clearly whiter than the surrounding brain (Fig.
be T1-weighted or T2-weighted according to the time interval 1.10A). On the other hand, air in CT poorly attenuates x-rays,
in milliseconds between each exciting radio wave. This is called has a low CT number, and appears black. An area of ischemia in
repetition time (TR). The time interval, in milliseconds, required CT is hypodense; its appearance is shifted toward that of air (or
to collect these radio waves from the relaxing protons is called cerebrospinal fluid) and is darker than the surrounding brain (Fig.
echo time (TE). With spin-echo pulse sequences, the shorter 1.10B, arrows). When the lesion, or tissue damage, appears basi-
the TR and TE, the more the image is considered T1-weighted. cally the same as the surrounding brain, it is specified as isodense
The longer the TR and TE, the more the image is considered (Fig. 1.10C, arrow).
T2-weighted. Also described before, an MR image is produced when the
The contrast material used to enhance tumors and blood vessels patient is exposed to a magnetic field, and the effects of this
is the paramagnetic rare earth gadolinium. It is used in solution field on protons within the body are measured. Under the
for intravenous injection. The gadolinium causes an increase in influence of an external magnet, these protons align them-
signal by shortening the relaxation time for T1. Owing to a break- selves parallel to the source. When the external source is
down of the blood-brain barrier, intravascular gadolinium enters removed, the protons “relax”; those that relax more slowly
the pericellular spaces, where it increases the relaxation state from a lower energy level produce a T1-weighted image,
of water protons and generates a bright signal on T1-weighted whereas those that relax more rapidly from a higher energy
images (Table 1.1). level produce a T2-weighted image. Hyperintense, hypoin-
Acute subarachnoid hemorrhage is poorly imaged by MRI on tense, and isointense specify various abnormal states in
T1-weighted images but well imaged by CT (Table 1.2). Some MRI in the clinical setting. In the normal patient, fat (T1)
MRI sequences are sensitive for detection of acute bleeding, but and cerebrospinal fluid (T2) appear distinctly more white. A
other factors may limit this method of examination. Special MRI lesion that is hyperintense in MRI appears whiter than the
techniques can also determine if a brain infarct or ischemia is surrounding brain—for example, a meningioma and the sur-
acute (about 1 to 3 hours old) or subacute (about 4 hours old rounding edema (Fig. 1.10D). An example of a tumor that is
or more). Contraindications to MRI are cardiac pacemakers, hypointense is a medulloblastoma in the posterior fossa; this
cochlear implants, implantable cardioverter-defibrillators, ferro- lesion appears darker than the surrounding brain (Fig. 1.10E,
magnetic foreign bodies in the eye, and certain aneurysm clips. arrows). In between these extremes are lesions that are isoin-
Large metallic implants or ferromagnetic foreign bodies in the tense; these lesions have basically the same appearance as the
body may heat up. The general appearance of the brain and adja- surrounding brain (Fig. 1.10F, G, between arrows).
cent structures in health and disease on MRI and CT is summa-
rized in Tables 1.1 and 1.2. Imaging of the Brain and Skull
Patients lie in the supine (face up) position for imaging of the
Image Density and Intensity brain or spinal cord and the surrounding bony structures (Fig.
As described before, a CT scan is produced when the patient is 1.11). In this position, the posterior (dorsal) surface of the brain-
placed between a source of x-rays and detectors; the degree to stem and spinal cord and the caudal aspect (occipital pole) of the
which the tissues of the body attenuate these x-rays is a measure cerebral hemispheres face down. The anterior (ventral) surface
of its density. The various textures of gray seen in CT are a repre- of the brainstem and spinal cord and the frontal pole are face up
sentation of this relative tissue density. Hyperdense, hypodense, (Fig. 1.11).
and isodense are terms used in the clinical setting to specify vari- Images of the brain are commonly made in coronal, axial
ous abnormal states in CT. Bone in CT greatly attenuates x-rays, (horizontal), and sagittal planes. To illustrate the basic orienta-
has a high CT number, and appears white. Acute subarachnoid tion of the CNS in situ, we shall look at examples of images
blood in CT is hyperdense; its appearance is shifted toward that in all three of these planes as they appear in the clinical set-
ting (Figs. 1.11 and 1.12). Coronal imaging planes are oriented
perpendicular to the rostrocaudal axis of the forebrain but are
Table 1.2 Differences in CT Density and MRI Signals in nearly parallel to the rostrocaudal axis of the brainstem and
Representative Clinical Examples spinal cord. Therefore a coronal image obtained at a relatively
rostral level of the cerebral hemispheres (Fig. 1.11A) will show
MRI only forebrain structures, and these structures will appear in
CLINICAL cross section (perpendicular to their long axis). As the plane
PROBLEM CT* T1† T2†
of imaging is moved caudally, brainstem structures enter the
Acute SAH ↑↑↑ 0 0 picture (Fig. 1.11B), but the brainstem is cut nearly parallel to
Subacute SAH ↑↑ 0–↑ 0 its rostrocaudal axis.
Tumor 0 0 ↑–↑↑ Axial images, in contrast, are oriented parallel to the rostrocau-
dal axis of the cerebral hemispheres but nearly perpendicular to
Enhanced tumor ↑↑↑ ↑↑↑ ↑↑↑
the long axis of the brainstem and spinal cord. Consequently, an
Acute infarct 0 0–↑ ↑–↑↑ axial image obtained midway through the cerebral hemispheres
Subacute infarct 0–↑ 0–↓↓ ↑↑–↑↑↑ (Fig. 1.11D) will show only forebrain structures, with the rostral
Acute ischemia 0 0–↓ ↑–↑↑ (frontal) end of the forebrain at the top of the image and the
Subacute ischemia 0–↑ 0–↓↓ ↑↑–↑↑↑ caudal (occipital) end at the bottom. As the plane of imaging is
moved farther anteriorly (ventrally) relative to the forebrain, the
Edema 0–↑ 0–↓ ↑–↑↑
brainstem appears (Fig. 1.11C). The brainstem, however, is cut
*Measures tissue density. nearly in cross section and is oriented with the anterior (ventral)
†Measures tissue signal.
surface “up” (toward the top of the image) and the posterior
↑↑↑–↑ represents very white to light gray:
(dorsal) surface “down.”
↓–↓↓↓↓ represents light gray to very black:
Images made in the sagittal plane are at, or parallel to, the
0 represents no change from normal. midsagittal plane of the brain or spinal cord. This is the plane
CT, computed tomography; MRI, magnetic resonance imaging; SAH, subarachnoid running through the middle (midline) of the head from rostral
hemorrhage.
   to caudal (along the frontal to occipital axis) or along the midline
12 Essential Concepts

A B C

D E F

G
Fig. 1.10 Examples of density and intensity as seen in clinical images. In CT, subarachnoid blood is
hyperdense (A), an area of infarct is hypodense (B, arrows), and a lesion causing herniation that appears
the same texture as the brain is isodense (C, at arrow). In MRI, the edema surrounding a meningioma
is hyperintense (D, T2-weighted), a nonenhanced medulloblastoma is hypointense (E, T1-weighted, at
arrows), and a nonenhanced pituitary tumor that appears like the brain is isointense (F, T1-weighted; G,
T2-weighted, between arrows).
 Orientation to the Structure and Imaging of the Central Nervous System 13

Coronal
view

or
Axial view

ri
e A
Ant
B
Po
Anterior (ventral) steri o r

Posterior (dorsal)

C D

A B C D

Fig. 1.11 The relation of imaging planes to the brain. The diagram shows the usual orientation of a patient
in an MRI machine and the planes of the four scans (T1-weighted images) that are shown. A and B, Coro-
nal scans. C and D, Axial scans.
14 Essential Concepts

of the spinal cord in a rostrocaudal axis. Sagittal images of the

brain, be they at the midline (Fig. 1.12A) or off the midline (Fig.
1.12B), are oriented such that the frontal area is to the left and
the occipital area is to the right. The various directions within
the brain can be appreciated with a comparison of the midsagittal
MR image with a drawing in the comparable orientation (com-
Frontal

Occipital
pare Fig. 1.7A with Fig. 1.12).
A point also needs to be made about how the clinician views
CT or MRI scans. Coronal scans are viewed as though the cli-
nician is facing the patient, whereas axial scans are viewed as
though the clinician is standing at the patient’s feet looking up
toward the patient’s head from below as the patient lies supine
in the machine. Axial scans, in other words, show the cerebral
A
hemispheres from anterior (the more inferior portion of the
hemisphere) to posterior (the more superior portion of the hemi-
sphere), with the patient’s frontal area and orbits at the top of
the image and the occiput at the bottom. In both coronal and
axial views, the patient’s left side is to the observer’s right when
viewing MRI and CT images. This is an absolutely essential con-
cept to remember as one examines MRI and CT scans and makes
Occipital
Frontal

diagnostic judgments.

Sources and Additional Reading

The complete list is available online at www.studentconsult.com.

B
Fig. 1.12 MRI of the brain in the median sagittal plane (A) and in the sagittal
plane but off the midline (B). The frontal lobe is to the left, and the occipital lobe
is to the right. Other directions within the brain in this plane are appreciated by
a comparison with Fig. 1.7.
Sources and Additional Reading
Grossman CB. Magnetic Resonance Imaging and Computed Tomography of the
Head and Spine. 2nd ed. Baltimore: Lippincott Williams & Wilkins; 1996.
Jackson GD, Duncan JS. MRI Neuroanatomy: A New Angle on the Brain. New
York: Churchill Livingstone; 1996.
Kirkwood JR. Essentials of Neuroimaging. New York: Churchill Livingstone;
1990.
Kramer EB, Lischka MF, Egger TP, Riedl M, Gruber H. The motorneuronal or-
ganization of the spinal accessory nuclear complex. In: Advances in Anatomy
Embryology and Cell Biology. Vol. 103. Berlin: Springer-Verlag; 1987:1–62.
Kretschmann HJ, Weinrich W. Cranial Neuroimaging and Clinical Neuroanat-
omy: Magnetic Resonance Imaging and Computed Tomography. 2nd ed. New
York: Thieme Medical Publishers; 1992.
Lachman N, Acland RD, Rosse C. Anatomical evidence for the absence of a
morphologically distinct cranial root of the accessory nerve in man. Clin
Anat. 2002;15:4–10.
Ryan S, Blyth P, Duggan N, Wild M, Al-Ali S. Is the cranial accessory nerve
really a portion of the accessory nerve? Anatomy of the cranial nerves in the
jugular foramen. Anat Sci Int. 2007;82:1–7.
Osborn AG. Diagnostic Neuroradiology. St. Louis: Mosby; 1994.
14.e1
 Chapter 2
The Cell Biology of Neurons and Glia
G.A. Mihailoff and D.E. Haines
organs, is the greatest consumer of oxygen and glucose. These
Overview-15 energy requirements arise directly from the metabolic demand
Structure of Neurons-15 placed on cells, which have large surface areas and concentrate
Dendrites-16 biomolecules and ions against an energy gradient. Along with
Cell Body-16 maintaining its metabolism, each neuron (1) receives informa-
Axons and Axon Terminals-19 tion from either the environment or other nerve cells, (2) pro-
Axonal Transport-20 cesses information, and (3) sends information to other neurons
Axonal Transport as a Research Tool-20 or effector tissues.
Glial cells control the CNS environment within which neurons
Classification of Neurons and Groups of Neurons-21 function. They shuttle nutritive molecules from blood vessels to
Electrical Properties of Neurons-21 neurons, remove waste products, and maintain the electrochemi-
cal surroundings of neurons. Glia also communicate directly with
Neurons as Information Receivers-22 nearby neurons through glial receptors and release mechanisms
Sensory Neural Information-22 for certain neurotransmitters. During nervous system devel-
Other Neural Information-22 opment, glia guide neuronal migration and promote synapse
Neurons as Information Transmitters-22 formation.
Synapses-22 For neurons to carry out the three tasks of receiving, pro-
Chemical Synapses-22 cessing, and sending information, they must have specialized
structures that contribute to each of these functions. The main
Neurotransmitters-24 components of a neuron are shown in Fig. 2.1. In addition, spe-
Disorders of Neurotransmitter Metabolism-24 cialized mechanisms and structures are required to solve some
Glia-25 special problems specific to neuron function. Two such problems
are immediately apparent. First, the mix of ions inside neurons
Astrocytes-25 is different from the mix outside the cell. Maintaining this dif-
Structural Support and Response to Injury-26 ference requires extraordinary amounts of energy because ions
Growth Factors and Cytokines-26 must be pumped against electrical and diffusion gradients. The
Environmental Modulation-26 large surface area of neurons compounds this problem. Second,
Influence on Neurotransmission-26 those neurons that send information over long distances must
Regional Heterogeneity-26 have a way to supply these distant sites with macromolecules and
Astrocytes at the Blood-Brain Barrier-26 energy. For the cell biology of neurons to be fully appreciated, it
Control of Local Blood Flow Within the Central is important to see the biochemical, anatomic, and physiologic
Nervous System-27 properties of neurons as part of an integrated whole, the machin-
ery that permits the neuron to do its specialized functions. In the
Oligodendrocytes-28 following sections, we examine how specializations in neuronal
Microglia-29 architecture and chemistry contribute to meeting these special
demands.
Tumors of the Central Nervous System-29
Glia-Derived Tumors-29 STRUCTURE OF NEURONS
Tumors in Children-31 Although the architecture of neurons is especially diverse, our
Benign Primary Brain Tumors-31 focus will be on the characteristic features of an archetypical
Metastatic Brain Tumors-31 neuron bounded by a continuous plasma membrane and consist-
Supporting Cells of the Peripheral Nervous ing of a cell body, or soma, from which dendrites and an axon
System-31 arise (Figs. 2.1 and 2.2). The cell body contains the nucleus sur-
rounded by a mass of cytoplasm that includes the organelles nec-
Degeneration and Regeneration-32 essary for protein synthesis and metabolic maintenance. Most
neurons (multipolar neurons) have several dendrites extending
from the cell body (Figs. 2.1 and 2.2). These are usually rela-
The number of cells in the adult human central nervous system tively short processes that taper from a thick base and, in doing
(CNS) has been estimated at 100 billion. All arise from a rela- so, branch extensively. In contrast, there is a single axon, which
tively small population of precursors, yet a diversity of cell types is a relatively long process (extending from a few millimeters to
is seen in the adult. Their most basic classification is as neurons more than a meter) with a uniform diameter. The axon has few
and glia (glial cells). if any branches along most of its length, branching extensively
only near the distal end (the terminal arbor) (Figs. 2.1 and 2.2).
OVERVIEW In most neurons, information normally flows from the dendrites
Nerve cells (neurons) manipulate information. Doing so to the cell body to the axon and its terminals, then to the next
involves changes in the bioelectrical or biochemical proper- neuron or an effector tissue such as muscle. These components
ties of the cell, and these changes require a vast expenditure of of the neuron are described in the order in which information is
energy for each cell. The nervous system, compared with other processed.

15
16 Essential Concepts

Axon terminals
Dendrites:
Secondary
Primary Dendrite

Dendritic spines

Neuron cell body

Golgi apparatus

Mitochondrion

Axon hillock Axon

Rough
endoplasmic Mitochondrion
reticulum Axon
Microtubule

Smooth
endoplasmic
Recurrent reticulum
axon collateral Neurofilaments

Axodendritic synapse
Mitochondrion

Dendrite

Dendrite Synaptic cleft

Synaptic vesicles
Nucleus Axosomatic
Terminal bouton
synapse
Microtubule

Axon Neuron cell body

Axon hillock
Fig. 2.1 Diagrammatic representation of a typical multipolar neuron. Dendrites, with their variety of
spines (top inset), branch in the immediate vicinity of the cell body, whereas the single axon, with its occa-
sional recurrent collaterals, may travel great distances to the next neuron. The cell body contains the organ-
elles essential for neuronal function. Microtubules (middle and bottom insets) are important structures for
the transport of substances within the axon. The axon ends as a terminal arbor that forms many terminal
boutons (bottom inset), each containing the necessary machinery for synaptic transmission.

Dendrites between the smallest dendrites and axons is difficult to discern.

Dendrites receive signals either from other neurons through axonal
contacts (synapses) formed on their surfaces (Figs. 2.1 and 2.3D).
Dendrites usually branch extensively in the vicinity of the cell body,
giving the appearance of a tree or bush (Figs. 2.1 to 2.3A). Small bud-
like extensions (dendritic spines, Fig. 2.3C) of a variety of shapes are
frequently seen on the more distal dendrites (Figs. 2.1 and 2.3B, C).
These are sites of synaptic contacts (discussed later). The branches
of dendrites increase in thickness as they coalesce and approach the
cell body.
Observed in thin distal dendrites are sparse numbers of micro-
tubules and neurofilaments along with small triangular-shaped
clusters of agranular reticulum and ribosomes at some branch
points. These structures are believed to be sites of protein synthe-
sis and associated with memory formation. Often the distinction
However, as dendrites begin to coalesce and become thicker, the
number and type of organelles present increases until the cyto-
plasm of proximal (primary) dendrites appears no different from
that observed in the soma (Figs. 2.3D, E and 2.4). Numerous
types of endoplasmic reticulum, vesicles, mitochondria, micro-
tubules, neurofilaments, Nissl bodies, polyribosomes, and free
ribosomes can be seen in the primary dendrites.
Cell Body
The cell body of a neuron is also called the soma (plural, somata)
or perikaryon (plural, perikarya) (Figs. 2.2 and 2.4). The peri-
karyon is the metabolic center of the nerve cell. Abundant mito-
chondria reflect the high energy consumption of the cell. Active
protein synthesis is indicated by the large size of the nucleus and
 The Cell Biology of Neurons and Glia 17

Multipolar cells Pseudounipolar cell

Cerebellar
nucleus Cerebellar
cortex
Receptor
Axon
Skin

Axon:
Peripheral branch
Central branch
Dendrites

Dendritic
spines

A Posterior root
ganglion
Stellate cell

Pyramidal
cell
Spinal cord
D
Bipolar cells

Axon

E Rods and cones

of retina
Olfactory epithelium

Dendritic
B spines

Axon Soma

Dendritic Olfactory
branches bulb
C F
Fig. 2.2 Examples of various types of neurons showing the dendrites, somata, and axons of multipolar
cells from the cerebellar cortex (A) and from the cerebral cortex (B and C). Compare these with a pseu-
dounipolar cell of the posterior root ganglion (D) and with bipolar cells from the retina (E) and olfactory
epithelium (F).

its content of diffuse chromatin (euchromatin) and at least one
prominent nucleolus (the site of ribosomal RNA synthesis). In
the cytoplasm, ribosomes are abundant, and the rough endoplas-
mic reticulum (rER) and Golgi complex are extensive (Fig. 2.1).
The rER is basophilic (binds basic dyes) as a result of the large
amount of ribosomal RNA attached to the endoplasmic mem-
brane. These extensive, stacked layers of rER are seen as patches
of basophilic staining (called Nissl substance) in histologic prepa-
rations of nerve cells.
Neurons are classified into three general types on the basis of
the shape of the cell body and the pattern of processes emerg-
ing from it. These types are the multipolar, pseudounipolar, and
bipolar cells (Table 2.1; see also Fig. 2.2).
The cell bodies of multipolar neurons vary widely in shape,
so their profiles in tissue sections may appear fusiform, flask
shaped, triangular, polygonal, or stellate (Fig. 2.2A-C). Variations
of a stellate polygon are most common. This shape results from
the presence of multiple, tapering dendrites that emerge from
the soma. Typically the cell body also emits a single axon that
generally appears thin relative to the cell’s dendrites. More than
99% of all neurons are multipolar neurons, and the different
kinds of these have characteristic patterns of processes, some of
which are listed in Table 2.1.
The pseudounipolar (or unipolar) neuron has a spherical
cell body with a centrally placed (concentric) nucleus. The cell
body emits a single process that courses only a short distance
before bifurcating into a long peripheral branch and a long cen-
tral branch (Fig. 2.2D). The peripheral branch courses as part of
a peripheral nerve to convey sensory information from a somatic
or visceral structure, such as the skin, skeletal muscle, or wall of
intestine. The distal end of the peripheral process is dendrite-
like in the sense that its terminal branches receive information
18 Essential Concepts

Terminal
Dendrites bouton
Cell body
Synapses
Dendrite

A
Spines Dendrite
Spine

B C

Axon
Terminal
Dendrite bouton

Microtubules
Microtubules
Terminal Synapse
bouton Synapse
Dendrite
Neurofilaments

Mit
rER Neurofilaments
Dendrite

D E
Fig. 2.3 Elements of dendrite structure. Dendritic tree of a multipolar neuron (A) and dendritic spines
(B), both in Golgi-stained cortical tissue. Ultrastructural features of dendrites, showing an axonal terminal
bouton synapsing on a dendritic spine (C), a cross section of a dendrite with characteristic cytoskeletal
elements and organelles (D), and a longitudinal section of a dendrite in the anterior horn of the spinal cord
(E). MIT, mitochondrion; rER, rough endoplasmic reticulum.

Myelin
Neuronal
plasmalemma

Golgi
complex Neuropil

Lipofuscin
granule
Euchromatin
Mitochondrion

Nuclear envelope
rER

Nucleolus

Fig. 2.4 The cell body of a multipolar neuron as seen on electron micrograph and in a Golgi-stained
preparation (inset). rER, rough endoplasmic reticulum.
 The Cell Biology of Neurons and Glia 19

either by functioning as sensory receptors or by contacting receptor cells and the neurons that send long axons from the
other structures that function as receptors. The central branch retina to the thalamus (output cells). In the olfactory system,
courses as part of a nerve root to convey the sensory information they function as both the receptors and the output neurons, with
to the CNS. In effect, the distal and central processes function their axons projecting to the olfactory bulb; in the vestibular and
together as a single axon. The cell bodies of pseudounipolar cells auditory systems, they are the output cells that send information
are found primarily in the sensory ganglia of cranial and spinal to the brainstem.
nerves. Unless special staining methods are used, the cell body of a
Bipolar neurons have a round or oval perikaryon, with a single neuron has the appearance of being the entire cell when it is
process emanating from each end of the cell body (Fig. 2.2E, viewed in histologic sections. However, the volume of the cell
F). They are commonly found in structures associated with the body of a neuron constitutes only a small fraction, often less than
special senses. In the retina, bipolar cells are interposed between 1%, of the volume of the axon and dendrites even though the cell
body synthesizes and continually replaces all structural molecules
Table 2.1 A Few of the Neuronal Types Found in the of these processes.
Nervous System
Axons and Axon Terminals
TYPE OF NEURON LOCATION OF CELL BODIES The axon arises from the cell body at a small elevation called
Pseudounipolar Posterior root or cranial nerve ganglion the axon hillock. The proximal part of the axon, adjacent to the
Bipolar Retina axon hillock, is the initial segment. The cytoplasm of the axon
Olfactory epithelium (axoplasm) contains dense bundles of microtubules and neuro-
Vestibular ganglion filaments (Figs. 2.1 and 2.5A, B). These function as structural
Auditory (spiral) ganglion
elements, and the microtubules also play key roles in the trans-
Multipolar port of metabolites and organelles along the axon. Axons are typi-
Stellate (star shaped) Many areas of CNS cally devoid of ribosomes, a feature that distinguishes them from
Fusiform (spindle shaped) Many areas of CNS dendrites at the ultrastructural level.
Pyriform (pear shaped) Many areas of CNS
In contrast to dendrites, axons may extend for long distances
before branching and terminating. An example is the axon of a
Pyramidal Hippocampus; layers II, III, V, and VI
of cerebral cortex
corticospinal tract neuron with a cell body in the motor cortex
and an axon that reaches the caudal portion of the spinal cord.
Purkinje Cerebellar cortex
The axon of such a neuron accounts for approximately 99.8%
Mitral Olfactory bulb of the total volume of the neuron. The surface area of an axon
Chandelier Visual areas of cerebral cortex can be several thousand times the surface area of the parent cell
Granule Cerebral and cerebellar cortex body. Axons are sometimes referred to as nerve fibers, although
strictly speaking, a nerve fiber includes both the axon and a
Amacrine (axonless) Retina
sheath that is provided by support cells (described in a subse-
CNS, central nervous system.
  
quent section).

Myelin

Mitochondrion Mitochondrion Neurofilaments

Microtubules Microtubules
Loops of
oligodendrocyte
cytoplasm
Astrocyte
Neurofilaments processes

Myelin
A B

Axon

Terminal
boutons
C
Fig. 2.5 Elements of axon structure. Ultrastructural features of a small myelinated axon in a cross section
of a peripheral nerve (A) and a longitudinal view at a node of Ranvier of a myelinated axon in the central
nervous system (B). Drawing of the complete terminal arbor of an axon in the thalamus reconstructed
from serial sections (C).
20 Essential Concepts

Table 2.2 Characteristics of Axonal Transport

DIRECTION OF TRANSPORT SPEED OF TRANSPORT PROPOSED MECHANISM SUBSTANCES CARRIED
Anterograde Fast (100-400 mm/day) Kinesin, microtubules Proteins in vesicles
Neurotransmitters in vesicles,
mitochondria
Slow (∼1 mm/day) Unknown Cytoskeletal protein components (actin, myosin, tubulin)
Neurotransmitter-related cytosolic enzymes
Retrograde Fast (50-250 mm/day) Dynein, microtubules Macromolecules in vesicles, “old” mitochondria
Pinocytotic vesicles from axon terminal

Axons in the CNS often end in fine branches known as termi-

nal arbors (Fig. 2.5C). In most neurons, each axon terminal is
capped with small terminal boutons (boutons terminaux, termi-
nal buttons) (Figs. 2.1 and 2.3C, E). These correspond to func-
tional points of contact (synapses) between nerve cells. In some
cells, boutons are found along the length of the axon, where they
are called boutons en passant. Other axons contain swellings, or
varicosities, that are not button-like but still can represent points
of cell-to-cell information transfer.
The site at which an axon terminal communicates with a sec-
ond neuron, or with an effector tissue, is called a synapse (from
the Greek word meaning “to clasp”). In general, the synapse can
be defined as a contact between part of one neuron (usually its
axon) and the dendrites, cell body, or axon of a second neuron.
The contact can also be made with an effector cell such as a skel-
etal muscle fiber. Synapses are considered later in this chapter in
the section Neurons as Information Transmitters. Microtubules

Axonal Transport
Nerve cells have an elaborate transport system that moves
organelles and macromolecules between the cell body and the
axon and its terminals. Transport in the axon occurs in both
directions (Table 2.2; Fig. 2.6). Axonal transport from the cell
body toward the terminals is called anterograde or orthograde;
transport from the terminals toward the cell body is called
retrograde.
Anterograde axonal transport is classified into fast and slow
components. Fast transport, at speeds of up to 400 mm/day,
is based on the action of a protein called kinesin. Kinesin, an
adenosine triphosphatase (ATPase), moves macromolecule-con-
taining vesicles and mitochondria along microtubules in much
the same manner as a small insect crawling along a straw. Slow
transport carries important structural and metabolic components
from the cell body to axon terminals; its mechanism is less well
understood.
Retrograde axonal transport allows the neuron to respond to
molecules, for example, growth factors, that are taken up near
the axon terminal by either pinocytosis or receptor-mediated
endocytosis. In addition, this form of transport functions in the
continual recycling of components of the axon terminal. Retro-
grade transport along axonal microtubules is driven by the pro-
tein dynein rather than by kinesin.
Axonal transport is important in the pathogenesis of some
human neurologic diseases. The rabies virus replicates in muscle
tissue at the site of a bite by a rabid animal and is then trans-
ported in a retrograde direction to the cell bodies of neurons
innervating the muscle. The neurons produce and shed copies
of the rabies virus, which in turn are taken up by the terminals
of adjacent cells. In this way, the infection becomes distributed
throughout the CNS, causing the behavioral changes associated
with this disease. From the CNS, the virus travels to the sali-
vary glands by means of anterograde axonal transport in neurons
innervating these glands. The infected salivary glands, in turn,
shed the virus in the saliva.
The toxin produced by the bacterium Clostridium tetani is also
transported in a retrograde direction in nerve cells whose axons
Retrograde Anterograde
(dynein (kinesin
mediated) mediated)
Endocytotic
vesicle Synaptic vesicle
Fig. 2.6 Anterograde and retrograde axonal transport.
terminate at the site of infection. Tetanus toxin is released from
the nerve cell body and taken up by the terminals of neighboring
neurons. However, unlike the rabies virus, which is replicated in
the cell body, the tetanus toxin is diluted as it passes from cell
to cell. In spite of this dilution effect, patients infected with C.
tetani may have a range of neurologic deficits.
Axonal Transport as a Research Tool
The ability of neurons to transport intracellular materials is
exploited in investigations of neuronal connections. For example,
when the enzyme horseradish peroxidase (HRP) or a fluores-
cent substance is injected into regions containing axon terminals,
it is taken up by these processes and transported in a retrograde
direction to the cell body. After histologic preparation, the cell
bodies containing these retrograde tracers can be visualized. The
presence of the label in a cell body indicates that the neuron has
axon terminals at the site of injection.
Tracer studies can also exploit the anterograde transport sys-
tem of neurons. For example, if radioactively labeled amino
acids are injected into a group of neuronal cell bodies, they
will be incorporated into neuronal proteins and transported
in an anterograde direction. The axons containing the labeled
 The Cell Biology of Neurons and Glia 21

Table 2.3 Terms Used to Describe Groupings of Neuronal Components

NAME
CNS Structures
Nucleus (plural, nuclei)
Column
La
yer, lamina (laminae),
stratum (strata)
Tract, fasciculus (fasciculi),*
lemniscus (lemnisci)
Funiculus (funiculi)†
PNS Structures
Ganglion (ganglia)
Nerve, ramus (rami), root
DESCRIPTION EXAMPLES
A group of functionally related nerve cell bodies in the CNS Inferior olivary nucleus, nucleus ambiguus, caudate
nucleus
Inthe cerebral cortex, a group of nerve cell bodies that are related in func- The ocular dominance and orientation columns of
tion and in the location of the stimulus that drives them and that form a the visual cortex
column oriented perpendicular to the plane of the cortex
Inthe spinal cord, a group of functionally related nerve cell bodies that form Clarke column
a longitudinal column extending through part or all of the length of the
spinal cord
Agroup of functionally related cells that form a layer oriented parallel to the Layer IV of cerebral cortex, the stratum opticum of
plane of the larger neural structure that includes it the superior colliculus
A bundle of parallel axons in the CNS Optic tract, corticospinal tract, medial longitudinal
fasciculus, fasciculus gracilis, medial lemniscus
A group of several parallel tracts or fasciculi An
terior, posterior, and lateral funiculi of spinal
cord
Agroup of nerve cell bodies located in a peripheral nerve or root; it forms Posterior root ganglia, trigeminal ganglion
a visible knot
A peripheral structure consisting of parallel axons plus associated cells Facial nerve, ventral roots of spinal nerves, gray and
white rami of spinal nerve roots

*Latin for “bundle.”

†Latin for “cable.”

CNS, central nervous system; PNS, peripheral nervous system.

  

proteins can then be detected by autoradiography. Another
commonly used anterograde tracer is HRP conjugated to the
glycoprotein-binding molecule (lectin) wheat germ agglutinin
(WGA-HRP). Anterograde tracers are used to identify the dis-
tribution patterns of axons arising from a specific population of
neuronal cell bodies.
The fact that the cell body is the trophic center of the neu-
ron provides two other methods of studying connections in the
nervous system. If the cell body is destroyed, the axon under-
goes anterograde (Wallerian) degeneration. These degenerated
axons can be visualized when neural tissue is impregnated with
silver nitrate. Variations on this method make it possible to con-
duct studies on human material obtained at autopsy. Conversely,
injury to the axon will result in a set of changes in the cell body
that are referred to as chromatolysis. The cell body swells, the
nucleus assumes an eccentric position, and the Nissl substance
disperses. (This breakup of the dye-binding parts of the cell gives
chromatolysis its name.) This technique has also been used in
animal experimentation and in human autopsy material.
CLASSIFICATION OF NEURONS AND GROUPS OF
NEURONS
Functionally related nerve cell bodies and axons are often aggre-
gated to form distinct structures in the nervous system. Table 2.3
lists the main terms used for such structures. In the CNS, a
cluster of functionally related nerve cell bodies is most com-
monly called a nucleus (plural, nuclei); cell bodies that are
arranged in a layer may be called a layer, lamina, or stratum,
and columnar groups of cell bodies may be called columns. This
last term is used for two types of structures. In the cerebral cor-
tex, it refers to a group of cells that are related by function and
by the location of the stimulus that drives them. These func-
tional groups form columns oriented perpendicular to the plane
of the cortex. The second type of column is found in the spinal
cord and refers to a longitudinal group of functionally related
cells that extend for part or all of the length of the brainstem
or spinal cord.
Bundles of axons in the CNS are called tracts, fasciculi, or
lemnisci. These are typically composed of specific populations of
functionally related nerve fibers (as in the corticospinal tract and
medial lemniscus). A group of several tracts or fasciculi is called
a funiculus or, in certain cases, a system.
In the peripheral nervous system (PNS), collections of cell
bodies form a ganglion (plural, ganglia), which may be either
sensory (dorsal root, cranial nerve) or motor (visceromotor or
autonomic); and axons make up nerves, rami, or roots.
As noted previously, neurons can be classified into multipolar,
pseudounipolar, or bipolar neurons on the basis of shape of the
cell body and the number and arrangement of processes. Neurons
may also be classified on the basis of functional characteristics.
A neuron that conducts signals from the periphery toward the
CNS is called afferent; one that conducts signals in the opposite
direction is called efferent. Neurons with long axons that convey
signals to a distant target are called projection neurons, whereas
neurons that act locally (because their dendrites and axons are
limited to the vicinity of the cell body) are called interneurons
or local circuit cells.
Neurotransmitter specificity also can be used to describe neu-
rons and their axons. For example, cells that contain the neu-
rotransmitter dopamine are called dopaminergic neurons. The
neurons whose axons form the corticospinal tracts produce the
neurotransmitter glutamate and are called glutamatergic.
The distinctions among categories based on shape, projection
type, or transmitter type are not as clear as those implied in the
preceding discussion. For example, most neurons only vaguely
resemble the “ideal” multipolar cell. In addition, neurons may
overlap several categories of classification. In practice, references
to ganglia, nuclei, and tracts commonly use a blend of these
terms. For example, posterior root ganglion cells are pseudouni-
polar (their shape), sensory (type of input), and afferent (infor-
mation conveyed toward the CNS), and many are peptidergic
(they contain peptides such as substance P).
ELECTRICAL PROPERTIES OF NEURONS
The communicative function of neurons is carried out by fluctua-
tions in their electrical potential. Chapter 3 explains the elec-
trical properties of neurons in depth; at this point, only a brief
introduction is needed.
Neurons carry a negative electrical charge relative to the
extracellular fluid bathing them. The negative charge is required
22 Essential Concepts
because there is a preponderance of negatively charged pro-
tein molecules within the cell and is the result of the electro-
chemical gradient of the relatively permanent potassium ion,
with more potassium being inside the cell than outside. The
uneven distribution of charged particles is maintained by the
neuronal plasma membrane, which limits passage of ions, per-
mitting them to cross only when specific ion channels open.
The plasma membrane is selectively permeable because certain
ions can cross at certain times, but there is not a free exchange
across the membrane.
The opening and closing of specific ion channels can be con-
trolled by chemical signals, including neurotransmitters. Chan-
nels in some sensory receptor neurons can be controlled by
mechanical distortion of the membrane. Still other channels
are controlled by voltage changes in the neuron. These allow
an explosive feed-forward amplification from a small, chemi-
cally induced voltage change to a much larger action potential
that occurs with the simultaneous opening of a large number
of channels. The small, chemically induced voltage changes are
restricted to tiny local areas within the neuron. They result in
depolarization of the neuron if positive (sodium) ions enter the
cell, reducing its net negative charge, or hyperpolarization if
positive (potassium) ions exit, increasing the concentration of
negative charge inside the cell.
When the sum of all tiny, local depolarizations and hyperpolar-
izations reaches a threshold of depolarization at the initial segment
of the axon, the voltage-controlled sodium channels open, produc-
ing an action potential. The action potential is large enough that
it does not remain local but is propagated anterogradely along the
entire length of the axon and reaches all of the axon terminals.
Arrival of the action potential at the axon terminals causes release
of neurotransmitter at synapses, stimulating ion channel opening
and local electrical voltage changes in the next neuron in the chain
of communication, the postsynaptic neuron.
NEURONS AS INFORMATION RECEIVERS
Neurons collect, transform, and transmit information. Collection
of information by the nerve cell occurs when the neuron receives
input either from other neurons or directly from the environ-
ment. Sensory information enters the nervous system by the lat-
ter of the two routes.
Sensory Neural Information
Neurons that receive information from the environment are
called primary sensory neurons. These include photoreceptors,
chemoreceptors, mechanoreceptors, thermoreceptors, and noci-
ceptors. Further information on these receptor types is found in
the chapters describing sensory systems. For most primary sen-
sory neurons, a stimulus results in a graded depolarizing poten-
tial, called a generator potential.
The process of converting sensory input into a form interpre-
table by the nervous system is transduction. Each type of sensory
receptor transduces an external physical or chemical stimulus
into electrical or chemical changes, which then can be transmit-
ted as signals within the nervous system.
The rod and cone photoreceptors of the retina are specialized
for transducing light energy in the form of photons. As few as
three photons (possibly even a single photon) can be detected by
a trained human observer. As a photon strikes the photoreceptor,
it sets in motion a complex chain of events culminating in the
closing of a large number of sodium channels that normally are
open. As a result, the photoreceptor cell becomes hyperpolar-
ized. This makes the photoreceptor unique among sensory cells
in that the membrane potential becomes more negative on appli-
cation of the stimulus rather than more positive.
In humans, the taste and olfactory receptor cells mediate
the two primary types of chemoreception. Both receptor types
respond to the presence of specific chemicals dissolved in a
solution. Also included in this category are receptors in the hypo-
thalamus, which sense low blood glucose concentration, low oxy-
gen tension, or changes in blood pH; oxygen and pH receptors
are also found in the aortic sinus and the carotid body.
Mechanoreceptors transduce various qualities of physical
force into electrical signals that are transmitted by sensory neu-
rons. Such receptors are found in the vestibular, auditory, and
somatosensory systems.
Other types of sensory receptors include thermoreceptors,
which sense temperature changes in the skin and viscera, and
nociceptors, which transduce noxious (potentially harmful)
stimuli. These receptors mediate what is commonly called pain;
this is one of the most common complaints in clinical medicine.
Other Neural Information
Although sensory neurons transduce external stimuli, most nerve
cells rely on other neurons for input. In general, the direction of
information flow in a neuron is from dendrites to soma to axon, but
most cells also receive information at their cell bodies, and many
even receive information at the axon terminal. In all these cases,
the reception of information is mediated by synapses. Synapses
are the points of information transfer from one neuron to another.
NEURONS AS INFORMATION TRANSMITTERS
Synapses
The synapse is the location at which a process of one neuron
(usually an axon terminal) communicates with a second neuron
or an effector (gland or muscle) cell. In general, there are two
broad morphologic categories of synapses, chemical and electri-
cal (or electrotonic). The vast majority of synapses in the mam-
malian CNS are of the chemical type.
Chemical Synapses
The most common type of CNS synapse comprises an axon
terminal of one neuron that is apposed to a dendrite or den-
dritic spine of a second neuron. The prototypical chemical
synapse consists of a presynaptic element, a postsynaptic ele-
ment, and the intervening space (the synaptic cleft), which is
20 to 50 nm wide (Figs. 2.1 and 2.7). The presynaptic element
typically takes the form of an axonal bouton. The bouton con-
tains mitochondria, which supply energy for synaptic function,
and also a prominent collection of vesicles, which contain the
neurotransmitter that will be released into the synaptic cleft.
These vesicles are often aggregated near sites on the presynaptic
membrane called active sites (or zones), which are the sites of
neurotransmitter release. Directly across the synaptic cleft is
the postsynaptic membrane, which often appears thick and
dark in electron micrographs (Figs. 2.1 and 2.7). Mitochondria,
but not vesicles, are typically present in its vicinity.
As explained in detail in Chapter 4, communication across the
synapse is mediated by the neurotransmitter stored in the pre-
synaptic vesicles (Figs. 2.1 and 2.8). Neurotransmitter release is
initiated by the arrival of an action potential, which depolarizes
the presynaptic terminal. In the terminal, depolarization causes
calcium channels to open. The resulting influx of calcium into
the cell initiates a sequence of events that cause synaptic vesicles
to fuse with the presynaptic plasma membrane and to release
their neurotransmitter into the cleft (see Chapter 4 for more
detail). The transmitter diffuses across the cleft and binds to
specific receptors on the postsynaptic membrane, and this event
triggers an electrochemical or biochemical change in the postsyn-
aptic cell. This change represents the information as received by
the postsynaptic cell.
Two functional properties of chemical synapses should be
noted. First, they are unidirectional; that is, they transmit
information only in the direction from the presynaptic cell to
the postsynaptic cell. This directionality results because only
the presynaptic cell releases the neurotransmitter, and only the
 The Cell Biology of Neurons and Glia 23

Axon Asymmetric synapses

(Gray type l)
Spine

Synaptic vesicles
Presynaptic membrane Dendritic
spine
Synaptic cleft
Postsynaptic membrane Spine

Mitochondrion
A Dendrite

Mitochondrion
Dense-cored Astrocyte
vesicles
Pleiomorphic
vesicles
Axon terminal
Round
vesicles
Symmetric synapse
(Gray's type ll)
Neuronal cell body

B C
Fig. 2.7 Ultrastructural elements of a chemical synapse (A) and three principal forms of synaptic vesicles
(B). Examples of asymmetric and symmetric synapses in visual cortex (C).

Microtubule

1 Arrival of
action potential Mitochondrion

Transmitter precursor
pump
Packaging
into Ac–
2 Opening of vesicles Ch+
Ca2+ channels
Ca2+
5 Breakdown of
neurotransmitter
Vesicle ACh
fusion Conversion
3 Fusion of
vesicles of transmitter
Active Inactive

4 Binding of neurotransmitter
Receptor by receptor
channels Receptors that
that allow trigger a biochemical
efflux of ions cascade
when bound
Nucleo- Cyclic nucleotides
tides
Receptor
channels Receptor channels Activation of
that allow that block ion proteins
entry of ions flow when bound
when bound
Fig. 2.8 Diagrammatic representation of the events occurring at a generalized chemical synapse. Ac−,
acetate; ACh, acetylcholine; Ch+, choline.
24 Essential Concepts
Table 2.4 Morphologic Characteristics of Gray Type I and
Type II Synapses
Gray Type I Synapses
Dense material present on postsynaptic membrane but not presynaptic mem-
brane (so that the synapse is visibly asymmetric)
Synaptic cleft 30 nm wide
Synaptic vesicles round and large (30-60 nm), with clear centers
Synaptic region up to 1-2 μm long
Gray Type II Synapses
Dense material present on both the presynaptic and the postsynaptic mem-
branes (so that the synapse appears symmetric)
Synaptic cleft 20 nm wide
Synaptic vesicles oval, flattened, or pleomorphic (variable) in shape
Synaptic region less than 1 μm long
postsynaptic cell expresses the receptor protein that will elicit
the normal postsynaptic response to the neurotransmitter. Sec-
ond, the strength of the effect on the postsynaptic membrane is
variable and depends partly on the amount of neurotransmitter
released into the synapse. Each synaptic vesicle contains a fixed
amount of neurotransmitter (called a quantum), so the amount
of neurotransmitter released depends on the number of vesicles
that fuse with the presynaptic membrane in response to calcium
influx.
With light microscopy, chemical synapses are visible only as
the terminal boutons of an axon; but in the early years of elec-
tron microscopy, two basic morphologic types of synapse became
apparent. They were named Gray type I and type II synapses.
The characteristics of these synapse types are listed in Table 2.4
and illustrated in Fig. 2.7C. At one time, it was believed that
type I synapses were excitatory in function and type II synapses
were inhibitory. We now know that the excitatory or inhibitory
function of a synapse depends on the nature of the receptors
present on the postsynaptic membrane and cannot be reliably
predicted from the ultrastructural characteristics of the presyn-
aptic bouton. Nevertheless, the scheme is still a useful way to
classify chemical synapses. For example, synapses using acetyl-
choline often have the Gray type I morphology, whereas those
using γ-aminobutyric acid (GABA) usually resemble Gray type
II synapses.
Although the vesicles of Gray type I and type II synapses differ
in size and shape, the centers of the vesicles appear clear (electron
lucent) in both cases. Vesicles with an electron-dense core are also
seen in some synaptic endings; these dense-cored vesicles are gener-
ally thought to contain neuropeptides or serotonin as a neurotrans-
mitter. This type of synapse is not included in the Gray classification.
NEUROTRANSMITTERS
As we have seen, neurotransmitters are a means by which infor-
mation is exchanged among nerve cells as well as between nerve
cells and effector cells. Neurotransmitters are considered fully
in Chapter 4 and are mentioned here briefly in relation to the
structure of a typical neuron.
Some neurotransmitters appear to consistently elicit either
excitatory (e.g., glutamate) or inhibitory (e.g., GABA) responses.
However, the effect (excitation or inhibition) of a neurotransmit-
ter on a responsive postsynaptic neuron is not due to any inherent
property of the signaling molecule itself. Rather, the nature of
the specific receptor on the postsynaptic membrane dictates the
response. For example, neurons that respond to the neurotrans-
mitter dopamine can express either of two types of dopamine
receptors. Binding of dopamine to one of these, the D1 recep-
tor, results in activation of adenylate cyclase, whereas binding of
dopamine to the other, the D2 receptor, results in inhibition of
adenylate cyclase activity.
Neurotransmitters may be biogenic amines (e.g., acetylcho-
line, dopamine, norepinephrine, epinephrine, serotonin, hista-
mine), amino acids (e.g., glutamate, GABA), nucleotides (e.g.,
adenosine), neuropeptides (e.g., substance P, cholecystokinin,
somatostatin), or even gases (e.g., nitric oxide, carbon monoxide).
Many of these neurotransmitters are stored in and released from
synaptic vesicles in the axon terminal as described previously, but
in other cases (e.g., nitric oxide), generation and release of the
neurotransmitter does not involve conventional vesicular release.
Biogenic amines (acetylcholine) and amino acid neurotrans-
mitters (GABA) are synthesized in the axon terminal, although
the enzymes necessary for their synthesis are produced in the
cell body and shipped to the terminal by axonal transport. The
axon lacks the machinery to synthesize proteins (or membrane
lipids) and thus must obtain these materials from the cell body.
Thus axonal transport is always necessary to support synaptic
function.
Disorders of Neurotransmitter Metabolism
Disorders of neurotransmitter metabolism account for a large
variety of neurologic and psychiatric illnesses, but the etiology is
not well understood in many cases. This category of diseases is
under intensive investigation, and four examples are briefly dis-
cussed here.
Parkinson disease affects dopamine-synthesizing neurons
located in an area of the brainstem known as the substantia
nigra. For unknown reasons, these dopaminergic cells begin
dying at an accelerated rate. The loss of dopamine results in
a characteristic tremor and inability to properly control move-
ment. Originally, therapy involved administration of supple-
ments of l-dopa, a precursor for dopamine. This treatment
increases dopamine synthesis by mass action but loses its
effectiveness with time. Currently, therapy involves a combi-
nation of l-dopa with carbidopa, which inhibits the enzyme
l-aromatic amino acid decarboxylase. Because carbidopa can-
not cross the blood-brain barrier (defined later), it decreases
the metabolism of l-dopa in peripheral tissues, making more
l-dopa available to the CNS for dopamine synthesis in the
remaining neurons.
Bipolar disorder affects several million Americans and appears
to be caused by imbalances in the phosphatidyl inositol (PI)-
linked neurotransmitter systems. An increase in PI turnover is
a biochemical change triggered by some subcategories of acetyl-
choline, serotonin, norepinephrine, and histamine receptors. It is
thought that a pathologic imbalance in PI turnover may result in
mood changes. The drug lithium carbonate stabilizes PI turnover,
thereby stabilizing the patient’s mood.
Alzheimer disease affects more than 1 million Americans.
Although the accuracy of diagnosis by psychological testing has
improved, a definitive diagnosis can be made only by postmortem
microscopic examination of brain tissue. Alzheimer disease is char-
acterized by the degeneration of neurons in basal forebrain nuclei,
the loss of synapses in the cerebral cortex and hippocampus, and
the presence of pathologic structures called neurofibrillary tan-
gles and senile plaques. Cortical cells normally receive terminals
from cholinergic (acetylcholine-releasing) cells in the basal fore-
brain nuclei. In Alzheimer disease, these terminals are lost, and
the activity of choline acetyltransferase (the enzyme responsible
for acetylcholine synthesis) in the cortex and hippocampus of dis-
eased patients is extremely low. Other neurotransmitter systems,
particularly neuropeptides, are also affected by this disease.
In many cases of myasthenia gravis, the patient’s immune sys-
tem produces antibodies to the nicotinic acetylcholine receptor,
a ligand-gated channel found at the synapse between primary
motor neurons and skeletal muscle fibers. Binding of these anti-
bodies to the receptor results in pathologic destruction of the
neuromuscular junctions, which in turn causes the muscle weak-
ness characteristic of this disease.
 The Cell Biology of Neurons and Glia 25

Pia mater

Glial limiting membrane

Neuron
Blood vessel

Protoplasmic
astrocyte

Microglial
cell

Perineuronal
oligodendrocyte
Fibrous
astrocyte
Perivascular Unmyelinated axon
feet Axons

Capillary
endothelium

Myelin

Basement Myelinated
membrane axons Interfascicular
oligodendrocytes
Fig. 2.9 Relationships of central nervous system glial cells to neuronal cell bodies, axons, blood vessels,
and pia mater.

Table 2.5 Types of Glial Cells and Their Locations and Functions
CELL TYPE LOCATION FUNCTION
CNS
Astrocytes Throughout the CNS; contact neuronal cells bodies, den- Maintenance of extracellular ionic environment; secretion of growth factors;
drites, axons, and synapses and form a complete lining structural and metabolic support of neurons; neuronal communication
around the external surfaces of the CNS and around
CNS blood vessels; gray matter astrocytes are called pro-
toplasmic and white matter astrocytes are called fibrous
Oligodendrocytes
Myelinating Form myelin sheaths around CNS axons Myelination
Satellite cells Surround CNS neuronal cell bodies Unknown
Microglia Gray and white matter of CNS Scavenging and phagocytosis of debris after cell injury and death; immune pro-
tection of the CNS
PNS
Schwann cells Form myelin sheaths around myelinated axons and ensheath Myelination; biochemical and structural support of myelinated and unmyelin-
unmyelinated axons ated axons
Satellite cells Surround neuronal cell bodies in PNS ganglia Unknown

CNS; central nervous system; PNS, peripheral nervous system.

  

GLIA and synapses. Other astrocyte processes end in expansions called

Unlike neurons, glial cells do not propagate action potentials.
Rather, they provide neurons with structural support and main-
tain the appropriate microenvironment essential for neuro-
nal function. In addition, one type of glial cell, the astrocyte,
can modulate synaptic activity in its vicinity by releasing small
amounts of neurotransmitters.
Glia account for most of the cells in the nervous system, and
normal brain function requires them. The major types of glial
cells in the CNS (Fig. 2.9; Table 2.5) are astrocytes and oligoden-
drocytes, derived from neuroectoderm, and microglia, derived
from mesoderm. The analogous cell types in the PNS are the
satellite cells, Schwann cells, and macrophages.
ASTROCYTES
Astrocytes occur throughout the CNS. They are highly branched
cells with processes that contact most of the surfaces of neu-
ronal dendrites and cell bodies as well as some axonal surfaces
end-feet (Fig. 2.9). Astrocyte end-feet join together to com-
pletely line the interfaces between the CNS and other tissues.
The outer surface of the brain and spinal cord, where it meets the
inner surface of the pia mater (the innermost of the meningeal
membranes that enclose the CNS), is covered with a coating of
several layers of joined end-feet called the glia limitans (or glial
limiting membrane). Similarly, every blood vessel in the CNS is
jacketed by a layer of end-feet that separates it from the neural
tissue.
As shown in Fig. 2.9, the astrocytes of gray matter, called pro-
toplasmic astrocytes, differ in shape from the astrocytes of white
matter, called fibrous astrocytes because of their greater content
of intermediate filaments. Astrocytes can be distinguished immu-
nohistochemically (for purposes of research and diagnosis) by the
presence of intermediate filaments with a distinctive marker pro-
tein, glial fibrillary acidic protein (GFAP). The GFAP content of
protoplasmic astrocytes increases in pathologic conditions.
26 Essential Concepts
Structural Support and Response to Injury
During development, astrocytes (in the form of radial glial cells)
provide guides for neuronal migration. In the adult brain, astro-
cytes frame certain clusters of neurons, for example, the columns
or barrels of the somatosensory cortex of rodents. In white mat-
ter, they also enclose bundles of unmyelinated axons.
When injury to the CNS results in destruction of cells, the
space created by the breakdown of debris is filled by prolif-
eration or hypertrophy (or both) of astrocytes, resulting in
the formation of an astrocytic scar. That astrocytes retain the
ability to proliferate in the mature brain (and thus are more
susceptible to events that disrupt the control of cell division)
explains why the majority of CNS tumors are of astrocytic
origin.
Growth Factors and Cytokines
Current research on astrocytes indicates that they secrete growth
factors vital to normal function of some neurons. In disease pro-
cesses, astrocytes may secrete cytokines and immune mediators
such as interleukin (IL)-1, tumor necrosis factor-α, and prosta-
glandin. Thus astrocytes as well as microglia contribute to the reg-
ulation of inflammatory processes in the CNS. In development,
astrocytes induce synapse formation through their secretion of
thrombospondins. Thrombospondins are a family of extracellular
matrix proteins that bind to neuronal surface molecules (calcium
channel subunits, integrins, and neuroligin synaptic adhesion pro-
teins). Other astrocyte products, such as cholesterol and lipopro-
teins, are also thought to enhance synaptic plasticity.
Environmental Modulation
The ionic composition and pH of the extracellular fluid are
buffered by astrocytes. These cells have ion channels in their
membranes that are different from those in neurons. For exam-
ple, potassium ions released from neurons during firing of an
action potential are cleared from the extracellular space by
astrocytes via plasma membrane ion channels. Astrocytes are
connected to each other by gap junctions and act as syncytia
through which excess potassium ions are shunted to perivas-
cular spaces, restoring balance after heavy local activity. Astro-
cytes also propagate calcium waves, which spread through gap
junctions between astrocytes to cover broad areas. Intracellular
calcium levels in astrocytes, as in all cells, regulate secretory
activity.
Influence on Neurotransmission
Astrocytes are present at synapses and participate in neurotrans-
mitter metabolism. Their membranes have receptors for some
neuroactive substances and uptake systems for others. Astro-
cytic uptake systems serve to quickly terminate the postsyn-
aptic effect of some neurotransmitters by removing them from
the synaptic cleft. For example, the amino acid neurotransmit-
ter glutamate is taken up by astrocytes and is then inactivated
by the enzymatic addition of ammonia to produce glutamine
(catalyzed by the enzyme glutamine synthetase). Glutamine
released from astrocytes can be taken up and reconverted to
glutamate in neurons. This astrocytic pathway also detoxifies
ammonia in the CNS.
Furthermore, in addition to this metabolic support role,
astrocytes’ secretion of the amino acids glutamate and d-ser-
ine modulates synaptic efficacy. That is, the strength of indi-
vidual synapses is adjusted in correlation with their activity
patterns, so that a synapse undergoes long-term potentiation
or long-term depression. Astrocytes respond to neuronal activ-
ity by secreting glutamate or d-serine, which binds to neuronal
N-methyl-d-aspartate (NMDA) receptors and modulates syn-
aptic activity. This reciprocal signaling arrangement is illus-
trated in Fig. 2.10.
A more specific role for astrocytes in brain communication
has been shown in recent studies involving neighboring neuro-
nal and astrocytic processes in the striatum of the basal nuclei.
Incoming cerebral cortical presynaptic axons and some resident
astrocyte processes contain receptors for endocannabinoids
(eCBs, Fig. 2.11), substances released from striatal neuron
dendrites. When eCB receptors on presynaptic cortical axons
(Fig. 2.11B) are activated by eCB release, glutamate release
at nearby corticostriatal synapses (Fig. 2.11A) is decreased
because the firing rate of incoming cortical axons is suppressed
(depolarization-induced suppression). This leads to dimin-
ished excitation of its associated striatal neuron. In contrast,
when eCBs bind to receptors on nearby astrocyte processes
(Fig. 2.11C), internal stores of calcium in the astrocyte pro-
cess are uncaged, leading to the release of glutamate from the
astrocyte process. This glutamate binds to metabotropic gluta-
mate receptors on nearby presynaptic glutamatergic corticos-
triatal axons (Fig. 2.11D). Activation of this circuit now leads
to enhanced excitation of striatal neurons (Fig. 2.11E), with the
implication being that neurons and associated astrocytes might
function as key elements in a signaling network. It remains for
future studies to determine if such circuits involving this type
of signaling between neurons and astrocytes might be a charac-
teristic feature of other brain regions.
Astrocytes also release other neurotransmitters. The inhibi-
tory neurotransmitter GABA is released from astrocyte anion
channels. Its sustained mode of release causes tonic inhibition of
synapses in the surrounding area. In contrast, adenosine triphos-
phate (ATP) is released by astrocytes in response to neuronal
signaling. It is metabolized to the neurotransmitter adenosine,
which is involved in cellular energy regulation and the sleep-wake
cycle.
Regional Heterogeneity
Astrocytes vary biochemically between gray matter (pro-
toplasmic astrocytes) and white matter (fibrous astrocytes)
and from one region of the CNS to another. White matter
astrocytes differ from gray matter astrocytes in terms of their
ion channels, neurotransmitter receptors and uptake systems,
and other special properties. For unknown reasons, astrocyte
tumors of particular types occur in characteristic distributions
rather than with random frequency throughout the CNS. For
example, the malignant tumor glioblastoma multiforme devel-
ops most frequently in the frontal or temporal lobe of the
cerebral cortex.
Astrocytes at the Blood-Brain Barrier
In many tissues, solutes can pass freely between the capil-
lary plasma and the interstitial space by diffusing through gaps
between endothelial cells. In the CNS, vessels are induced by
the surrounding jacket of astrocyte end-feet to form extensive
tight junctions, so solutes can reach the neural tissue only by
passing through the endothelial cells (Fig. 2.12A). The result-
ing restricted exchange constitutes the blood-brain barrier. In
a strict sense, the blood-brain barrier is formed by the tight
junctions of the endothelium. However, many people refer to
the blood-brain barrier more inclusively as the physical com-
plex of endothelium, basal lamina, and astrocyte end-feet sur-
rounding each CNS vessel (see also Chapter 8). Water, gases,
and lipid-soluble small molecules can diffuse across the endo-
thelial cells, but other substances must be carried across by
transport systems, and their exchange is highly selective. This
selectivity is further enhanced by a reduction in pinocytotic
transport. In most tissues of the body, a high level of pinocy-
totic activity by endothelial cells transports solutes nonspe-
cifically from the blood plasma to the perivascular space. In
contrast, endothelial cells of capillaries in most parts of the
 The Cell Biology of Neurons and Glia 27

A
Glutamate Astrocyte
Synaptic glutamate receptor
Astrocyte glutamate receptor
Astrocyte glutamate transporter

Gap junction

Synaptic cleft
Postsynaptic dendritic spine
Presynaptic axon terminal

Gap junction

B
Glutamine
Glutamine synthetase
Intracellular calcium increase

C
Extrasynaptic glutamate receptors
Glutamate release from astrocytes
Neuronal glutamine uptake

Fig. 2.10 Astrocytes participate in neural transmission. Glutamatergic transmission is affected in two
ways. First, glutamate (red circles) diffusing from active synapses is taken up by the astrocyte glutamate
transporter (on uppermost astrocyte in A, B, and C) to be metabolized to glutamine (B and C, green
diamonds). Glutamine in turn is transported into the presynaptic axon terminal for recycling into glu-
tamate (B and C). Second, astrocyte cell surface receptors for glutamate (blue squares) also respond to
the neurotransmitter, increasing intracellular calcium (indicated by gray shading of astrocytes in B and C;
darker gray represents greater increase in calcium concentration, lighter gray indicates less increase). The
calcium increase passes via gap junctions to neighboring astrocytes. The increase in intracellular calcium
causes astrocytes to release small amounts of glutamate, affecting extrasynaptic glutamate receptors on
neighboring neurons (C). Activation of extrasynaptic glutamate receptors on the presynaptic axon terminal
modulates transmitter release; on the postsynaptic neuron, it modulates responses (excitatory and inhibi-
tory postsynaptic responses) to synaptic transmission.

CNS show little pinocytotic activity. The blood-brain bar-
rier is of major clinical importance because it largely excludes
many drugs from the CNS.
CONTROL OF LOCAL BLOOD FLOW WITHIN THE
CENTRAL NERVOUS SYSTEM
In a person at rest, 20% of the body’s energy is consumed by the
brain, mostly to restore ion concentration gradients across neuro-
nal membranes. Therefore blood flow increases in regions where
neurons are active. This process is called neurovascular coupling,
and the increase, functional hyperemia, is the basis of functional
magnetic resonance imaging. Clinically, neurovascular coupling is
defective in conditions such as migraine, stroke, hypertension,
spinal cord injury, and Alzheimer disease. As our understanding
of the mechanisms increases, therapeutic interventions may be
within reach.
Both astrocytes and neurons cooperate in neurovascular cou-
pling through glutamate signaling. They produce an increase
in local blood flow that is at least four times greater than the
increase in consumption of oxygen and ATP by the local neu-
rons. In neurons, glutamate acts on NMDA receptors to increase
intracellular calcium, to increase the enzyme activity of neuro-
nal nitric oxide synthase, and to release nitric oxide, leading to
vasodilation. Both arteriolar smooth muscle and the contractile
28 Essential Concepts

Basal lamina

GLu Cerebral Cerebral GLu

release cortex axons cortex axons release Endothelial cells
a e
b d

eCB Tight junctions

Astrocyte

c
eCB

A Astrocyte perivascular
end-feet
SN SN
dendrite dendrite

Astrocyte

Excitation Excitation
suppressed enhanced
Fig. 2.11 Schematic representation of one form of neuronal signaling between
astrocytes and neurons. Medium spiny striatal neurons (SN) receive glutamater-
gic (GLu) input from cerebral cortex axons (a, e). SN neuron dendrites release
endocannabinoids (eCBs, reader’s left), which bind to receptors located on incom-
ing (presynaptic) cortical axon terminals (b). This has the effect of decreasing
the release of glutamate from the corticostriatal axon terminals and in so doing
suppresses excitation of the SN cells (red neuron, reader’s left). Similarly, eCBs
Perivascular
released from SN neuron dendrites (green neuron, reader’s right) bind to recep- feet
tors on adjacent astocytes (c), where intracellular calcium stores are unblocked,
leading to the release of glutamate from astrocyte processes (d). The additional
glutamate binds to metabotropic receptors on nearby cortical axon terminals (e),
resulting in enhanced excitation of SN cells (green neuron, reader’s right).
Blood vessel
B
pericytes of capillaries are relaxed by nitric oxide. In astrocytes,
Fig. 2.12 The relationship of astrocytes to central nervous system (CNS) blood
glutamate acts through neuroligin glutamate receptors to increase vessels. A, Perivascular end-feet cover blood vessels of the CNS. B, Golgi-stained
intracellular calcium, to increase the enzyme activity of phos- astrocyte with end-feet apposed to a blood vessel.
pholipase A2, to increase arachidonic acid in the cell membrane,
and to increase production of the arachidonic acid derivatives Oligodendrocyte
prostaglandins and epoxyeicosatrienoic acids, leading to vasodi- Myelin segments cell body
lation. The neuronal and astrocytic pathways interact, and both
are regulated by oxygen tension. So the exact balance between
neuronal and astrocytic control of local blood flow varies accord-
ing to conditions and region.
In spreading depression, reduced blood flow lasts for hours
and may damage neurons. Considering the nitric oxide pathway
and its regulation by oxygen tension, it is possible that a negative Myelin
feedback loop operates in spreading depression, such that reduced Nodes of Ranvier,
membrane
oxygen leads to reduced production of nitric oxide, which leads exposed axons
to reduced blood flow (failure of vessels to relax), which leads to
even lower availability of oxygen. This pathway and pharmaceuti-
cal modulators of it can now be tested experimentally.
Oligodendrocyte
OLIGODENDROCYTES cytoplasm
Oligodendrocytes, like astrocytes, occur in both gray matter
Fig. 2.13 Myelin sheath formation by processes of an oligodendrocyte. The
and white matter (Fig. 2.9). The function of oligodendrocytes is cytoplasm of the oligodendrocyte is trapped on the edges of the cell membrane
myelination, that is, the provision of an electrochemically insu- as it wraps around the axon.
lating sheath around all but the smallest axons in the white mat-
ter (Figs. 2.9 and 2.13). Other oligodendrocytes lie adjacent to
and surround neuronal cell bodies in the gray matter, but they do sheaths and high conduction velocities; smaller diameter axons
not make myelin, and the significance of this arrangement is not have thinner myelin sheaths and slower conduction velocities;
well understood. and the smallest axons are unmyelinated and have the slowest
A myelin sheath is a membranous wrapping around an axon conduction velocities.
that greatly increases the speed of conduction of action poten- Myelin is formed by a cell-cell interaction in which an axon
tials along the axon. Large-diameter axons have thick myelin destined for myelination is recognized by proteins on the

oligodendrocyte surface. Developing oligodendrocytes also
receive electrochemical signals from active axons. The oligoden-
drocyte responds by producing a flattened, sheet-like process
that wraps repeatedly around the axon (Fig. 2.13). As the lay-
ers of membrane accumulate, all cytoplasm is excluded, so that
the mature myelin sheath consists of layers of oligodendrocyte
plasma membrane firmly pressed together. Cytoplasm remains
only in the innermost and outermost turns of the oligodendro-
cyte process.
The myelin sheath surrounding an axon is not continuous along
its entire length. Rather, the axon is covered by a series of myelin
segments, each formed by an oligodendroglial cell. The interrup-
tions between segments are called nodes of Ranvier (Fig. 2.5B).
Morphologic specializations at the nodes include a dense under-
coating of the axonal membrane, as seen at the initial segment
of the axon, and contact by an astrocyte process. The rapid ionic
exchanges across the axonal membrane essential for generating
the action potential and propagating it down the axon occur at
the nodes of Ranvier. The depolarization is then passively con-
ducted along the axon (as a graded potential) to the next node.
This method, saltatory conduction, is faster and requires much
less energy than having ionic exchanges occur continuously along
the length of the axon.
The segments of myelin between adjacent nodes of Ranvier are
called internodal segments, or internodes. Although the name
oligodendrocyte means “cell with few branches,” some of these
cells give rise to myelinating processes forming internodal seg-
ments on as many as 40 axons.
Myelination occurs in the human CNS from birth through
adolescence. Even in adults, there is evidence from imaging stud-
ies that white matter changes occur when subjects learn skills
like juggling or playing the piano.
In demyelinating diseases, such as multiple sclerosis, groups
of oligodendrocytes and their corresponding myelin segments
degenerate and are replaced by astrocytic plaques. This loss of
myelin results in an interruption of the propagation of the action
potential down these axons. Demyelinated axons survive tempo-
rarily, and some remyelination is possible by the growth of oli-
godendrocyte precursor cells that reside in the adult CNS. The
particular array of motor, visual, or general sensory losses in a
patient with multiple sclerosis reflects the locations of the demy-
elinating lesions.
MICROGLIA
Microglial cells are the immune effector cells of the CNS, and
thus they are the predominant cells involved in CNS inflamma-
tion. The precise embryonic origin of the microglial cells has been
controversial, but these cells clearly differ from other neural and
glial cells of the CNS in that microglia do not arise from neuroec-
toderm. Rather, they are descendants of myeloid progenitor cells
arising from the yolk sac and entering the CNS early in embry-
onic development. Microglia make up about 1% of the CNS cell
population (Fig. 2.9). During health, they are considered to be
sessile, or quiescent.
Like astrocytes, each microglial cell spreads its processes
to cover a unique territory that does not overlap with that of
neighboring microglia. Unlike astrocytes and oligodendrocytes,
however, microglia are not connected by gap junctions. In the
healthy CNS, the microglial cell body remains fixed in place,
but its branched processes continually move in protective sur-
veillance of surrounding tissue. Microglia are versatile in their
responses to any threats that may be discovered. In certain dis-
ease states, such as viral encephalitis caused by human immuno-
deficiency virus-1 (HIV-1), subacute sclerosing panencephalitis,
lead encephalopathy, and neurosyphilis, microglia withdraw and
reshape their processes to form long rod cells closely apposed
to affected neurons. In cases of trauma or severe tissue injury,
The Cell Biology of Neurons and Glia 29
they become motile, ameboid phagocytes capable of migrating
to the site of injury and proliferating. At the injury site, they
phagocytose tissue debris.
Metabolic activation of microglia may be even more impor-
tant to their functioning than the dramatic shape changes
observed pathologically. As immune cells, microglia can be
stimulated to secrete cytokines, such as interleukins and
tumor necrosis factor-α, and other immune mediators, such
as arachidonic acid derivatives prostaglandin E2 and platelet-
activating factor. Like macrophages, they also secrete growth
factors, for example, brain-derived neurotrophic factor. The
broad range of microglial products thus includes potentially
neurotoxic and neuroprotective mediators of inflammation
and tissue repair. Current research is aimed at determining
what combinations of these products are triggered by specific
stimuli that enter the CNS.
The net effects of microglial activation can be beneficial and
protective, as in the case of synaptic stripping. This term is applied
to a situation in which the facial nerve (a motor nerve) has been
cut peripherally. Microglia then surround the motor neuron cell
bodies located in the brainstem and displace or remove all syn-
apses from the surface of the neurons. Once the peripheral axon
has grown back and reconnected with its target muscles, new
synapses form around the neurons.
In other cases, microglial activation can be harmful. For
example, in bacterial meningitis in children, as microglia
phagocytose particles of bacteria killed by penicillin, they are
stimulated to secrete IL-1β. IL-1β acts on endothelial cells
to loosen their tight junctions, allowing leukocytes and blood
plasma to enter CNS tissue, escalating the inflammation to a
level that can be fatal. When researchers and physicians pre-
vented this secondary inflammation by administering steroids
before giving penicillin, microglial cytokine secretion was
inhibited, and the survival rate for bacterial meningitis in chil-
dren vastly improved.
Microglial cells are the CNS cells targeted by human immu-
nodeficiency virus (HIV), the virus that causes acquired immu-
nodeficiency syndrome (AIDS). The mechanism by which HIV
infection of microglia leads to neuronal damage and dementia is
not yet fully understood.
TUMORS OF THE CENTRAL NERVOUS SYSTEM
Primary brain tumors arise from the cells that make up the struc-
ture of the brain and spinal cord as well as its coverings. Indi-
vidual cells belonging to any of the cell populations found in brain
tissue or the leptomeninges can give rise to a brain tumor, pro-
vided genetic and environmental stimuli favor cell proliferation.
However, neurons give rise to tumors only rarely, as would be
expected of a cell type that is postmitotic and highly differenti-
ated morphologically.
Glia-Derived Tumors
Glial cells are a frequent source of primary brain tumors in
adults and children, and of these, astrocytomas are the glial
tumors encountered most often. An evaluation of astrocyto-
mas is traditionally made on the basis of how closely or how
little the neoplastic cells resemble nonneoplastic astrocytes
(degree of differentiation), and this helps predict the outcome
for the patient. This grading of astrocytomas is an attempt
to better define the biologic aggressiveness of the tumor and
to estimate the tumor’s effect on the life span of the patient
(prognosis).
Grade 1 astrocytomas, uncommon tumors, resemble differ-
entiated astrocytes that react to an injury within brain tissue
(Fig. 2.14A). They usually arise from fibrillary astrocytes in the
white matter, which have many stubby processes (Fig. 2.14E).
They grow slowly, and gradual enlargement may be the main
30 Essential Concepts

White matter

Gray matter

A Grade 1 B Grade 2

Tripolar mitosis

Binucleate astrocytes

C Grade 3 D Grade 4

Live tumor

Necrotic zone

Transitional zone

E F
Fig. 2.14 The grades of astrocytomas are 1/I (A, E), 2/II (B), 3/III (C), and 4/IV (D, F). Grade 1: The
density of astrocytes, cells with vesicular chromatin and stubby processes, is increased in white matter com-
pared with that in gray matter (A, compare upper right with lower left). Within the gray matter, these cells
are clustered around neurons (A, arrows). These enlarged astrocytes have homogeneous nuclei (E, arrows),
nucleoli, conspicuous cytoplasmic bodies, and stellate processes (E). Grade 2: Astrocyte nuclei vary in shape;
the staining intensity and cell density are increased (B). Grade 3: Heterogeneity of astrocyte size and shape
(pleomorphism) is more apparent (C). Cells with enlarged nuclei or with two nuclei (binucleate astrocytes)
are present. Abnormal tripolar mitotic figures and mitotic figures on spindles (C, inset) signify a heightened
level of cell proliferation. The clear spaces between cells indicate microcystic edema. Grade 4: Spindle-
shaped, oval, elongated, and curved nuclei are abundant, indicating the extreme pleomorphism of this grade,
which is also known as glioblastoma multiforme (D). Large, complex vascular structures with clusters of
cells surrounding the lumina (D, arrows) are characteristic of glioblastoma. Another feature is the sharp
border and the transitional zone between the live tumor and the necrotic zone (F).

clue that a neoplasm does exist. On occasion, protoplasmic
astrocytes, denizens of gray matter with fewer processes, may
form tumors that contain fluid-filled cysts.
The astrocytes of grade 2 astrocytoma, which have prominent
processes filled with glial filaments, infiltrate between myelinated
axons in white matter and increasingly cluster around neurons in
cortical gray matter (Fig. 2.14B). Although they are commonly
encountered in adult patients, years may elapse before these
tumors are symptomatic. However, if they recur after surgery,
these astrocytomas may become more aggressive, transforming
into a higher grade. In general, grade 1 and grade 2 astrocytomas
are slowly growing masses.
Grade 3 astrocytomas have nuclei that are often enlarged, with
increased density of chromatin. Uniformity of nuclear appear-
ance is lost. Mitotic figures, consisting of chromosomes on spin-
dles (Fig. 2.14C), may be frequently noted in tumor cells and
are one indicator of rapid cell proliferation. The density of blood
vessels is increased. These are rapidly growing, malignant tumors.
Another random document with
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The Project Gutenberg eBook of College girls
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Title: College girls

Author: Abbe Carter Goodloe

Illustrator: Charles Dana Gibson

Release date: September 29, 2023 [eBook #71753]

Most recently updated: December 2, 2023

Language: English

Original publication: NYC: Charles Scribner's Sons, 1895

Credits: Chuck Greif and the Online Distributed Proofreading Team at

http://www.pgdp.net (This file was produced from images
available at The Internet Archive)

*** START OF THE PROJECT GUTENBERG EBOOK COLLEGE

GIRLS ***
College Girls

“IS IT THIS?"

College Girls
By

Abbe Carter Goodloe

Illustrated by

Charles Dana Gibson

 New York
Charles Scribner’s Sons
1895

Copyright, 1895, by
Charles Scribner’s Sons

TROW DIRECTORY
PRINTING AND BOOKBINDING COMPANY
NEW YORK
 CONTENTS
Page
A Photograph, 1
An Aquarelle, 17
“La Belle Hélène”, 37
As Told by Her, 67
A Short Career, 95
An Episode, 107
Her Decision, 145
Revenge, 163
The College Beauty, 187
A Telephoned Telegram, 203
“Miss Rose”, 213
A Short Study in Evolution, 225
The Genius of Bowlder Bluff, 243
Time and Tide, 267
 LIST OF ILLUSTRATIONS
“Is it this?” Frontispiece
Facing page
She stopped and her face grew whiter, 12
“They wanted him to put them in his stories,” 14
The political economist, 76
“It has been a long while since you were a student here,” 78
“How kind you are,” 90
“You cannot imagine how anxious the girls are to see you,” 174
“Play!” 176
A rather chilling influence, 230
She had stolen furtive glances at her, 232
When the two women were within a few feet of each other, 240
 A PHOTOGRAPH

T HERE was a great deal of jangling of bells, and much laughter and talk,
and the chaperon, who was an assistant Greek professor, looked as if she
had never heard of Aristophanes, and listened apparently with the most
intense interest to a Harvard half-back eagerly explaining to her the
advantages of a flying wedge; and when the College loomed in sight, with its
hundreds of lights, and the sleigh drew up under the big porte cochère, and
while a handsome youth was bidding his sister, the hostess of the party, an
unusually affectionate good-by, she explained to the rest how very sorry she
was she could not invite them in. But the Harvard men, in a feeling sort of
way, said they understood, and after much lifting of hats and more laughter,
the sleigh went off, and the chaperon and her charges were left standing in
the “Centre.”
She confessed then that she was extremely tired and that she did not think
she ever cared again to see the “winter sports.” She thought the sight
afforded her that afternoon, of two nice boys, very scantily clothed and with
bloody faces, banging away at each other until they could hardly stand,
compared with the view of those same young gentlemen the week before at
the College, immaculately dressed and with very good-looking noses and
eyes, was entirely too great a strain on her. So she went off to her study and
left the excited and pleased young women to stroll down the corridor to Miss
Ronald’s room, to talk it over and to decide for the twentieth time that
Somebody of ’94 ought to have come off winner in the fencing match,
instead of Somebody else of ’93.
The room they went into was a typical college room, with its bookstands
and long chairs and cushions and innumerable trophies, of which Miss
Ronald was rather proud. She was a stylish girl, with New York manners and
clothes, and a pretty, rather expressionless face, strongly addicted to fads,
and after almost four years of college life still something of a fool. She had
become popular through her own efforts and the fact that she had a brother at
Harvard. If a girl really wishes to be a favorite in college she must arrange to
have some male relative at a neighboring university.
The sleighing party over to Harvard for the winter sports had been an
especial success, so her guests took off their wraps and settled themselves in
her chairs in a very cordial sort of way, and discussed amiably the merits of
the tug-of-war, while someone made chocolate. After a while, when they had
all had their say about the pole-vaulting and the running jumps, the
conversation flagged a little and the room came in for its share of attention.
There was a comparative stranger among the guests—a Miss Meredith—
to whom Miss Ronald could show her numerous souvenirs for the first time.
She was especially glad to have them to show to this particular girl because
she thought they would impress her—although it would have been a little
difficult for a casual observer to understand just why, for as Miss Meredith
was led around the room by her hostess, from the screen made of cotillion
favors and the collection of lamp-post signs presented to her by Harvard
admirers afflicted with kleptomania, over to the smoking-cap and tobacco-
pouch of some smitten undergraduate, anyone could see what a handsome
girl she was, and though more plainly dressed than the others, that she
seemed to be thoroughly at her ease. Perhaps Miss Ronald expected her to be
impressed because she had taken her up, and had first introduced her to this
set and made a success of her. No one had known anything about her or her
people, and she had entered shortly before as a “special student,” and
therefore belonged to no particular class. She was evidently a little older
than Miss Ronald and her friends, and her face was somewhat sad, and there
was a thoughtful look in the eyes. She seemed to be rather haughty, too, and
as if afraid she would be patronized. But Miss Ronald, whose particular
craze in the beauty line was a cream complexion, gray eyes, and red-brown
hair, had declared the new-comer to be lovely, and even after she had
discovered that this handsome girl was not of her own social standing, that
her people were unknown and unimportant, she still declared her intention of
cultivating her. She had found this harder to do than she had expected, and
so, as she led her around the room, she rather delighted in the belief that she
was impressing this girl by the many evidences of a gay social career.
The others, who had seen all the trophies many times before, and who
knew just which one of Miss Ronald’s admirers had given her the Harvard
blazer, and where she had got the Yale flag and the mandolin with the tiger-
head painted on it—for Miss Ronald, being a wise young lady, cultivated
friends in every college—sat back and talked among themselves and paid
very little attention to what the other two were doing. They were a little
startled, therefore, by a low exclamation from the girl with Miss Ronald. She
had stopped before a long photograph-case filled with pictures of first
violins and celebrated actors and college men—all the mute evidences of
various passing fancies. Miss Ronald, who was putting away the faded
remains of some “Tree-flowers” and some pictures of Hasty Pudding
theatricals, looked over at the girl.
“What is it?” she said, carelessly, and then noting her pallor and the
direction of her gaze she laughed in an embarrassed little way and went over
to her.
“Is it this?” she said, taking a half-hidden photograph from among the
jumble of pictures and holding it up to the view of all.
It was the photograph of a young man, a successful man, whose name had
become suddenly famous and whose personality was as potent as his talents.
He was not handsome, but his fine face was more attractive than a handsome
one would have been. There was a look of determination in the firmly closed
lips and square-cut jaw, and an indefinable air of the man of the world about
the face which rendered it extremely fascinating. On the lower edge of the
picture was written his name, in a strong, bold hand that corresponded with
the look on the face.
“My latest craze,” said Miss Ronald, smiling rather nervously and
coloring a little as she still held the picture up. There was a slight and
awkward pause, and then half a dozen hands reached for it. There was not a
girl in the room who had not heard of this man and wished she knew him,
and who had not read his last book and the latest newspaper paragraphs
about him. But their interest had been of the secretly admiring order, and
they all felt this girl was going a little too far, that it was not just the thing to
have his picture—the picture of a man she did not know. And as she looked
around and met the gray eyes of the girl beside her she felt impelled to
explain her position as if in answer to the unspoken scorn in them. She was
embarrassed and rather angry that it had all happened. She could laugh at the
first-violins and the opera-tenors and the English actor—they had only been
silly fancies—but this one was different. Without knowing this man she had
felt an intense interest in him and his face had fascinated her, and she had
persuaded herself that he was her ideal and that she could easily care for
him. She suddenly realized how childish she had been and the ridiculousness
of it all, and it angered her.
“Of course I know it isn’t nice to have his picture—in this way—” she
began defiantly, “but I know his cousin—it was from him that I got this
photograph—and he has promised to introduce us next winter.” She seemed
to forget her momentary embarrassment and looked very much elated.
“Won’t that be exciting? I shan’t know in the least what to say to him. Think
of meeting the most fascinating man in New York!”
“Be sure you recognize him,” murmured one of the girls, gloomily, from
the depths of a steamer-chair. “I met him last winter. I had never seen a
photograph of him then, and not knowing he was the one, I talked to him for
half an hour. When I found out after he had gone who he was, I couldn’t get
over my stupidity. My mother was angry with me, I can tell you!”
Each one knew something about him, or knew someone who knew him,
or the artist who illustrated his stories, or the people with whom he had just
gone abroad, or into what thousandth his last book had got. They all thought
him a hero and fascinatingly handsome, and they declared with the
sentimental candor of the very young girl, that they would never marry
unless they could marry a man like that—a man who had accomplished great
things and had a future before him, and who was so clever and interesting
and distinguished-looking.
The girl who had had the singular good fortune to meet him was besieged
with questions as to his looks and manner of talking, and personal
preferences, to all of which she answered with a fine disregard for facts and
a volubility out of all proportion to her knowledge. They wondered whether
his play—he had just written one, and the newspapers were saying a great
deal about its forthcoming production—would be as interesting as his
stories, and they all hoped it would be given in New York during the
Christmas holidays, and they declared that they would not miss it for
anything.
Only one girl sat silent, her gray eyes bright with scorn—she let them talk
on. Their opinions about his looks, and whether he was conceited or only
properly sensible of his successes, and whether the report was true that he
was going to Japan in the spring, seemed indifferent to her. She sat white and
unsmiling through all their girlish enthusiasm and sentimental talk about this
unknown god and their ideals and their expectations for the future—and
when the photograph, which had been passed from hand to hand, reached
her, she let it fall idly in her lap as though she could not bear to touch it. As
it lay there, a hard look came into her face. When she glanced up, she found
Miss Ronald gazing at her with a curious, petulant expression.
Suddenly she got up and a look of determination was upon her face and
in her eyes. Their talk was all very childish and silly, but she could see that
beneath their half-laughing manner there was a touch of seriousness. This
man, with his fine face and his successes and personal magnetism, had
exercised a strange fascination over them, and most of all over the pretty,
sentimental girl looking with such a puzzled expression at her.
After all, this girl had been good to her. She would do what she could.
She stood tall and straight against the curtains of the window facing the rest
and breathing quickly.
“Yes—I know of him,” she said, answering their unspoken inquiry. “You
think you know him through his books and the reviews and newspaper
notices of him.” Her voice was ringing now and she touched the picture
lightly and scornfully with her finger.
“I know him better than that. I know things of him that will not be told in
newspaper paragraphs and book reviews.” She paused and her face grew
whiter. “You read his stories, and because they are the best of their kind, the
most correct, the most interesting, because his men are the men you like to
know, men who are always as they should be to men, because there is an
atmosphere of refinement and elegance and pleasing conventionality about
them—you think they must be the reflex of himself. O yes! I know—the
very last story—you have all read it—who could be more magnificent and
correct than Roscommon? And you think him like his hero! There is not one
of you but would feel flattered at his attentions, you might easily fall in love
with him—I dare say you would scarcely refuse him—and yet”—she broke
off suddenly.
“There was a girl,” she began after a moment’s hesitation, in a tone from
which all the excitement had died, “a friend of mine, and she loved him.
Perhaps you do not know that before he became famous he lived in a small
Western town—she lived there too. They grew up together, and she was as
proud of him—well, you know probably just how proud a girl can be of a
boy who has played with her and scolded her and tyrannized over her and
protected her and afterward loved her. For he did love her. He told her so a
thousand times and he showed it
 SHE STOPPED AND HER FACE GREW WHITER

to her in a thousand ways. And she loved him! I cannot tell you what he was
to her.” They were all looking curiously at her white face and she tried to
speak still more calmly.
“Well, after a time his ambition—for he was very ambitious and very
talented—made him restless. He wanted to go East—he thought he would
succeed. She let him go freely, willingly. His success was hers, he said.
Everything he was to do was for her, and she let him go, and she told him
then that he could be free. But he was very angry. He said that he would
never have thought of going but to be better worthy of her. He succeeded—
you know—the world knows how well he has succeeded, and the world likes
success, and what wonder that he forgot her. She was handsome—at least
her friends told her so—but she was not like the girls he knows now. She
was not rich, and she had never been used to the life of luxury and
worldliness to which he had so quickly accustomed himself. But,” she went
on, protestingly, as if in reply to some unspoken argument or some doubt
that had assailed her, “she could have been all he wished her. She was quick
and good to look at, and well-bred. She could have easily learned the world’s
ways—the ways that have become so vital to him.”
She stopped, and then went on with an air of careful impartiality, as if
trying to be just, to look at both sides of the question, and her beautiful face
grew whiter with the effort.
“But, of course, she was not like the girls he had met. He used to write to
her at first how disgusted he was when those elegant young ladies would pet
him and make much of him and use him and his time as they did everything
else in their beautiful, idle lives. He did not like it, he said; and then I
suppose it amused him, and then fascinated him. They would not let him
alone. They wanted him to put them in his stories, and he had to go to their
dinners and to the opera with them. He said they wanted someone to ‘show
off’; and at first he resented it, but little by little he came to like it and to find
it the life he had needed and longed for, and to forget and despise the simpler
one he had known in his youth——”
She stopped again and pulled nervously at the silk fringe of the curtain,
and looked at the strained faces of the girls as if asking them whether she
had been just in her way of putting the thing. And then she hurried on.
 “And so she released him. He had not been back in two years—not since
he had first gone away, and she knew it would be easier to do it

“THEY WANTED HIM TO PUT THEM IN HIS STORIES”

before she saw him again. And so when she heard of his success and how
popular he was, and that he was the most talked about of all the younger
authors, she wrote him that she could not be his wife. But she loved him, and
she let him see it in the letter. She bent her pride that far—and she was a
proud girl! She told herself over and over that he was not worthy of her—
that success had made a failure of him, but she loved him still and she let
him see it. She determined to give him and herself that chance. If he still
loved her he would know from that letter that she, too, loved him. Well, his
answer—she told me that his answer was very cold and short. That if she
wished to give him up he knew she must have some good reason.”
Someone stirred uneasily, and gave a breathless sort of gasp.
 “That was hard,” she went on. She was speaking now in an impassive sort
of way. “But that was not the hardest. She saw him again. It was not long
ago——” She stopped and put one hand to her throat. “She had gone away.
She desired to become what he had wished she was, although she could
never be anything to him again, and she was succeeding, and thought that
perhaps she would forget and be happy. But he found out where she was, and
went to her. Something had gone wrong with him. You remember—he was
reported to be engaged to a young girl very well known in society—the
daughter of a senator, and a great beauty. Well, there was some mistake. He
came straight to my friend and told her that he did not know what he had
been doing, that she was the only girl he had ever loved and he asked her
forgiveness. He told her that his life would be worthless and ruined, that his
success would mean less than nothing to him if she did not love him, and he
implored her to be what she had once been to him and to marry him.”
Miss Ronald looked up quickly, and the petulant expression in her eyes
had given place to a look of disdain.
“What did she say then?” she asked.
The girl shook her head, mournfully.
“She could not,” she said, simply. “She would have given her soul to
have been able to say yes, but she could not!”
When the door had quite closed behind her, they sat silent and hushed.
Suddenly Miss Ronald walked over to the window, and picking up the
photograph where it had fallen, face downward, she tore it into little bits.
 AN AQUARELLE

A LLARDYCE felt both aggrieved and bored when he found that his sister
had gone off with a walking-party and was not likely to return for an
hour or two. He had this unwelcome bit of news from the young woman
in cap and gown who had come from the office into the reception-room and
was standing before him, glancing every now and then from his face to the
card she held, with a severely kind look out of her gray eyes.
“I telegraphed her I was in Boston and would be out,” remarked
Allardyce, in an injured tone.
“Yes,” assented the young woman, “Miss Allardyce had left word in the
office that she was expecting her brother, but that as he had not come by the
2.30 or 3.10 train, she had concluded he was detained in Boston, and that if
he did arrive later he was to wait.” She added that he would be obliged to do
so in any case, as there was no express back to Boston for two hours, and
that if he would like to see the college while he waited she would send
someone to take him over it.
But Allardyce seemed so doubtful as to whether he cared to become
better acquainted with the architecture of the college, and so disappointed
about it all, that the kindly senior felt sorry for him and suggested
sympathetically that he “might amuse himself by strolling through the
grounds.” She could not have been over twenty, but she had all the
seriousness and responsibility of an undergraduate, and Allardyce suddenly
felt very young and foolish in her presence and wondered hotly how old she
thought he was, and why she hadn’t told him to “run out and play.” He
decided that her idea was a good one, however, so he took his hat and stick
and wandered down the south corridor to the piazza. Standing there he could
see the lake and the many private boats lying in the bend of the shore, each
fastened to its little dock, and beyond, the boat-house with the class practice-
barges, slim and long, just visible in the cool darkness beneath. He thought it
all looked very inviting, and there was a rustic bench under a big tree half-
way down the hill where he could smoke and get a still better view of the
water.
So he settled himself quite comfortably, lit a cigarette, and looked
gloomily out over the lake. He assured himself bitterly that after having been
abroad for so many years, and after having inconvenienced himself by taking
a boat to Boston instead of a Cunarder to New York—his natural destination
—in order to see his sister, that she was extremely unkind not to have waited
for him. He was deep in the mental composition of a most reproachful note
to her when he discovered that by closing his eyes a little and looking
intently at the Italian Gardens on the opposite side of the water, he could
easily fancy himself at a little place he knew on Lake Maggiore. This
afforded him amusement for a while, but it soon palled on him, and he was
beginning to wonder moodily how he was ever to get through two hours of
the afternoon, when he saw a young girl come out of the boat-house with a
pair of sculls and make her way to one of the little boats. She leaned over it,
and Allardyce could see that she was trying to fit a key into the padlock
which fastened the boat to its dock, and that after several attempts to undo it
she looked rather hopelessly at the lock and heavy chain. He went quickly
down the hill and along the shore. He was suddenly extremely glad that he
was in America, where he could be permitted to speak to and help a girl,
even if a total stranger, without having his assistance interpreted as an insult.
“I beg your pardon,” he said, lifting his hat. “Can I be of any help?”
The girl looked up a little startled, but when she saw the tall, good-
looking youth, she smiled in a relieved sort of way and rose quickly from her
knees.
“Indeed, yes,” she said, without any embarrassment. “I can’t unlock this;
perhaps you can.”
Allardyce took the key, and kneeling down fitted it in its place and turned
it with very little effort. The girl looked rather ruefully at him as he jumped
up.
“Thank you,” she said in a politely distant way. “I don’t see why I could
not have done that. I am very strong in my hands, too.”
Allardyce smiled indulgently. All girls were under the impression that
they were strong. At any rate this one was tremendously pretty, he decided—
much prettier than the stately senior he had encountered up at the college,
and he was glad there were no cap and gown this time. He was aware, of
course, that he ought to lift his hat and move on, and not stand there staring
at her, but his previous solicitude had made him feel sociable.
“Perhaps you will let me put the oars in for you,” he suggested. He was
rather alarmed after he had spoken, but when he glanced at the girl to see
how she had taken his further self-invited assistance he found her looking at
him in a very friendly way. All at once he felt quite elated and at his ease. It
had been a long while since he had had much to do with American girls, and
he concluded that all that had been said about their charming freedom and
cordiality of manner had not been exaggerated. But when he had put the
sculls in the boat it occurred to him that it would not do to presume too far
on that freedom and cordiality, and that if he was not to depart immediately
—and he felt no inclination to do so—he must offer some sort of explanation
of himself.
“I am waiting for my sister,” he remarked genially.
“Oh! your sister,” echoed the girl.
“Yes—Miss Allardyce. Perhaps you are in the same class,” he hazarded.
She looked at him for a moment in a slightly surprised way, and then out
across the water, and Allardyce saw, as she turned her head away from him,
that she was smiling.
“No,” she said slowly, “but I know her quite well.”
“Ah! I’m glad of that,” said the young man, boldly and cheerfully. “Now
I feel quite as if I had been properly introduced! ‘Les amis de nos amis,’ you
know!”
The girl smiled back at him. “I am Miss Brent. By the way, your sister
has the distinction of being the only Allardyce in college. It’s a rather
unusual name.”
“Yes,” assented Allardyce, delightedly. “Scotch, you know.” And then in
a sudden burst of confidence—“My people were Scotch and French. I have
been educated abroad and have come home for the law course at the
University. Awfully glad to be in America again, too, for, after all, I am an
American through and through.” He pulled himself up sharply in some
confusion and amusement at his unusual loquacity.
But the girl before him did not seem to find it strange, and was quite
interested and politely attentive.
“And where is your sister?” she demanded.
“Oh, that’s the essential, and I forgot to mention it,” he replied, laughing
a little and digging his stick into the soft earth. “She’s gone off walking!”
and then he went on insinuatingly and plaintively—“And I don’t know a
soul here—never was here before in my life—and there’s no train to Boston,
and I have to wait two hours for her!”