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NETTER’S
ATLAS OF NEUROSCIENCE
4th Edition

David L. Felten, MD, PhD

Associate Dean of Clinical Sciences
University of Medicine and Health Sciences
New York, New York

M. Kerry O’Banion, MD, PhD

Professor and Vice Chair
Department of Neuroscience
Del Monte Neuroscience Institute
Director of the Medical Scientist Training Program
University of Rochester School of Medicine
Rochester, New York

Mary Summo Maida, PhD

Adjunct Professor of Neuroscience
Department of Neuroscience
Del Monte Neuroscience Institute
University of Rochester School of Medicine
Rochester, New York

Illustrations by
Frank H. Netter, MD
Contributing Illustrators
James A. Perkins, MFA, CMI, FAMI
Carlos A.G. Machado, MD
John A. Craig, MD
1600 John F. Kennedy Blvd.
Ste. 1600
Philadelphia, PA 19103-­2899

NETTER’S ATLAS OF NEUROSCIENCE, FOURTH EDITION ISBN: 978-­0-­323-­75654-­9

Copyright © 2022 by Elsevier, Inc. All rights reserved.

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ABOUT THE AUTHORS

DAVID L. FELTEN, MD, PhD, is currently Associate Dean of Clinical Sciences at the
University of Medicine and Health Sciences. He counsels and advised MD candidates to assist
them in passing the USMLE clinical board exams (Step 2 CK and CS) and the basic sciences
board exam (Step 1). He was formerly Vice President for Research and Medical Director of
the Research Institute at William Beaumont Health System in Royal Oak, Michigan and the
Founding Associate Dean for Research at Oakland University William Beaumont School of
Medicine. He previously served as Dean of the School of Graduate Medical Education at Seton
Hall University in South Orange, New Jersey; the Founding Executive Director of the Susan
Samueli Center for Integrative Medicine and Professor of Anatomy and Neurobiology at the
UC Irvine School of Medicine; the Founding Director of the Center for Neuroimmunology
at Loma Linda School of Medicine; and the Kilian J. and Caroline F. Schmitt Professor and
Chair of the Department of Neurobiology and Anatomy, and Director of the Markey Chari-
table Trust Institute for Neurobiology and Neurodegenerative Diseases and Aging at the Uni-
versity of Rochester School of Medicine in Rochester, New York. He received a bachelor of
science degree from Massachusetts Institute of Technology and MD and PhD degrees (Anat-
omy, Institute of Neurological Sciences) from the University of Pennsylvania School of Med-
icine. Dr. Felten carried out pioneering studies of autonomic innervation of lymphoid organs
and neural-­immune signaling that underlie the mechanistic foundations for psychoneuroim-
munology and many aspects of integrative medicine. Dr. Felten is the recipient of numerous
honors and awards, including the prestigious John D. and Catherine T. MacArthur Foundation
Prize Fellowship, two simultaneous NIH MERIT awards from the National Institutes of Men-
tal Health and the National Institute on Aging, an Alfred P. Sloan Foundation Fellowship, an
Andrew W. Mellon Foundation Fellowship, a Robert Wood Johnson Dean’s Senior Teaching
Scholar Award, the Norman Cousins Award in Mind-­Body Medicine, the Building Bridges of
Integration Award from the Traditional Chinese Medicine Would Foundation, and numerous
teaching awards.
Dr. Felten co-­authored the definitive scholarly text in the field of neural-­immune inter-
actions, Psychoneuroimmunology (Academic Press, 3rd edition, 2001) and was a founding co-­
editor of the major journal in the field, Brain, Behavior and Immunity, with Drs. Robert Ader
and Nicholas Cohen of the University of Rochester School of Medicine. He also is the author
of three editions of Netter’s Neuroscience Flash Cards (fourth edition now in process) and,
with Dr. Mary Maida, the first edition of Netter’s Neuroscience Coloring Book. Dr. Felten is the
author of more than 210 peer-­reviewed journal articles and reviews, many on links between
the nervous system and immune system. His work has been featured on Bill Moyer’s PBS series
and book, “Healing and the Mind,” “20/20,” and many other media venues. He served for over
a decade on the National Board of Medical Examiners, including Chair of the Neurosciences
Committee for the US Medical Licensure Examination. He has served on many Study Sections
for the National Institutes of Health. Dr. Felten was named one of the “30 Most Influential
Neuroscientists Alive Today” by Online Psychology Degree Guide, 2017.

M. KERRY O’BANION, MD, PhD, is Professor and Vice Chair of the Department of
Neuroscience, member of the Del Monte Neuroscience Institute, and Director of the Medical
Scientist Training Program at the University of Rochester School of Medicine in Rochester,
New York. He received a bachelor of science degree and medical and doctoral degrees from
the University of Illinois at Champaign-­Urbana. As a postdoctoral fellow at the University of
Rochester, Dr. O’Banion cloned cyclooxygenase-­2 and discovered its critical role in mediating
inflammation.

v
vi About the Authors

Dr. O’Banion has worked for more than 25 years in the field of neuroinflammation, with
particular interests in how cytokines mediate disease pathology. His current work, funded by
NIH and NASA, focuses on possible beneficial effects of modulating inflammation in Alzhei-
mer disease, the persistent effects elicited by brain irradiation, and the potential risk of neuro-
degenerative disease in individuals exposed to cosmic radiation.
Dr. O’Banion has authored over 120 peer-­reviewed journal articles and reviews on these
and other topics.
Since 1997, Dr. O ‘Banion has co-­directed the Medical Neural Science course (now called
Mind, Brain, and Behavior I) at the University of Rochester School of Medicine, a role he
assumed from Dr. Felten. Dr. O’Banion also helped design and direct Mind, Brain, and Behav-
ior II, a basic science course that accompanies medical clerkships in neurology and psychiatry
for third-­year medical students. He has been program director of the University of Rochester
MSTP since 2000 and has served on multiple national committees related to medical and doc-
toral training.

MARY E.S. MAIDA, PhD, divides her time among research, teaching, mentoring future
medical scientists, mentoring future entrepreneurs, and leading a company she founded
focused on translational research. She is an adjunct faculty member of the Department of
Neuroscience at the University of Rochester School of Medicine, as well as an annually invited
MBA Mentor for Entrepreneurship at the University of Rochester Simon School of Business.
During her academic training she received bachelor of science degrees in microbiology/immu-
nology, as well as finance and operations management. She returned to academic medicine as
a nontraditional student after having raised her children, commencing at the University of
Miami School of Medicine and subsequently at the University of Rochester School of Med-
icine, where she completed a master of science degree in neurobiology and anatomy, and a
doctoral degree in molecular neuroscience under the mentorship of Drs. M. Kerry O ‘Banion,
John Olschowka, Richard Phipps, and Denise Figlewicz.
Because her return to medical and basic sciences training resumed after she raised her
children, her interest turned from microbiology/immunology to the broader field of neuroim-
munology, which seeks to pinpoint how the CNS and immune systems are intricately involved
in a delicate and elaborate dance of connectivity, everyday cross-­talk, more elaborate com-
munication when pathogens or damage is involved, give-­and-­take vs. give-­and-­go between
the two systems (and among other systems), and many more descriptions than words can
adequately capture.
Dr. Maida has received several honors and awards across many disciplines, including
Outstanding Alumni of Distinction Award from Excelsior College, New York State Hall of
Distinction Award, Partners in Lifelong Learning Award, Greater Rochester Excellence in
Achievement Technology Award, Winning Mentor for Mark Ain Business Competition,
43North Semifinalist distinction, and winning finalist in several open invitation awards.
A firm proponent of fostering and living the spirit-­mind-­body relationship that clearly
underlies optimal neural-­immune health, Dr. Maida is devoted to her family, her Catholic
faith, and the privilege of being a Eucharistic Minister. She is honored to be a community vol-
unteer and board member for The EquiCenter, which provides equine therapy and other pro-
grams for US military veterans, developmentally and physically disabled children, and their
families. She is a member of the board of trustees for Daystar Kids, which provides early edu-
cation and respite care for medically fragile children and their families. Dr. Maida also serves
as a board member for Boots on the Court, which brings weekend tennis fun to military bases
across the United States. She has founded a scholarship fund at Excelsior College, named in
honor of her parents. Dr. Maida is a fun-­loving and enthusiastic competitor in tennis, pickle-
ball, golf, cross-­fitness training, and equestrianism and a lover of the arts as a patron, musician,
and active performer.
 DEDICATION

In memory of Walle J.H. Nauta, MD, PhD, Institute Professor of

Neuroscience at the Massachusetts Institute of Technology
A distinguished, brilliant, and pioneering neuroscientist
An outstanding and inspirational teacher
A kind, supportive, insightful, and gracious mentor
An incredible role model and human being
and
To my wife, Mary E.S. Maida, PhD
A wonderful wife, partner, and friend
My inspiration and motivation
A superb researcher, teacher, scientific innovator, and business
leader
A woman who has it all—brains, beauty, kindness, and ac-
complishment
David L. Felten

In memory of Teresa Bellofatto, Joe Summo, Robert Summo, and

Nicholas Summo
Beloved family and friends who faced overwhelming health
challenges with determination and an unwaivering joy
for life.
Daily, they demonstrated the strength of the human spir-
it and unshakable human kindness, even in the face of
daunting physiological challenges.
They taught us that it is possible to live life fully, to laugh,
and to be the best version of humanity in spite of the ab-
sence of a cure.
May their memory forever inspire us to strive for a better un-
derstanding of the molecular, physiological, and systemic
mechanisms that underlie health and disease.
David L. Felten
Mary E.S. Maida

vii
viii Dedication

In memory of Fred Coyner and Nellie Rogers, sweet souls

changed in old age, who turned my attention to brain dys-
function and neuroscience research,
and
To my parents, Terry O’Banion and Mary Rogers, who both
served as educators, teaching me the values of service in the
name of learning and inspiring me to pursue my love of na-
ture despite the piles of fossils, the stench of chemistry exper-
iments, and some small fires they may still not know about,
and
To my spouse, Dorothy Petrie, also an educator, for her love,
her unconditional support through late nights and weekends
of writing and looming deadlines, and her consistent remind-
er that the opportunity to do science is a gift to be shared with
all.
M. Kerry O’Banion

In honor of my mother, Mary D. Summo, MS, who endlessly

gave her love, time, talent, intellect, and wise advice to the 6
of us, her children, and her 10 grandchildren, and still does to
this very day. Thank you, Mom.
and
In memory of my father, Dr. Anthony J. Summo, a true Re-
naissance man who embraced and promoted the reality of
psychobiology, biopsychology, and PTSD well before they
became accepted into mainstream medicine. And whose
Ciba-­Geigy Netter “green books” with the flip-­over acetate
pages sitting on our living room coffee table fascinated me
and formed the basis of my love for science and medicine,
and
To my husband, David L. Felten, MD, PhD, and my sons
­Michael and Matthew Maida, without whose love, encour-
agement, and support I would never be the woman I am
­today. In the spirit and words of our ancestors’ family motto:
Avanti! Sempre Avanti!
Mary E.S. Maida
ACKNOWLEDGMENTS

For decades, Dr. Frank Netter’s beautiful and informative artwork has provided the visual basis
for understanding anatomy, physiology, and relationships of great importance in medicine.
Generations of physicians and healthcare professionals have “learned from the master” and
have carried Dr. Netter’s legacy forward through their own knowledge and contributions to
patient care. There is no way to compare Dr. Netter’s artwork to anything else because it stands
in a class of its own. For many decades, the Netter Collection volume on the nervous system
has been a flagship for the medical profession and for students of neuroscience. It was a great
honor to provide the framework, organization, and new information for the updated first,
second, and third editions, and now the fourth edition, of Netter’s Alas of Neuroscience. The
opportunity to make a lasting contribution to the next generation of physicians and healthcare
professionals is perhaps the greatest honor anyone could receive.
I also gratefully acknowledge Walle J.H. Nauta, MD, PhD, whose inspirational teaching
of the nervous system at MIT contributed to the organizational framework for this atlas.
Professor Nauta always emphasized the value of an overview; the plates in the beginning of
Section II, Regional Neurosciences, on the conceptual organization of sensory, motor, and
autonomic systems, especially reflect his approach. I am particularly honored to contribute to
these updated editions of Netter’s Atlas of Neuroscience because I first learned neurosciences
as an undergraduate in Professor Nauta’s laboratory at MIT through his personal mentorship,
masterful insights, and explanations—using the first Nervous System “green book” volume by
Dr. Frank Netter. It is my hope that continuing generations of students can benefit from the
legacy of this wonderful teacher and great scientist.
I thank our outstanding artist and medical illustrator, James Perkins, MS, MFA, for his
clear, creative, and beautiful contributions to this revised atlas. Jim is an excellent anatomist,
with great insights for bringing otherwise complex systems and mechanisms into understand-
able illustrations. His accomplishments have received wide acclaim and many awards.
Special thanks go to the outstanding editors at Elsevier Clinical Solutions: Marybeth Thiel,
Senior Content Development Specialist, Elyse O’Grady, Senior Content Strategist, and Carrie
Stetz, Senior Project Manager. They helped guide the process of the fourth edition and gave
us the latitude to introduce new components, such as the new molecular plates (especially in
Chapter 1 ), new additions to forebrain anatomy, a new chapter on Global Neurological Func-
tions, and new clinical correlations.
I also acknowledge and thank my friend, colleague, and co-­author of this atlas, Kerry
O’Banion. His insights, spanning from the molecular details to the systemic interactions of neu-
ral systems, are amazing. For more than 30 years we have had the privilege of working together,
both in teaching and research arenas. As one of the premier experts on brain inflammation and
a highly knowledgeable molecular neurobiologist, his expertise has been invaluable.
Continuing thanks also go to Ralph Jozefowicz, MD, the consummate neurology educator.
It was a delight to work with him in the University of Rochester medical neurosciences course
and to learn from him through his amazing insights into clinical neurology, and his ability to
make those insights come alive for the benefits of both his students and colleagues.
And finally, to my wife Mary (Mary E.S. Maida), I again thank you for your unwavering
love and your support and encouragement to continue this challenging project, and for your
patience with the long hours and seemingly endless clutter of papers and folders you tolerated
along the way. Your expertise as a molecular neuroscientist and your outstanding ability to take
complex plates and explanations and help to clarify and re-­express them in understandable
terms for the readers has been a valuable addition.
David L. Felten

ix
x Acknowledgments

First, I thank David Felten not only for the opportunity to contribute to this fourth edition
but also for his long-­standing support, encouragement, and friendship. Second, I thank Ralph
Jozefowicz, MD, Professor of Neurology at the University of Rochester, who together with
David Felten served as outstanding mentors for how to teach neuroscience. Finally, I am
indebted to my professional colleagues and students, past and current, for the opportunity to
learn new things as we pursue science together.
M. Kerry O’Banion

To this very day, I remember my fascination with the original Netter “green books” that sat
prominently displayed on the coffee table in the living room of my childhood home. I would
sit for hours turning each page, which added another colorful layer to the beauty and intricacy
of the human body’s anatomy and physiology—and day after day trying to recall what I saw, let
along make sense of it all. These original tomes that contained the original illustrations of Dr.
Frank Netter in part formed the basis of my interest in, and pursuit of, science and medicine.
I thank my parents, Dr. Anthony J. and Mary D. Summo, for having provided us with such
an enriched environment at home and for encouraging and allowing us to pursue our dreams.
I thank the University of Rochester School of Medicine and Dentistry Graduate Program
in Neuroscience for providing me the opportunity to pursue my dreams as a nontraditional
student. I also extend my deepest gratitude to my mentors M. Kerry O’Banion, MD, PhD, John
Olschowka, PhD, Richard Phipps, PhD, and Denise Figlewicz, PhD, whom I have the privilege
to know as friends as well as research colleagues.
Finally, I express my deepest gratitude to my husband, David Felten, and to my sons
Michael and Matthew Maida—my biggest cheerleaders in life—who help me achieve far more
than I believe I am capable of achieving and who adeptly help to keep my immune system
healthy with the daily dose of humor and laughter we share.
Mary E.S. Maida
PREFACE

As in the three prior editions, Netter’s Atlas of Neuroscience, 4th edition, combines
the richness and beauty of Dr. Frank Netter’s illustrations with key information about
the many regions and systems of the brain, spinal cord, and periphery. Jim Perkins
and John Craig have contributed outstanding illustrations to complement the original
Netter illustrations.
The first edition included cross-­sectional illustrations through the spinal cord and
brainstem, as well as coronal and axial (horizontal) sections. The second edition built
on the first edition with several additional illustrations and extensive new imaging
using computed tomography (CT), magnetic resonance imaging (MRI), both T1-­
and T2-­weighted, positron emission tomography (PET) scanning, functional MRI
(fMRI), and diffusion tensor imaging (DTI), which provides pseudocolor images of
central axonal commissural, association, and projection pathways. Full-­plate MRIs
were included for direct side-­by-­side comparisons with Dr. John Craig’s illustrations
of the brainstem cross sections and axial and coronal sections. More than 200 “clinical
boxes” were added to offer succinct clinical discussions of the functional importance
of key topics. These clinical discussions were intended to assist the reader in bridg-
ing the anatomy and physiology depicted in each relevant plate to important related
clinical issues.
The third edition added many new components. Chapter 1, in the Overview
section, “Neurons and Their Properties,” was extensively revised and reorganized.
Approximately 15 new plates on molecular and cellular topics such as astrocytes,
microglia, oligodendrocytes, axonal transport, growth and trophic factors, nuclear
transcription factors, neuronal stem cell biology, and others were added. Almost 50
new plates were added throughout the atlas. Many of these plates reflect Jim Perkins’
outstanding ability to represent molecular and cellular concepts in lucid and beautiful
form. We added histological cross sections of the spinal cord and brainstem to match
the previous illustrations. We also added brainstem sections illustrating the major
vascular syndromes of the medulla, pons, and midbrain. Many photomicrographs
were introduced to plates throughout the atlas to add clarity to the illustrations. The
third edition received three book awards: (1) Highly Commended, British Medical
Association (2017); (2) Award of Merit, Association of Medical Illustrators (2016);
and (3) Top 10 Neuroscience Textbooks (#2), Wiki Award (2018).
This fourth edition of this Atlas adds significant components that were not present
in earlier editions, and are often are minimally covered in other sources. The Systemic
Neurosciences Section has a new chapter, Chapter 17, Global Brain Functions. This
chapter includes several plates on dementias, neuropsychiatric disorders, traumatic
brain injury (TBI) and chronic traumatic encephalopathy (CTE), aphasias, nondomi-
nant hemispheric functions and dysfunctions, brain substrates of addictive behaviors,
consciousness and coma, and aging and the nervous system.
Chapter 16, on Autonomic-­Hypothalamic-­Limbic Systems, includes new plates on
circumventricular organs and their functions, hypothalamic regulation of sleep, bed
nucleus of the stria terminalis, insular cortex, prefrontal cortex, and the functional
role of major limbic and cortical regions.

xi
xii Preface
Several other new plates include molecular techniques for
studying neurons, genetic models for studying neurons and their
diseases, normal pressure hydrocephalus, postnatal and adult
neurogenesis, fetal alcohol syndrome, endogenous opioid sys-
tems, endogenous cannabinoid systems, somatosensory nuclei
neuronal organization (dorsal column and thalamic nuclei),
mechanisms of migraine headaches, neural mechanisms of swal-
lowing (central and peripheral), surgical approaches to move-
ment disorders, and others.
The fourth edition retains the organization of the previous
three editions: (I) Overview, (II) Regional Neurosciences, and
(III) Systemic Neurosciences. Further subdivisions in these
sections into component chapters aides in ease of use. We have
provided succinct figure legends to point out some of the major
functional aspects of each illustration, particularly as they relate
to problems that a clinician may encounter in the assessment of a
patient with neurological symptoms. We believe that it is import-
ant for an atlas of the depth and clarity of Netter’s Atlas of Neuro-
science to let the illustrations provide the focal point for learning,
not long and detailed written explanations that constitute a full
textbook in itself. However, the figure legends, combined with the
excellent illustrations and the clinical discussions, provide con-
tent for a thorough understanding of the basic components, orga-
nization, and functional aspects of the region or system under
consideration.
Netter’s Atlas of Neuroscience, 4th edition provides a compre-
hensive view of the entire nervous system, including the periph-
eral nerves and their target tissues, central nervous system,
ventricular system, meninges, cerebral vascular system, develop-
mental neuroscience, and neuroendocrine regulation. We have
provided substantial but not exhaustive details and labels to per-
mit the reader to understand the basics of human neuroscience,
including the nervous system information usually presented in
medical neurosciences courses, the nervous system compo-
nents of anatomy courses, and neural components of physiology
courses in medical school.
We are confronted with an era of rapid changes in health-
care and exploding knowledge in all fields of medicine, par-
ticularly with the continuing revolution in molecular biology.
Medical school curricula are under enormous pressure to add
more and more non-­basic sciences components. It has become
dangerously tempting to emphasize high-­ technology tests,
readouts, imaging, and automated EMR drop-­down menus as
a substitute for the real foundations of medical practice—the
history and the physical examination. Many medical schools
strive to “decompress” the intensity of teaching and to incor-
porate more problem-­based and small group teaching exercises
(which we applaud), with a goal of hastening students into clin-
ical experiences.
In the long run, much of the additional information crammed
into the medical curriculum has come at the expense of the basic
sciences, particularly anatomy, physiology, histology, and embry-
ology. We believe that there is a fundamental core of knowledge
that every physician must know. It is not sufficient for a medical
student to learn only 3 of the 12 cranial nerves, their functional
importance, and their clinical applications, as “representative
examples,” in order to further reduce the length of basic sciences
courses. Although medical students are always anxious to get
into the clinics and see patients, they need a substantial fund of
knowledge to be even marginally competent, particularly if they
strive to apply evidence-­based practice, instead of rote memory,
to patient care.
ORGANIZATION OF NETTER’S ATLAS OF
NEUROSCIENCE
The Overview section of the atlas is a presentation of the basic
components and organization of the nervous system, a “view
from 30,000 feet”; this view is an essential foundation for under-
standing the details of regional and systemic neurosciences. The
Overview includes chapters on neurons and their properties, an
introduction to the forebrain, brainstem and cerebellum, spinal
cord, meninges, ventricular system, cerebral vasculature, and
developmental neuroscience.
The Regional Neurosciences section provides the structural
components of the peripheral nervous system, the spinal cord,
the brainstem and cerebellum, and the forebrain (diencephalon
and telencephalon). We begin in the periphery and move from
caudal to rostral. The peripheral nervous system section includes
details about the somatic and autonomic innervation of periph-
eral nerves; we do not leave the learner at the boundary of CNS
and PNS, and hope that they can find out about peripheral and
autonomic nerves from a gross anatomy course. This detailed
regional understanding is necessary to diagnose and understand
the consequences of a host of lesions whose localization depends
on regional knowledge—this includes strokes, local effects of
tumors, injuries, specific demyelinating lesions, inflammatory
reactions, a host of neuropathies, and many other localized prob-
lems. In this section many of the clinical correlations assist the
reader in integrating a knowledge of the vascular supply with
the consequences of infarcts (e.g., brainstem syndromes), which
requires a detailed understanding of brainstem anatomy and
relationships.
The Systemic Neurosciences section evaluates the sensory
systems, motor systems (including cerebellum and basal ganglia,
acknowledging that they also are involved in many other spheres
of activity besides motor), autonomic-­hypothalamic-­limbic sys-
tems (including neuroendocrine), and global neural functions
and dysfunctions, now named as a fourth section. We have orga-
nized each sensory system, when appropriate, with a sequential
presentation of reflex channels, cerebellar channels, and lemnis-
cal channels, reflecting Professor Nauta’s conceptual organization
of sensory systems. For the motor systems, we begin with lower
motor neurons and then show the various systems of upper motor
neurons followed by cerebellum and basal ganglia, whose major
motor influences are ultimately exerted through regulation of
upper motor neuronal systems. For the autonomic-­hypothalamic-­
limbic system, we begin with the autonomic preganglionic and
postganglionic organization and then show brainstem and hypo-
thalamic regulation of autonomic outflow, and finally limbic and
cortical regulation of the hypothalamus and autonomic outflow
The newly added Chapter 17 addresses global functions and
dysfunctions of the nervous system. The systemic neurosciences
constitute the basis for carrying out and interpreting the neuro-
logical examination. We believe that it is necessary for a student
of neuroscience to understand both regional organization and
systemic organization. Without this dual understanding, clinical

evaluation of a patient with a neurological problem would be
incomplete.
In a discipline as complex as the neurosciences, the acquisition
of a solid organization and understanding of the major regions
and hierarchies of the nervous system is not just a “nice idea”
or a l­uxury—it is essential. The fact that this approach has been
stunningly successful for our students in a course organized and
taught for 35 years by both authors of the first edition (David L.
Felten, MD, PhD, and Ralph F. Jozefowicz, MD), and by M. Kerry
­O’Banion, MD, PhD, and Ralph F. Jozefowicz, MD, for more than
15 years is an added benefit but is not why we organized this Atlas
as we have. A working competence for students in basic and clinical
Preface xiii
neuroscience, and its value for delivering outstanding patient care,
are always the main focus of our efforts. We truly value success
in this arena. Knowledgeable and highly competent students are
the finest outcome of our teaching that we could ever achieve. We
hope that our students will come to appreciate both the beauty and
the complexity of the nervous system and be inspired to contrib-
ute to the knowledge and functional application to patients of this
greatest biological and medical frontier, which constitutes the sub-
strate for human behavior and our loftiest human aspirations and
endeavors.
David L. Felten
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ABOUT THE ARTISTS

FRANK H. NETTER, MD was born in 1906 in New York City. He studied art at the
Art Students League and the National Academy of Design before entering medical school at
New York University, where he received his medical degree in 1931. During his student years,
Dr. Netter ‘s notebook sketches attracted the attention of the medical faculty and other physi-
cians, allowing him to augment his income by illustrating articles and textbooks. He continued
illustrating as a sideline after establishing a surgical practice in 1933, but he ultimately opted to
give up his practice in favor of a full-­time commitment to art. After service in the United States
Army during World War II, Dr. Netter began his long collaboration with the CIBA Pharma-
ceutical Company (now Novartis Pharmaceuticals). This 45-­year partnership resulted in the
production of the extraordinary collection of medical art so familiar to physicians and other
medical professionals worldwide.
In 2005, Elsevier, Inc. purchased the Netter Collection and all publications from Icon
Learning Systems. There are now more than 50 publications featuring the art of Dr. Netter
available through Elsevier, Inc. (in the US: www.us.elsevierhealth.com/Netter; outside the US:
www.elsevierhealth.com).
Dr. Netter’s works are among the finest examples of the use of illustration in the teaching
of medical concepts. The 13-­book Netter Collection of Medical Illustrations, which includes the
greater part of the more than 20,000 paintings created by Dr. Netter, became and remain one
of the most famous medical works ever published. Dr. Netter’s Atlas of Human Anatomy, first
published in 1989, presents the anatomical paintings from the Netter Collection. Now trans-
lated into 16 languages, it is the anatomy atlas of choice among medical and health professions
students the world over.
The Netter illustrations are appreciated not only for their aesthetic qualities, but, more
important, for their intellectual content. As Dr. Netter wrote in 1949, “. . . clarification of a
subject is the aim and goal of illustration. No matter how beautifully painted, how delicately
and subtly rendered a subject may be, it is of little value as a medical illustration if it does not
serve to make clear some medical point.” Dr. Netter’s planning, conception, point of view, and
approach are what inform his paintings and what makes them so intellectually valuable.
Frank H. Netter, MD, physician and artist, died in 1991.
Learn more about the physician-­artist whose work has inspired the Netter Reference col-
lection: http://www.netterimages.com/artist/netter.htm.

CARLOS MACHADO, MD was chosen by Novartis to be Dr. Netter’s successor. He con-

tinues to be the main artist who contributes to the Netter Collection of medical illustrations.
Self-­taught in medical illustration, cardiologist Carlos Machado has contributed meticu-
lous updates to some of Dr. Netter’s original plates and has created many paintings of his own
in the style of Netter as an extension of the Netter collection. Dr. Machado’s photorealistic
expertise and his keen insight into the physician/patient relationship inform his vivid and
unforgettable visual style. His dedication to researching each topic and subject he paints places
him among the premier medical illustrators at work today.
Learn more about his background and see more of his art at: http://www.netterimages.
com/artist/machado.htm.

JAMES A. PERKINS, CMI, FAMI is Professor of Medical Illustration at Rochester Insti-

tute of Technology (RIT) where he teaches courses in anatomy, digital illustration, and scien-
tific visualization. He is a Board Certified Medical Illustrator and Fellow of the Association of
Medical Illustrators.

xv
xvi About The Artists

An expert in visualizing biological processes, Professor Perkins has illustrated more than 40
medical textbooks, particularly in the areas of pathology, physiology, and molecular biology.
For more than 20 years, he has been the sole illustrator of the “Robbins” series of pathology
texts published by Elsevier, including the flagship of the series, Robbins and Cotran Pathologic
Basis of Disease. He has been a contributor to the Netter Collection since 2001, creating most
of the new art for Netter’s Atlas of Human Physiology, Netter’s Illustrated Pharmacology, and
Netter’s Atlas of Neuroscience and contributing to many other titles.
Professor Perkins received a bachelor degree in biology and geology from Cornell Univer-
sity and studied vertebrate paleontology and anatomy at the University of Texas and University
of Rochester. He received a Master of Fine Arts degree in medical illustration from RIT and
spent several years working in medical publishing and the medical legal exhibit field before
returning to RIT to join the faculty. Learn more about his background and see more of his art
at: http://www.netterimages.com/artist/perkins.htm
CONTENTS

Section I OVERVIEW OF THE NERVOUS SYSTEM

1 Neurons and Their Properties �������������������������������������������� 3

Anatomical and Molecular Properties ������������������������������������������ 4
Electrical Properties �������������������������������������������������������������������� 23
Neurotransmitter and Signaling Properties �������������������������������� 38
2 Skull and Meninges ����������������������������������������������������������� 47
3 Brain ����������������������������������������������������������������������������������� 53
4 Brainstem and Cerebellum ����������������������������������������������� 73
5 Spinal Cord ������������������������������������������������������������������������ 78
6 Ventricles and the Cerebrospinal Fluid ���������������������������� 85
7 Vasculature ������������������������������������������������������������������������ 94
Arterial System ��������������������������������������������������������������������� 95
Venous System ������������������������������������������������������������������� 119
8 Developmental Neuroscience ����������������������������������������� 128

Section II REGIONAL NEUROSCIENCE

9 Peripheral Nervous System �������������������������������������������� 161

Introduction and Basic Organization ���������������������������������������� 162
Somatic Nervous System ��������������������������������������������������������� 180
Autonomic Nervous System ����������������������������������������������������� 204
10 Spinal Cord ���������������������������������������������������������������������� 239
11 Brainstem and Cerebellum ��������������������������������������������� 254
Brainstem Cross-­Sectional Anatomy ��������������������������������������� 255
Cranial Nerves and Cranial Nerve Nuclei ��������������������������������� 270
Reticular Formation ������������������������������������������������������������������ 287
Cerebellum �������������������������������������������������������������������������������� 291
xvii
xviii Contents

12 Diencephalon ������������������������������������������������������������������� 294

13 Telencephalon ������������������������������������������������������������������ 299

Section III SYSTEMIC NEUROSCIENCE

14 Sensory Systems ������������������������������������������������������������� 361

Somatosensory Systems ���������������������������������������������������������� 362
Trigeminal Sensory System ������������������������������������������������������ 372
Sensory System for Taste ��������������������������������������������������������� 376
Auditory System ����������������������������������������������������������������������� 378
Vestibular System ��������������������������������������������������������������������� 385
Visual System ��������������������������������������������������������������������������� 388
15 Motor Systems ���������������������������������������������������������������� 401
Lower Motor Neurons ��������������������������������������������������������������� 402
Upper Motor Neurons ��������������������������������������������������������������� 405
Cerebellum �������������������������������������������������������������������������������� 420
Basal Ganglia ���������������������������������������������������������������������������� 427
16 Autonomic-­Hypothalamic-­Limbic Systems��������������������� 434
Autonomic Nervous System ����������������������������������������������������� 435
Hypothalamus and Pituitary������������������������������������������������������ 437
Limbic System �������������������������������������������������������������������������� 465
Olfactory System ���������������������������������������������������������������������� 479

Section IV GLOBAL BRAIN FUNCTIONS

17 Global Brain Functions����������������������������������������������������� 483

VIDEO CONTENTS

3.­1 Sagittal Brain

3.­2 Axial DT Imaging with Color Depiction of Pathways
6.­1 Axial Sections with Surface Anatomy
6.2 Brain: High-­Resolution Axial T2
7.1 Circle of Willis: Left to Right
7.­2 Circle of Willis: Head to Foot
7.­3 Carotid Artery: Left to Right
7.­4 Carotid Artery: Head to Foot
7.­5 Brain: Magnetic Resonance Venogram, Left to Right
7.­6 Brain: Magnetic Resonance Venogram, Head to Foot
  13.­1 Axial Brain
  13.­2 Coronal Brain
 13.­3 Brain: Axial from Axial, Rotation Left to Right
 13.­4 Brain: Sagittal from Sagittal, Rotation Left to Right

xix
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Section I OVERVIEW OF THE
NERVOUS SYSTEM

1. Neurons and Their Properties

Anatomical and Molecular Properties

Electrical Properties

Neurotransmitter and Signaling Properties

2. Skull and Meninges

3. Brain

4. Brainstem and Cerebellum

5. Spinal Cord

6. Ventricles and the Cerebrospinal Fluid

7. Vasculature

Arterial System

Venous System

8. Developmental Neuroscience

1
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 1
NEURONS AND
THEIR PROPERTIES

 Anatomical and Molecular Properties 1.24 Action Potentials

1.1 Neuronal Structure 1.25 Propagation of the Action Potential

1.2 3D Neuronal Structure and Neurohistology 1.26 Node of Ranvier and Conduction Velocity

1.3 Neuronal Ultrastructure 1.27 Classification of Peripheral Nerve Fibers by Size and
Conduction Velocity
1.4 Types of Synapses
1.28 Electromyography and Conduction Velocity Studies
1.5 Neuronal Cell Types
1.29 Presynaptic and Postsynaptic Inhibition
1.6 Molecular Techniques for Studying Neurons
1.30 Spatial and Temporal Summation
1.7 Genetic Models for Studying Neurons and Their Disorders
1.31 Normal Electrical Firing Patterns of Cortical Neurons and
1.8 Glial Cell Types the Origin and Spread of Seizures
1.9 Astrocyte Biology 1.32 Electroencephalography
1.10 Microglial Biology 1.33 Types of Electrical Discharges in Generalized Seizures and
Sites of Action of Antiseizure Medications
1.11 Oligodendrocyte Biology
1.34 Visual and Auditory Evoked Potentials
1.12 Neuronal Growth Factors and Trophic Factors

1.13 Stem Cells in the CNS: Intrinsic and Extrinsic Mechanisms Neurotransmitter and Signaling Properties
1.14 Stem Cell Therapy 1.35 Synaptic Morphology

1.15 Blood-­Brain Barrier 1.36 Mechanisms of Molecular Signaling in Neurons

1.16 Inflammation in the CNS 1.37 Neurotransmitter Release

1.17 Axonal Transport in the CNS and PNS
1.18 Myelination of CNS and PNS Axons
1.19 Development of Myelination and Axon Ensheathment
1.38 Multiple Neurotransmitter Synthesis, Release, and
Signaling from Individual Neurons
1.39 Neuronal Signal Transduction: Local Regulation of
Synaptic Strength at an Excitatory Synapse

Electrical Properties 1.40 Neuronal Signal Transduction: Regulation of Nuclear

Signaling
1.20 Neuronal Resting Potential
1.41 Glucocorticoid Regulation of Neurons and Apoptosis
1.21 Neuronal Membrane Potential and Sodium Channels
1.42 Chemical Neurotransmission
1.22 Graded Potentials in Neurons

1.23 Mechanisms of Excitatory Postsynaptic Potentials and

Inhibitory Postsynaptic Potentials
3
4 Overview of the Nervous System
ANATOMICAL AND MOLECULAR PROPERTIES
1.1 NEURONAL STRUCTURE
Neuronal structure reflects the functional characteristics of the
individual neuron. Incoming information is projected to a neuron
mainly through axonal terminations on the cell body and den-
drites. These synapses are isolated and are protected by astrocytic
processes. The dendrites usually make up the greatest surface
area of the neuron. Some protrusions from dendritic branches
(dendritic spines) are sites of specific axodendritic synapses. Each
specific neuronal type has a characteristic dendritic branching
pattern called the dendritic tree, or dendritic arborizations. The
neuronal cell body varies from a few micrometers (μm) in diame-
ter to more than 100 μm. The neuronal cytoplasm contains exten-
sive rough endoplasmic reticulum (rough ER), reflecting the
massive amount of protein synthesis necessary to maintain the
neuron and its processes. The Golgi apparatus is involved in pack-
aging potential signal molecules for transport and release. Large
numbers of mitochondria are necessary to meet the huge energy
demands of neurons, particularly those related to the mainte-
nance of ion pumps and membrane potentials. Each neuron has
a single (or occasionally no) axon, usually emerging from the cell
body or occasionally from a dendrite (e.g., some hippocampal CA
neurons). The cell body tapers to the axon at the axon hillock, fol-
lowed by the initial segment of the axon, which contains the Na+
channels, the first site where action potentials are initiated. The
axon extends for a variable distance from the cell body (up to 1 m
or more). An axon larger than 1 to 2 μm in diameter is insulated
by a sheath of myelin provided by oligodendroglia in the central
nervous system (CNS) or Schwann cells in the peripheral nervous
system (PNS). An axon may branch into more than 500,000 axon
Dendrites
Dendritic spines
(gemmules)
Rough endoplasmic
reticulum (Nissl substance)
Ribosomes
Mitochondrion
Nucleus Axon
Nucleolus
Axon hillock
Initial segment of axon
Neurotubules
Golgi apparatus
Lysosome
Cell body (soma)
Axosomatic synapse
Glial (astrocyte) process
Axodendritic synapse
terminals and may terminate in a highly localized and circum-
scribed zone (e.g., primary somatosensory axon projections used
for fine discriminative touch) or may branch to many disparate
regions of the brain (e.g., noradrenergic axonal projections of the
locus coeruleus). A neuron whose axon terminates at a distance
from its cell body and dendritic tree is called a macroneuron or
a Golgi type I neuron; a neuron whose axon terminates locally,
close to its cell body and dendritic tree, is called a microneuron,
a Golgi type II neuron, a local circuit neuron, or an interneuron.
There is no typical neuron because each type of neuron has its
own specialization. However, pyramidal cells and lower motor
neurons are commonly used to portray a so-­called typical neuron.
CLINICAL POINT
Neurons require extraordinary metabolic resources to sustain their
functional integrity, particularly that related to the maintenance of
membrane potentials for the initiation and propagation of action
potentials. Neurons require aerobic metabolism for the generation
of adenosine triphosphate (ATP) and have virtually no ATP reserve,
so they require continuous delivery of glucose and oxygen, generally
in the range of 15% to 20% of the body’s resources, which is a dis-
proportionate consumption of resources. During starvation, when
glucose availability is limited, the brain can shift gradually to using
beta-­hydroxybutyrate and acetoacetate as energy sources for neuronal
metabolism; however, this is not an instant process and is not available
to buffer acute hypoglycemic episodes. An ischemic episode of even 5
minutes, resulting from a heart attack or an ischemic stroke, can lead
to permanent damage in some neuronal populations such as pyramidal
cells in the CA1 region of the hippocampus. In cases of longer ischemia,
widespread neuronal death can occur. Because neurons are postmitotic
cells, except for a small subset of interneurons, dead neurons are not
replaced. One additional consequence of the postmitotic state of most
neurons is that they are not sources of tumor formation. Brain tumors
derive mainly from glial cells, ependymal cells, and meningeal cells.
 Neurons and Their Properties 5

Dendrites
Axon

Purkinje neurons Dendrite Axon Dendrite

A. Spinal cord lower motor neuron.
Nissl substance (rough endoplasmic
reticulum) stains purple. The
nucleolus is stained in the clear
nucleus. Cresyl violet stain.
B. Cerebellar Purkinje neurons.
Large dendrites branch from the cell
body. Intraneuronal neurofibrils and
background neural processes
(neuropil) stain densely. Silver stain.
C. Spinal cord neuron. Many large
dendrites emerge from the cell body,
and the smaller axon extends from
the large neuron at the 3 o'clock
position. Ink stain.
D. Reticular formation neuron.
Heavy metal impregnation of
selective neurons revealing the cell
body and all processes. Golgi stain.

Neuronal
cell bodies

Interface
E. Spinal cord ventral horn. Neuronal F. Superior mesenteric-celiac G. Superior mesenteric-celiac H. Superior mesenteric-celiac
cell bodies and the tangle of axons ganglion. Glyoxylic acid ganglion. Immunohistochemical stain ganglion. Acetylcholinesterase
and dendrites seen in the neuropil of fluorescence histochemistry demonstrating the presence of (AChE) histochemical stain
the ventral horn. The interface demonstrating noradrenergic cell interleukin-2 receptors in these demonstrating the presence of this
between gray matter and white bodies. neurons. enzyme, which cleaves acetylcholine
matter is conspicuous. Cajal stain. to choline and acetyl coenzyme A.

Parenchyma

Astrocytes End feet

Vasculature

I. Neurons in superior
mesenteric-celiac ganglion stained
with fluorogold, which has been
transported retrogradely from an
injection site into immune tissue
innervated by NA fibers from these
NA ganglion cells in a rat.
J. Immunocytes in the marginal zone K. CNS astrocytes with processes
of the spleen. In-situ hybridization
demonstrating the presence of
corticotropin-releasing factor (CRF)
gene in these darkly staining
nonneuronal cells. CRF is an
important releasing factor secreted by
neurons into the hypophyseal portal
system in the hypothalamus. CRF
also is present in, and secreted by,
nonneuronal cells in the immune
system.
extending into the gray matter and
“end feet” extending to the surface of
CNS blood vessels with a
blood-brain barrier. Silver stain.
L. Axons from NA sympathetic
postganglionic neurons innervating
the vasculature and parenchyma (T
lymphocyte zone and marginal zone)
of the spleen. Immunohistochemical
stain for tyrosine hydroxylase (TH),
the rate-limiting enzyme for the
synthesis of catecholamines from
tyrosine.

Myelin
sheaths
Nodes of
Ranvier

M. Same NA axons as in part L.
Stained for norepinephrine with
glyoxylic acid fluorescence
histochemistry.
N. Same NA axons as in part M, with O. Myelinated fascicles in a P. Axons in a peripheral nerve cut in
added injection of gel ink (dark blue) peripheral nerve cut in cross-section. longitudinal section. Oil red O stain
to demonstrate the vasculature. Gel Osmic acid stain reveals myelinated demonstrating longitudinal axons
ink also is picked up by macrophages axons but not unmyelinated axons. surrounded by myelin sheaths
in the marginal zone. (light-colored areas), with
conspicuous appositions of sheaths at
nodes of Ranvier.

1.2 3D NEURONAL STRUCTURE AND

NEUROHISTOLOGY
6 Overview of the Nervous System
Reprinted with permission from Felten DL, Peterson RG, McConnell J, Wood JG. X-ray analytical electron microscopy of central serotonergic
neurons. J Histochem Cytochem 30(8):774–779, 1982.
1.3 NEURONAL ULTRASTRUCTURE
Neuron of nucleus raphe obscurus, standard transmission elec-
tron microscopy. The nucleolus (nc) is prominent and the chro-
matin is dispersed throughout the nucleus (n). The bounding
nuclear envelope (ne) follows an uneven contour. Within the
cytoplasm of the cell body are Nissl bodies (nb) with their char-
acteristic lamellar organization of rough endoplasmic reticulum,
scattered ribosomes, arrays of Golgi apparatus (ga), mitochondria
(m), and dense particles (large arrows). These dense particles
demonstrate the presence of serotonin when stained with chro-
mium and examined with x-­ray analytical electron microscopy.
Axon terminals (a) synapse on the neuronal membrane. A small
somatic spine (s) is present near one of these synapses. This speci-
men was fixed in 4% glutaraldehyde, osmicated, and stained with
uranyl acetate and lead citrate. Bar = 1 um. Original magnifica-
tion × 15,000.
 Neurons and Their Properties 7

A. Simple axodendritic or axoso- B. Dendritic spine synapse C. Dendritic crest synapse

matic synapse

Dendrite or cell body

Axon

Dendrite

Dendrite
Dendritic
spine
Axon (gemmule)
Glial
process Axon

D. Simple synapse plus E. Combined axoaxonic and

axoaxonic synapse axodendritic synapse F. Varicosities (“boutons en passant”)
Dendrite

Dendrite
Dendrite or cell body

I. Serial synapse
G. Dendrodendritic synapse H. Reciprocal synapse

Dendro-

Dendrite
Dendrite or cell body
Dendrite dendritic
synapse
Dendrite

K. Inner plexiform layer of retina

Ganglion cell
J. Cerebellar glomerulus Granule cell dendrites
Glial capsule
Bipolar cell axon
Golgi cell axon

Müller cell (supporting)

Golgi cell
dendrite
Amacrine cell processes
Mossy cell axon

1.4 TYPES OF SYNAPSES
A synapse is a site where an arriving action potential, through
excitation-­secretion coupling involving Ca2+ influx, triggers the
release of one or more neurotransmitters into the synaptic cleft
(typically 20 μm across). The neurotransmitter acts on receptors
on the target neuronal membrane, altering the membrane poten-
tial from its resting state. These postsynaptic potentials are called
graded potentials. Most synapses carrying information toward a
target neuron terminate as axodendritic or axosomatic synapses.
Specialized synapses, such as reciprocal synapses or complex
arrays of synaptic interactions, provide specific regulatory control
over the excitability of their target neurons. Dendrodendritic syn-
apses aid in the coordinated firing of groups of related neurons
such as the phrenic nucleus neurons that cause contraction of the
diaphragm.
CLINICAL POINT
The configurations of the synapses of key neuronal populations in
particular regions of the brain and of target cells in the periphery
determine the relative influence of that input. At the neuromuscular
junction, a sufficient amount of acetylcholine is usually released by
an action potential in the motor axon to guarantee that the muscle
end plate potential reaches threshold and initiates an action poten-
tial. In contrast, the neuronal inputs into reticular formation neurons
and many other types of neurons require either temporal or spatial
summation to allow the target neuron to reach threshold; this orches-
tration involves coordinated multisynaptic regulation. In some key
neurons such as lower motor neurons (LMNs), input from brainstem
upper motor neurons (UMNs) is directed mainly through spinal cord
interneurons and requires extensive summation to activate the LMNs;
in contrast, direct monosynaptic corticospinal UMNs input onto
some LMNs, such as those regulating fine finger movements, termi-
nate close to the axon hillock/initial segment; and can directly initiate
an action potential in the LMNs. Some complex arrays of synapses
among several neuronal elements, such as those seen in the cerebel-
lum and retina, permit modulation of key neurons by both serial and
parallel arrays of connections, providing lateral modulation of neigh-
boring neuronal excitability.
8 Overview of the Nervous System

Central nervous system (CNS) Peripheral nervous system (PNS)

Bipolar cell of cranial nerve VIII
Multipolar (pyramidal) cell
of cerebral motor cortex Unipolar cell of sensory ganglia of
cranial nerves V, VII, IX, or X
Associational, commissural,
and thalamic endings Satellite cells
Astrocyte Schwann cell
Striated Interneurons
Myelinated fibers
(somatic) Blood vessel
muscle Free nerve endings (unmyelinated fibers)
Encapsulated ending
Motor
Specialized ending
end plate
Muscle spindle
Multipolar somatic motor cell Unipolar sensory cell of spinal dorsal
of nuclei of cranial nerves III, root ganglion
IV, V, VI, VII, IX, X, XI, or XII Satellite cells
Interneuron
Multipolar cell of caudal
brain motor centers Myelinated afferent fiber of spinal nerve
Astrocyte
Oligodendrocyte

Corticospinal (pyramidal) fiber Myelin sheath

Multipolar visceral
Axodendritic ending motor (autonomic)
Axosomatic ending cell of spinal cord Red: Motor neurons, preganglionic
Autonomic preganglionic autonomic neuron
Axoaxonic ending Blue: Sensory neuron
(sympathetic or para-
Purple: CNS neurons
sympathetic) nerve fiber
Multipolar somatic motor cell Gray: Glial and
Myelin sheath neurilemmal
of anterior horn of spinal cord
Autonomic postganglionic cells and myelin
Nissl substance neuron of sympathetic or
Astrocyte parasympathetic ganglion Note: Cerebellar cells not shown here
Collateral Satellite cells
Unmyelinated nerve fiber
Renshaw interneuron (feedback)
Schwann cells
Myelinated somatic motor Myelin sheath
fiber of spinal nerve
Myelin sheath Schwann cells
Motor end plate with Endings on
Schwann cell cap cardiac muscle Unmyelinated fibers
or nodal cells
Striated (voluntary) muscle Free nerve endings
Beaded
varicosities
and endings on Encapsulated ending
smooth muscle
and gland cells Muscle spindle

1.5 NEURONAL CELL TYPES

Local interneurons and projection neurons demonstrate char-
acteristic size, dendritic arborizations, and axonal projections.
In the CNS (denoted by dashed lines), glial cells (astrocytes,
microglia, oligodendroglia) provide support, protection, and
maintenance of neurons. Schwann cells and satellite cells provide
these functions in the PNS. The primary sensory neurons (blue)
provide sensory transduction of incoming energy or stimuli into
electrical signals that are carried into the CNS. The neuronal out-
flow from the CNS is motor (red) to skeletal muscle fibers via
neuromuscular junctions, or is autonomic preganglionic (red)
to autonomic ganglia, whose neurons innervate cardiac muscle,
smooth muscle, secretory glands, metabolic cells, or cells of the
immune system. Neurons other than primary sensory neurons,
LMNs, and preganglionic autonomic neurons are located in the
CNS in the brain (enclosed by upper dashed lines) or spinal cord
(enclosed by lower dashed lines). Neurons and glia are not drawn
to scale.
CLINICAL POINT
Neuronal form and configuration provide evidence of the role of
that particular type of neuron. Dorsal root ganglion cells have virtu-
ally no synapses on the cell body; the sensory receptor is contiguous
with the initial segment of the axon to permit direct activation of the
initial segment upon reaching a threshold stimulus. This arrangement
provides virtually no opportunity for centrifugal control of the initial
sensory input; rather, control and analysis of the sensory input occurs
in the CNS. Purkinje neurons in the cerebellum have huge planar den-
dritic trees, with activation occurring via hundreds of parallel fibers
and the background excitability influenced by climbing fiber control.
This type of array allows network modulation of Purkinje cell output,
via neurons of the deep cerebellar nuclei, to UMNs, a control mech-
anism that permits fine-­grained, ongoing adjustments to smooth and
coordinated motor activities. Small interneurons in many regions
have local and specialized functions that have local circuit connec-
tions, whereas large isodendritic neurons of the reticular formation
receive widespread, polymodal, nonlocal input, which is important for
general arousal of the cerebral cortex and consciousness. Damage to
these key neurons may result in coma. LMNs and preganglionic auto-
nomic neurons receive tremendous convergence upon their dendrites
and cell bodies to orchestrate the final pattern of activation of these
final common pathway neurons through which the peripheral effector
tissues are signaled and through which all behavior is achieved.
 Neurons and Their Properties 9

Immunohistochemistry In situ hybridization

Chromogenic Fluorescence
Chromogenic,
Colorless Brightly Fluorophore UV light fluorescent, or
substrate colored (e.g., fluorescein, radiolabeled marker
product rhodamine, GFP)
Bound enzyme Complementary
(e.g., horseradish nucleotide
peroxidase) probe
Antibody Antibody DNA or
Target Target RNA strand
molecule molecule

“Omics” (genomics, transcriptomics, proteomics, etc.) Clustering of data points reveals differences in gene expression
between cell types or at different times in one cell type
Single-cell RNA sequencing (scRNA-seq)
Cell 1

Gene group B
Cell 2
Cell 1

Cell 2 Gene group A

Isolate Lyse cells, Reverse transcribe Add unique nucleic acid Amplify cDNA, sequence,
individual cells purify mRNA mRNA to cDNA “bar codes” and analyze data
Viral tracers Synaptic propagation of virus
Viral DNA Anterograde
or RNA

Retrograde

Viral vector (herpes, adeno-associated Intracerebroventricular, intravitreal,

virus, rabies, etc.) genetically modified intramuscular, intravascular, or
to encode fluorescent marker other mode of delivery
Chemogenetics Viral vector delivers gene
for a DREADD (designer Optogenetics
receptor exclusively Activated Viral vector delivers
activated by designer by CNO gene for a light-
drug) to specific cell types activated protein Light

DREADD, often a G-protein-coupled Gene codes

receptor, activated by a designer drug for DREADD Light-activated protein, often
(e.g., clozapine-N-oxide or CNO) a light-gated ion channel

1.6 MOLECULAR TECHNIQUES FOR STUDYING

This technology is used to (1) label neuronal pathways, including
NEURONS
transsynaptic connections, and (2) deliver engineered G-­protein-­
Multiple molecular approaches are used to investigate neurons
coupled receptors or light-­sensitive ion channels to modulate
and their complex interactions. Traditional methods localize spe-
neural function directly with exogenous stimuli. Viral vectors are
cific proteins or mRNA species using immunohistochemistry and
being developed for gene replacement or gene targeting in human
in situ hybridization, respectively. New technologies (OMICS) can
disease; some of these therapies are already approved, such as a
tag RNA from single cells to investigate patterns of gene expres-
treatment for spinal muscular atrophy.
sion and their changes in disease states. Some viruses can trans-
duce specific cell types, particularly neurons, and provide precise
and efficient means to express molecules in the nervous system.
10 Overview of the Nervous System

Transgenic Mouse Models of Human Disease

Transgenic mouse

Gene of Reporter of
interest gene expression
(e.g., Green
Fluorescent Protein)
Genetic material injected into Implantation of embryo into hormonally Transgenic offspring. Fluorescence
male pronucleus of fertilized egg induced “pseudo-pregnant” female indicates location of gene expression
Knockout and
Knockout
knockin mouse

Functional gene replaced

with non-functional copy
Modified stem cells
Embryonic stem cells Knockin inserted into blastocyst
harvested from blastocyst of a mouse with a Chimeric mouse with If modified cells are incorporated into
of a mouse with a certain different coat color mix of coat colors and germline (ova and sperm), subsequent
coat color (e.g., white) (e.g., gray) mix of modified and breeding can yield pure strains of
wild type genes genetically modified mice
Novel gene inserted
CRISPR-Cas9 knockin mouse Cas9
enzyme
Mouse
DNA
Guide RNA
DNA breaks
Viral or non-viral
Novel gene inserted
delivery of guide RNAs
at DNA breaks
and Cas9 enzyme in vivo
Cre transgenic mouse
Cre-Lox Technology Cre Cre can be modified to require
Cre
activation (e.g., by tamoxifen)
Cre recombinase is an Cre
enzyme that recombines enzyme
short DNA segments
between two target sequences Breeding
called LoxP. Cre and LoxP are LoxP Gene of LoxP Depending on the orientation
derived from the bacteriophage interest of LoxP sites, Cre may cause
P1 virus, which uses them to insertion, deletion, inversion,
insert its DNA into the host or translocation of target gene,
cell genome. LoxP transgenic mouse generating new strains of
Cre-LoxP hybrid knockout, knockin, and
transgenic mouse transgenic mice.
LoxP Gene of LoxP
interest
Transgenic Disease Model – Alzheimer’s Disease Plaque formation: Aβ surrounded
by a tangle of neurites and tau protein
Overexpression of APP Overproduction of Atrophy of cerebral cortex
Aβ, and hippocampus. Cognitive
forming plaques deficits measured with mazes,
Presenilins involved object recognition, and other tests
in cleaving APP into Tau
Aβ
Transgeneic mouse with
overexpression of
amyloid-β (Aβ) precursor protein (APP), Breakdown of Tau protein Y-maze
Hyperphosphorylation microtubules, deposits in
mutant presenilin proteins, and/or
of tau protein releasing tau nerve cells
mutant tau protein

1.7 GENETIC MODELS FOR STUDYING
NEURONS AND THEIR DISORDERS
Genetic manipulation of mammalian DNA, initially in mice, is a
powerful experimental tool to explore the effect of the introduc-
tion or deletion of specific genes. Transgenic mice, in which a
new gene or set of genes is introduced, are widely used in mod-
els of human disease. Gene function or disease phenotypes can
also be investigated using knockout or knockin technologies,
which have been made increasingly efficient by the discovery
of systems such as CRISPR-­Cas9. This system provides direct,
targeted gene insertion or deletion. Other genetic technologies
such as Cre-­Lox, adapted from bacteriophages, provide meth-
ods for cell-­specific expression or deletion of genes, depending
on which cells express Cre, as well as temporal control of expres-
sion or deletion with the use of modified Cre, which can be acti-
vated by a drug or hormone. The latter approach is especially
useful for avoiding the impact of genetic manipulation during
development.
 Neurons and Their Properties 11

Ventricle

Ependyma Microglial
cell
Tanycyte

Neuron
Oligodendrocyte

Axon

Astrocyte

Astrocyte foot processes

Perivascular
Pia mater pericyte
Capillary

1.8 GLIAL CELL TYPES
Astrocytes provide structural isolation of neurons and their syn-
apses and provide ionic (K+) sequestration, trophic support, and
support for growth and signaling functions to neurons. Oligo-
dendroglia (oligodendrocytes) provide myelination of axons in
the CNS. Microglia are scavenger cells that participate in phago-
cytosis, inflammatory responses, cytokine and growth factor
secretion, and some immune reactivity in the CNS. Perivascular
cells participate in similar activities at sites near the blood ves-
sels. Schwann cells provide myelination, ensheathment, trophic
support, and actions that contribute to the growth and repair of
peripheral neurons. Activated T lymphocytes normally can enter
and traverse the CNS for immune surveillance for a period of
approximately 24 hours.
12 Overview of the Nervous System

Non-overlapping, 3D polyhedral domains “Bushy” processes fill space Astrocyte Physiology

within 3D domains Metabolic support of neurons:
- Provide lactate to neurons
- Glycogenesis
Ionic balance:
- K+ buffering
- pH balance
Neural growth factors
Glial scar formation
100-200µm

Neuron
(not to scale)

Lactate

K+

Synapse

Insulation
Glutamine
of synapse

Gap junctions between adjacent

Glutamate
astrocytes forming a syncytium Ionic
and GABA
balance
Arteriole reuptake
K+
Endothelial cell

Astrocyte end-foot processes:

- Ensheath arterioles and capillaries
- Water transport via aquaporin 4 Astrocyte processes:
- Release “gliotransmitters” - Surround and insulate synapses
(glutamate, ATP, adenosine, etc.) - Ionic balance (K+ and pH buffering)
- Regulate formation of endothelial - Glutamate and GABA reuptake from synapse
tight junctions? - Inactivation of glutamate to glutamine and
- Regulate vasodilation and End-foot Vascular smooth recycling of glutamine
cerebral blood flow? processes muscle cell

1.9 ASTROCYTE BIOLOGY
Astrocytes are the most abundant glial cells in the CNS. They arise
from neuroectoderm and are intimately associated with neural
processes, synapses, vasculature, and the pial-­glial membrane
investing the CNS. Astrocytes in gray matter are called protoplas-
mic astrocytes, and in white matter are called fibrous astrocytes.
The somas vary in diameter from a few micrometers to 10 or
more micrometers. Astrocytes are arrayed in nonoverlapping 3D
polyhedral domains of 100–200 μm across (up to 400 μm in hom-
inids). Structurally, astrocytic processes interdigitate, forming a
syncytium to protect synapses (as close as 1 μm to these struc-
tures). Astrocytic endfeet associate with vascular endothelial cells
and associated smooth muscle cells. Astrocytic processes invest
the entire pial membrane from the inside.
Physiologically, astrocytic processes affect ion balance
(sequester K+), transport water via aquaporin 4 channels, uptake
and recycle glutamate and gamma-aminobutyric acid (GABA),
provide metabolic support to neurons, and can become reactive
after CNS injury and lay down glial scar tissue. Astrocytes also
can release growth factors and bioactive molecules (termed glio-
transmitters) such as glutamate, ATP, and adenosine. In develop-
ment, specialized astrocytes, called radial glia, provide a scaffold
for orderly neural migrations in the CNS. Astrocytes are able to
transfer mitochondria to neurons damaged by a stroke.
 Neurons and Their Properties 13

“Resting” Microglia
Microglial processes
constantly sample
local environment Microglial processes make frequent
contact (~once per hour) with
synapses and sense synaptic activity

Neuron
Response to injury (not to scale)
or pathogens
Cell injury, apoptosis Pathogens

ATP Synapse remodeling

PAMPs from and removal
(bacterial LPS, damaged (”synaptic stripping”)
DAMPs viral RNA, etc.) cells plays a role in
synaptic plasticity

K+
Ion flux

Toll-like receptors
(TLRs) Purinergic
NOD-like receptors receptor-
NF-B, MAPK (NLRs) regulated
Caspase-1 channels

Pro-IL-1β IL-1β
ACTIVATION
Activated Microglia
Nucleus Pro-IL-18 IL-18 Ameboid shape
Processes fewer, shorter, thicker
Release signaling molecules

Interleukins,
cytokines

Release of:
- Reactive oxygen species (•O2–)
Interaction with - Reactive nitrogen species (NO)
T cell
T cells may determine - Proinflammatory cytokines
microglia phenotype Antigen (IL-1, IL-6, TNF-)
(M1, M2) presentation - Matrix metalloproteinases
- Neurotrophic factors (NGF, TGF-,
Phagocytosis of pathogens neurotrophin-4/5, GDNF, FGF)
and cellular debris

1.10 MICROGLIAL BIOLOGY
Microglial cells are mesenchymal cells derived from yolk sac
that come to reside in the CNS. They are a unique resident popu-
lation with the capacity for self-­renewal. Microglia provide con-
stant surveillance of the local microenvironment, with processes
moving back and forth up to 1.5 μm/min. Microglial processes
can grow and shrink up to 2–­3 μm/min. They have a territory
15–30 μm wide, with little overlap with each other. Resting
microglia have soma of 5–­6 μm diameter, and activated micro­
glia are ameboid in appearance, with soma of approximately 10
μm diameter.
Microglia can carry out phagocytosis of debris and apoptotic
cells, remodel and remove synapses in developing and adult CNS,
and respond to injury or pathogens. Microglia have receptors
for multiple types of stimuli, such as ATP (indicator of local
damage), toll-­like receptors (TLRs) that respond to molecules
released from dying cells (DAMPS: damage-­associated molecular
patterns) or pathogens (PAMPS: pathogen associated molecu-
lar patterns) such as LPS on gram-­negative bacteria, or double-­
stranded RNA in viruses. Reactive microglia produce reactive
oxygen species (ROS), reactive nitrogen species (RNS, such as
NO), proinflammatory cytokines (IL-­1β , IL-­6, TNF-­α), matrix
metalloproteinases (MMPs), and neurotrophic factors (such as
NGF, TGF-β, neurotrophin 4/5, GDNF, FGF). Such signal mole-
cules from activated microglia can affect neurons and astrocytes,
inducing dysfunction. Recent evidence suggests that peripheral
macrophages can transfer mitochondria to assist primary sensory
neurons in inflamed tissue.
14 Overview of the Nervous System

Oligodendrocyte Maturation
Functional activity in neurons triggers myelination by oligodendrocyte precursor cells (OPCs)

“Myelinate me” signals may include

ATP, K+, glutamate, GABA,
cell adhesion molecules

NG2+ OPC

Oligodendrocyte Physiology

Adjacent segments of axons are

myelinated by different oligodendrocytes

An individual oligodendrocyte
myelinates an average of 30 axons

Myelin Sheath
Monocarboxylate Transporter 1 (MCT1)
delivers lactate, pyruvate, ketone bodies from
oligodendrocyte to axons through the myelin sheath
Node of
Ranvier

Na+ channels
Mitochondria
Fused layers of oligodendrocyte Minute masses of cytoplasm
cell membrane wrapped around trapped between fused
axon of central nervous system layers of cytoplasm

1.11 OLIGODENDROCYTE BIOLOGY
Oligodendrocytes are neuroectodermally derived glial cells
that have the major role of myelinating central axons. The
trigger for myelination may include associated axonal size
and signal molecules (such as ATP, K+, glutamate, GABA, and
some cell adhesion molecules). Each oligodendrocyte can
myelinate individual intermodal segments of an average of 30
separate axons (as high as 60 axons); adjacent internodal seg-
ments are myelinated by different oligodendrocytes. This pat-
tern of central myelination leaves periodic nodes of Ranvier
bare, with sodium channels, at which action potentials (APs)
are reinitiated as they travel down the myelinated axon and
its branches (called saltatory conduction). Oligodendrocytes
can be attacked by antibodies directed at specific oligodendro-
cyte proteins in multiple sclerosis, leading to oligodendrocyte
death and axonal dysfunction. Oligodendrocyte precursor
cells can replicate following such insults and remyelinate the
denuded central axon segments. Oligodendrocyte membranes
possess monocarboxylate transporter 1 (MCT 1), which can
deliver lactate, pyruvate, and ketone bodies to the axon. Oli-
godendrocyte precursor cells (OPCs) are present in the adult
CNS and have NG2 and PDGFα receptors.
 Neurons and Their Properties 15

I. Growth (e.g., neuronal differentiation, axonal outgrowth)

Neuron Growth factors

Target tissue

Axonal outgrowth

II. Autocrine and paracrine signaling between and among neurons

Neuron

Autocrine
signaling Paracrine signaling

Signaling inhibits apoptosis, promotes neuron survival, maintains synapses

III. Reciprocal signaling (e.g., neuromuscular junction)

Maintenance
of neuron
Neuron (e.g., GDNF)
Muscle
Maintenance
of muscle
(e.g., agrin)

Growth Factor Source Receptor Critical for:

NGF Skin, hippocampus? TrkA, p75 Cutaneous nociceptive neurons (small DRG neurons)
Sympathetic neurons
Basal forebrain cholinergic neurons (not the only factor required)
BDNF Many sites TrkB, p75 Synaptic plasticity
In periphery, BDNF KO mice show loss of vestibular ganglion neurons
NT3 Golgi tendon organs TrkC, p75 Loss of proprioceptive sensory neurons in DRG
and muscle spindles No gamma motorneurons; mice die at birth
NT4 Multiple sites TrkB, p75 No robust phenotype
GDNF Muscle Grf1, Ret Partial loss of muscles
CNTF Muscle? CNTFR, gp130 KO of CNTFR partial loss of muscles, but CNTF KO no loss due to LIF working
IGF-1 Muscle IGFR-1, IGFR-2 Partial loss of muscles
VEGF Muscle Flk-1, Flt-1, Flt-4 Embryonic lethal (required for angiogenesis)
NGF, nerve growth factor; BDNF, brain-derived neurotrophic factor; NT3 and NT4, neurotrophic 3 and 4; GDNF, glial cell line–derived neurotrophic factor;
CNTF, ciliary neurotrophic factor; IGF-1, insulin-like growth factor 1; VEGF, vascular endothelial growth factor; Trk, tyrosine kinase; KO, knock out; LIF, leukemia
inhibitory factor

1.12 NEURONAL GROWTH FACTORS AND
TROPHIC FACTORS
Neuronal growth factors and trophic factors are signal molecules
produced by neurons, glia, and target tissues that can influence
neuronal differentiation, growth of neurites, establishment of
contacts for signaling, maintenance of neural contacts with their
central or peripheral targets, and other functions. These factors
act through specific receptors and can induce the production of
specific molecules, such as agrin for the maintenance of nicotinic
cholinergic receptors at the neuromuscular junction. Several
identified growth factors, along with their sourced receptors and
possible roles, are provided in the table above.
16 Overview of the Nervous System

Superior horn of lateral ventricle

Subventricular
zone (SVZ) of
lateral ventricle

Inferior horn of
lateral ventricle

Dentate gyrus of Subgranular zone (SGZ)

hippocampus of dentate gyrus

I. Subventricular zone (SVZ) of lateral ventricle

Radial glia-like Transient amplifying
cells (B cells) cells (C cells) Neuroblasts migrate
Asymmetric Neuroblasts into olfactory bulb
division
SVZ Olfactory memory
Olfactory fear-conditioning
Ependyma Pheromone-linked behavior

Ventricle
Olfactory bulb

II. Subgranular zone (SGZ) of dentate gyrus

Type I radial Type II Immature Mature granule

glia-like cells progenitor cells Neuroblast neuron cell neuron
Asymmetric
Hilus
division Spatial and episodic memory
SGZ Object recognition memory
Emotional regulation
Granule
cell layer

Molecular
layer

III. Oligodendrocyte progenitor cells (OPCs)

OPCs widely distributed Myelin turnover

throughout adult brain Myelin repair
and spinal cord (~5% of
all cells in CNS) NG2+ OPC

1.13 STEM CELLS IN THE CNS: INTRINSIC AND
EXTRINSIC MECHANISMS
Embryogenesis involves the proliferation of stem cells, followed
by differentiation and migration of the resultant cell types. In the
CNS, neuronal stem cells, derived from the neural tube, persist
in the subventricular (or subependymal) zone of the lateral ven-
tricles (I). Waves of neuronal proliferation, differentiation, and
migration occur during prenatal CNS development. After birth,
stem cells in the subventricular zone continue to proliferate and
produce granule cells (neurons) for many brain regions; this pro-
cess is driven by postnatal environmental stimuli. Throughout
adulthood radial glial-­like cells, in the subgranular zone of the
dentate gyrus, give rise to neuroblasts that contribute new gran-
ule cell neurons (II). In addition, oligodendroglial progenitor cells
throughout the CNS can proliferate and then differentiate into
mature oligodendrocytes (III). This process can occur after a
demyelinating lesion and helps to remyelinate CNS axons (e.g.,
after a multiple sclerosis lesion).
 Neurons and Their Properties 17

1. Induced pluripotent stem cells Peripheral neurons

OSKM cocktail of transcription factors Additional transcription factors Cortical neurons
(Oct4, Sox2, Klf4, c-Myc) delivered by GABAergic neurons
viral vectors, plasmids, mRNA, etc. Glutamatergic neurons
Dopaminergic neurons
Oct4 Sox2 Klf4 c-Myc etc.

Astrocytes

Differentiated somatic cells Induced pluripotent stem cells Neural stem cells
(e.g., skin fibroblasts) (iPSCs) self-assemble into rosettes, Oligodendrocytes
mimicking neural tube
formation in the CNS
2. Spinal cord injury
Traumatic injury Acute Phase (1–14 days) Chronic Phase (>14 days)
Descending Severed axons Glial scar formation by
upper motor Distal segments degenerate activated astrocytes
neuron axon Vascular changes Inhibition of axonal
Ischemia regeneration by
Ascending Edema chondroitin sulfate
secondary Lipid peroxidation proteoglycans and
sensory axon Inflammation myelin-associated
Inflammatory cytokines proteins
Excitatory neurotransmitters
Free radicals
Loss of oligodendrocytes
Demyelination

3. Transplant of exogenous stem cells

Transplant during subacute
Human embryonic phase (7–14 days)
stem cells (hESC)
Human Embryoid Neurospheres Direct benefit:
embryo bodies Differentiation of
neurons, astrocytes,
oligodendrocytes
Skin
Bone marrow Indirect benefit:
Umbilical cord (3D aggregates (free floating Trophic support
Oct4 of stem cells) clusters of neural
blood Sox2 Substrate for
Human induced stem cells) axonal growth
Klf4
c-Myc pluripotent stem Modulate
cells (hiPSC) inflammation

4. In situ modulation of endogenous spinal cord stem cells

Two populations of
endogenous stem cells: Proliferation of ependymal stem cells

Infusion of fibroblast
growth factor-2
(FGF-2)

with or without
epidermal growth
factor (EGF)
Ependymal cells Cells scattered
around central canal throughout Enhanced oligodendrocyte differentiation
parenchyma and maturation in parenchyma

1.14 STEM CELL THERAPY
Recent approaches to stem cell therapy after a spinal cord injury
are depicted here. 1. Induced pluripotent stem cells can be gener-
ated from somatic cells (e.g., skin biopsy) and differentiated into
neural lineage cells for therapy. 2. The pathologic process of spinal
cord injury shows acute and chronic responses. 3. Use of exogenous
stem cells transplanted during the subacute phase leads to differen-
tiation of neurons and glia, and trophic support and modulation of
inflammation. 4. In situ modulation of endogenous stem cells uses
infusion of growth factors. These approaches remain experimental
but offer possible applications of knowledge derived from stem cell
biology to treat devastating conditions such as spinal cord injury.
18 Overview of the Nervous System

Cell
membrane Basement
Tight membrane
junction
proteins

Cytoplasm

Red
blood
cell

Capillary Astrocyte
lumen foot processes

Perivascular Perivascular
macrophage pericyte

Tight Capillary
junction endothelial
cell
Astrocyte

1.15 BLOOD-­BRAIN BARRIER
The blood-­brain barrier (BBB) is the cellular interface between the
blood and the CNS. It serves to protect the brain from unwanted
intrusion by many large molecules and potentially toxic sub-
stances and to maintain the interstitial fluid environment to
ensure optimal functioning of the neurons and their associated
glial cells. The major cellular basis for the BBB consists of the cap-
illary endothelial cells, which have an elaborate network of tight
junctions; these tight junctions restrict access by many large mol-
ecules, including many drugs, to the CNS. Endothelial cells in the
CNS also exhibit a low level of pinocytotic activity across the cell,
providing selected specific carrier systems for the transport of
essential substrates of energy production and amino acid metab-
olism into the CNS. Astrocytic endfoot processes abut the endo-
thelial cells and their basement membranes; these processes help
to transfer important metabolites from the blood to neurons and
can influence the expression of some specific gene products in
the endothelial cells. These astrocytic processes also can remove
excess K+ and some neurotransmitters from the interstitial fluid.
CLINICAL POINT
The BBB, anatomically consisting mainly of the capillary tight junctions
of the vascular endothelial cells, serves to protect the CNS from the intru-
sion of large molecules and potentially damaging agents from the periph-
eral circulation. The neurons need protection of their ionic and metabolic
environment, which is aided by glial cells and the BBB. There are selected
areas (windows on the brain) where the BBB is not present, such as the
median eminence, the area postrema, the organum vasculosum of the
lamina terminalis, and others, and where specialized cells can sample
the peripheral circulation and can initiate corrective brain mechanisms
to protect the neuronal environment. The presence of the BBB presents
a challenge for pharmacotherapy aimed at the CNS; many antibiotics and
other agents will not penetrate the BBB and must be coupled to a carrier
molecule that does cross or must be injected intrathecally. In some patho-
logical circumstances, such as the presence of a brain tumor, neuronal
degeneration resulting from a neurodegenerative disease, the presence of a
high concentration of a solute, or a stroke, the BBB is disrupted extensively,
exposing the internal CNS milieu to molecules in the peripheral circula-
tion. Therapeutic strategies now are being tested that will achieve transport
of desired pharmacotherapeutic agents across the BBB and will protect the
brain from unwanted disruption of the BBB in pathological circumstances.
  
 Neurons and Their Properties 19

I. Response to intrinsic damage (acute stroke, trauma, bacterial infection, etc.)

A. Rapid inflammatory response B. Delayed inflammatory response C. Healing

Tissue damage Cytokines, Breakdown of

chemokines blood-brain
DAMPs
TLRs barrier

PAMPs ROS, RNS

Pathogens
Conversion of astrocytes
from supportive role
to scar formation
Activated microglia Ingestion of pathogens Recruitment of Neuronal
and cellular debris peripheral blood dysfunction
elements (macrophages, neutrophils, T cells) and loss

II. Response to extrinsic stimuli

Activation of local microglia Inflammatory Mediators

Cytokines/chemokines:
IL-1
Extrinsic inflammatory stimuli TNF-
such as infection and chronic CCL2
disease (e.g., CVD, arthritis) TGF-
acting via: ROS (e.g., superoxide)
1. Crossing blood-brain barrier Cytokines, RNS (e.g., NO)
2. Action on endothelium to PGE2 chemokines, Prostaglandins (e.g., PGE2)
produce prostaglandins PGE2,
3. Peripheral stimulation of the ROS, RNS
sensory part of the vagus n.

Recruitment of peripheral Neuronal dysfunction

blood elements and loss

III. Response to intrinsic proteinopathy or neurodegenerative process (e.g., Alzheimer’s disease)

A plaque
Ingestion of
amyloid- (A)
and tau Astrocyte reactivity
and loss
Slow, chronic inflammation
Age-related
with progressive synaptic
“priming”
dysfunction and loss
of microglia
of neurons
Cytokines,
chemokines Tau neurofibrillary
Activated microglia; tangles
little or no
recruitment of peripheral Production of
blood elements excess A and tau

1.16 INFLAMMATION IN THE CNS of inflammatory mediators crossing the blood-­brain barrier,

Inflammatory responses in the CNS occur under several dif-
ferent conditions. I. Inflammatory response to intrinsic damage
such as stroke, trauma, or infection involves an acute inflam-
matory response, a delayed inflammatory response, and a
healing phase. II. Response to extrinsic inflammatory stimuli
such as infection and chronic disease usually involves a host
triggering release of prostaglandins and central neuronal dys-
function and loss. III. Response to intrinsic proteinopathy or
neurodegenerative processes such as aberrant amyloid-β plaque
or tau neurofibrillary tangles in Alzheimer’s disease is a slow,
chronic inflammatory response that leads to synaptic dysfunc-
tion and neuronal loss.
20 Overview of the Nervous System

I. Fast Anterograde Axonal Transport

100–400 mm/day in a saltatory
fashion (start-stop-start)
Vesicle Kinesin Membrane organelles
Cargo includes:
- Synaptic vesicles and
synaptic vesicle precursors
- Mitochondria and other
membrane organelles Nucleus
- Integral membrane proteins
- Secretory polypeptides
- Neurotransmitters Microtubule
- Elements of smooth
endoplasmic reticulum

II. Fast Retrograde Axonal Transport

200–270 mm/day
Cargo includes: Microtubule
- Endosomes
- Damaged mitochondria and
other organelles
- Elements of smooth Nucleus
endoplasmic reticulum
- Regulatory signals (growth
factors and neurotrophins)
- Viruses and toxins (e.g., tetanus, Dynein Damaged Endosome
herpes simplex, rabies, polio) organelles

III. Slow Axonal Transport (Anterograde Only)

Different substances move at

two different speeds: Neurofilaments move Short segments
on their own or carried of microtubules
Slow component a (SCa) along microtubules carried by dynein
0.2–2.5 mm/day (rate of neurite
elongation)
- Microtubules
- Neurofilaments Nucleus
- Cytoskeletal proteins
(e.g., - and -tubulin)

Slow component b (SCb)

5.0–6.0 mm/day
- Cytosolic proteins
- Clathrin Pre-assembly of
- Calmodulin microtubule segments
- Soluble enzymes and other proteins

1.17 AXONAL TRANSPORT IN THE CNS AND PNS
Intracellular organelles and molecules are transported both away
from the cell body down the axon (anterograde transport) and
toward the cell body from the axon (retrograde transport). I. Fast
anterograde transport moves vesicles, organelles, membrane pro-
teins, neurotransmitter elements, and smooth endoplasmic retic-
ulum components at a rate of 100–­400 mm/day in a stop-­start
fashion, using kinesin as a transport mechanism. II. Fast retro-
grade transport returns endosomes, damaged organelles, growth
factors and trophic factors, and some viruses and toxins at a rate
of 200–­270 mm/day, using dynein as a transport mechanism.
Fast anterograde and retrograde transport mechanisms have
been exploited in experimental neuroanatomical studies using
labeled compounds (e.g., horseradish peroxide, fluorogold) for
retrograde tract tracing and radiolabeled proteins for antero-
grade tract tracing. III. Slow anterograde transport carries micro-
tubules, neurofilaments, and some cytoskeletal proteins at 0.2–2.5
mm/ day (slow component a) and other enzymes and proteins at
5.0–­6.0 mm/day (slow component b). This slow transport pro-
cess is the rate-­limiting factor governing axonal recovery after
injury or insult; recovery usually proceeds (if it occurs at all) at
approximately 1 mm/day.
 Neurons and Their Properties 21

CENTRAL NERVOUS SYSTEM PERIPHERAL NERVOUS SYSTEM

Sensory neuron Satellite

cell body cells

Pia mater
Oligo-
dendrocyte

Schwann cells associated with

myelin sheaths of myelinated axons
Capillary
Astrocyte
Boutons of association neurons synapsing Postganglionic neuron of
with preganglionic autonomic neuron of sympathetic or parasympathetic
brainstem or spinal cord ganglion

Oligo- Schwann cells associated with Satellite cells

dendrocyte myelin sheaths of myelinated axons

Boutons of
association neurons
synapsing with somatic
Node of Ranvier
motor neurons of brain
or spinal cord

Axons terminating
on motor end plates of
striated (voluntary) muscle

1.18 MYELINATION OF CNS AND PNS AXONS

Central myelination of axons is provided by oligodendroglia.
Each oligodendroglial cell can myelinate a single segment of
several separate central axons. In the PNS, sensory, motor, and
preganglionic autonomic axons are myelinated by Schwann cells.
A Schwann cell myelinates only a single segment of one axon.
Unmyelinated sensory and autonomic postganglionic autonomic
axons are ensheathed by a Schwann cell, which provides a single
enwrapping arm of cytoplasm around each of several such axons.
The space between adjacent myelin segments of an axon is called
a node of Ranvier; this site of axon membrane contains sodium
channels and allows the reinitiation of action potentials in the
course of propagation down the axon, a process called saltatory
conduction.
CLINICAL POINT
The integrity of the myelin sheath is essential for proper neuronal
function in both the CNS and the PNS. Disruption of the myelin
sheath around axons in either system results in the inability of the
formerly myelinated axons to carry out their functional activities.
In the CNS, the myelin sheath of central axons can be attacked in an
autoimmune disease such as multiple sclerosis, resulting in a variety
of symptoms, such as blindness, diplopia caused by discoordinated
eye movements, loss of sensation, loss of coordination, paresis, and
others. This condition may occur episodically, with intermittent remy-
elination occurring as the result of oligodendroglia proliferation and
remyelination. In the PNS, a wide variety of insults, including expo-
sure to toxins and the presence of diabetes or autoimmune Guillain-­
Barré syndrome, result in peripheral axonal demyelination, which is
manifested mainly as sensory loss and paralysis or weakness. Remy-
elination also can occur around peripheral axons, initiated by the
Schwann cells. Clinically, the status of axonal conduction is assessed
by examining sensory evoked potentials in the CNS and by conduc-
tion velocity studies in the PNS.
22 Overview of the Nervous System

SHEATH AND SATELLITE CELL FORMATION

A. Two postganglionic autonomic neurons of a sympathetic or parasympathetic ganglion
Endings of preganglionic autonomic neuron Axons ending on gland or smooth (involuntary)
synapsing with cell bodies of postganglionic muscle or cardiac muscle cells
neurons
Satellite cells

Schwann sheath of Schwann cell surrounding

unmyelinated axons of two neurons

B. Somatic or visceral sensory neuron of a spinal ganglion or sensory ganglion of cranial nerves V, VII, IX, or X
1. During development Dividing Neuron Dividing Neuron endings of
satellite cell body Schwann peripheral process
Neuron endings of central cell cell within an organ
process within spinal cord
or brainstem

2. Mature Satellite cells

Nodes
Node

Schwann sheath surrounding a myelinated axon

Axon Neurilemmal cell Periaxonal space

C. Unmyelinated axons
of peripheral neurons
(sensory, somatic motor
or visceral motor)
being surrounded by
cytoplasm of a
neurilemmal (Schwann)
Axons
cell

D. Myelinated axon Axon

of peripheral neuron
(sensory, somatic motor
or visceral motor)
being surrounded by
a wrapping of cell
membrane of a
neurilemmal (Schwann)
Neurilemmal cell
cell

Axons

E. Myelinated axons
of CNS neurons
being surrounded by
a wrapping of cell
membrane of an
oligodendrocyte.
Unmyelinated axons
Axon
of CNS neurons are
left unprotected.
Oligodendrocyte

1.19 DEVELOPMENT OF MYELINATION AND
AXON ENSHEATHMENT
Myelination requires a cooperative interaction between the neu-
ron and its myelinating support cell. Unmyelinated peripheral
axons are invested with a single layer of Schwann cell cytoplasm.
When a peripheral axon at least 1 to 2 μm in diameter triggers
myelination, a Schwann cell wraps many layers of tightly packed
cell membrane around a single segment of that axon. In the CNS,
an oligodendroglia cell extends several arms of cytoplasm, which
then wrap multiple layers of tightly packed membrane around a
single segment of each of several axons (or occasionally two auto-
nomic preganglionic axons). Although myelination is a process
that occurs most intensely during development, Schwann cells
may remyelinate peripheral axons following injury, and oligoden-
droglial cells may proliferate and remyelinate injured or demye-
linated central axons in diseases such as multiple sclerosis.
 Neurons and Their Properties 23

Extracellular fluid Membrane Axoplasm

+ –
+ –
–
Na
–
+ Diffu
sio –
n
+
Mitochondrion
+ Na
ti
Ac ve ATP
+ ATPase
anspo

rt
tr
ADP
+
+ K
n
sio –
K D iffu
–
+
–
+
Cl Diffusion Cl

+ –
+
Protein _
+ (anions)
–
+
–

ENa
gNa1 50 mV
Resistance

EK
gK100 90 mV

Equivalent circuit diagram;

g is ion conductance across
the membrane
ECl
70 mV
gCl50 to 150

+ RMP –
–70 mV

ELECTRICAL PROPERTIES
1.20 NEURONAL RESTING POTENTIAL
Cations (+) and anions (–­) are distributed unevenly across the
neuronal cell membrane because the membrane is differentially
permeable to these ions. The uneven distribution depends on
the forces of charge separation and diffusion. The permeability
of the membrane to ions changes with depolarization (toward 0)
or hyperpolarization (away from 0). The typical neuronal resting
potential is approximately –­90 mV with respect to the extracellu-
lar fluid. The extracellular concentrations of Na+ and Cl–­ of 145
and 105 mEq/L, respectively, are high compared to the intracellu-
lar concentrations of 15 and 8 mEq/L. The extracellular concen-
tration of K+ of 3.5 mEq/L is low compared to the intracellular
concentration of 130 mEq/L. The resting potential of neurons
is close to the equilibrium potential for K+ (as if the membrane
were permeable only to K+). Na+ is actively pumped out of the
cell in exchange for inward pumping of K+ by the Na+-­K+-­ATPase
membrane pump. Equivalent circuit diagrams for Na+, K+, and
Cl−­, calculated using the Nernst equation, are illustrated in the
lower diagram.
Another random document with
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fell and prepare timber, it was pretended that it was for pleasure-
boats wherewith to entertain him. Under the able direction of Martin
Lopez aided by Alonso Nuñez, the master carpenters, they were
completed within a few weeks, and provided with four guns and tiers
of oars, affording transport for three hundred men.
A hunting-trip to one of the imperial reserves across the lake was
at once arranged.[553] The largest vessel had been provided with
awnings and other comforts for the reception of Montezuma, his
suite, and a strong guard, while other notables were accommodated
in the other craft. A volley from the guns announced their arrival, and
did more probably to inspire respect than even the presence of
majesty. The vessels were accompanied by a fleet of canoes, some
holding forty or more courtiers, hunters, or attendants. All were
curious to see how the winged water-houses would behave, for their
immense size was supposed to render them slow and clumsy. A fair
breeze was blowing, however, and as the large sails unfurled, the
vessels bounded forward with a speed that in a few moments left the
occupants of the canoes far behind. Montezuma was delighted, and
the trip was repeated. Hunting parties were likewise formed; for the
royal captive enjoyed the chase and used the blow-pipe with great
skill.[554]

FOOTNOTES
[517] ‘Le dió en guarda á un capitan, é de noche é de dia siempre estaban
españoles en su presencia.’ Tapia, Rel., in Icazbalceta, Col. Doc., ii. 580. This
captain appears to have been Juan Velazquez, whose place was taken by Olid,
when required. Bernal Diaz, Hist. Verdad., 77, 86.

[518] ‘Se quiso echar de vna açutea de diez estados en alto, para que los suyos le
recibiessen, sino le detuuiera vn Castellano.... Denoche y de dia procurauan de
sacarle, oradando a cada passo las paredes, y echando fuego por las azuteas.’
 The result was an increase of the guard, Álvarez Chico being placed with 60
men to watch the rear of the quarters, and Andrés de Monjarraz the front, with the
same number, each watch consisting of twenty men. Herrera, dec. ii. lib. viii. cap.
iii. Bernal Diaz intimates that the guarding of Montezuma proved a severe strain
on the soldiers; but, situated as they were, vigilance was ever required, and still
greater must have been the danger had he not been in their power.

[519] Herrera calls him Peña, which may have been one of his names, dec. ii. lib.
viii. cap. v. Bernal Diaz assumes that Montezuma asked Cortés to give him the
page, after the execution of Quauhpopoca. Hist. Verdad., 75.

[520] The bride was named Francisca. Hist. Verdad., 77. As an instance of
Montezuma’s eagerness to gratify the Spaniards, and at the same time to exhibit
his own power, it is related that one day a hawk pursued a pigeon to the very cot
in the palace, amid the plaudits of the soldiers. Among them was Francisco the
dandy, former maestresala to the admiral of Castile, who loudly expressed the
wish to obtain possession of the hawk and to tame him for falconry. Montezuma
heard him, and gave his hunters orders to catch it, which they did. Id.; Gomara,
Hist. Mex., 125.

[521] Duran states that the soldiers discovered a house filled with women,
supposed to be wives of Montezuma, and hidden to be out of the reach of the
white men. He assumes that gratitude would have made the Spaniards respect
them; or, if the women were nuns, that respect for virtue must have obtained.

[522] Cortés’ protégée being named Ana. Quite a number of the general’s
followers declare in their testimony against him, in 1528, that he assumed the
intimate protectorship of two or even three of Montezuma’s daughters, the second
being called Inés, or by others Isabel, the wife of Grado, and afterward of Gallego.
‘Tres fijas de Montezuma e que las dos dellas an parido del e la otra murio
preñada del quando se perdio esta cibdad.’ Tirado, in Cortés, Residencia, ii. 39,
241, 244; i. 63, 99, 221, 263. Intrigues are mentioned with other Indian princesses.
Vetancurt assumes that two noble maidens were given, one of whom Olid
received. Teatro Mex., pt. iii. 133; Torquemada, i. 462. Bernal Diaz supposes that
this is the first daughter offered by Montezuma, and he believes evidently that
Cortés accepts her, to judge by a later reference. Hist. Verdad., 85, 102.

[523] Herrera states that Cortés’ order was prompted by a consideration for the
heavy expense to Montezuma. The latter remonstrated at this economical fit, and
commanded that double rations should be provided for the exiled. dec. ii. lib. viii.
cap. iv.

[524] Tapia, Rel., in Icazbalceta, Col. Doc., ii. 580. ‘Purchè non tocchino disse il
Re, le immagini degli Dei, nè ciò che è destinato al loro culto, prendano quanto
vogliono,’ is Clavigero’s free interpretation of Ojeda’s version. Storia Mess., iii. 97;
Gomara, Hist. Mex., 125.

[525] ‘Lo q̄ vna vez daua no lo auia de tornar a recibir.’ ‘Las caxas donde la ropa
estaua, eran tan grandes que llegauan a las vigas de los aposentos, y tan anchas,
q̄ despues de vacias, se alojauã en cada vna dos Castellanos. Sacaron al patio
mas de mil cargas de ropa.’ Herrera, ii. viii. iv.

[526] ‘Casa de Cacao, de Motecuhçuma, adonde avia mas de quarenta mil

Cargas, que era Gran Riqueça, porque solia valer cada Carga quarenta
Castellanos.’ Alvarado alone emptied six jars of 600 loads. Torquemada, i. 472.

[527] The man had insisted that Montezuma should have a search made for two of
his missing female attendants. The emperor did not wish Spaniards punished for
pilfering, as he told Cortés, only for offering insult and violence. In such cases he
would have his own courtiers lashed. Herrera, dec. ii. lib. viii. cap. v.

[528] ‘Tinie el marques tan recogida su gente, que ninguno salie un tiro de
arcabuz del aposento sin licencia, é asimismo la gente tan en paz, que se
averiguó nunca reñir uno con otro.’ Tapia, Rel., in Icazbalceta, Col. Doc., ii. 586.

[529] Bernal Diaz, Hist Verdad., 77. ‘Un giuoco, che gli Spagnuoli chiamavano il
bodoque.’ Clavigero, Storia Mess., iii. 97. Bodoque signifies balls in this
connection. When Alvarado lost, he with great show of liberality paid in
chalchiuites, stones which were highly treasured by the natives, but worth nothing
to the Spaniards. Montezuma paid in quoits, worth at least 50 ducats. One day he
lost 40 or 50 quoits, and with pleasure, since it gave him the opportunity to be
generous. B. V. de Tapia testifies that Alvarado used to cheat in playing cards with
him and others. Cortés, Residencia, i. 51-2. Another way of gratifying this bent
was to accept trifles from the Spaniards and liberally compensate them. Alonso de
Ojeda, for instance, had a silk-embroidered satchel with many pockets, for which
Montezuma gave him two pretty slaves, beside a number of robes and jewels.
Ojeda wrote a memoir on the conquest, of which Herrera makes good use. dec. ii.
lib. viii. cap. v.

[530] ‘Fué muchas veces á holgar con cinco ó seis españoles á una y dos leguas
fuera de la ciudad.’ Cortés, Cartas, 92. Both the times and the number of the
Spaniards are doubtful, however. ‘Quando salia a caçar.... Lleuaua ocho o diez
Españoles en guarda de la persona, y tres mil Mexicanos entre señores,
caualleros, criados, y caçadores.’ Gomara, Hist. Mex., 124; Ixtlilxochitl, Hist.
Chich., 297.

[531] Bernal Diaz intimates that more sacrifices were made in their presence. ‘Y
no podiamos en aquella sazon hazer otra cosa sino dissimular con èl.’ Hist.
Verdad., 78.

[532] Bernal Diaz admits that he knows not what occurred between governor and
monarch, but Herrera claims to be better informed. Barefooted, and with eyes
upon the floor, Quauhpopoca approached the throne and said: ‘Most great and
most powerful lord, thy slave Quauhpopoca has come at thy bidding, and awaits
thy orders.’ He had done wrong, was the reply, to kill the Spaniards, and then
declare that he had orders so to do. For this he should suffer as a traitor to his
sovereign and to the strangers. He was not allowed to make any explanations,
dec. ii. lib. viii. cap. ix. It is not unlikely that Montezuma commanded him not to
reveal anything that might implicate his master, hoping that Cortés would out of
regard for his generous host inflict a comparatively light punishment.

[533] ‘Examinaron los segunda vez, con mas rigor, y amenazas de tormento, y sin
discrepar todos confessaron,’ says Herrera, loc. cit.

[534] ‘En vna de las casas reales dicha Tlacochalco.’ Herrera, loc. cit. ‘É serien
mas que quinientas carretadas.’ Tapia, Rel., in Icazbalceta, Col. Doc., ii. 584.

[535] ‘Me has negado no auer mãdado a Couatlpopocà q̄ matasse a mis

compañeros, no lo has hecho como tan gran señor que eres, ... porque no quedes
sin algun castigo, y tu y los tuyos sepays quanto vale el tratar verdad, te mãdare
echar prisiones.’ Herrera implies with this that Cortés laid more weight on the
disregard for truth than on the authorization of the outrage. dec. ii. lib. viii. cap. ix.
‘Que ya que aquella culpa tuuiesse, que antes la pagaria el Cortès por su
persona, que versela passar al Monteçuma.’ Bernal Diaz, Hist. Verdad., 75.

[536] ‘Esto hizo por ocuparle el pensamiento en sus duelos, y dexasse los ajenos.’
Gomara, Hist. Mex., 129. ‘Todo à fin de espantarle mas.’ Ixtlilxochitl, Hist. Chich.,
298.

[537] Solis seems to say that the bodies were burned after execution, Hist. Mex., i.
461-2, but Cortés and others are frank enough about the actual burning, which
was not regarded in that cruel age with the same aversion as by us. Instances are
to be found in the Native Races, ii.-iii., where this ordeal was undergone by
criminals as well as temple victims among the Aztecs. Bernal Diaz gives the
names of two of Quauhpopoca’s companions in misfortune, Quiabuitle and Coatl.
Hist. Verdad., 75. Prescott, Mex., ii. 173, states that the execution took place in
the court-yard; but this is probably a misprint, to judge by his own text.

[538] ‘Á lo que entendimos, ê lo mas cierto, Cortés auia dicho á Aguilar la lengua,
que le dixesse de secreto, que aunque Malinche le mandasse salir de la prision,
que los Capitanes nuestros, è soldados no querriamos.’ Bernal Diaz, Hist.
Verdad., 75.
[539] ‘Fué tanto el buen tratamiento que yo le hice, y el contentamiento que de mí
tenia, que algunas veces y muchas le acometi con su libertad, rogándole que
fuese á su casa, y me dijo todas las veces que se lo decia, que él estaba bien allí,’
etc. Cortés, Cartas, 91. ‘No osaua, de miedo que los suyos no le matassen ... por
auerse dexado prender,’ is one of the suppositions of Gomara, who calls him a
man of little heart. Hist. Mex., 129-30. Peter Martyr appears to be moved rather by
pity for him. dec. v. cap. iii. ‘Non gli conveniva ritornare al suo palagio, mentre
fossero nella Corte gli Spagnuoli.’ Clavigero, Storia Mess., iii. 102.

[540] ‘Como este castigo se supo en todas las Prouincias de la Nueua-España,

temieron, y los pueblos de la costa, adonde mataron nuestros soldados, bolvieron
á servir.’ Bernal Diaz, Hist. Verdad., 75-6, comments upon the daring of the
Spaniards in carrying out these and similar high-handed acts. For a short time
after this, says Herrera, the soldiers were ordered to sleep on their arms, in case
of any demonstration. dec. ii. lib. viii. cap. ix. Clavigero regards the burning as
unjustifiable, since the emperor was regarded as having authorized it. If he was
not guilty, the Spaniards were ungrateful to treat him as they did. Storia Mess., iii.
101. Robertson finds some excuse for Quauhpopoca’s punishment, but calls the
humiliation of Montezuma a wanton display of power. Hist. Am., ii. 63, 453-4.
Prescott, on the other hand, regards the humiliation as politic, on the ground that
by rendering the monarch contemptible in the eyes of his subjects, he was obliged
to rely more on the Spaniards. Mex., ii. 177. But this would hardly have been
necessary since he was in their power, and considering that the object of keeping
him so was to control the country, it would have been better not to degrade him.

[541] ‘Donde mas oro se solia traer, que era de vna Provincia que se dize,
Zacatula ... de otra Provincia, que se dize Gustepeque, cerca de donde
desembarcamos ... é que cerca de aquella Provincia ay otras buenas minas, en
parte que no son sujetos, que se dizen, los Chinatecas, y Capotecas.’ Bernal
Diaz, Hist. Verdad., 81. Montezuma detailed two persons for each of four
provinces where gold was to be had, and Cortés gave two Spaniards for each
couple. The provinces named were Cuzula, Tamazulapa, Malinaltepeque, Tenis.
Cortés, Cartas, 92-3. Of the eight Indians, four were miners or goldsmiths, and the
others guides. Gomara, Hist. Mex., 130. Chimalpain names the provinces:
Tamazólan, in upper Miztecapan, Malinaltepec and Tenich, both on the same river,
and Tututepec, twelve leagues farther, in the Xicayan country. Hist. Conq., i. 254-
5.

[542] ‘Con tal, que los de Culùa no entrassen en su tierra.’ They were reassured
and dismissed with presents. Herrera, dec. ii. lib. ix. cap. i.

[543] ‘Cortés se holgô tanto con el oro como si fueran treinta mil pesos, en saber
cierto que avia buenas minas.’ Bernal Diaz intimates beside that Umbría and his
two companions had provided themselves with plenty of gold. Hist. Verdad., 81-2.

[544] A young man of 25 years, whom Cortés treated as a relative. With him went
four Spaniards who understood mining, and four chiefs. Id.

[545] ‘En granos crespillos, porque dixeron los mineros, que aquello era de mas
duraderas minas como de nacimiento.’ Id., 82.

[546] Bernal Diaz names them, ‘Barriẽtos, y Heredia el viejo, y Escalona el moço,
y Cervantes el chocarrero,’ and says that Cortés, displeased at soldiers being left
to raise fowl and cacao, sent Alonso Luis to recall them. Hist. Verdad., 82;
Herrera, dec. ii. lib. ix. cap. i. He is evidently mistaken, as shown by his own later
text, for Cortés himself states that he sought to form plantations in that direction.
The recall was made later and for a different reason.

[547] ‘Estaban sembradas sesenta hanegas de maíz y diez de frijoles, y dos mil
piés de cacap [cacao] ... hicieron un estanque de agua, y en él pusieron
quinientos patos ... y pusieron hasta mil y quinientas gallinas.’ Cortés, Cartas, 94;
Peter Martyr, dec. v. cap. iii. Oviedo writes that farms were established for the king
in two or three provinces, one in Chimanta [Chimantla]. The two Spaniards left in
the latter were saved, but elsewhere, subject to the Aztecs, they were killed during
the uprising originated by Alvarado. iii. 376. Tapia refers to an expedition at this
time against a revolted province, 80 leagues off. Rel., in Icazbalceta, Col. Doc., ii.
584.

[548] ‘Por aquella causa llaman oy en dia, donde aquella guerra passò,
Cuilonemiqui.’ Bernal Diaz, Hist. Verdad., 82.

[549] Herrera, loc. cit. ‘Creyan lo que desseauan,’ remarks Gomara, Hist. Mex.,
131.

[550] Cortés, Cartas, 95, 116; Gomara, Hist. Mex., 131-2. Bernal Diaz throws
doubt on the expedition of Velazquez, but is evidently forgetful. Hist. Verdad., 81-
2. ‘El señor de la provinçia ... luego hiço seys [casas] en el assiento é parte que
para el pueblo se señaló.’ Oviedo, iii. 293. Peter Martyr calls these buildings
‘Tributaries’ houses.’ dec. v. cap. iii.; Cortés, Residencia, ii. 6, 49.

[551] He had served as equerry in the noble houses of the Conde de Ureña and
Pedro Giron, of whose affairs he was always prating. His propensity for tale-telling
lost him many friends, but he managed to keep intimate with Sandoval, whose
favors he afterward repaid with ingratitude. Bernal Diaz, Hist. Verdad., 76, 246.
Gomara insists on naming him as the comandante, but this dignity he attained
only after Sandoval and Rangel had held it. Cortés, Residencia, i. 256;
Torquemada, i. 456.
[552] ‘Luego que entré en la dicha ciudad di mucha priesa á facer cuatro
bergantines ... tales que podian echar trecientos hombres en la tierra y llevar los
caballos.’ Cortés, Cartas, 103; Peter Martyr, dec. v. cap. iv. ‘Quatro fustas.’
Gomara, Hist. Mex., 146. ‘Dos vergantines.’ Bernal Diaz, Hist. Verdad., 76. The
cedars of Tacuba, numerous enough at this period, yielded much of the timber,
and the slopes of Iztaccihuatl and Telapon the harder portion for masts, keels, etc.
Mora, in Soc. Mex. Geog., Boletin, ix. 301.

[553] ‘En la laguna á vn peñol, que estaua acotado, q̄ no ossauan entrar en èl á

montear, por muy principales que fuessen, so pena de muerte.’ Bernal Diaz, Hist.
Verdad., 78.

[554] Native Races, ii. 411. ‘Qãdo yua a caça de monteria, le lleuauan en ombros,
con las guardas de Castellanos, y tres mil Indios Tlascaltecas.... Acompañauanle
los señores sus vassallos.’ Herrera, dec. ii. lib. viii. cap. iv.
 CHAPTER XIX.
POLITICS AND RELIGION.

1520.

Growing Discontent among the Mexicans—Cacama’s Conspiracy—He

openly Defies both Montezuma and Cortés—The Council of Tepetzinco
—Seizure of Cacama—The Tezcucan Ruler Deposed—Cuicuitzcatl
Elevated—Montezuma and his People Swear Fealty to the Spanish King
—Gathering in the Tribute—Division of Spoils—The Spaniards Quarrel
over their Gold—Uncontrollable Religious Zeal—Taking of the
Temple—Wrath of the Mexicans.

With their hand so securely on the spring that moved a mighty

empire, there is little wonder that these Spanish adventurers became
somewhat insolent toward the people they so injured. The Mexicans
were not slow to mark this, and there were those among them, and
others beside them, who began to think of taking matters into their
own hands, of destroying the invaders and releasing the emperor.
Montezuma’s occasional appearance in public, and the assertion
that he remained with the Spaniards of his free-will, and because the
gods desired it, had for a time satisfied the nobles; but the hard irons
on his limbs and the cruel burning of patriotic men had opened their
eyes somewhat to the true state of affairs. No one knew when his
turn might come. Life was insecure enough subject to the caprice of
their own sovereign, but the dark uncertain ways of these emissaries
of evil were past finding out. These things were thought of and talked
of in high places. Race aversions and the political systems of the
tripartite alliance caused more than one party to be formed, each
with aspirations that could not be entertained by the others. The
most prominent leader at this time was Cacama, who had at first
favored the strangers in their character as envoys. And now he
began the endeavor to direct the movement of the Aztec nobility, but
jealousy of Acolhua influence rose uppermost, and his efforts tended
only to create a reaction in favor of abiding by the will of the emperor.
[555]

Although there were enough of sympathizers in Mexico for his

purpose, Cacama found that he must rely almost wholly on the
northern provinces, and in connection with Cuitlahuatzin,
Totoquihuatzin II. of Tlacopan, his own brothers, and others, he
organized a conspiracy which had for its aim the expulsion of the
Spaniards and the release of his uncle. Beneath this was harbored a
design upon the Aztec throne, which would probably become vacant;
and even if Cacama was not sure of gaining this for himself, he had
at least the expectation of assuming the leadership of the Anáhuac
confederacy.[556] He presented to the council in the most dismal
aspect the purposes of the Spaniards, who evidently sought to
become absolute masters and reduce them all to slavery. It was time
to rise for religion and liberty. Their honor and welfare demanded it,
and this before the Spaniards rendered themselves too powerful by
reinforcements and alliances. With heedless confidence he vaunted
that Mexico should be his within a few hours after setting out against
her, for there were many of her citizens ready to aid in such a work.
The Spaniards were overrated, and could effect little, surrounded as
they were on all sides, and without other supplies than those
provided by the Mexicans.
The motives and the necessity were recognized, though the
means proposed met with some objections; but when the question of
spoils and rewards came forward there were still greater differences.
Among others, the brave and powerful lord of Matlaltzinco advanced
pretensions, founded in part on his close relationship to Montezuma,
which Cacama above all could not admit. The result was
disagreement, followed by the withdrawal of several members.[557]
No attempt had been made to keep the movement, or its
ostensible motive, a secret from Montezuma, nor could it have been
kept from him who was the still powerful ruler of a servile race; but,
even if the deeper lying aim was not revealed him, he could not fail
to foresee the troubles that might arise, particularly under such a
leader. He still hoped the Spaniards would soon leave, or that his
release might be effected by other means, for he dreaded a conflict
with the powerful invaders, involving perhaps the destruction of the
city and his own death. He sent to tell the conspirators that they
need not concern themselves about his imprisonment. The
Spaniards had more than once proposed that he should return to his
own palace, but the gods had decreed it otherwise. He could not
allow his people to be needlessly exposed to war, or his capital to
destruction. Remember Cholula. Their stay would not be long.
This message was not without its effect even among the
Tezcucans, for, although the fate of the Aztec capital and king may
have concerned them but little, there were many who could not
forget that the impetuous and proud Cacama had obtained the
throne by favor of Montezuma, to the prejudice of an elder brother,
Tetlahuehuetquizitzin.Their father, Nezahualpilli, had died in 1515,
without naming a successor, and the choice devolving on the royal
council, in conjunction with the rulers of Mexico and Tlacopan,
Cacama was elected. Cohuanacoch, the third brother, acquiesced,
but the youngest, the fiery Ixtlilxochitl, protested in favor of the eldest
heir, and denounced the selection as due to Montezuma, who hoped
to mould the new king to his own will and so again to control. He
even resorted to arms in support of his views, and enlisting the
northern provinces in his favor, after a short campaign he obliged
Cacama to consent to a division of the kingdom with himself.[558]
His ready success proved that Cacama had no very great hold
on the people, and now, when came the warning of Montezuma,
more than one chief counselled prudence from other motives than
fear. But the king stamped all these objections as cowardly, and
appears even to have placed under restraint several of those whose
want of sympathy he had reason to suspect.[559] His blood was hot,
and relying on the promises of his supporters, he considered himself
strong enough to bid defiance to his opponents. He sent word to his
uncle that if he had any regard for the dignity of his station and the
honor of his person and ancestry, he would not quietly submit to the
bondage imposed by a handful of robbers, who with smooth tongue
sought to cover their outrages against him and the gods. If he
refused to rise in defence of his religion, throne, and liberty, Cacama
would not.[560]
This outspoken utterance of the nephew whom he had assisted
to rulership amazed Montezuma as much as it wounded his pride,
and he no longer hesitated to take counsel with Cortés, who had
already obtained an inkling that something was stirring.[561] With
characteristic promptness the latter suggested that, since Cacama’s
real object was evidently to usurp the throne, a Mexican army should
be given to aid the Spaniards in laying waste the territory of the
conspirators and in capturing them. The emperor had probably
entertained a hope that the news would frighten his guest and make
it safe to urge a retreat from Mexico, thus ending the whole trouble.
He was therefore somewhat startled by this proposal, the true tenor
of which he well understood. He feared a fratricidal war of doubtful
result, wherein he would appear as arrayed against the defenders of
national religion and liberty; and being now weak and cowed he
hesitated to arm at all, preferring peaceful measures. To this Cortés
was not averse, for he recognized on second thought that
aggressive steps might become the signal for a general uprising
which would overwhelm him, since Aztec troops could never be
relied on.
He accordingly sent messages to Cacama, reminding him of
their friendly intercourse, and representing the danger of offending
the Spanish king by proceedings which could only react on himself
and lead to the destruction of his kingdom. Montezuma supported
this by asking the king to come to Mexico and arrange the difficulty.
Cacama had not gone so far to be restrained by what he termed an
empty threat, and regardless of the warnings from a timid minority he
replied that he knew not the king of the Spaniards, and would never
accept the friendship of men who had oppressed his country and
outraged his blood and religion. He had had enough of their
promises, but would declare his determination when he saw them.
[562] To Montezuma he sent word that he would come, “not with the
hand on the heart, however, but on the sword.”[563]
There was considerable meaning in this threat, for Cacama had
with great energy set about to mass his forces at Oztoticpac, and
they in conjunction with those of his allies would make a formidable
host.[564] Cortés was aware of this, and seeing that no time was to
be lost he firmly represented to Montezuma the necessity of securing
the person of the king, openly or by stealth; and when he still
hesitated, the significant hint was given that the Spaniards would
regard a refusal with suspicion. This decided him, and he promised
that it should be done, if possible. Cortés broke forth in expressions
of good-will, and again offered him that freedom which Montezuma
well knew he would never grant.
In placing Cacama on the throne, the emperor had seized the
opportunity to introduce into the Acolhua government offices several
creatures of his own, who were paid to maintain Aztec influence in
the council[565] and to watch operations. To these men he sent an
order, weighted with presents, to seize the king and bring him to
Mexico.[566] They accordingly prevailed on their victim to hold a
council at Tepetzinco for finally arranging the campaign. This palace
was situated on the lake, near Tezcuco, and approached by canals.
Here Cacama was seized and thrown into a boat prepared for the
occasion, and carried to the Aztec capital.[567]
Ashamed, perhaps, of his share in the transaction, and unwilling
to face the taunts of the captive, Montezuma refused to see him, and
he was surrendered to Cortés, who, regardless of royalty, applied the
fetters as the surest means against escape.[568] This seizure
scattered the conspirators and their schemes to the winds, and the
demoralization was completed by the arrest of several of the more
important personages, such as the king of Tlacopan and the lords of
Iztapalapan and Coyuhuacan, who were also shackled.[569] Thus we
see that Montezuma’s captivity did not greatly affect his power, since
he could so readily place under restraint the confederate kings, in
their own provinces; and it was not wholly unwelcome to him to find
his misfortune shared by other prominent men, since this made his
disgrace less conspicuous.
He now resolved, with the approval of Cortés, to depose the
Tezcucan ruler, as a rebel against his authority, and to place on the
throne a more dutiful subject, a younger natural brother of Cacama,
named Cuicuetzcatl,[570] whom his ill-treatment had driven to Mexico
for protection. The nomination was for the sake of appearance
submitted for ratification to a convention of loyal Tezcucan chiefs,
many of whom hoped no doubt to obtain greater influence under this
youth. The new king was escorted to the gates of Mexico by Cortés
and Montezuma, and received at Tezcuco with triumphal arches and
processions.[571]
 And now, with the three confederate rulers and a number of
leading caciques in his power, the great king-maker thought the time
had come to exact a formal acknowledgment of Spanish sovereignty.
He reminded Montezuma of his promises to pay tribute, and
demanded that he and his vassals should tender allegiance. Instead
of the objections expected, Cortés was surprised to hear a prompt
acquiescence. Montezuma had evidently been long prepared for the
demand, and said that he would at once convene his chiefs for
consultation. Within little more than a week the summoned
dignitaries had arrived, and at a meeting, attended by no Spaniards
save the page, he intimated to the leading personages, so far as he
dared before this witness, that the concession demanded of them
was to satisfy the importunate jailers. “The gods, alas! are mute,”
concluded Montezuma; “but by and by they may signify their will
more clearly, and I will then say what further is to be done.”[572] All
declared sorrowfully that they would do as he bade, and Cortés was
informed that on the following day the required ceremony would take
place.
On this occasion the chiefs mustered in force before
Montezuma, who was seated on a throne having on either side the
new king of Tezcuco and he of Tlacopan.[573] All being prepared, the
Spanish general entered with his captains and a number of soldiers.
The emperor now addressed his vassals, reminding them of the
relation so long and happily maintained between them—as dutiful
subjects on the one side, and a line of loving monarchs on the other.
Comparing the Quetzalcoatl myth and other indications with the
advent of white men from the region of the rising sun, he showed
that they must be the long expected race, sent to claim allegiance for
their king, to whom the sovereignty evidently belonged. The gods
had willed it that their generation should repair the omission of their
ancestors. “Hence I pray that as you have hitherto held and obeyed
me as your lord, so you will henceforth hold and obey this great king,
for he is your legitimate ruler, and in his place accept this captain of
his. All the tribute and service hitherto tendered me give to him, for I
also have to contribute and serve with all that he may require. In
doing this you will fulfil not only your duty, but give me great
pleasure.”[574]
His concluding words were almost lost in the sobs which his
humiliated soul could no longer stifle. The chiefs were equally
affected, and the sympathies even of the flint-hearted Spaniards
were aroused to a degree which moistened many an eye. With some
of the lately arrived dignitaries, who had not had time to fully grasp
the situation at the capital, indignation struggled with grief at the
dismal prospect. Others recalled the prophecy that the empire would
terminate with Montezuma, whose very name appeared fraught with
evil omen,[575] and were quite reconciled to the inevitable. So were
most of them, for that matter, either through belief in the myth or from
a sense of duty to their master. One of the eldest nobles broke the
oppressive silence by declaring his sorrow at witnessing the grief of
their beloved sovereign and hearing the announcement of coming
changes. But since the time had come for the fulfilment of divine
decrees, they, as devout and dutiful subjects, could only submit.
Again their grief broke forth, though many a bitter glance was called
up by the allusion to changes in store for them. Observing the bad
impression, Cortés hastened to assure them that Montezuma would
not only remain the great emperor he had always been, and his
vassals be confirmed in their dignities and possessions, but that their
domain and power would be increased. The changes proposed were
merely intended to stop wars, to enlighten them on matters with
which they were as yet unacquainted, and to promote general
welfare. One after another, beginning with Montezuma, they now
swore allegiance, and gave promise of service and tribute, after
which they were dismissed with thanks for their compliance.[576]
 The submission of the sovereigns appears to have been quietly
accepted throughout the country, and the impunity with which even
single Spaniards moved about shows that no hostility had been
aroused by the act, in the provinces at least. Evidently the people
hovered between fear of men who so few in number could yet
perform so great achievements, and awe of divine will as indicated
by the prophecies and traditions. Cortés was not slow in making use
of his new power by representing to the emperor that, his king being
in need of gold for certain projects, it would be well for the new
vassals to begin tribute payments as an earnest of their loyalty.
Montezuma had expected this, and it was readily agreed that he
should send officers, accompanied by Spaniards, to the different
provinces and towns of the empire for contributions.[577] These
demands were met with more or less alacrity, and in poured gold and
silver, in dust, and quoits, and leaves, and trinkets, which formed to a
certain extent a medium for trade. Many towns remote from the
mines had nothing to offer save a few jewels, which were perhaps
heirlooms among the chiefs.[578]
When the collectors returned, Montezuma summoned the
Spanish leaders, and surrendered what they had brought. In addition
to this, he offered them the treasures kept in his own palace,
regretting that he had not more to give; but previous offerings had
diminished what he possessed. “When you transmit it to your king,”
he said, “tell him that it comes from his good vassal, Montezuma.”
He requested that certain fine chalchiuite stones, each valued at two
loads of gold, and some finely chased and inlaid blow-pipes, should
be given to the king alone.[579] This liberality evoked the most
profound protestations of gratitude, as may be supposed, for they
had not expected so great an addition to the glittering heaps already
in their possession. Tapia and another officer were despatched in all
haste with the imperial mayordomo to receive the treasure. It was
stored in a hall and two smaller chambers of the aviary building,[580]
and consisted of gold, silver, and precious stones, in setting and in
separate form, with feathers, robes, and other articles, all of which
were transferred to the Spanish quarters.[581]
These valuables, together with the collections from the provinces
and the previously surrendered treasures of Axayacatl, were given to
Cortés, who placed them in charge of the treasurer, Gonzalo Mejía,
and the contador, Alonso de Ávila. The famed smiths of Azcapuzalco
were called in to separate the gold and silver settings from the jewels
of less delicacy and beauty, which it had been determined to melt.
This took about three days. They were then melted into bars, three
fingers in breadth, and stamped with the royal arms.[582] Iron weights
were made of one arroba and downward, not very exact, it seems,
yet suitable for the purpose, and with these the value of the melted
gold was found to be somewhat over 162,000 pesos de oro,
according to Cortés’ statement; the silver weighed over 500 marcos,
and the unbroken jewels and other effects were estimated at over
500,000 ducats, not counting the workmanship.[583] The jewels were
set with feathers, pearls, and precious stones, fashioned chiefly in
animal forms, “so perfect as to appear natural.” A number of trinkets
for the royal share had also been fashioned by the goldsmiths after
designs by the Spaniards, such as saintly images, crucifixes,
bracelets, and chains, all made with wonderful fidelity to originals.
The silver for the same share was made into plates, spoons, and
similar articles. The feathers presented a brilliant variety of colors
and forms, and the cotton, some of the most delicate texture and
color, was both plain and embroidered, and made into robes,
tapestry, covers, and other articles. Turquoises, pearls, toys, and
trinkets were also among the treasures.[584]
Cortés proposed to defer the distribution till more gold and better
weights were obtained; but the men, who with good reason, perhaps,
suspected that a delay might diminish rather than increase the
treasures, clamored for an immediate division. The troops were
accordingly called, and in their presence the partition was made: first
of the royal fifth;[585] then of the fifth promised to Cortés when
appointed captain-general; after this a large sum was set apart to
cover expenditures by Cortés and Velazquez on the fleet and its
outfit, and the value of the horses killed during the campaign,[586]
and another sum for the expenses and shares of the procuradores in
Spain, while double or special shares were assigned to the priests,
the captains, those owning horses, and the men with fire-arms and
cross-bows.[587] After all these deductions but little remained for the
rank and file—a hundred pesos, if we may credit Bernal Diaz.[588]
This, many indignantly refused to accept; others took it, but joined in
the clamors of the discontented.
It is almost too much to ask of vultures not to quarrel over their
prey. The murmur against the royal fifth was loud enough, but the
second fifth for Cortés raised quite an outcry. “Are we to have a
second king?” they asked. Others inquired, “For whose fleet are we
paying?” They further wished to know whether the fame and
promotion acquired for the general by his men could not satisfy
some of his claims, for the present, at least. They had once before
surrendered hard-earned money to please him and to promote his
credit with the king, and now, when they had been led to expect
reward, it was again snatched from them. Some said that a large
proportion of the treasures had been secured by Cortés and his
favorites before the distribution began; and the value of the heavy
gold chains and other ornaments displayed by them was significantly
pointed at as out of proportion to their share.
The suspicion was confirmed by a quarrel which occurred shortly
after between Velazquez de Leon and Treasurer Mejía respecting
the payment of the royal fifth on certain unbroken jewels found in
Velazquez’ possession, and received by him before the
apportionment. It was enough, said Mejía, for Cortés to appropriate
unassessed treasures. Velazquez refusing to comply, they came to
blows, and if friends had not interfered there might have been an
officer or two less in the camp. As it was, both received slight
wounds, and subsequently shackles. Mejía was released within a
few hours; but his antagonist retained the fetters for two days,
persuaded to submit with grace thereto by Cortés, it was said, in
order to allay suspicions and to show that the general could be just,
even when it affected a friend.[589]
Finding that the murmurs were becoming serious, Cortés
brought his soothing eloquence to bear upon the troubled spirits. He
represented that all his thoughts, efforts, and possessions were for
the honor of his God, his king, and his companions. With them he
had shared every danger and hardship, and for their welfare he had
watched, rendering justice to all. The division had been fairly made
in accordance with previous arrangement. But he was not avaricious;
all he had was theirs, and he would employ it for them as might a
father. He would surrender the fifth which had been assigned him, if
they wished it, retaining only his share as captain-general; and he
would also help any one in need. The treasure thus far secured was
insignificant compared to what lay before them. What mattered a few
hundred pesos more or less in view of the rich mines, the large
tracts, and the immense number of towns, which were all theirs, so
long as they held loyally together? “I will make a lord of every one of
you,” he concluded, “if you will but have peace and patience.”[590]
And to give greater effect to this harangue he bribed with gifts and
promises the more influential to sound his praises; whereupon the
murmurs died away, though rancor still remained with many, awaiting
opportunity.[591]
A large proportion of the soldiers imitated the example of the
heavy sharers in the spoils by converting their allotment, with the aid
of Azcapuzalcan goldsmiths, into chains, crosses, and other
adornments for their persons, so that the display of wealth became
quite dazzling. Others yielded to the infatuation for gambling, then so
prevalent, and lost without a murmur the hard-earned share.[592]
But one thing now remained to complete the triumph of the
conqueror. The manacled kings were subservient, and the people
displayed their loyalty by pouring tribute into his coffers. But his god
was not theirs, and this the pious pilferer could not endure. He and
his priests had lost no opportunity to preach the faith to emperor and
subjects;[593] but the hearts of the natives were obdurately fixed on
the idols of the pyramid. He never beheld the temple without being
tempted to lay low the effigies of Satan, and it was owing only to
Father Olmedo’s prudent counsel that the temptation was resisted.
Repeatedly had he urged on the weak emperor to begin the great
work by some radical reform, but could obtain only the promise that
human sacrifices would be stopped. Finding that even this was not
observed, he consulted with his captains, and it was agreed to
demand the surrender of the great temple for Christian worship, so
that the natives might be made to feel the holy influence of its
symbols and rites. Montezuma was prepared with excuses, but the
deputation declared with fierce vehemence that if this were refused
they would forcibly remove the idols and kill the priests who resisted.
“Malinche,” exclaimed the monarch in alarm, “do you then seek the
destruction of the city? Our gods are incensed against us, and the
people imbittered. Even your lives will not be safe. Wait, I entreat
you, till I call the priests for consultation.”[594]
Cortés saw that nothing more could then be attained, but with
the indiscreet zeal for religion which often blinded him he determined
that there should be no further delay. He apprehended no uprising
among a people which had so patiently submitted to all exactions,
yet he feared that the priests, if warned, might prevent an entry into