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Essentials of Modern
Neuroscience
This page intentionally left blank
 A LANGE medical book

Essentials of Modern
Neuroscience
Editors
Franklin R. Amthor, PhD David G. Standaert, MD, PhD
Professor ofPsychology John N. Whitaker Professor and Chair
University ofAlabama at Birmingham Department ofNeurology
Birmingham, Alabama University ofAlabama at Birmingham
Birmingham, Alabama
Anne B. Theibert, PhD
Professor ofNeurobiology Erik D. Roberson, MD, PhD
University ofAlabama at Birmingham Rebecca Gale Endowed Professor
Birmingham, Alabama Department ofNeurology
University ofAlabama at Birmingham
Birmingham, Alabama

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Contents
About the Authors ix
Contributors xi
Preface xiii
6 Resting Membrane Potential &
Action Potential 109
PART I Franklin R. Amthor

ANATOMY &FUNCTION OF THE 7 Mechanisms of Synaptic Transmission 123

NERVOUS SYSTEM Anne B. Theibert

8 Neurotransmitter Systems I:
SECTION
Acetylcholine & the Amino Acids 141
Organization Bi Structure of
I the Nervous System 1
Anne B. Theibert

9 Neurotransmitter Systems II: Monoamines,

Purines, Neuropeptides, &Unconventional
1 Organization & Cells of the Nervous Neurotransmitters 159
System 3
Anne B. Theibert
Anne B. Theibert
10 Synaptic Plasticity 177
2 Development of the Nervous System 27
Cristin F. Gavin & Anne B. Theibert
Lucas Pozzo-Miller & Anne B. Theibert

3 Functional Anatomy of the Nervous

System I: Cerebrum & Subcortical SECTION
Systems Neuroscience:
Structures 45 Sensory Bi Motor
Anne B. Theibert Ill Systems 197
4 Functional Anatomy of the Nervous
System II: The Brainstem, Cerebellum, 11 Visual System I: The Eye 199
Spinal Cord, Peripheral Nervous Franklin R. Amthor
System, & Supporting Systems 67
12 Visual System II: Central Visual Pathways 217
Anne B. Theibert
Franklin R. Amthor

13 Auditory &Vestibular Systems 227

SECTION Cellular Bi Molecular Franklin R. Amthor
Neuroscience: Eledrical
II Signaling Bi Synaptic
Transmission 93
14 Chemical Senses: Olfactory &
Gustatory Systems 243
Franklin R. Amthor
5 Movement of Ions Across Biological
Membranes: Ion Transporters & 15 Somatosensory System 257
Channels 95 Franklin R. Amthor, Stacie K. Totsch, &
Robin AJ. Lester Robert E. Sorge
y
vi CONTIHl'S

16 Pyramidal Motor System 273 25 Neurooncology 393

Franklin R. Amthor Paula Warren

17 Extrapyramidal Motor Systems: Basal 26 Headache Disorders & Neurologic

Ganglia &Cerebellum 281 Pain Syndromes 409
Franklin R. Amthor Cristina Woh/gehagen

18 Autonomic Nervous System: Sympathetic, 27 Epilepsy 425

Parasympathetic, & Enteric 297 Ashley Thomas
Franklin R. Amthor
28 Movement Disorders 437
Victor W. Sung
SECTION
Cognitive 29 Age-Associated Cognitive Disorders
& Dementia 449
IV Neuroscience 313
Marissa C. Nate/son love &
RabiaJamy
19 Consciousness 315
30 Neuroimmunology & Neuroinflammatory
Franklin R. Amthor
Disorders 461
20 Learning &Memory 329 William Meador
Cristin F. Gavin & Anne B. Theibert
31 Neuromuscular Disorders 475
21 Language 341 Mohamed Kazamel
Daniel Mirman
32 Neurologic Infections 489
22 Emotion 351 Shruti P. Agnihotri
Franklin R. Amthor
33 Neurotrauma 507
23 Circadian Rhythms & Sleep 359 Angela Hays Shapshak
Christopher M. Ciar/eg/io, Rachel C. Besing,
34 Sleep Disorders 523
& Karen L. Gamble
Joseph T. Daley

35 Pediatric Neurology 537

Lydia Marcus
PART II
NERVOUS SYSTEM
SECTION
DISORDERS &THERAPEUTICS
Ear&EyeDisorders 551
SECTION
VI
v Neurologlc & Neurosurglcal
Disorders 377 36 Neurotology & Ear Disorders 553
Yoon-Hee Cha

24 Stroke & Neurovascular Disorders 379 37 Ocular Disorders 567

Michael Lyerly Brion Samuels
 CONTENTS Vii

SECTION
Psychiatric Disorders 591
VII
38 Thought Disorders 593
Nina Kraguljac
39 Mood Disorders 605
Lili
40 Anxiety Disorders 619
Jesse Tobias C. Martinez, Jr.
G Personality Disorders 635
Merida Grant
43 Substance Use Disorders 641
Stephen Brackett, Samantha Schiavon,
Michelle Sisson, &Karen Cropsey
44 Child & Adolescent Psychiatry 651
YesieYoon
Answers 659
Index 675

41 Somatic Symptom Disorder &Related

Disorders 627
Aaron D. Fabian & Lindsey Elliott
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About the Authors
Franklin R. Amthor, PhD, is a professor of Psychology at the
University of Alabama at Birmingham (UAB). Dr. Amthor's
research interests evolved from his undergraduate electrical
engineering background at Cornell University into artificial
intelligence simulations involving Perceptrons, and then visual
neuroscience. His Ph.D. work was done at Duke University
in Biomedical Engineering on quantitative analysis of retinal
ganglion cell responses. He did a postdoctoral fellowship at
the School of Optometry at UAB, and then was an NEI RO 1
funded principal investigator who led a team determining the
relationship between mammalian ganglion cell physiology,
morphology, and central projections. More recently, he has
worked on retinal circuitry underlying the responses of dif-
ferent retinal ganglion cell classes, and on assistive devices for
the blind.
Anne B. lheibert, PhD, is a professor of Neurobiology at the
University of Alabama at Birmingham (UAB). Dr. Theibert
is a researcher, teacher, and course director in both the UAB
College of Arts and Sciences and School of Medicine (SoM).
She received her B.A. in Chemistry from Goucher College, and
Ph.D. in Biological Chemistry from Johns Hopkins University.
Following a postdoctoral fellowship in the Neuroscience
Department at Johns Hopkins, she was recruited to the SoM
faculty at UAB in 1991, and directed an NIH-funded basic
research program for 17 years, concentrating on cell signaling
during neuronal development, with a focus on understanding
pathways disrupted in neurodevelopmental disorders. In 2008,
Dr. Theibert cofounded the UAB Undergraduate Neuroscience
Program (UNP) and served as Director of the UNP during
its first decade. She currently teaches neuroscience and ner-
vous system development to UAB professional and graduate
students, and directs and teaches undergraduate courses in
cellular, molecular, systems and cognitive neuroscience.
David G. Standaert, MD, PhD, is a professor and chair
of the Department of Neurology at the University of
Alabama at Birmingham (UAB), where he holds the John N.
Whitaker Endowed Chair in Neurology. He is a physician-
scientist with interests in Parkinson disease and other
disorders of movement. He received his A.B. with high
honors from Harvard College, and M.D. and Ph.D. degrees
from Washington University in St. Louis. He was a resident in
neurology at the Hospital of the University of Pennsylvania,
and a fellow in movement disorders at Massachusetts
General Hospital. He joined the faculty of Harvard Medical
School in 1995, and relocated to UAB in 2006. Currently he
directs the NIH-funded Alabama Morris K. Udall Center of
Excellence in Parkinson's Disease Research. He is Chairman
of the Scientific Advisory Board of the American Parkinson
Disease Association, Deputy Editor of the journal Movement
Disorders, a Fellow of both the American Neurological
Association and the American Academy of Neurology, a
Councilor of the Association of University Professors of
Neurology, and a member of the NIH/NINDS Board of
Scientific Counselors. His lab has a long-standing interest in
the basic mechanisms underlying Parkinson disease as well
as the complications of therapy.
Erik D. Roberson, MD, PhD, is the Rebecca Gale endowed
professor of Neurology and Neurobiology at the University of
Alabama at Birmingham (UAB). Dr. Roberson is a physician-
scientist whose research is dedicated to reducing the impact
of age-related cognitive disorders. He received his A.B. with
highest honors from Princeton University and then earned his
M.D. and Ph.D. in neuroscience at Baylor College of Medicine.
He was a resident and chief resident in neurology at the
University of California San Francisco, where he also com-
pleted a clinical fellowship in behavioral neurology. In addi-
tion to his laboratory focused on understanding mechanisms
and identifying new treatments for dementia, Dr. Roberson
directs the Alzheimer's Disease Center and the Center for
Neurodegeneration and Experimental Therapeutics at UAB.
He also cares for patients in the UAB Memory Disorders Clinic
and leads clinical trials testing new dementia treatments.
ix
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Contributors
Shruti P. Agnihotri, MD Aaron D. Fobian, PhD
Assistant Professor of Neurology Assistant Professor of Psychiatry
University of Alabama at Birmingham University of Alabama at Birmingham
Birmingham, Alabama Birmingham, Alabama
Chapter32 Chapter41

Rachel C. Beslng, PhD Karen L. Gamble, PhD

Assistant Professor of Psychology Associate Professor of Psychiatry
Brescia University University of Alabama at Birmingham
Owensboro, Kentucky Birmingham, Alabama
Chapter 23 Chapter 23

Stephen Brackett, MD Cristin F. Gavin, PhD

Clinical Assistant Professor of Psychiatry Assistant Professor of Neurobiology
University of Alabama at Birmingham University of Alabama at Birmingham
Birmingham, Alabama Birmingham, Alabama
Chapter43 Chapters 10 & 20

Yoon-Hee Cha, MD Merida Grant, PhD

Associate Professor of Neurology Associate Professor of Psychiatry
University of Minnesota University of Alabama at Birmingham
l\1inneapolis,l\1innesota Birmingham, Alabama
Chapter36 Chapter42

Christopher M. Clarlegllo, PhD Rabia Ja my, MD

Chair of Science and Director of the Advanced Neurology Resident
Science Academy University of Alabama at Birmingham
l\1orris Catholic High School Birmingham, Alabama
Denville, New Jersey Chapter 29
Chapter 23
Mohamed Kazamel, MD
Karen Cropsey, PsyD Assistant Professor of Neurology
Professor of Psychiatry University of Alabama at Birmingham
University of Alabama at Birmingham Birmingham, Alabama
Birmingham, Alabama Chapter31
Chapter43
Nina Kraguljac, MD
Joseph T. Daley, MD Assistant Professor of Psychiatry
Associate Professor of Neurology University of Alabama at Birmingham
University of Alabama at Birmingham Birmingham, Alabama
Birmingham, Alabama Chapter 38
Chapter34
Robin AJ. Lester, PhD
Lindsey Elliott, PhD Professor of Neurobiology
Graduate Student University of Alabama at Birmingham
University of Alabama at Birmingham Birmingham, Alabama
Birmingham, Alabama Chapters
Chapter41

xi
Xii CONTRIBUTORS

Li Li, MD, PhD Angela Hays Shapshak, MD

Associate Professor of Psychiatry Associate Professor of Neurology
University of Alabama at Birmingham University of Alabama at Birmingham
Birmingham, Alabama Birmingham, Alabama
Chapter39 Chapter 33
Michael Lyerly, MD Michelle Sisson, MA
Associate Professor of Neurology Graduate Student
University of Alabama at Birmingham University of Alabama at Birmingham
Birmingham, Alabama Birmingham, Alabama
Chapter 24 Chapter43
Lydia Marcus, MD Robert E. Sorge, PhD
Assistant Professor of Pediatrics Associate Professor of Psychology
University of Alabama at Birmingham School of Medicine
Birmingham, Alabama University of Alabama at Birmingham
Chapter 35 Birmingham, Alabama
Chapter 15
Jesse Tobias C. Martinez, Jr., MD
Assistant Professor of Psychiatry Victor W. Sung, MD
University of Alabama at Birmingham Associate Professor of Neurology
Birmingham, Alabama University of Alabama at Birmingham
Chapter40 Birmingham, Alabama
Chapter 28
William Meador, MD
Associate Professor of Neurology Ashley Thomas, MD
University of Alabama at Birmingham Associate Professor of Neurology
Birmingham, Alabama University of Alabama at Birmingham
Chapter 30 Birmingham, Alabama
Chapter27
Daniel Mirman, PhD
Senior Lecturer Stacie K. Totsch, PhD
The University of Edinburgh Division of Pediatric Hematology and Oncology
Edinburgh, United Kingdom Department of Pediatrics
Chapter 21 University of Alabama at Birmingham
Birmingham, Alabama
Marissa C. Natelson Love, MD Chapter 15
Assistant Professor of Neurology
University of Alabama at Birmingham Paula Warren, MD
Birmingham, Alabama Neurooncologist
Chapter 29 Hattiesburg Clinic
Hattiesburg, Mississippi
Lucas Pozzo-Miller, PhD Chapter 25
Professor of Neurobiology
University of Alabama at Birmingham Cristina Wohlgehagen, MD
Birmingham, Alabama Headache Specialist and Founder
Chapter 2 International Headache Center
Dallas, Texas
Brian Samuels, MD, PhD Chapter 26
Associate Professor of Ophthalmology
University of Alabama at Birmingham Yesie Yoon, MD
Birmingham, Alabama Assistant Professor of Psychiatry
Chapter 37 University of Alabama at Birmingham
Birmingham, Alabama
Samantha Schiavon, MA Chapter44
Graduate Student
University of Alabama at Birmingham
Birmingham, Alabama
Chapter43
Preface
Why does the world need another neuroscience text? Students
study neuroscience for a variety of purposes that range from
molecular basic science, to systems, to clinical. Although there
are many neuroscience texts that cover some of these areas
well, few attempt to cover the entire range. Moreover, texts
that attempt to cover such a broad range of neuroscience con-
tent are often too large to be tractable, or differentiate poorly
between basic science and clinical sections.
Essentials of Modern Neuroscience has been written for
students in the medical and other health professions with the
goal of being accessible, coherently organized, and universal
in its coverage of basic science and clinical neuroscience. It
is thus divided into two main parts, the first being a thor-
ough treatment of the basic science of the anatomy and
function of the nervous system, and the second compris-
ing an extended treatment of nervous system disorders and
therapeuties.
Part I, Anatomy & Function of the Nervous System, was writ-
ten with two goals: (1) It stands alone as a concise introduc-
tory text for neuroscience, and could be used as such, and
(2) its organization allows it to be used as a good reference
for the clinical sections when basic science background is
needed. Section I gives a systematic explanation of the layout
of the central and peripheral nervous systems, concentrating
on their role in nervous system function. Section II then cov-
ers modern molecular neuroscience, starting with a complete
treatment of the cellular biophysics underlying the resting and
action potentials, then covering synaptic transmission, neu-
rotransmitter systems, and synaptic plasticity. Section III, Sys-
tems Neuroscience: Sensory & Motor Systems, considers all
the sensory systems from transduction to central processing.
It then moves to motor systems, covering the pyramidal and
extrapyramidal cortical-spinal pathways, and then the auto-
nomic and enteric nervous systems. Section IV is Cognitive
Neuroscience, investigating the neural basis of conscious-
ness, learning and memory, language, emotion, and circadian
rhythms.
Part II, Nervous System Disorders & Therapeutics, intro-
duces students to the major disorders of the nervous system
and commonly used therapeutics, building on the founda-
tion laid down in Part I, and is organized by clinical specialty.
Section V is comprised of 12 chapters surveying disorders
treated by neurologists and neurosurgeons. Section VI covers
otological, vestibular, and ophthahnological disorders. Finally,
Section VII covers the world of psychiatric disorders with
seven chapters ranging from thought and mood disorders
to addiction and functional disorders. Written by clinicians,
the chapters of Part II are intended to prepare students for
initial clinical encounters in each of these specialty areas. Each
chapter begins with a description of disease prevalence and
burden to help students understand which disorders they are
most likely to encounter and which have the biggest impact
Discussions of the diagnosis, key features, and treatment of
these disorders are aimed at preparing students for board-type
examinations. Case studies help consolidate the presentation
of classic diseases.
Acknowledgment
F.R.A. would like to thank Prof. Karlene Ball, chair of the UAB
Psychology Depl while the book was being written, who sup-
ported F.R.A:s academic efforts.
xiii
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 PART I
ANATOMY & FUNCTION OF THE NERVOUS SYSTEM
This page inJentionally left blank
 CHAPTER

Organization & Cells of

the Nervous System
Anne B. Theibert

• Outline the major anatomic components of the central nervous system (CNS}
and perlpheral nervous system (PNS).
• Diagram the functional areas of the brain and spinal cord.
• Describe the types of nerves and ganglia in the PNS and their structure.
• Distinguish the different categories of neurons.
• Identify the neuronal organelles and their blochemlcal functions.
• Diagram the specialized neuronal processes and their functions.
• Describe the main CNS and PNS glial cells and their functions.

OVERVIEW: THE NERVOUS
SYSTEM
The nervous system mediates a wide range offunctions. from
detection ofenvironmental stimuli, to control of muscle con-
traction, to problem solving, language, and memory. The
nervous system is divided into 2 main parts, the central ner-
vous system (CNS) and the peripheral nervous system (PNS)
(Figures 1-1 and 1-2). Anatomically, the CNS is divided
into the brain and spinal cord. whereas the PNS is composed
of ganglia and nerves, including cranial and spinal nerves
and their branches. Functionally. the PNS can be divided
into the somatic, autonomic (visceral), and enteric nervous
systems. In the overall flow of information, the PNS detects
and relays sensory information about the external and inter-
nal environments to the CNS. The CNS receives, integrates.
and stores information and controls the output to the PNS to
generate responses and behavior.
At the cellular level, the nervous system is composed of
neurons and glial cells (Figure 1-3). Neurons (also called
nerve cells or neuronal cells) are the main signaling cells that
communicate with other neurons, muscles, or glands. Neu-
rons can be categorized by their function as sensory neurons.
motor neurons. or interneurons or by their morphology or
neurotransmitter. Glial cells (also called neuroglia or glia) are
the support cells in the nervous system. Astrocytes and sat-
ellite cells provide structural and metabolic support. oligo-
dendrocytes and Schwann cells furnish myelination of amns.
pericytes regulate capillaries, ependymal cells synthesize cere-
brospinal fluid (CSP). microglia are immune cells, and enteric
glia are part of the gastrointestinal (GI) tract. Neurons have
a cell body where the nucleus and majority of cellular organ-
elles are located and many biochemical activities occur. Neu-
rons also contain specialized processes and regions that allow
them to send and receive signals rapidly and precisely: The
axon is a process by which electrical signals are conducted and
where signals are sent to other neurons or target cells. The
dendrites are branched processes that receive signals from
other neurons. The synapse is a structure where signals are
transmitted. via synaptic transmission, from the axon to its
target. Neurons can receive thousands of synaptic inputs, can
form neural circuits, and function in networks that under-
lie sensations, cognitive functions, and the generation of
responses and behavior.
CNS COMPONENTS, COVERINGS,
lrVASCULATURE
The brain and spinal cord compose the CNS. The brain is
enclosed within the cranial cavity and is protected by the cra-
nium. (skull) and meninges (Figure l-4). The meninges are a
3-membrane system that covers, protects, and nourishes the
brain and spinal cord. The outer dura mater is a thick tough
membrane that is connected to the cranium and protects the
brain. The middle membrane, called the arachnoid mater,

3
4 PARTI Anatomy& Function oftheNl!M>us Synem

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

Twoc nal cord

nGM

Elements
of vertebral
Splni: column

FIGURE 1-1 Anatomic divisions of the nervous system and their structures: CNS and PNS. Forming the CNS, the brain (encased In
the skull) is continuous with the spinal cord (encased in the spinal column}. Forming the PNS, cranial nerves emerge from the brainstem,
while spinal nerves emerge from the spinal cord. In the PNS, nerves are associated with spinal, cranial or autonomic ganglia, which are
not shown.

cushions the brain. Below the arachnoid is the suharachnoid
space, which contains CSF and where specialized regions
called arachnoid granulations resorb CSF. The innermost
layer, the pia mater, is a thin layer that adheres to the surface of
the brain and follows its contours, forming a barrier but with
many capillaries that nourish the brain and spinal cord.
The brain bas 3 main regions: the forebrain, brainstem,
and cerebellum. The inner spaces of these regions form the
ventricles, which produce and circulate CSF and are con-
nected to form the ventricular system (Figure l-5). Both the
meninges and brain are highlyvascularized. Two main pairs of
arteries supply blood to the brain (Figure 1-6). The internal
carotid arteries, which are branches from the common carotid
artery, supply the anterior brain, whereas the vertebral arter-
ies, which are branches from the subclavian artery. supply the
posterior brain and brainstem. The main venous blood out-
flow from the brain is via the jugular veins.
CNS capillaries are specialized in that their vascular endo-
thelial cells form tight junctions and are enveloped in glial
cells, together producing the blood-brain barrier (BBB). The
BBB is a selective permeability barrier that prevents the direct
movement of unwanted molecules, immune cells, and patho-
gens into the brain. The BBB allows the passage of water, oxy-
gen, carbon dioxide, and lipid-soluble molecules, including

l
CNS PNS
Brain Ganglia
Spinal cord Cranlal and aplnal nelV88
I
l
'
Samallc dlvlalan
J
l
lllolor nwrona
Sensory information Motor impulses
from skin, skeletal from CNSto
muscles, and joints skeletal muscles
toCNS
FIGURE 1-2 Functional divisions of the nervous system: CNS and PNS.
steroid hormones, by passive diffusion. Astrocytes selectively
transport ions and molecules such as glucose and amino acids
and release them into the extracellular fluid to supply neW'Ons
and other glia with essential nutrients.
BASIC BRAIN ANATOMY
The forebrain is the largest part of the brain and contains the
cerebrum and diencephalon (Figure 1-7). The cerebrum is
formed by the large left and right cerebral hemispheres, which
are separated by the medial longitudinal fissure, and contains
the outer cerebral cortex. inner cerebral white matter, and
subcortical nuclei. The cerebrum encloses the lateral ventri-
cles and overlies the diencephalon, a structure that contains
the thalamus and hypothalamus and that surrounds the third
ventricle. Functionally, the forebrain is involved in receiving
sensory information from the PNS and generating outgoing
motor information, and is where executive and cognitive func-
tions are generated. The oldest part ofthe brain, the brainstem,
is composed of the midbrain, pons, and medulla and serves to
relay information from the spinal cord and cerebellum to the
forebrain and vice versa. In addition, the brainstem regulates
vital functions, such as breathing, consciousness, and control
of body temperature. The cerebral aqueduct and fourth ven-
tricle lie inside the brainstem. Connected to the pons, the cer-
ebellum forms the posterior-most region of the brain and is
involved in control and coordination of movement and some
cognitive tasks.
Examination of postmortem fixed brain tissue reveals
that each of these brain regions contains gray and white mat-
ter areas (Flgu.re 1-8). In living tissue. gray matter appears
pinkish light brown. Gray matter contains mainly neuronal
CHAPnR 1 01911nlmlon &Cellsofthe Nerwus System S
l I
Seneory neurons
Autonmnlc dlvlalan
I
Enlierlc
Sensory informa1ion Motor impulses from
from visceral CNS 10 smooth muscle,
organs to CNS cardiac muscle, and glands
cell bodies, their dendrites, and associated glial cells. In the
brain, 2 types of gray matter are present Cortical gray mat-
ter forms the outer regions of the cerebrum and cerebellum
and is distinguished by its layered organization of neurons.
The other type of gray matter is called a nucleus, an aggregate
of cell bodies with similar morphology and function found
below the cortex (subcortical nuclei) and in the brainstem and
cerebellum. White matter contains predominantly myelinated
axons (which, because of their fatty rich myelin membrane,
produce the white appearance) and white matter glial cells.
White matter contains bundles of myelinated axons that are
referred to as tracts in the CNS. In the brain, the white mat-
ter tracts include projection tracts that connect neurons in the
forebrain to neurons in the brainstem or spinal cord, associa-
tion tracts that connect one cortical region to another, and
commissural tracts, which connect areas from one side of the
brain to the other.
The exterior surface of the cerebrum is distinguished by
many gyri (singular: gyrus) and sulci (singular: sulcus) that
produce the characteristic folded appearance of the human
and many mammalian brains. A sulcus is a groove or furrow
in the cerebral cortex. whereas a gyrus is a crest or ridge. The
folding created by gyri and sulci facilitates a larger surface area
of cerebral cortex to :fit inside the skull Deep sulci separate
the cortex into 4 cortical lobes on each side, called the frontal.
parietal, temporal, and occipital lobes, named for the cranial
bones that overlie each (Figure 1-9). The central sulcus forms
the division between the frontal and parietal lobe. The lateral
sulcus (also called the Sylvian. fissure) separates the temporal
lobe from the frontal and parietal lobes. The parieto-ocdpital
sulcus forms the boundary between the parietal and occipi-
tal lobes. Many additional sulcl and gyri are present in the
6 PART I Anatomy & FunC11on ofVie Nerwus System

FIGURE 1-3 Cellular components of the nervous system. A. Micrograph showing neuronal cell bodies (N) and smaller glial (G) cells
that surround them In the CNS. Use of a hematoxylln stain with gold chloride shows the neuropll (Np), which Is the dense network of axons
and dendrites. B. Neurons and glla In the CNS. A typical projectlon/pr1ndpal lnterneuron has a cell body (or soma), multiple dendrites, which
receive synaptic responses, and an axon, which sends electrical signals and Is Insulated by a myelln sheath dertved from specialized membrane
processes ofollgodendrocytes. Astrocytes perfcnn supportive roles In the CNS, and. their processes are closely associated with neuronal
synapses and eaplllarles. (Part A. reproduced with pennlsslon from Young 8, Heath JW: Wheatet's Functlonal Hlsto/ogy: A Tl!Jlt andColourAtlas. EdlnbuTgh: Oiurchlll
l.lvtngstone; 2000; part B, reproduced with pennlsslon from Katzung BG: Basic& CJ/nlml Pharmamlogy, 14th ed. New York, NY: Mr::GlilW HUI; 2018.)

cerebral cortex. with all cortical gyri and sulcl containing an
outer layer of cortical gray matter and a thin layer of underly-
ing white matter. Each of the 4 main lobes contains distinct
anatomic and functional areas.
BASIC SPINAL CORD ANATOMY
The spinal cord emerges caudally from the brainstem, within the
spinal canal, and is protected by the vertebral column (also called
the spine) and meninges (Figure 1-10). Along their length, the
vertebral column and spinal cord inside are separated into 5
regions, called cervical. thoracic. lwnbar, sacral. and coccygeal
segments. Similar to the brain, the spinal cord is composed of
gray and white matter regions but with an opposite organi7.ation.
Spinal gray matter, composed of neuronal cell bodies, dendrites,
and glia. is located medially and is surrounded by spinal white
matter, which contains tracts and g1ia, located in the lateral areas
of the spinal cord. The gray matter surrounds the inner central
canal, which provides CSP to the spinal cord. Spinal gray matter
is separated anatomically and functionally into dorsal (poste-
rior) and ventral (anterior) horns on each side. Sensory infor-
mation is carried by afferent axons of spinal nerves, which enter
the cord via the dorsal roots. These sensory axons branch, and
one branch can synapse on intemeurons in the dorsal horn,
whereas the other branch can ascend to the brain. These axons
form the ascending tracts in the spinal cord. Descending tracts
in the white matter provide outgoing motor information from
the cerebrum or brainstem. The axons in the descending tracts
synapse on motor neuron cell bodies in the ventral/anterior
horns. The ventral horn motor neurons extend their axons out
of the cord via the ventral root, and their axons form the motor
components of the spinal nerves. Because the lower motor neu-
rons cell bodies lie in the spinal cord, while their axons form the
motor components ofthe spinal nerves, they are considered part
of both the CNS and PNS. The anatomy of the brain and spinal
cord is described in greater detail in Chapter 3.
 CHAPnR 1 01911nlmlon &Cellsofthe Nervous System 7

~------------- Superior sagittal sinus

- - - - - - - - - - - - - Arachnoid vlllus
- - - - - - - - - - - Skin of scalp
- - . , , - - - - - - - Pertosteum

Perlosteal layer }
~:;n.,-- Menlng881 layer Dura mater
1:~,...::;=--'3--Subdural space (poten11al space)
~~~---.....-;r---Arachnold

--==----=::-'!--- Subarachnold space

- - - -- ------Arachnoid trabecula:e
Pia mllfllr
Cerebral cortex
-----VVhite matter

FIGURE 1-4 Meninges around the brain. Composed of the dura mater, arachnoid mater, and pla mater, the meninges form a membrane
system that surrounds the brain and the spinal cord. The diagram also show the subarachnold space filled with cerebrosplnal fluid (CSF), and
arachnoid villi, which function to resorb CSF and transfer it into the blood. (Repnxluc:ed with permts.slon from McKJnley MP, O'l.Dughlln VO, BidleTS.Anatomy
andl'hyslology:Attlnt:tgrarJvl/!Appmadl. NewYort. NY: McGraw Hll~ 2013~

PNS: FUNCTIONAL DIVISIONS
The PNS has 3 functional divisions: the somatic, autonomic
(also calledvisceral), and enteric nervous systems. The somatic
nervous sy5tem mediates conscious/voluntary movement via
regulation ofskeletal muscle contraction and provides sensory
information from the skin. muscles, and joints. The autonomic
nervous system involves unconscious/involuntary control
of cardiac muscle, smooth muscle, and glands. Its sensory

FIGURE 1-5 The ventricular system.A.Three-dimensional lateral view of the ventricles of the brain. 8. Coronal section d the brain showing the
ventricles. 'The ventricles are lined with ependymal cells, and contain the choroid plexus, which synthesize cerebrospinal fluid (CiF). lhe two lateral
ventrldes lie within the left and right cerebrum, the third wntlkfe (between the hallles of ttie dlenc:ephalon), the cerebral aqueduct.. and the fourth
'W!ntride within the brainstem. (Reprodua'Jd wl1h penTil5*>n from Marton DA. Foremiln IQ\.Albenlne ICH.1lit'.81gPklun!:Gnm~ 2nd ed. New'Ycril. NY: Mc:Graw'HI; 2019~
8 PARTI Anatomy& Function oftheNem>us Symm

~--- Lsft vertebral

~ ,• artery
·' FIGURE 1-8 Brain grayand white mllttera~ Coronal section from
A-
.
~
Lsft Internal
1 carotid artery postmcrtem human brain. (Reprockla!d with peimlsslonfrom Kl!mpWI.. Burns DK.
Travis Brown ni. Pr.ithology: Thi! IYg Picture. NewYaric, NY: McGraw Hll~ 2008.)
I _Left common
---~--- carotjd artery
component. often called the visceral sensory system. pro-
'---- vides information from the viscera. the internal organs. and
vasculature. The autonomic motor system is divided into
the sympathetic and parasympathetic nervous systems.
The sympathetic nervous system. referred to as the •fight or
flight.. system, is activated under conditions requiring mobi-
f -- - - Left subclavlan lization of energy. The parasympathetic nervous system.
artery
referred to as the "rest and digest.. or "feed and breed• sys-
tem. is activated when organisms are in a relaxed state. The
- - - Aorta enteric nervous system. which is also under involuntary con-
trol, governs the GI system. Although it receives consider-
able input from the autonomic nervous system, the enteric
nervous system can function independently and is consid-
FIGURE 1-6 Blood supply to the brain and the major ered a separate system in the PNS.
cerebral arteries. Arterial blood for the brain enters the cranial
cavity by way of two pairs of large vessels. The pair of internal
carotid arteries supplies arterial blood to most of the forebraln
while the pair of vertebral arteries supplies the bralnstem,
PNS: ANATOMIC COMPONENTS
cerebellum, occipital lobe, and parts of the thalamus. (Reproduced Anatomically, the PNS is composed of ganglia and nerves.
with permission from 'Wa>nnan SG. Qin/ml Neuroanatomy, 28th ed. New York. NY: Ganglia are clusters of functionally related neuronal cell
McGraw Hiii; 2017.)
bodies and their accompanying glial cells in the PNS.

- Diencephalon

FIGURE 1-7 Major anatomic divisions of the brain. A. Illustration of the mldsaglttal plane. a. Magnetic resonance Image of a
mldsaglttal section through the head. (Reproduced with permission from Waxman SG. CJ/nlcal Neuroanatomy, 28th ed. NewYortc. NY: McGraw Hll~ 2017.)

Pre central
gyrus
Frontal lobe
Lateral sulcus
Temporal lobe-__....
FIGURE 1-9 Lateral view of the brain. This view illusI.Tates the left cerebral hemisphere with its major sulci and gyri, cortical areas, and
several subcortical structures. (Reproduced with permtu1on from Morton OA. Foreman Kil, AlberUne KH. T1lt Big Pfctutt:Glou A1latomy.. 2nd ed. New York. NY:
McGraw Hll~ 2019.)
Cell bodies of somatic sensory neurons form the dorsal
root ganglia, whereas cell bodies of autonomic neurons
form the sympathetic and parasympathetic ganglia. The
sympathetic ganglia lie outside of but close to the spinal
cord and communicate to form. the sympathetic chain. The
parasympathetic ganglia in the body lie close to the organ
they innervate. The cranial ganglia contain parasympa-
thetic or sensory cell bodies.
Nerves are bundles of amns ensheathed in connective
tissue that innervate all parts of the body, sending messages
to and receiving messages from the CNS (Figure 1-11). The
neuronal cell bodies that give rise to nerves do not lie within
the nerves themselves. Rather, their cell bodies reside within
the brain, spinal cord. or ganglia. Nerves can contain both
efferent and afferent axons. Efferent amns transmit motor
signals from the CNS to the PNS and can be somatic or auto-
nomic. Afferent axons transmit sensory signals from the PNS
to the CNS; afferents can be somatic or visceral. Afferent and
efferent amns are protected by several layers ofconnective tis-
sue, which together with glia and blood vessels form nerves.
Spinal and cranial nerves supply input to and output from
the CNS. There are 31 pairs of spinal nerves, which emerge
from and travel to the spinal cord and which are named for
the spinal cord segment to which they connect (Figure 1-11).
CHAPnR 1 Of91lnlmlon &Cellsofthe Nervous System 9
Central Postcentral
\ sulcus gyrus
\
/
-~--...... Occipital
lobe
----- - eerebellum
Spinal nerves are mixed nerves, containing both motor effer-
ents and sensory afferents and containing both somatic and
autonomic components. As they leave or enter the spinal cord.
the afferents from the dorsal root and efferents from the ven-
tral root bundle together, but then branch to form the rami
(singular: ramus). The gray and white rami contain auto-
nomic components, whereas the dorsal/posterior and ventral/
anterior rami contain both somatic and autonomic compo-
nents. Some rami form a nerve ple:xus, a network of intercon-
necting nerves. In the somatic motor system, axons emerge
from lower motor neurons in the spinal cord. travel in the
spinal nerves, and directly innervate skeletal muscles. In
the autonomic nervous system, motor neurons in the spinal
cord (called pregangli.onic neurons) send their amns to syn-
apse onto a postganglionic neuron (whose cell bodies lie in
the autonomic ganglia). which then send axons to innervate
the target organ. Some nerve components form large distinc-
tive bundles or branches and are referred to by their specific
names, such as the splanchnic nerves or sciatic nerve.
Sensory and motor information for the head and neck
(and several other parts of the body) is supplied by the 12
pairs of cranial nerves. The majority (10 of 12) of the cranial
nerves are part of the PNS, with their cranial nerve nuclei
located in the brainstem and nerves traveling outside the CNS.
10 PART I Anatomy &Function ofthe NerYOllS System

Glialcell Neuronal Myelinated

Ne...ron nucleus pl'OCe$Se$ axons
l 1.

Gray matter White matter

B

Thoracic

_;..,.-- Nerve roots

---- (and meninges)

L.umbosacral
enlargement
Conus ....,
medullarls Lumbar

··... .....
'\

--~,,......_..._ Denticulate
··· ·~ ...~.... llgament
l ....,
root
..,._~ Ventral
of nerve
·'-~ Pia

A c
FIGURE 1-10 SpinaI cord anatomy. A. Schematic dorsal view ofan Isolated splnal cord and proximal regions of splnal nerves, Indicating
the major anatomic regions along the cord. B. Cross section through the spinal cord, showing gray matter (which contains neuronal and gllal
cell bodies, axons, dendrites, and synapses) and white matter (which contains myelinated axons and associated glial cells). Spinal gray matter
is called the dorsal and ventral horns. Spinal cord white matter contains ascending and descending tracts. C. Dorsal view of the spinal cord
showing the three meninges membranes and part of the vertebrae. The spinal net'Ve.s emerge from the ventral roots and enter vta the dorsal
roots. The spinal (dorsal root) ganglia that contain the sensory neuron cell bodies are shown. (Plln A, reproduced Wllh permission from waxman SG.
e.
Cilnk:JJI Nt!uloanarDmy, 28th ed. NewYorlc,, NY: McGniw Hiii; 2017; part reproduced with permission from Junquelra LC. C. metro J, Kelley RO: Basic Hlsrolo!Jy: Tm &Altos.
11th ed. McGraw Hiii, 2005; part C. reproduced with penntsslon from Bul:tefworth JF, Mackey DC, Wi!Sllldc JO. Morgan and Ml/dJall's Qfflk:aJAn~ Sth ed. NewYorlr, NY:
McGraw Hiii; 2013.)
 CHAPTER1 Org1nlzatfon&CellsoftheNem>usSystem 11

Cord segment
\~
Cervical Spina! nerves

2
3
4 Communicaang _ thetl
5 ram us ...., ...pa c
6 chain gangllon
Thoracic 7
8
9 ..J'C~-----==---------
10 B

2 Axon
Lumbar _...I
4
\
6 -- Myelin sheath

2
Sacral

A n- c
FIGURE 1-11 Spinal card, vertebral column, and spinal nerve organization. A. Schematic view of the spinal card, vertebral cclumn, and
spin al nerves along the anterior-posterior axis. B. Spinal nerves emerge from and enter Into the spinal cord. Motor axons (from both somatic
and autonomic motor ne\lrons) emerge via the ventral n:IOts whlle sensory axons (from both somatic and visceral sensory neurons) enter Into
the cord via the dorsal roots. After a splnal nerve forms from the dorsal and ventral roots, It branches Into the dorsal ramus and ventral ramus.
The spinal (dorsal root) ganglia contain cell bodies of somatic sensory neurons, and lie adjacent to the cord. Autonomic ganglia are not shown.
C. Nerves contain myelinated axons, unmyelinated axons, the myelinating Schwann cells (not shown), and blood vessels. Nerve components are
ensheathed In layers ofcannectlve tissue called the endoneurtum, pertneurlum, and eplneurfum.

Two cranial nerves, the olfactory nerve (CN I) and the optic
nerve (CN II). are CNS nerves because they emerge from
the cranium and travel within the CNS. Many of the cranial
nerves are mixed, with both somatic and autonomic effer-
ents and afferents, but a few are dedicated to either motor
or sensory functions. Cranial nerves with sensory or para-
sympathetic components have associated ganglia, which lie
Just outside of the brainstem. Furthermore, sensory afferents
can mediate both general, somatic sensations, such as touch,
pain, and temperature, and special sensations, such as taste,
hearing, vision, and smell.
FUNCTIONAL CATEGORIES
OF NEURONS
The 2 main cellular components ofthe nervous system are neu-
rons and glial cells. In addition. the CNS and PNS are highly
vasc:ularlzed and contain numerous blood vessel cells. How-
ever, because vascular endothelial and smooth muscle cells
derive from mesoderm and are also found outside the nervous
system, they are not considered cells of the nervous system.
The brain is estimated to contain approximately 86 billion
neurons and about the same number of or more glial cells.
Neurons are signaling cells that transmit electrical and
chemical signals. The vast majority of neurons are electrically
excitable, meaning they can produce and conduct actlon poten-
tials (Figure 1-12). Most neurons functlon as part of neuronal
circuits. Neurons are distinguished from other cells by a vari-
ety of features. Morphologically. they extend specialized mem-
brane processes including axons (for sending information).
dendrites and small protrusions called dendritic spines (for
receiving information). and membrane subdomains called syn-
apses (where infO.rmation is transformed and transferred from
the u:on to the receiving cell). Biocb.emically, neurons synthe-
size. package. and release neurotl'ansmitters. Physiologically.
they produce and conduct action potentials along the axon and
graded potentials along the dendrites and cell bodies, and their
receptors can detect different forms ofenergy, such as light and
sound waves, and convert those into electrical or c:hemical sig-
nals. Each of these specialized functions ensures that neurons
c:ommunicate specific:ally and rapidly with their targets.
12 PART I Anatomy &Function ofthe NerYOllS System

FIGURE 1-12 Prototyplcal CNS lnterneurons and motor

neuron. A. Two typlcal projectlon/prlnctpal lnternet.1rons. The cell
body {also called the soma or perikaryon) contains the nucleus and
nucleous. The cytcplasm contains Nlssl substance, which Includes
free polyrlbosomes and rough endoplasmic retlculum {RER,), where
proteins are synthesized. Numerous dendrites extend from the cell
soma, receiving inputs at synapses from other neurons. A long axon
transmits electrical Impulses from the cell soma and Is covered by
a myeltn sheath formed from the membrane of ollgodendrocytes
or Schwann cells. Axons can form many branches, which end In the
pre synaptic regions that form synapses on target neurons or cells.
B. Micrograph of a motor neuron showing the large cell body and
nucleus (N), a long axon (A) emerging from an axon hillock (AH), and
several dendrites D. Nlssl substance (NS) can be seen throughout the
cell body and cytoskeletal elements can be detected In the precesses.
Nuclel of scattered gllal cells (G) are seen among the surrounding
tissue (X100; H&E stain). C. Schematic of a lower motor neuron. The
cell body lies in the CNS (spinal cord or brainstem) while the axon
emerges to form part of the PNS (spinal or cranial nerves). (Parts A.and e.
rep!Oduced with petmlsslon from MdCtnley MP, O'Loughlln VO, Bidle TS. Anatomy
A
and PhYflology. ltn lnregratlvf!A.pptooch. New York, NY: McGl'ilW' Hll~ 2013; part C.
reproduced with pl!mllssion from Junqllelra i.e. Carnelro J, Kelley RO: Basic Hlstology:
Text&lttlas, 11th ed. New York, NY: McCinlwHll~2005.)

-- 0
Initial Sflgment of axon - ,
Oligodendrocyte ) , /- Myelin sheeth
*.-Z
'i;'l_, - -,1R- ::.:.
d!-
\ I' I
Node°' Ranvier-~=r- _---~~~~!~!-~~
l -
• \ , ~ Schwann cell
c
...
,,.,_____~
FIGURE 1-12 {Continued)
Hundreds of different types of neurons have been identi-
fied in the human nervous system. One way neurons can be
categorized is by their general function, as sensory neurons,
motor neurons, or interneurons. There are 3 types of sensory
neurons (also called afferent neurons) that detect and convey
signals from the external and internal eJIV.ironments. Special
sense neurons are located in special sense organs of the CNS
(eg. photoreceptor cells) or the PNS (eg, hair cells). Somatosen-
sory and visce.ra1 sensory neuron cell bodies are found in the
PNS, although their axons enter the CNS and branches form
components ofascending sensory tracts in the CNS. Four types
of motor neuros (also called efferent neurons) are involved in
control of the somatic and autonomic motor sy5tems. Upper
motor neuron cell bodies are located in either the motor cortex
or brainstem, and their axons project to lower motor neurons,
and those lie entirely in the CNS. Somatic and autonomic (pre-
ganglionic) lower motor neuron cell bodies are found in the
spinal cord or brainstem, with their axons emerging from those
regions to form the motor efferents of the spinal and cranial
nerves. Thus, lower motor neurons are considered part of both
the CNS and PNS. Both the cell bodies (in sympathetic or para-
sympathetic ganglia) and axons of postganglionic autonomic
motor neurons lie entirely in the PNS.
CHAPTER 1 Org1nlzatfon &Cellsofthe Nem>usSystem 13
.#=~~m
{~\~ ~ neuron
~ ~~. Synapse
Perlkaryon
--.. Axon hlllocl<
Axon
Collatsral
axonal
branch
Perfphtnll nervou• IY818m
1••
..
Motor end plalBS
All of the other neurons in the CNS are called inter-
neurons (or in some cases, just neurons). There are 2 types
of interneurons, which are distinguished by whether they
function locally or send their axons to other parts of the
CNS. Local interneurons (also called loc:al circuit neu-
rons) work within the same brain region, usually have
short unmyelinated axons, and form circuits with nearby
neurons. Projection neurons (also called principal or relay
neurons) extend their axons, which are usually long and
myelinated, to another brain or spinal cord region. Inter-
neurons are also named by their morphology, neurotrans-
mitter they release, type of response they produce in their
target cells, electrophysiology properties, and/or by the
person who first discovered them.
CLASSIFICATION OF NEURONS BY
MORPHOLOGY
Morphologically, neurons vary widely with respect to their size
and level of dendritlc branching (Figure 1-13). Most interneu·
rons and motor neurons have a single axon and multiple den·
drites and are called multipolar neurons. A few populations of
intemeurons called bipolar neurons contain a single axon and
14 PART I Anatomy &Function ofthe NerYOllS System

A Unipolar cell B Bipolar cell C Pseudo-unipolar cell

- 0en<1r11H
Dandrl!Ba
- - - ~hara! Q)IOn
1o akin and
muecle
1
- ee11bocly

- - - Slngle blfurcatet:I
,- Cellboctf PIOC888

J- Axon - - - Central

-
aJCDn

Axon terminals

ln\18118brate neuron Bipa&ar cell of 19tina Ganglion call of Clonsal root

D Three types of multipolar cells

- Apical
' t:landrtta

- Axon

Motor neuron ol aplool cord Pyramidal cell of hlppocampus PurklnJ& cell of cerebellum

FIGURE 1-13 Morphologic categories of neurons as unipolar, bipolar, or multipolar based on the number of processes that originate from
the cell soma. A. Unipolar cells have a single process emanating from the cell soma and are characteristic of the invertebrate nefVOus system.
L Blpclar ceUs have a slngle dendrite that receives electrlcal signals and an axon that transmits signals to other cells. C. Pseudo-unipolar cells
transmit somatosensory Information. They contain one axon branch that extends to the skin or muscle, and another axon branch extends to the
spinal cord. D. Multlpolar cells have a single axon and many dendrites. The most common type of ne..iron In the mammalian nervous system,
three examples are shown. Spinal motor neurons Innervate skeletal musde flbers. Pyramidal cells are found In the cerebral cortex, and have a
roughly triangular cell body; apical dendrites emerge from the apex and the basal dendrites from the base. Purkinje cells of the cerebellum are
characterized by an extensive dendrltlc tree that accommodates enormous synaptic Inputs. (Parts A and B.. reproduced with permis.sion from Kandel ER.
SchwartzJH,JessellTM,etal:Prfnc/plll!sofNewu/Sclena!, Sthed.NewYorlc, NV: McGrawHm;l013;partsCand D,adaptl!ldwlth permission from Ram6ny,Cajal S: Histology, toth
ed. Balttmore, MD: Wood; 1933J

only a single dendrite. Unipolar neurons, which contain only 1
process, are common in insects but are found in only a few brain
regions in mammals. Sensory neurons do not have typical den-
drites because they do not receive information from synapses,
but rather have specialized sensory receptor regions to detect
signals from the environment Some sensory neurons (eg. pho-
toreceptor, t.aste. and hair cells) also do not have axons but syn-
apse onto another neuron that relays its sensory infonnation. In
other sensory neurons (eg, somatosensory neurons), the recep-
tive region is connecred to an axon, which transmits the sensory
signal past the cell body and via its other axon branch into the
CNS. These are called pseudounipolar neurons.
Some neurons (also called cells) are named based on their
morphology (Figure 1-14). Pyramidal neurons are located in
the cerebral c.ortex. hippocampU$, and amygdala and have trian-
gle-shaped cell bodies, with l large apical dendrite and several
basal dendrites. Their dendrites contain many dendrltic spines.
Located in layers 3 to 6 of the cerebral cortex. many pyramidal
neurons are projection neurons that send their axons out of the
cerebral cortex. Spindle neurons are a subtype of pyramidal cell
 CHAPTER 1 Org1nlzatfon &Cellsofthe Nem>usSystem 1S

10
1a
1b
--- 1c
2
-:;;::::-- - 3a1

Sa2

3b

4
5a

5b

A B c D
FIGURE 1-14 Neuronal organization of the cerebral cortex. A. Golgi neuronal stain. B. Nissl cellular stain. C. Weigert myelin stain.
D. Neuronal connections. Roman and Arabic numerals lndkate the layers of the neocortex; 4, external llne of Balllarger (llne of Gennarl In
the occipital lobe); Sb, internal line of Baillarger. (Pans A·C. reprodl.ICl!d with peimlliSlon from Ran.son SN/, Clark SL: The Anaromyafw Nervous s~ 10th ed.
Phlladefphla. PA: Saunders; 1959; part D. reprodl.ICl!d with pe!ITllsslon from Ganong WF: Rt!W!wafM«J1C11J Phy:sJology, 22nd ed. New Yori(. NY: Appleton & l.Jlnge; 2005.)

with an elongated cell body and only a single apical dendrite and
are found in only 3 regions in the cerebral cortex. Stellate cells/
neurons have a star shape with multiple dendrites that radiate
from the cell's body. Found in many brain regions, including the
cerebral cortex. cerebellum, and striatum. stellate cell dendrites
can either contain (spiny) or lack (aspiny) dendritic spines.
Many stellate cells are local circuit neurons. Granule cells are
also found in a variety of brain regions. including the cerebel-
lum. hippocampus, cerebral cortex. and olfactory bulb, and are
characterized by having a very small cell body. Many granule
cells are local intemeurons. Basket cells are another type oflocal
intemeuron, also found in the cerebellum. cerebral cortex. and
hippoc:ampus. Their name derives from the basket-like nest that
their axons form around their target cells.
CLASSIFICATION OF NEURONS BY
NAMES lr NEUROTRANSMITTER
Neurons have also been named by the researchers who first
identi£.ed them. Purkinje neurons, discovered by Jan Purkinje.
are very large projection neurons that send the sole output
from the cerebellar cortex. Underneath the cerebellar Purkinje
neurons are a population of neurons called Lugaro cells. iden-
tified by Ernesto Lugaro. These spindle-shaped neurons have
2 dendrites that emerge from opposite poles of the cell body
and provide information to many cells in the cerebellum. Also
located in the cerebellum are the Golgi cells, discovered by
Camillo Golgi, which are located in the granule cell layer and
provide inputs to the granule cells. First described by Vladimir
Betz. Betz cells are very large pyramidal neurons, a type of
projection neuron. with the upper motor neurons located in
layer 5 of the primary motor cortex. Discovered by Birdsey
Renshaw, Renshaw cells are intemeurons found in the spinal
cord gray matter that provide and receive inputs to and from
lower motor neurons. Constantin von Economo first identi-
fied and named the spindle neurons described earlier, which
are found in only hominids, whales. dolphins. and elephants.
Other criteria by which neurons can be classified are by
their neurotransmitter and the response they produce in their
targets, which can be excitatory, inhibitory, or modulatory.
Approximately 9096 of brain neurons use either glutamate or
y-aminobutyric acid (GABA) as the.it neurotransmitter, with
the other 1096 of neurons using acetylcholine or one of the
biogenic amines (ie, norepinephrine, epinephrine, dopamine,
or serotonin). Neurons that release glutamate are called gluta-
matergi.c neurons. Glutamatergic neurons are found through-
out the brain and spinal cord. Although glutamate can act on
several types of postsynaptic receptors, the majority (in terms
of numbers) of glutamate receptors are ionotrop:l.c receptors
that produce an excitatory response. Therefore, glutamatergic
neurons are also referred to u excitatory neurons. An impor-
tant class of glutamaterglc neurons are the pyramidal neurons
in the hippocampus and cerebral. cortex. many of which are
projection/principal neurons.
16 PART I Anatomy &Function ofthe NerYOllS System
Neurons that release GABA as their neurotransmitter
are GABAergic neurons. The most prevalent effect of GABA
is an inhibitory response, and accordingly. GABAergi.c neu-
rons are categorized as inhibitory intemeurons. Inhibitory
intemeurons are found throughout most regions of the brain
and are abundant in the cerebral. cortex, cerebellum, and
striatum. Cerebellar Purkinje neurons are GABAergic and
are one of the few types of projection/principal. neurons that
are inhibitory. The neurotransmitter glycine al.so produces
inhibition, and glycinergic neurons, as well as GABAergic
neurons, are inhibitory interneurons in the spinal cord.
Other brain neurons release acetylcholine (called cholinergic
neurons) or one of the monoamines. In the brain, many cho-
linergic neuron cells bodies are located in the basal forebrain
and project to many areas of the cerebrum. Neurons that
release biogenic amines, called noradrenergic, adrenergic,
dopaminergic, or serotonergic neurons, have cell bodies
located in the brainstem. Because these neurons produce a
variety of excitatory, inhibitory, and modulatory effects on
their targets, they are usually named for their neurotransmitter.
In the PNS, somatic lower motor neurons are classified as
excitatory neurons because they release acetyicholine at the
neuromuscular junction, which al.ways produces an excit-
atory response in the muscle cell.
NEURONAL ORGANELLES lr
GENE EXPRESSION
Similar to other cells, neurons possess a plasma membrane
that functions as a selective permeability barrier to the e:xtra-
cellular fluid and that encloses the cytoplasm containing the
nucleus, cytosol. and typical complement ofcellular organelles
and biochemical activities (Figure 1-15). The cell body of the
neuron, also called the cell soma, can vary in diameter from
approximately 100 pm to approximately 10 pm. The organelles
Microtubules
FIGURE 1-15 Neuronal organelles located In the cell body.
ER, endoplasmic reUculum.
include the nucleus, smooth and rough endoplasmic reticu-
lum (ER), Golgi apparatus, lysosomes, proteasomes, and mito-
chondria, several of which are al.so localized in the axon and
dendrites. Neurons contain a robust cytoskeleton with typical
filaments and cytoskeletal motor proteins, which are impor-
tant in the development, structure, and function of axons and
dendrites.
After neW'Ons undergo their final division during embry-
onic development, they become postmit.otic, and the vast
majority of neurons do not proliferate in the postnatal and
adult brain. However, in the mammalian dentate gyrus of the
hippocampus and striatum and the olfactory bulb in rodents,
adult neurogenesis can lead to the generation of new neurons.
The precursors for adult neurogenesis in the hippocampus
have been identified as neural precursor cells that lie in the
subgranular zone. The newly produced neurons migrate, dif-
ferentiate into mature neurons, and form connections with
existing neurons. Shown to be stimulated by exercise and
activity, adult neurogenesis has been implicated in learning
and memory, and errors in neurogenesis have been proposed
to contribute to depression and schizophrenia.
Because mature neurons do not divide, the main activities
that occur in the nucleus are transcription, the synthesis of RNA
from the DNA, assembly of nbosome subunits, and the modifica-
tion ofDNA and DNA-binding proteins in what are referred to as
epigenetic changes. Ribosomal RNA combines with proteins to
form the ribosome subunits in the nucleolus. mRNA and tRNA
are transcribed and transported through the nuclear pores to the
cytoplasm, where they control translation, which is the synthesis
of proteins by the nbosomes. In the nucleus. mRNAs are tran-
scribed as precur80rs that undergo modifications and splicing to
form mature mRNAs that are then transported out ofthe nucleus
and translated using the genetic code (Figure 1-16).
Translation is the process by which ribosomes synthesize
proteins, with the sequence of amino acids determined by the
codons in the mRNA and its parent gene. Translation occurs in
the cytoplasm on either free or ER-bound nbosomes. Proteins
that are entirely water soluble, called cytoplasmic or cytosolic
proteins, are synthesized on free ribosomes that. as they trans-
late the mRNA, form polysomes. Proteins that have hydropho-
bic stretches of amino acids, alled transmembrane spanning
domains, that cause them to integrate into the membrane are
synthesized on ribosomes that associate with the ER. called rough
ER. Transmembrane proteins are also called integral membrane
proteins. Once a transmembrane protein has been synthesized,
it must traffic to ils location in the plasma membrane or intra-
ce11ular membrane compartment The rough ER also synthemes
proteins and peptides destined to be secreted from neurons.
It is estimated that the human genome contains approxi-
mately 20,000 protein-coding genes. Through the process ofalter-
native splicing. different protein variants of many genes can be
produced. The control of the types and amounts ofproteins that a
cell expresses is referred to as gene expression (Figure 1-16). The
regulation ofgene expression can occur at many points along the
path from DNA to protein, including at the transcriptional level
by control of transcription factors and epigenetic modifications,
 CHAPTER 1 Org1nlzatfon &Cellsofthe Nem>usSystem 17

contain cholesterol and sphingolipids. In neurons, lipids are

NUCieus
synthesized in the smooth ER or, in the case of cholesterol,
obtained from the diet or liver. Transmembrane proteins
become incorporated into the ER membrane during transla-
tion. Following translation in the rough ER, transmembrane
and secreted proteins and peptides are transported via small
vesicles to the Golgi, where they are further modified and
then sorted and packaged into vesicles, called secretory ves-
icles, at the trans-Golgi network to be transported to their
final destination. Called the biosynthetic or secretory path-
way. it is involved in the synthesis and delivery of lipids and
transmembrane proteins to the plasma membrane; the secre-
tion of proteins and peptides outside the neuron; formation
of organelles in the endosomal pathway, including the early
endosome and lysosome; and production of the precursors
Cylaeol RNA transport and needed to form synaptic vesicles. Proteins and lipids move
localization control
between membrane compartments by a process called mem-
brane trafficking.
Proteins and lipids are al.so retrieved from the plasma
membrane through trafficking in the endosomal path-
way. Plasma membrane lipids and transmembrane proteins
O mRNA degradation undergo endocytosis, where a small patch of the membrane
control folds inward into the cytoplasm and pinches off to form a
small endocytic vesicle. This vesicle then traffics to and
11\aCUve mRNA
fuses with the early endosome, where the proteins are sorted
0 Protein activity into small vesicles that bud off and are trafficked to differ-
and degradation ent compartments. Transmembrane proteins can travel by
control recycling vesicles back to the plasma membrane. A specific
type of endocytosis, called receptor-mediated endocytosis,
Inactive protein is used to bring key nutrients such as cholesterol and iron
into the cell. In this process, the receptors bind and deliver
e::i.ms their nutrients to endosomal compartments and can recycle
back to the plasma membrane. Transmembrane proteins that
have been damaged will traffic to the late endosome and then
FIGURE 1-1 f; Regulation of gene expression In neurons. fuse with the lysosome. A lysosome is a membrane-bound
compartment with an acidic pH that contains a variety of
degradative enzymes inside, which can degrade proteins,
mRNA processing, export and turnover, and in the processes of nucleic acids, and lipids. Lysosomes can also function to
tramlation and protein degradation. Gene expression and con- degrade cytoplasmic proteins or damaged organelles, such as
trol of protein expression determine the morphologic and func- mitochondria, by fusing with compartments in the autoph-
tional phenotype ofa cell. Neurons express approximately 14,000 agy pathway. Another intracellular compartment, called the
protein-coding genes, with approximately 8000 ofthese expressed proteasome, is involved in degrading mainly cytoplasmic
in other cells and involved in fundamental cellular processes proteins. Located in the cytoplasm or nucleus, proteasomes
and metabolism. .Approximately 6000 protein-coding genes are are large complexes of proteins that lack membranes. Protea-
neuronal specific genes that are only expressed in neurons and somes bind damaged proteins, unravel them, and then cleave
include types of transporters, channels, neurotransmitter syn- them with proteases to produce small peptides that can be
thetic enzymes. cytoskeletal wociated proteins, scaffolding pro- further degraded to amino acids.
teins, and receptors.

NEURONAL MEMBRANES&
TRAFFICKING
The neuronal plasma membrane and other membrane-
enclosed organelles are formed from a phospholipid bilayer
and transmembrane proteins (Figure 1-17). Membranes al.so
NEURONAL ENERGETICS
It has been estimated that the bra.in consumes approximately
20% of the energy and oxygen in the body, although it only
composes approximately 2% of the body's mass. In order
to meet its energy demands. neurons require energy sub·
strates, oxygen. and mitochondria located in the cell soma.
axons. and dendrites. The main energy currency in the cell
18 PART I Anatomy &Function ofthe NerYOllS System

Sugar chain
..-- of glycolipid

• 4

FIGURE 1-17 The neuronal plasma membrane is composed of the lipid bilayer and transmembrane proteins. A. The fluid mosaic model
of membrane structure emphasittS that the phospholipid bilayer of a membrane contains proteins inserted in it or associated with its surface
(perlpheral proteins) and that many of these proteins move within the fluld. llpld phase. Integral proteins embedded In the llpld layers are
called transmembrane proteins. B. When cells are frozen and fractured (cryofracture), the llpld bllayer of membranes Is often deaved along the
hydrophobic center. Electron microscopy of ayofracture preparation replicas provides a useful method for studying membrane structures. Most
of the protruding membrane parades seen (1) are proteins or aggregates of proteins that remain attached to the halfof the membrane adjacent
to the cytoplasm (P or protoplasmic face). Fewer particles are found attached to the outer half of the membrane (E or extracellular face). Each
protein bulging on one surface has a corresponding depression (2) on the opposite surface. CRetiroductd with pennis:sion from Meteher A1..J11t1q11eito.'I
B4SIC Histology: Tatf Atfos, 15,h ed. NewYOl'k',. NY: Mc:Gr~ Hiii; 2018.)

is adenosine triphosphate (ATP). ATP can be generated by

gl.ycolysis, an anaerobic process that takes place in the cyto-
plasm, converting glucose into pyruvate, reduced nicotin-
amide adenine dinucleotide (NADH), and ATP. Pyruvate
can be converted to lactate or shuttled with NADH into
mitochondria, which synthesize ATP via the enzymes in the
Krebs cycle and oxidative phosphorylation, with a yield of
approximately 16 ATP molecules per pyruvate/NADH. Neu-
rons do not contain large stores of glucose in glycogen, and
therefore, they depend on nearby astrocytes to take up glu-
cose from capillaries and release glucose and its glycolytic
product lactate into the extracellular space. Neurons convert
lactate back. into pyruvate via lactate dehydrogenase and
shuttle the pyruvate into mitochondria. Neurons are highly
dependent on mitochondria for the synthesis of ATP, and
conditions that lead to anoxia can rapidly lead to neuronal
damage and cell death.
THE AXON
The axon is a structure that is unique to neurons (Figure 1-18).
It is a process that is specialized for the generation and conduc-
tion of electrical signals called action potentials. which are sent
along the axon, in some cases over long distances, to the end
of the axon called the presynapti.c terminus. At the terminus,
the action potential electrical signal is converted into a chemi-
cal signal in the form of neW'Otransmitter release. Axons can be
small or large in diameter, ranging from less than 1 to 10 µm.
Axons can be long or short and unmyelinated or myelinated
Projection neurons and sensory neurons extend the longest
axons, which are usually myelinated and can be centimeters to a
meter in length. Local circuit neurons are usually unmyelinated
and only a few millimeters in length. Axons can be unbranched
with 1 main output or be highly branched, with the branches
called collaterals, each of which can form a separate output
 CHAPTER 1 Organization & Cells of lhe Nerw:ius System 19

lnHlal segment
of axon

~=---
I ~rr-::""'==£;::_ :;
""-Axon ~illock '-

Terminal buttons

FIGURE 1-18 Neuron with a myelinated axon. A neuron is composed of a cell body (soma) with a nudeus, several processes called
dendrites, and an axon that originates from the axon hillock. The first portion of the axon is called the initial segment. When myelinated as
shown, a myelin sheath forms from an oligodendrocyte (CNS) or Schwann cell (PNS) and surrounds the axon, except at its ending and at the
nodes of Ranvier. Terminal buttons (boutons) are located atthe tenninal endings. (Reproduced wllh permls$kln from Barrett KE. Barmen SM. Brooks HL et el:
Gonong's Review ofMedJa1 Physiology. 26'lh ed. New York, NY; McGraw Hll t 2019.)

All axons have several common features. The axon
emerges from the neuronal cell body at a region called the
axon hillock. which tapers to form the initial segment The
axon hillock helps provide a barrier to the random diffusion
of organelles, and many organelles require axonal transport to
move from the cell body to the axon. The axon hillock also
blocks diffusion of plasma membrane proteins from the cell
body membrane to the axonal membrane. The initial seg-
ment is adjacent to the axon hillock and is the region where
the action potential is generated. Even in myelinated axons,
the initial segment is unmyelinated and is the regions where
voltage-gated sodium channels are highly concentrated. The
end of the axon is called the axon terminal, presynaptic termi-
nus, or synaptic bouton. If the axon is myelinated, the myelin
membrane does not cover the presynaptic terminus.
Axons contain cytoskeletal proteins that provide structure
and important functions. The largest filaments, called mkro-
tubules (MTs), give the axon stability and provide tracks to
move organelles and large protein complexes up and down the
axon. MTs are formed by polymerization of tubulin subunits
with microtubule-associated proteins (MAPs) that associate
and regulate polymerization and bundling of MTs. In addition,
MT-based motors bind MTs and use the energy released by ATP
hydrolysis to move cargoes along MT filaments in fast axonal
transport. a type of axoplasmic transport (Figure 1-19). The
kinesin family of MT-based motors moves cargoes from the
cell body in the anterograde direction to the axon terminus,
whereas the dynein family of MT-based motors moves cargoes
in the retrograde direction, from the axon terminus to the cell
body. Important cargoes moved in fast axonal transport include
mitochondria, .lysosomes, mRNA, ribosomes, and vesicles.
Vesicles provide lipids and transmembrane proteins destined
for the amnal plasma membrane, synaptic vesicle components,
and peptides destined for secretion by the presynaptic terminus.
Many soluble proteins and cytoskeletal components use slow
axonal transport to travel along the axon.
Two other cytoskeletal filaments, an intermediate filament
called neurofilament and the microfilaments composed of
actin, are expressed in neurons. Mechanically strong, neurofil-
aments serve a mainly structural role and ensure the diameter
of the axon does not diminish along its length. Actln micro-
filaments are found associated with the plasma membrane,
along with dozens of actin-binding proteins that regulate the
assembly, disassembly, and bundling ofthe actin filaments and
binding to the plasma membrane. During development. actin
filaments and the actin-based motor, called myosin, are used
to provide the mechanical forces that drive the motility of the
growing axon. In mature axons, actin is localized in a mesh
that underlies the axonal plasma membrane and at the pre-
synaptic terminus. Because MTs do not extend into the axon
terminus, actin and myosin are involved in transporting car-
goes in the axon terminal and providing scaffolds that tether
transm.embrane proteins at specific regions of the 1W1nal or
presynaptic membrane.
DENDRITES a SYNAPSES
Dendrites are branched processes that are specialized for
receiving information (Figure 1-20). Presynaptic axon ter-
minals form synapses on dendrites, which then produce
postsynaptic signals that are passively transmitted to the cell
body. Dendrites can be highly branched and referred to as
the dendritic tree or arbor. The number of inputs that a neu-
ron receives is proportional to its dendritic area. Dendrites
can be distinguished from axons by their appearance. Unlike
axons, which have a constant diameter, dendrites taper as
they extend from the cell body. Dendrites are usually shorter
than axons and may be studded with dendritic spines. Simi-
lar to the axon, dendrites contain mitochondria, secretory
and endocytic vesicles, early endosomes, and an organized
cytoskeleton, including MTs, microfilaments, and their regu-
latory proteins and motors. In addition, axons and dendrites
20 PART I Anatomy &Function ofthe NerYOllS System

Cell body

Lr-~--.it,-Dyneln
protein

- - - - - -Recycled
membrane
vesicle

FIGURE 1-19 lhe axonal c:ytoskeleton and fast axonal transport (FAD. FAT occurs at a rate of about 400 Involves the ttansport of vesicles
and organelles along microtubules (MT) and involves MT based motor proteins dynein and kinesin. Anterograde (orthograde) transport occurs
along microtubules from the cell body to the presynaptic region, while retrograde transport occurs from the presynaptic terminus to the cell
body. ~roduc:ed with permission f'romWidmaiel'EP. Raff H. Strang KT. VOfldet'sHumonPllyiiology. NewYoitr. NY: Mc.<iraw Hi11;2009.)

FIGURE 1-20 Dendrites and dendrltlc spines. A. lhe large Purklnje neuron In this silver-stained section of cerebellum has many
dendrites (D) emerging from Its cell body (CB) and forming branches. Each of the small dendrltlc branches has many tiny projecting
dendrltlc spines (DS) spaced closely along their length, each of which Is a site of a synapse with another neuron. Dendrltlc spines are
highly dynamic. the number and morphology of synapses can change (X6SO; Sliver stain). B. Dendrite from a pyramidal neuron In the
motor cortex. Note the spines on the main dendrite and on its smaller branches, and note that spines have different lengths and shapes.
=
Scale 10 µm. (Part A, reproduced wtth permission from Berman I. Co/'or Atlas ofBmlc Hlstolorw. 3rd ed. New York. NY: McGraw Hiii; 2003; part B, used with
permission from Dr. Andrew Tan, Yale University.)
 CHAPTER1 Org1nlzatfon&CellsoftheNem>usSystem 21

contain ribosomes and mRNA that mediate local protein
synthesis within these processes. The dendrites of some neu-
rons contain dendritic spines along their length. Dendritic
spines are actin-rich small protrusions that can have a bul-
bous head and are the regions where the majority of excit-
atory glutamate synapses occur on the dendrite. Spines are
dynamic structures that can undergo changes in shape, size,
and number, and this morphologic spine plasticity (and the
functional plasticity of the synapses they contain) has been
implicated in learning and memory.
The synapse is the structure where synaptic transmis-
sion occurs (Figure 1-21). The axon terminal is the part of
the axon that forms a synapse with another neuron, muscle,
or gland. When a neuron makes a synaptic connection with
another cell, it is said to innervate that cell. The connections
between an axon and a muscle or gland are also referred to as
junctions. In neurons, synapses occur between an axon and a
dendrite (axodendritic synapses). an axon and the cell body
(axosomatic synapses). or an axon and another axon (axoax-
onic synapses). If the axons form short branches at their
ends and synapse on dendrites or cell bodies, these branches
are called the terminal arbor. Some axons form bulbous
presynaptic swellings and synapse on a dendrite without ter-
minating there, but continue on to form additional synapses.
These are called the en passant synapses.
Two different types of synapses, named electrical and
chemical synapses, mediate transmission. Although fairly rare
in the human CNS, electrical synapses allow for the direct
tlow of ions (current) through gap junctions between the
pre- and post.synaptic neuron. The vast majority of synapses
in the human brain are chemical synapses, which involve the
release of neurotransmitter from the presynaptic terminus
and production of electrical and other signaling responses in
the postsynaptic neuron (Figure 1-22). ln chemical synapses,
the presynaptic terminus is distinguished by the presence of
synaptic vesicles and specializations called active zones. The
synaptic cleft (20 to 40 nm wide) separates the pre- and post-
synaptic membrane, although synaptic adhesion molecules
from the presynaptic and postsynaptic membrane hind across
the synaptic cleft to help produce the stability and specific-
ity of the synapse. The postsynaptic membrane contains neu-
rotransmitter receptors that are tethered at the synapse by
scaffolding and cytoskeletal proteins, forming a region called
the postsynaptic density in excitatory/glutamatergic synapses.

Nerve impulee- 1
A1rDrt of pmsynaptic neuR>n

Calcium--~:--..
cca 2 •) Ions

Synaptic V88icles
• - /containing
• , acetylchollne (ACh)

Ac8lylcholine
Amtylcholine binds
ID nlC8plDr protein,
C1USlng Ion gates
... '
Sodium ~-~'
Poatsynaptic
membrane
ID open (Na+) lone Receptor protein
PoS1$ynepllc neuron
A B

FIGURE 1-21 Synapse structure: major components of the synapse. A. Diagram showing a synapse releaslng neurotransmitter <Nn
by exoc:ytosls from the termlnal bouton. Presynaptfc termlnals always contain a large number of synaptic vesicles containing NT, numerous
mitochondria, and endoplasmic reticulum ER. B. Electron micrograph showing a large presynaptictermlnal ('r1) filled with synaptic vesicles and
asymmetric electron-dense regions around 20- to 30-nm-wlde synaptic clefts (arrows). The postsynaptlc membrane contains NT receptors. The
postsynaptic membrane on the right is part of a dendrite (0), associated with fewer vesicles of any kind, showing this to be an axodendrilic
synapse. On the left is another presynaptic terminal (TJ, suggesting an axoaxonic synapse with a role in modulating activity of the other
terminal (x3S,OOO). (Part A. reJ1TOduced with pennl$$10n ti'orn McKinley MP. O'Loughlin vv. 1-R1mo11Anatom~ lrd ed. New York. NY: McGraw Hiii; 2012; part 8, reproduced
wl'lh penn1ss1on from Mescher AJ..Junquelta'sBaslcHlstology: Tat&lltf<n;. 15thed. NewYork. NY: Mc:Gr~Hlll;2018.)
22 PART I Anatomy &Function of the NerYOllS System

Postsynaptic
cell

Dendrite

Axodendriac

Axosomatic

\" - - Axoaxonal
;Ji
A

FIGURE 1-22 Synapse structure: mcrphologlc types of synapses. A. Diagram showing the three common morphologlc types of synapses.
Pre.synaptic axons synapse on either the dendrftlc shaft er dendritic spine fcnnlng axoclendrltlc synapses, and tend. to be excitatory synapses.
Axosomatic s)'5napses occur on the cell body/soma and tend to be inhibitory synapses. Less numerous axoaxonic synapses occur between a
presynaptic axon and a postsynaptic axon and. tend to modulate the release of neurotransmitter. B. Electron micrograph ofa synapse showing
the presynaptic knob (S) ending en the shaft of a dendrite (0) in the central nervous system. M, mitochondrion; P, postsynaptic density
(XS6,000). (Reproduced wl'lh permission from 811rrett KE, 811rrnan SM, 8n)Oks HLetal: Gonong's Rme!NofMedical PllyilOlogy.. 26th ed. New York, NY: Mc:Graw Hiii; 2019.)

GLIAL CELLS lr THEIR
FUNCTIONS
Neurons, a:mns, and synapses are surrounded by glial cells
that provide structural. metabolic, and functional support in
the CNS and PNS (Figures 1-23 and 1-24). Glial cells can be
categorized as macroglia and microglia. Similar to neurons,
macroglia are derived from the ectoderm, either the neu-
ral tube (CNS glia) or the neural crest cells (PNS glia), and
include astrocytes, satellite cells, pericytes, oligodendrocytes,
Schwann cells, ependymal cells, and enteric glia. There is only
I type of microglia cell, constituting approximately 15% to
20% of total cells in the brain and functioning as the resident
immune cells in the CNS. Originally thought to develop from
mesoderm, microglia are likely derived from the embry-
onic yolk sac and are distinguished by their small cell bodies
and short processes. Microglia exhibit both phagocytic and
antigen-presenting functions that defend the CNS from infec-
tion by bacteria, viruses, and fungi. In addition, microglia are
involved in maintaining overall brain health as they constantly
scavenge the CNS for extracellular protein aggregates called
plaques and damaged neurons and synapses. As phagocytic
cells, microglia have also been implicated in dendritic spine
removal underlying spine plasticity.
Astrocytes in the CNS and satellite cells in the PNS pro-
vide structural and metabolic support in the nervous system.
Deriving their name from their star-like appearance, astrocytes
(also called astroglia) are the most abundant glia in the CNS.
Gray matter, type I protoplasmic astrocytes support neuronal
cell bodies and dendrites, whereas white matter, type II fibrous
astrocytes support axons and their myelinating cells, the oli-
godendrocytes. Astrocytes form structures called end feet on
capillaries, a component of the BBB. Transporter proteins on
the end feet allow astrocytes to take up important molecules
such as glucose, lactate, amino acids, and other metabolites
from the blood and release them into the extracellular fluid
around neurons. Through this mechanism, astrocytes provide
key nutrients to nearby neurons, axons, and oligodendrocytes.
Astrocytes also express ion channels and ion transporters,
which enable them to regulate the ionic: concentration of the
extracellular fluid.
As a result of their proximity to synapses and expression
of neurotransmitter transporters, astrocytes can function in
the modulation of synaptic: transmission, forming the tripar-
tite synapse (Figure I -25). In addition, astrocytes express
neurotransmitter receptors and release gliotransmitters such
as ATP, which allow communication with neurons and among
astrocytes. Following injury to the CNS, astrocytes respond by
 CHAPTER 1 Org1nlzatfon &Cellsofthe Nem>usSystem 23

Functlone of~

1. Halpa form tl'la blood-brain banter

2. Regulates lntBrstltlal fluid
compoeltlon
a. Plovldes slruc:tural eupport and
Neurvn Perivucular
.-m
organization to the central
narwus (CNS)
4. A811818 wnn neuronal deWllopment
faat
5. Rapllcalas ta occupy space of
Capillary dying neurons

functloM of Ependymal Cell

1. Unes wntrlcles of brain and central

canal of spinal COid
2. Aali818 in production and c:in:ulation
Ventrideof of C818brDepinal ftuid (CSF)
brain

FUnctlons of Mlcrogllsl Cell

Functions of Ollgoclendrocyllt
\ 1. PhagDOJtic calla that move through

~ cell
Mlaagl..I t1'8CNS
2. Plalllct8 lhe CNS by angulftng
1. Myelln1118s and lneula!Bs CNS llllDns lnfactlous agents and othar
2. Allows faster ac:tlon potential propagadon al~ amns In the CNS potential harmful substances

FIGURE 1-23 Gllal cells of the central nervous system (CNS). There are five major types of gllal cells located In the CNS: ollgodendrocytes,
astrocytes, ependymal cells, mlcrogllal cells, and perlcytes. CNS glla are located In both the brain and spinal cord. The lnterrelatlonshlps and
major functions of these cells are shown diagrammatically here. Pericytes (which are not shown) are involved in regulating the blood-brain
barrier. (Reproduced with permission from McKinley MP. O'U>11ghlin VD, BidleTS.Malomyond Physiology:An tntegMfllrt Apptoocb. New York. NY: McGraw Hilt 2012J

Paetarlor "l°t gangllon

Functions of a.1911118 C.11

1. Electrically ineulalas PNS

cellbodlae.
2. Ragulatae nutrient and
walll8 &IOChanga for cell
bodlas In garvlla

Function• of Sclwnnn cell

1. Sumiunds and lneulales PNS

axons and myelinatea those
l'lllving large clamatal'9
2. Allowe fur fa8l8r action
potential prvpagation along
an UDn in the PNS

FIGURE 1-24 Gllal cells of the peripheral nerwus system (PNS). Two type.s of gllal cells are located In the PNS: Schwann cells (altemattwly
called neurolemmocytes}, which are located within and surround axons In nerves, and satellite ceUs, which surround the nerve cell bodies and
are thus found only In gangIla. Major functions of these cells are Indicated. (Reproduced with pennlsslori from MdClnley MP, 01.oughllri VO. Bidle TS.Anatomy
andPhyslology:Anfntegrati't!l!Approach. New York. NY: McGraw Hiii; 2012J
24 PART I Anatomy &Function of the NerYOllS System

-~-
(c Gl~no
\ I= :'\. Glutamate ~-----

\
FIGURE 1-25 Astrocytes contribute to the mpartite synapse. Schematic diagram ofa glutamate synapse. Astrocytes can regulate synaptic
glutamate levels at glutamateric synapses. Glutamine is imported into the presynaptic glutamatergic neuron (A) and ainverted into glutamate
by glutamlnase. The glutamate Is then transported In vesicles by the vesicular glutamate transporter. Upon release Into the synapse, glutamate
can bind to and activate AMPA and NMDA types of lonotroplc glutamate receptors (AMPAR, NMDAR} and with metabotroplc receptors (mGluR)
on the postsynaptlc neuron (8). Synaptic transmission Is terminated by transport of the synaptic glutamate Into a nelghborlng astrccyte (CJ (er
Into the presynaptlc and postsynaptlc neurons, which Is not shown} by a glutamate transporter. It Is converted Into glutamlne by glutamlne
synthetase and transported back into the extrac:ellular fluid where it can be taken up by the presynaptic axon. By regulating the levels of
glutamate, the magnitude and duration of the postsynaptic responses can be modulated. It has also been proposed that astrocytes may release
gliotransmitters into the synapse that can also modulate synaptic transmission (not shown). O\e9roduced with pennission from Katzung BG: Bosic &CJinicol
Phormacolo9y, l~h ed. New York:. NY: McGraw Hll~ 2018.)

transforming into reactive glia, releasing immune modulatory
factors, and forming glial scars. which can replace regions of
lost nemons but impede the regeneration ofaxons. In the PNS,
satellite cells are located in ganglia where they surround sen-
sory and autonomic neuronal cells bodies and perform similar
metabolic support functions.
Although the exact mecbanism(s) have not been deter-
mined, in response to neuronal activity. neurons and astrocytes
release vasodilators and vasoconstrictors that affect capillary
blood flow. By releasing vasomodulators, neurons and astrocytes
ma:y regulate vascular endothelial cells directly and/or through
another type of glia1 cell. the pericytes. Pericytes are contractile
cells that surround capillary endothelial cells and help form and
maintain the tight junctions that ensure the BBB (Figure l-26).
In addition, as contractile cells, pericytes can regulate contrac-
tion and relaxation that control capillary blood flow. Arterioles,
which are larger blood vessels lined with vascular smooth mus-
cle, ha:ve also been implicated as cells that respond to neuronal
activity-dependent regulation of brain blood tlow. Functional
magnetic resonance imaging (£MRI) is a functional neuroimag-
ing technique that detects changes in blood flow as an indirect
measure of neuronal activity.
Oligodendrocytes and Schwann cells are the myelinat-
ing cells in the nervous system, providing specialized plasma
membrane projections that WTap around the axon multiple
times. With its high lipid content (80% lipid and 20% pro-
tein). the myelin membranes form. an insulating sheath that
ensures fast and efficient conduction of action potentials by
salutatory conduction. In the CNS, each oligodendrocyte can
form 1 segment of myelin for many (up to 50) adjacent axons.
An individual axon (especially the longer ones) is myelinated
by multiple oligodendrocytes along its length. In the CNS,
axons larger than 1 µm are usually myelinated. Along the
axon, myelinated segments are separated by small unmyelin-
ated regions called nodes of Ranvier. The axon at the nodes
has access to the extracellular fluid and is the region where

Control of tight junction
opening by parlcytes
FIGURE 1-26 Glla and the blood·braln barrier. Diagram shows
the cellular components of CNS capillaries. The blood-brain barrier
is formed by specialized vascular endotttelial cells (pink) in CNS
capillaries, which form tight junctions that prevent the diffusion of
water-soluble molecules, and movement of immune and pathogenic
cells from the blood Into the CNS.lhe endothelial cells are covered
by perlcytes {blue}, a type of contractile gllal cell, which help regulate
the tight junctions and also control the diameter of ttte capillary and
modulate blood flow. Surrounding the pericytes are astrocytic end
feet {gR!en) lttat function to ttansport essential nutrients from the
blood into CNS tissue and release factors that affect contraction of
perlcytes.
the action potential is regenerated. Oligodendrocytes also
provide fl'ophic support to axons at the nodes. Similar to
reactive glia, oligodendrocytes form barriers to axon regen-
eration in the CNS. If oligodendrocytes become damaged or
die, oligodendrocyte precursor cells in the subventricular
zone can differentiate and replace oligodendrocytes to remy-
elinate axons.
In the PNS, sensory and motor axons are myelinated by
Schwann cells residing within the nerve. An individual Sc::hwann
cell is associated with only 1 axon, covering approximately
100 µm of the axon segment Therefore, an axon may require
many hundreds to thousands of Schwann cells to myelinate
it along its length. Schwann cells also associate with unmy-
elinated axons in nerves, providing trophic support to their
associated axons. In contrast to the CNS, following injury in
the PNS, axons regenerate, an activity promoted by Sch.wann
cells. Additional roles for Schwann cells include modulation of
neuromuscular synaptic activity and presentation of antigens
to immune cells. Nerves also contain capillaries with associated
pericytes. The presence of the pericytes and several layers of
connective tissue around the axons isolates the axons from the
capillaries and establishes the blood-nerve barrier.
CHAPTER1 Org1nlzatfon&CellsoftheNem>usSystem 25
Ependymal cells are glia cells found in the CNS where
they line the ventricles and central canal and fonn the choroid
plexus. Forming an epithelial layer, ependymal cells produce
and circulate CSP for the brain and spinal cord. Within the
4 brain ventricles (2 lateral ventricles and third and fourth
ventricles), a population of specialized ependymal cells and
capillaries together fonn a structure called the choroid plexus,
which produces the majority of CSP. CSP is formed as plasma
is filtered from the blood through the ependymal cells. Cho-
roid plexus ependymal cells actively transport sodium, chlo-
ride, and bicarbonate ions, with the accompanying water, into
the ventricles. Tight junctions formed between ependymal
cells establish the blood-CSP barrier, and cilia on their apical
surface facilitate the circulation of CSP. The other part of the
blood-CSP barrier is formed by the tight junctions between
the cells in the arachnoid membrane.
Other types of glia found in the PNS include cells that
surround several types of sensory neuron receptors and
enteric glia. Two major populations ofenteric glia are found in
the enteric nervous system and the epithelium throughout the
intestinal mucosa. Enteric glia may communicate with a vari-
ety ofcells in the GI system, including enteric neurons, enteric
endocrine cells, immune cells, and epithelial cells. Proposed
functions for enteric g1ia include regulation of fluid secretion,
intestinal motility, enteric neurotransmission, neurogenesis,
and immune signaling.
SUMMARY
• The nervous system has 2 major divisions: the CNS and
thePNS.
• The PNS detects information about the environment
and sends sensory information to the CNS. The CNS
receives, integrates, and stores information and sends
signals to the PNS, generating responses and behavior.
• The 2 major cell types in the nervous system are
neurons, which are the signaling cells, and glial cells,
which are the support cells.
• The CNS includes the brain and spinal cord. Both are
protected by bones and the meninges and are highly
vascularized. The brain surrounds the ventricles, which
produce and circulate CSP.
• The blood-brain barrier is formed by special vascular
endothelial cells and glial cells that prevent the entry of
unwanted molecules and cells into the CNS.
• The brain is composed of 3 major regions: the forebrain,
brainstem, and cerebellum.
• In the CNS, gray matter regions contain neuronal cells
bodies, dendrites, and glia. White matter regions are
enriched in myelinated axons and glia.
• Ridges (gyri) and furrows (sulci) create the folded
surface of the brain. Deep sul.ci divide the cerebral
cortex into the frontal, parietal, temporal, and
occipital lobes.
26 PART I Anatomy & Function of the Nervous System
• In the PNS, the somatic division controls skeletal muscle
contraction and receives sensory information from skin,
muscles, and joints. The autonomic division controls
smooth and cardiac muscles and glands and receives
sensory information from the viscera.
• The spinal cord is organized into the cervical, thoracic,
lumbar, sacral, and coccygeal segments. Dorsal gray
matter receives input from sensory afferents. Ventral
gray matter sends output via motor efferents.
• The PNS is organized into ganglia and nerves (spinal
and cranial), which enclose axons of sensory and motor
neurons.
• The neuronal plasma membrane encloses the cytoplasm
and nucleus; typical cellular organelles perform
transcription, translation, membrane trafficking, protein
turnover, and energy production.
• Axons generate and conduct action potentials, the
output signals from the neuron. Cytoskeletal proteins in
the axon are involved in structural support and fast and
slow axonal transport. The end of the axon forms the
presynaptic terminus.
• Dendrites receive inputs from axons via synapses. Some
dendrites contain dendritic spines, small protrusions
where synapses form. Synapses are also located on the
cell body and other axons.
• Glial cells are support cells in the CNS and PNS.
Astrocytes and satellite cells provide metabolic support;
oligodendrocytes and Schwann cells furnish myelination;
pericytes regulate capillaries; ependymal cells synthesize
CSF; microglia are immune cells; and enteric glia
function in the GI tracL
SELF-ASSESSMENT QUESTIONS
1. Following an injury in the workplace that affected a patient's
right arm, causing loss of movement of that limb, it was
determined that the injury had disrupted axoplasmic transport
in the sensory and motor nerves of that limb. Which of the
following statements accurately reflects a fundamental property
of axonal transport?
A. Large membranous organelles are transported by slow
axonal transport.
B. Cytosolic proteins are transported by fast axonal transport.
C. Retrograde transport is generally limited to a fixed rate of
movement of particles.
D. Anterograde transport is dependent on microtubules.
E. The motor protein kinesin specifically governs slow axonal
transport.
2. Which of the following best describes the characteristic of white
matter?
A. White matter contains neuronal cell bodies, dendrites, and
synapses.
B. White matter contains myelinated axons, astrocytes, and
oligodendrocytes.
C. White matter contains pericytes and ependymal cells.
D. White matter contains all neurons and glia in the central
nervous system (CNS).
E. White matter includes all tracts and nerves in the CNS and
peripheral nervous system (PNS).
3. Which of the following best describes the functions of
astrocytes?
A. Astrocytes form cerebral blood vessels and the blood-brain
barrier.
B. Astrocytes line the brain ventricles and form the brain
capillaries.
C. Astrocytes provide energy substrates for neurons and can
regulate blood flow.
D. Astrocytes are the major immune cells of the CNS and
become •reactive glia" following injury.
E. Astrocytes form the postsynaptic component of the
tripartite synapse.
4. Which of the following best describes neurons and their
processes?
A. All neurons are signaling cells that communicate via
electrical and/or chemical information with other neurons
or target cells.
B. All neurons are multipolar cells, with 1 large axon and
multiple branched dendrites.
C. All neuronal cell bodies are located in the CNS, but their
axons can extend into the PNS.
D. All axons are myelinated and highly branched at their
termini.
E. All dendrites contain small protrusions called dendritic
spines, which increase the surface area of the dendrite.
5. Which of the following best characterizes the blood-brain
barrier (BBB)?
A. The presence of the BBB prevents hydrophobic molecules
such as steroids and gases from entering into the neural
tissue of the brain.
B. The BBB prevents entry of most pathogenic cells but allows
the majority of immune cells into the brain to prevent
infection.
C. The majority of CNS neurons and astrocytes come in direct
contact with brain capillaries to ensure access to energy
substrates and oxygen.
D. The BBB forms during neurulation to prevent migration of
PNS neurons into the CNS.
E. The BBB is formed by vascular endothelial cells and
pericytes, with astrocytic end feet surrounding them.
 CHAPTER

Developm ent of the

Nervous System
Lucas Pozzo-Miller & Anne B. Theibert

• Outline the major stages, structures, and processes underlying the

development of the human nervous system.
• Diagram the S major brain vesicles and what regions they form In the brain.
• Describe the general ttme course for each of the major stages of CNS
development.
• Explain the identified cellular mechanisms underlying neurulation,
neurogenesis, neuronal migration, gliogenesls. neural apoptosis, axonal and
dendritic outgrowth, synaptogenesis, synaptic refinement, and myelination.
• Identify which processes depend on hardwlred genetic programs and which
ones are modified by experience-driven neuronal activity.
• Describe the underlying basis of congenital birth defects that affect the brain.

CENTRAL NERVOUS SYSTEM
DEVELOPMENT: OVERVIEW
lrTIMELINE
Development of the human nervous system involves the gen-
eration of the central nervous system (CNS) and peripheral
nervous system (PNS) and occurs during embryonic, fetal. and
postnatal periods. The study of nervous system development
allows a better undentanding of the structural organization of
the adult nervous system and helps in comprehending the basis
of congenital disorders that affect brain function and cause
cognitive di!orders. Key prenatal stage! in neural develop-
ment include gastrulation. neural induction (NI), neurulation,
neurogenesis, gliogenesis, neural migration, and synaptogen-
esis. Through these prenatal stages, the gross structures of
the brain, spinal cord, and nerves are furmed; most neuronal
and some glial populations are generated; some synapses are
furmed; and development is governed predominantly by hard-
wired intrinsic genetic prognum that control gene expression
aDd cell-cell interactions. .At birth, the mass of the human
brain is approximately 350 to 400 g. Postnatally, additional
glial cell populations develop, myelination rapidly takes place,
dendrites become highly branched, and many more synapses
are established. From birth through adolescence, synapses
are stabilized and pruned by activity-dependent processes fur
the construction of neural circuits. This enables experience-
driven neuronal activity to influence the wiring of the brain.
Postnatally, the human brain nearly quadruples its mass to
approximately 1300 to 1400 gin adults.
Errors in development of the nervous system can re.rult
from exposure to teratogens or genetic anomalies or mutations,
which can produce sensory, motor, behavioraL or cognitive
deficits and also make the brain susceptible to disorders that
develop in late adolescence or adulthood. A teratogen is defined
as a chemical, infectious agent. physical condition, or deficiency
that, upon exposure. may cause birth defects or impair future
intellectual, behavionl. or emotional functioning via a toxic
effect on the developing embryo, fetus, or child. Teratogens
include chemical agents such as alcohol. tobacco, environmen-
tal toxins, heavy metals, therapeutic drugs and drugs of abuse,
infectious agents such as bacteria and viruses, physical injury
and emotional stressors, and de6.ci.encies such as malnutrition
or hypoxia. The effects of teratogens are determined by the
dose or level, timing and duration of exposure, and interactions
with genetic factors. The developmental time when a particu-
lar organ is most 5114ceptible to teratogenic damage is during
the prenatal critical period, u.sually when morphogenesis, cell
proliferation. and cellular differentiation are occurring in that
organ (Fipre 2-1). The prenatal critical period for brain devel-
opment is from approximately 2 to 18 weeks (Fipre 2- 2).

27
28 PART I Anatomy &Function of the NerYOllS System

-----Em~icperlod (W99ks)--------- F8lal period (weab) -7'~ Full tann

2 3 4 5 6 7 8 9 16
Period ofdMdlng
zygot&, lmplantatlen,
and bllamlnaremt>ryo

E!IH

Usually not
- susceptible 10 -
teratogen

Prenatal daatl

FIGURE 2-1 Illustration of the critical or sensitive periods of human prenatal development. During t'he first 2 weeks of development, the
embryo is typically not susceptible to teratcgens. During these pre-differentiation stages, a substance either damages all or most of the cells of
the embryo, resulting In Its death, or It damages only a few cells, allowing the embryo to recover without developing defects. Dark blue denote
highly sensitive stages; llght blue denote stages that are less sensitive to teratogens. (Reprodlla!d with permission from MOOR! KL The Developing HumrJ11:
C1inio2fly0tifnttd Embtyology. 4th ed. Philadelphia, PA: Saunders/Elsevier; 1988J

However. because the brain continues to develop tluoughout
gestation. postnatally and tluough young adulthood, exposure
to teratogens after the prenatal critical period can also lead to
intellectual.. emotional. and behavioral disabilities.
EARLY DEVELOPMENT: THE
EPIBLAST It GASTRULATION
Human development begins with fertilization of the egg cell
(ovum.) by a sperm cell and is followed by the embryonic
period (up to 8 weeks after fertilization) and the fetal period
(8 weeks to birth at approximately 38 weeks; Pigure 2-3). All
developmental times here refer to after fertilization in humans.
The fertilized egg. called the iygote. undergoes a series
of cell divisions to produce the blastocyst. a fluid-filled cavity
containing the inner cell mass (ICM) and lined by trophoblasts.
Following implantation (between 8 and 10 days). the ICM of
the blastoc:yst reorganizes to form the bilaminar embryonic
disc. composed of the epiblast and underlying hypoblast The
epiblast is a flat disc ofcells that gives rise to the entire embryo.
The hypoblast forms the yolk sac. while the trophobl.asts form
the trophectoderm. which gives rise to the placenta. At about
day 16, the embryonic disc undergoes the process ofgastrulation
(Figure 2-4). First. cells in the mid.line of the epiblast disc form
a surface indentation called the primitive pit. which elongates
to generate the primitive streak. a morphologic groove in the
epiblast along the anterior-posterior axis of the embryo. During
gastrulation, epiblast cells proliferate and migrate, with migrat-
ing cells moving first medially toward the primitive streak. and
then ventrally. underneath the streak. and finally moving away
from the midline in a process called ingression. Cells ingress
in successive waves. Cells that migrate first push the hypoblast
cells aside and form the inner layer; the endoderm. which gives
rise to the lining of organs of the digestive and respiratory sys-
tems and several glands. Cells ingressing next will come to lie
on top of the endoderm and form the middle layer. the meso-
derm. which gives rise to the muscles. bones. cardiovascular
system. and blood cells. Cells that do not ingress remain on the
surface and become the outer layer. the ectoderm, which gives
rise to the entire nervous system. epidermis (skin), some con-
nective tissues. and related structures. Following gastrulati.on.
the embryonic disc is transformed into the 3 primary germ lay-
ers (the trilaminar gastrula). and all 3 axes of the embryo are
established: anterior-posterior (rostral-caudal). dorsal-ventral.
and medial-lateral ans.
 CJIAPTER2 Development ofthe Nem>UsS)'5tem 29

50 davs

5 rnonlhs 8 months

FIGURE 2-2 Prenatal growth and development of the human brain showing a series of embryonic and fetal stages. The numbers below
each Image refers to the gestatlcnal week used In human obstetrics, which Is the time after fert!llzatlon plus two weeks. (R4!t>roduCl!d with pennlsslori
from Balter L: PattndloodillAmerial: All fll~. Santa Balt)are, CA: A9C-OJO; 1999J

Gestation (weeks)
8 12 16 20 24 28 32
I I I I I I I /t

Neurutation

Neurogenesls

Neuronal
Migration

Glicgenesis

Neural Apoptoels

Axonal & Dendrhlc

OUtgrowth

Synaptogenesis

Synaptic
RB!inement

Myelination

FIGURE 2-3 Timellne of processes In human brain development Indicating general developmental events.
Another random document with
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The Project Gutenberg eBook of Percy's holidays
This ebook is for the use of anyone anywhere in the United States
and most other parts of the world at no cost and with almost no
restrictions whatsoever. You may copy it, give it away or re-use it
under the terms of the Project Gutenberg License included with this
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you are located before using this eBook.

Title: Percy's holidays

or, borrowing trouble.

Author: Lucy Ellen Guernsey

Illustrator: James W. Louderbach

Release date: October 6, 2023 [eBook #71823]

Language: English

Original publication: Philadelphia: American Sunday-School Union,

1872

*** START OF THE PROJECT GUTENBERG EBOOK PERCY'S

HOLIDAYS ***
Transcriber's note: Unusual and inconsistent spelling is as printed.

Percy's Holidays.—Frontispiece.
"I am sure I don't see anything here to cry about."
The Round Spring Stories.

PERCY'S HOLIDAYS;
OR,
 BORROWING TROUBLE.

BY

LUCY ELLEN GUERNSEY,

Author of "Irish Amy," "Opposite Neighbors," "Comfort

Allison,"

"The Tattler," "Nelly, or the Best Inheritance," "Twin Roses,"

"Ethel's Trial," "The Fairchilds," "The Sunday-School

Exhibition,"

"The Red Plant," &c.

 PHILADELPHIA:

AMERICAN SUNDAY-SCHOOL UNION,

NO. 1122 CHESTNUT STREET.

NEW YORK: 7, 8, & 10 BIBLE HOUSE, ASTOR PLACE.

Entered according to Act of Congress, in the year 1872, by the

AMERICAN SUNDAY-SCHOOL UNION,

in the Office of the Librarian of Congress at Washington.

 CONTENTS.

CHAPTER

I. MONDAY MORNING

II. PERSEVERANCE

III. A TERRIBLE TRIAL

IV. AUNT ACKERMAN

V. SEEING ONE'S SELF

 PERCY'S HOLIDAYS.

CHAPTER I.

MONDAY MORNING.

"PERCY, Percy!"

"Oh, dear me!" said a pale, thin little girl, all black hair and brown
eyes, who was sitting on the door-step, studying with all her might. "I
shall miss, I know I shall, and then I shall get marked again!"

"Percy! Perseverance!" called the voice again,—a somewhat high

but very pleasant and kindly voice. "Come here, my dear, I want to
see you!"

"There now! Aunt Zoe will want me to do some errand or other, I

know, and what will become of my lesson!" said Percy, impatiently,
closing her book, and rising. "I am sure I wouldn't mind, only for
missing!"

She went slowly up-stairs to the room from whence the voice
proceeded, and uttered a cry of delight, as she beheld Aunt Zoe
holding up a large folio like a scrapbook, which she seemed to have
just taken from the depths of a great chest she was rummaging.

"Mother's book of drawings! Oh, how glad I am! I felt sure I never
should see them again!"
"Well, you were worrying for nothing, you see, child, for here they are
all safe and sound. I thought all the time they would turn up; and this
morning I happened to think I had never taken the things out of this
chest. So I went to work at it, and here is the book all right. What are
you doing?"

"Learning my geography, aunt."

"But I thought you learned that Saturday night."

"I was going to, but Louise wanted me to help her clear off the table
and wash the dishes, and then—"

"And then she ran away and left you to do the whole, I suppose?"
said Aunt Zoe, as Percy paused. "That is her way exactly. Now,
Percy, there is one thing I am going to tell you, and you must mind
me. You must not indulge Louise by doing her work for her. She will
shirk quite enough without any help from you, and you are only doing
her an injury."

"She is so slow; and then she thinks I am cross if I don't do what she
asks me," replied Percy.

"Let her think so, then! She thinks every one is cross who will not let
her be just as idle as she wants to be. But don't you see, Percy, that
it is absolutely necessary for her own sake and mine, that Louise
should learn to work? I can't afford to keep her, unless she is some
help to me; and as she is now, she will never learn to get her own
living in the world."

"She thinks it is very hard that she cannot go to school, as I do,"

remarked Percy. "She says she knows she could do well enough, if
she could only have an education."

"Yes, I know. She thinks she would do anything better than her own
work; but what do you think she would do in school?"
"Not much, unless she did very differently from what she does now,"
replied Percy. "I told her so yesterday; and that Miss Van Ness and
Miss Reynolds would never have the patience with her that you do."

"And what did she say to that?"

"Oh, she said she should do differently, if she only had work that she
liked."

"Then why doesn't she learn the lessons I give her?" asked Aunt
Zoe. "All I can do, I can't make her learn the multiplication table nor
the definitions in the grammar; and half the days she manages so
that she has no time for her lessons at all."

"I told her of that, and she said it would be different in school. But
there, it is ten o'clock, and I must get ready. Oh, dear. I know I shall
miss in my geography!"

"Well, if you should, it won't break any bones," said Aunt Zoe, kindly.
"Why cannot you study your lesson on the boat?"

"I can," answered Percy; "I never thought of that. Thank you for
telling me. But, Aunt Zoe, don't you think I ought to wish to have my
lessons perfectly?"

"Of course, child. Learning lessons is your work, and you ought to do
it the best you can; but not be unhappy or fretful, if you do happen to
make a mistake. It would be a good thing if you and Louise could be
stirred together, and divided evenly," added Aunt Zoe, smiling again,
and drawing forth a pretty, old-fashioned writing-desk from the great
chest. "See, here is your mother's old writing-desk. Don't you want to
take it to school to help make your room look pretty? It is in very
good condition; and I have put your clothes into my hat-box, so you
will have plenty of room."

"Thank you, Aunt Zoe, I should like it very much; but how shall I
manage when I get to Round Springs? I can't carry the hat-box up
myself, you know."
"Oh, Percy, you do go beyond everybody I ever saw, for putting
mountains in your own way!" exclaimed Aunt Zoe, laughing. "Are
there no men, or boys, or carts, or wheelbarrows, down at the wharf
when the boat comes in? How do other girls get their trunks carried
up to the school?"

"To be sure: John Fisk is always down with his wagon," said Percy,
blushing a little. "I didn't think of that."

"Your box is all ready, and I told Harry to take it down for you," said
Aunt Zoe; "and I have put in some apples and pears, and a bag of
ginger-nuts, which you can eat or give away, as you please. You find
it pretty pleasant now, don't you—in the school, I mean?"

"Oh, yes, aunt; I like it better than any school I ever was at. The
teachers are so kind, and everybody is so good to me. I never saw
such nice girls anywhere."

"And you don't find it so very bad to go up and down in the boat,
either, do you?"

"No; I think it is very pleasant. I know what you mean, Aunt Zoe. I did
think it would be horrid when I began. I felt sure I should be left or
put off at the wrong place, or something."

"You would hardly do the last, unless you were very ingenious,
seeing there is not a single landing between here and Round
Springs," said Aunt Zoe. "But come, put away your desk and lock
your box, for it is time Harry was under way. You need not set out
yourself till you hear the boat-whistle, unless you like."

Percy packed up her desk and locked her box, and then went down
to find Harry. As she passed through the kitchen, she saw Louise
just finishing the washing of the breakfast-things—which were not
many, as there were only three in the family, even when Percy was
at home.
"Why, Louise!" exclaimed Percy, her eyes opening very wide,—which
was not necessary, seeing that they were large enough by nature.
"Haven't you finished your dishes yet? Well, if ever!"

"Oh, yes, it is all very well for you to say, 'Well, if ever!' when you are
all dressed up and going off to school on the boat," said Louise,
sulkily. "Wait till you have it to do, before you make so much fuss
about it!"

"But I have done it ever so many times: I washed the dishes all that
week you were at home, and I never had one thing round after nine
o'clock. You talk about going to our school; I can tell you, you
wouldn't do very well there, unless you had more ambition."

"That's what's in the way!" remarked Mrs. Swayne, the

washerwoman. "Louise hasn't a speck of ambition; and, like all such
folks, she thinks if she were only in a different place, it would be all
right. I am sure I often wonder at Miss Devine's patience with her. I
only wish my Maggy had the chance that she has."

"I thought Maggy went to the district school," said Percy.

"So she does, dear; but you see the school is very large, and Maggy,
though she is good as gold, isn't that quick at her book; and the
teacher doesn't have time nor patience to explain to her as Miss
Devine does to Louise. Ah, Louise, it's sinning your mercies you are,
child, and 't is a wonder if you don't lose them some day."

"What did you mean by Louise sinning her mercies, Mrs. Swayne?"
asked Percy, as, having dispatched Harry with her box, she came
back to the kitchen door, to watch for the first whistle of the little
steamer which lay in sight at the landing below.

"Oh, 't is just a by-word they have in Scotland," replied Mrs. Swayne.
"When a person is well off, and yet keeps grumbling and
discontented-like, and all the time wishing themselves elsewhere,
people say they are sinning their mercies. Louise has just as good a
place as any girl could have, and as kind a friend as ever lived in
your aunt; and yet you see she thinks, if she were only somewhere
else, or if things were only different—but there's the whistle. Good-
by, dear, and a pleasant voyage to you!"

"I wonder," said Percy to herself, as she established herself in a

snug corner on the upper deck of the steamer, and sat watching the
people who were coming on board, "I wonder if I ever sin my
mercies."

CHAPTER II.
PERSEVERANCE.

PERCY, or Perseverance, Denham was the orphan niece of Miss

Zoe Devine, who lived at Bridgeport, or "The Bridge," as the place
was familiarly called.

Percy's father had been an officer in the regular army. He was a man
respected and honoured in the army and out of it, and was in a fair
way of rising in his profession, when his career was cut short by an
Apache bullet; and his young wife was left without any earthly
consolations except her little girl, and the thought that at least her
husband had been granted a swift and easy passage to heaven,
instead of falling alive, like some of his less fortunate companions,
into the hands of those amiable savages, whom, by the way, he had
always befriended to the extent of his power.

Mrs. Denham was not very strong, and her life, like that of most
officers' wives, had been a trying one. In fact, her husband's death-
blow had been hers also; and she only lived long enough to write to
her husband's half-sister,—the only near relative he had,—and beg
her to take charge of his little girl. Miss Zoe Devine was, as she
described herself, a stay-at-home body in general; but she was one
of those people who can always do what seems necessary to be
done. She received her sister-in-law's letter in the morning, and set
out for the distant post, whence the letter was mailed, at six o'clock
that evening. She arrived only in time to see her sister die; and in
two or three weeks she was once more at home at "The Bridge" with
little Percy, then eleven years old, but so small of her age, and so
shy and retiring in her manners, that she might easily have passed
for three years younger.

But if Percy was backward in her growth and manners, she was by
no means so in her mind; and when she began to feel herself at
home with Aunt Zoe, she showed such a capacity for and eagerness
in learning, that Miss Devine at once decided to give her niece the
best education possible. This was not done without some self-
sacrifice on her part; for though "well off" as the phrase is, Miss
Devine was by no means rich, and the income of Percy's own little
property was not much more than enough to clothe her. Miss Devine
did not altogether like the school at "The Bridge." It was too large,
and was arranged and managed with so much "system," that there
seemed very little chance for improvement. There was a boarding
school at Round Springs, the next port on the lake, and to this school
Miss Devine determined to send Percy.

When Percy found that she was to go away to boarding school, she
was in despair. She had learned to love Aunt Zoe and to feel at
home with her; but she was totally unused to the society of girls of
her own age, and she dreaded them almost as much as the Indians
who had been her daily terror, who even yet haunted her dreams.
She knew that she should be perfectly miserable; and she was not at
all consoled when her aunt told her that she should come home
every Saturday and stay till the next Monday,—at least till the
steamers were laid up for the winter.
"But shall I have to go alone?"

"To be sure, child. Why, one would think that you were talking of
going to Australia! What do you think can happen to you, when you
go on board the boat within sight of your own door, and have nothing
to do but to sit still till you reach your stopping place? It will only be a
pleasant sail, for the lake is hardly ever rough. I know Captain
Seymour very well, and I will ask him to take care of you, and see
that you get safely ashore. However, you need not come home on
Saturdays, unless you like."

But Percy thought that staying at school week after week without
coming home would be even worse than the weekly journey on the
steamboat. She had sense enough to understand how greatly the
arrangement would be to her advantage; and she had no objection
to the lessons, for she was one of those rare children who love
learning for its own sake; and, in the wandering life she had led, she
had enjoyed very few advantages. But then those dreadful girls—
those girls who had always been to school, and who would know so
much more than she did—and the teachers would be shocked at her
ignorance and stupidity! Then she would be obliged to have a room-
mate, and Percy knew the said room-mate would be a cross,
disagreeable girl, or a very orderly and particular lady, who would be
shocked at her carelessness; or, worse still, one of those wicked,
worldly girls she had read about in books, who would hinder her from
reading her Bible, and laugh when she said her prayers, and who
would want her to do all sorts of bad things.

Percy was a good little Christian child, and she felt instinctively that it
would be very ungracious for her to object to a scheme which was so
much for her own advantage, and was at the same time so generous
on Aunt Zoe's part; so she never said a word about all these
bugbears which, to her fancy, were lying in wait for her at Hansen
school. But it was with a down-sinking heart and a decidedly long
face that she accompanied her aunt on board the steamer on that
first eventful Monday morning.
But in one thing Percy was very unlike many weak-spirited and timid
people: her fears and forebodings were no affectation. They were
very real, and they made her really and truly unhappy; so that she
was very glad to get rid of them when she could. The first thing that
brought her a drop of comfort was the steamer. It was such pretty
little boat, so clean and fresh and so tastefully furnished, and it rode
so lightly and easily in the water; and Captain Seymour seemed
such a kind old gentleman; and the banks of the lake were so pretty;
and it was so interesting to watch the gulls as they followed the boat
or sat twittering to each other on the water, that Percy began to
brighten up and think that the weekly sail would be very pleasant,
and that she should not be so much afraid after all. As they came
near the landing, Percy's great eyes were wide open to see all that
could be seen, and she presently exclaimed:

"Oh, Aunt Zoe, just see those young ladies rowing! Don't they look
pretty? See, there is another boat!"

"Those are the school boats," answered Aunt Zoe. "The girls go out
rowing a great deal in pleasant weather. See, they are managing to
get into the wake of the boat, so as to rock on the swells."

There was a wagon to carry up the trunks landed from the boat, and
Aunt Zoe and Percy walked up to the school.

"It doesn't look a bit as I expected," said Percy, surveying the

building.

"All the boarding school buildings I ever saw before looked like
barracks or factories. I think this house seems more like a home."

Nevertheless, Percy shrunk very close to her aunt's side as they

entered the house. School was out for the afternoon, and there was
a great buzz of young voices. Percy could see through an open door
into the library, where two or three young ladies had their heads
together over a volume of prints, and another was reading by herself
in a book which looked as if it had been a good deal used, but was
not a school book, nor a history. Percy loved books dearly, and she
had been kept on a pretty short allowance of them. She thought the
young ladies looked pleasant and not at all stuck-up or supercilious,
and she wondered whether either of them would turn out to be the
room-mate she had so much dreaded.

"Percy has always been used to sleeping alone," remarked Miss

Devine to Mrs. Richardson, the lady Principal. "I don't quite know
how she will get on with a room-mate."

"I think we can manage that matter nicely," replied Mrs. Richardson,
and then she looked into the library, and called:

"Blandina, my dear, will you come here?"

The young lady, who was reading, closed her book, and came
forward neither shyly nor boldly, but with a modest and self-
possessed air.

"This is Miss Blandina St. Clair," said Mrs. Richardson. "Blandina,

the little room which opens out of yours is unoccupied, I believe?"

"Yes, ma'am," answered Miss St. Clair: "Henrietta Hardy had it; but
she is not coming back."

"Then I think I shall ask you to take in this little girl—Miss Percy
Denham. Suppose you carry her off, and show her the room and the
house, while I talk with her aunt a while."

Percy looked rather miserable at being separated from her aunt; but
she could not be ungracious when every one was so kind, and she
rose to follow Miss St. Clair with more alacrity than her aunt
expected.

"Percy is very bashful," Miss Devine remarked, when the girls had
left the room; "but it is real shyness, and not affectation. She has
never been to school, but has lived with her father and mother in a
little world of her own, and she is as much afraid of children of her
own age as if they were Indians."