6

CHAPTER

Neuronal Signaling and the Structure

of the Nervous System

6.10 Activation of the Postsynaptic Cell

Binding of Neurotransmitters to
Receptors
Removal of Neurotransmitter from the
Synapse
Excitatory Chemical Synapses
Inhibitory Chemical Synapses
6.11 Synaptic Integration
6.12 Synaptic Strength
Presynaptic Mechanisms
Postsynaptic Mechanisms
Modification of Synaptic Transmission
by Drugs and Disease
6.13 Neurotransmitters and
Neuromodulators
Acetylcholine
Biogenic Amines
Amino Acid Neurotransmitters
Neuropeptides
Gases
Purines
Lipids
6.14 Neuroeffector Communication
False-color confocal micrograph of a section through the brain, showing an individual neuron of the
cerebellum with extensive processes arising from a cell body. ©David Becker/Science Source SECTION D

SECTION A Nature and Magnitude of the Structure of the Nervous System

Resting Membrane Potential
Cells of the Nervous System 6.15 Central Nervous System: Brain
Contribution of Ion
Concentration Differences Forebrain: The Cerebrum
6.1 Structure and Maintenance Forebrain: The Diencephalon
Contribution of Different Ion
of Neurons Permeabilities Hindbrain: The Cerebellum
6.2 Functional Classes of Contribution of Ion Pumps Brainstem: The Midbrain, Pons, and
Neurons Summary of the Development of a Medulla Oblongata

6.3 Glial Cells Resting Membrane Potential 6.16 Central Nervous System: Spinal
6.7 Graded Potentials and Cord
6.4 Neural Growth and
Action Potentials 6.17 Peripheral Nervous System
Regeneration
Graded Potentials 6.18 Autonomic Nervous System
Growth and Development of
Neurons Action Potentials
6.19 Protective Elements Associated
Regeneration of Axons with the Brain
SECTION C
Meninges and Cerebrospinal Fluid
SECTION B Synapses The Blood–Brain Barrier
6.8 Functional Anatomy Chapter 6 Clinical Case Study
Membrane Potentials
of Synapses
6.5 Basic Principles of Electrical Synapses
Electricity Chemical Synapses
6.6 The Resting Membrane 6.9 Mechanisms of
Potential Neurotransmitter Release

136
C
hapters 1–5 examined the general physiological principle system (Chapter 11). Unlike the relatively slow, long-lasting
of homeostasis, the basic chemistry of the body, and the signals of the endocrine system that are released into the
general structure and function of all body cells. Now we blood, the nervous system sends rapid electrical signals that
turn our attention to the structure and function of a specific organ communicate directly from one cell to another.
system and its cells—the nervous system. The nervous system is As you read about the structure and function of neurons
composed of trillions of cells distributed in a network throughout and the nervous system in this chapter, you will encounter
the brain, spinal cord, and periphery. It has a key role in the numerous examples of the general principles of physiology
maintenance of homeostasis of nearly all physiological variables. that were outlined in Chapter 1. Section A highlights how the
It does this by mediating information flow that coordinates structure of neurons contributes to their specialized functions in
the activity of widely dispersed cells, tissues, and organs, both mediating the information flow between organs, and integration
internally and with the external environment. Among its many of homeostatic processes. In Section B, controlled exchange
functions are activation of muscle contraction (Chapters 9 and of materials (ions) across cellular membranes and the laws of
10); integration of blood oxygen, carbon dioxide, and pH levels chemistry and physics will be key principles underlying the
with respiratory system activity (Chapter 13); regulation of electrical properties of neurons. Information flow that allows
volumes and pressures in the circulation by acting on elements of for integration of physiological processes between cells of the
the circulatory system (Chapter 12) and urinary system nervous system is the theme of Section C. In Section D, you will
(Chapter 14); and modulating digestive system motility and see how the nervous system illustrates the general principle of
secretion (Chapter 15). The nervous system is one of the two physiology that most physiological functions are controlled by
major control systems of the body; the other is the endocrine multiple regulatory systems, often working in opposition. ■

SECTION A
Cells of the Nervous System
The various structures of the nervous system are intimately inter- highly branched outgrowths of the cell that receive incoming
connected, but for convenience we divide them into two parts: (1) information from other neurons. Branching dendrites increase
the central nervous system (CNS), composed of the brain and a cell’s surface area—some CNS neurons may have as many as
spinal cord; and (2) the peripheral nervous system (PNS), con- 400,000 dendrites. Knoblike outgrowths called dendritic spines
sisting of the nerves that connect the brain and spinal cord with increase the surface area of dendrites still further. Thus, the struc-
the body’s muscles, glands, sense organs, and other tissues. ture of dendrites in the CNS increases a cell’s capacity to receive
The functional unit of the nervous system is the individ- signals from many other neurons.
ual cell, or neuron. Neurons operate by generating electri-
cal signals that move from one part of the cell to another part (a) (b)
of the same cell or to neighboring cells. In most neurons, the
electrical signal causes the release of chemical messengers—
Dendrites
neurotransmitters—to communicate with other cells. Most neu-
rons serve as integrators because their output reflects the balance
of inputs they receive from up to hundreds of thousands of other Cell body
neurons.
The other major cell types of the nervous system are non-
neuronal cells called glial cells. These cells generally do not par- Axon hillock
ticipate directly in electrical communication from cell to cell as Axon
do neurons, but they are very important in various supportive collateral
functions for neurons.
Axon
6.1 Structure and Maintenance
of Neurons
Axon
Neurons occur in a wide variety of sizes and shapes, but all share terminals
features that allow cell-to-cell communication. Long exten-
sions, or processes, connect neurons to each other and perform
Figure 6.1 (a) Diagrammatic representation of one type of
the neurons’ input and output functions. As shown in Figure 6.1, neuron. The break in the axon indicates that axons may extend for long
most neurons contain a cell body and two types of processes— distances; in fact, they may be 5000 to 10,000 times longer than the cell
dendrites and axons. body is wide. This neuron is a common type, but there is a wide variety
A neuron’s cell body (or soma) contains the nucleus and of neuronal morphologies, some of which have no axons. (b) A neuron
ribosomes and thus has the genetic information and machinery as observed through a microscope. Dendritic spines and axon terminals
necessary for protein synthesis. The dendrites are a series of cannot be seen at this magnification.
Neuronal Signaling and the Structure of the Nervous System 137
 The axon is a long process that extends from the cell (a)
body and carries outgoing signals to its target cells. In humans, Schwann cell Myelin
nucleus
axons range in length from a few microns to over a meter. The
region of the axon that arises from the cell body is known as
the axon hillock (or initial segment). The axon hillock is the Axon
location where, in most neurons, propagated electrical sig-
nals are generated. These signals then propagate away from Cell body
the cell body along the axon. The axon may have branches,
Terminal
called collaterals. Near their ends, both the axon and its col-
laterals undergo further branching (see Figure 6.1). The greater
the degree of branching of the axon and axon collaterals, the
greater the cell’s sphere of influence. (b)
Each branch ends in an axon terminal, which is responsible
for releasing neurotransmitters from the axon. These chemical
messengers diffuse across an extracellular gap to the cell opposite
the terminal. Alternatively, some neurons release their chemical
messengers from a series of bulging areas along the axon known
as varicosities.
The axons of many neurons are covered by sheaths of
myelin (Figure 6.2), which usually consists of 20 to 200 layers of Node of
highly modified plasma membrane wrapped around the axon by a Ranvier
nearby supporting cell. In the brain and spinal cord, these myelin-
forming cells are a type of glial cell called oligodendrocytes.
Each oligodendrocyte may branch to form myelin on as many as
40 axons. In the PNS, glial cells called Schwann cells form indi-
vidual myelin sheaths surrounding 1- to 1.5-mm-long segments at
regular intervals along some axons. The spaces between adjacent Oligodendrocyte
sections of myelin where the axon’s plasma membrane is exposed
to extracellular fluid are called the nodes of Ranvier. As we will
see, the myelin sheath speeds up conduction of the electrical sig- (c)
nals along the axon and conserves energy.
To maintain the structure and function of the axon, vari-
ous organelles and other materials must move as far as 1 meter
Myelin
between the cell body and the axon terminals. This movement,
sheath
termed axonal transport, depends on a scaffolding of microtu-
bule “rails” running the length of the axon and specialized types
of motor proteins known as kinesins and dyneins (Figure 6.3).
At one end, these double-headed motor proteins bind to their
cellular cargo, and the other end uses energy derived from the Axon
hydrolysis of ATP to “walk” along the microtubules. Kinesin
transport mainly occurs from the cell body toward the axon ter-
minals (anterograde) and is important in moving nutrient mol-
Schwann cell
ecules, enzymes, mitochondria, neurotransmitter-filled vesicles, cytoplasm
and other organelles. Dynein movement is in the other direction
(retrograde), carrying recycled membrane vesicles, growth fac-
tors, and other chemical signals that can affect the neuron’s mor-
phology, biochemistry, and connectivity. Retrograde transport is
also the route by which some harmful agents invade the CNS, Figure 6.2 (a) Myelin formed by Schwann cells, and
including tetanus toxin and the herpes simplex, rabies, and polio (b) oligodendrocytes on axons. (c) False color photomicrograph of a
viruses. section through a myelinated axon in the PNS. ©Don W. Fawcett/Science
Source

6.2 Functional Classes of Neurons cell types. Interneurons connect neurons within the CNS. As a
Neurons can be divided into three functional classes: afferent neu- rough estimate, for each afferent neuron entering the CNS, there
rons, efferent neurons, and interneurons (Figure 6.4a). Afferent are 10 efferent neurons and 200,000 interneurons. Thus, the great
neurons convey information from the tissues and organs of the majority of neurons are interneurons.
body toward the CNS. Efferent neurons convey information At their peripheral ends (the ends farthest from the CNS),
away from the CNS to effector cells like muscle, gland, or other afferent neurons have sensory receptors, which respond to

138 Chapter 6
 Secretory
vesicle

Kinesin
protein

Microtubule
Cell body Microtubule

Axon
Axon
terminal
Microtubule

Dynein
protein

Recycled
membrane
vesicle

Figure 6.3 Axonal transport along microtubules by dynein and kinesin.

various physical or chemical changes in their environment by gen- activates thigh muscles largely without interneurons—most of
erating electrical signals in the neuron. The receptor region may the afferent neurons interact directly with efferent neurons. In
be a specialized portion of the plasma membrane or a separate cell contrast, when you hear a song or smell a certain perfume that
closely associated with the neuron ending. (Recall from Chapter 5 evokes memories of someone you know, millions of interneu-
that the term receptor has two distinct meanings, the one defined rons may be involved.
here and the other referring to the specific proteins a chemical Table 6.1 summarizes the characteristics of the three func-
messenger combines with to exert its effects on a target cell.) tional classes of neurons.
Afferent neurons propagate electrical signals from their receptors The anatomically specialized junction between two neu-
into the brain or spinal cord. rons where one neuron alters the electrical and chemical activ-
Afferent neurons have a shape that is distinct from that dia- ity of another is called a synapse. At most synapses, the signal
grammed in Figure 6.1, because they have only a single process is transmitted from one neuron to another by neurotransmitters,
associated with the cell body, usually considered an axon. Shortly a term that also includes the chemicals efferent neurons
after leaving the cell body, the axon divides. One branch, the use to communicate with effector cells (e.g., a muscle cell).
peripheral process, begins where the afferent terminal branches The neurotransmitters released from one neuron alter the receiv-
converge from the receptor endings. The other branch, the cen- ing neuron by binding with specific protein receptors on the mem-
tral process, enters the CNS to form junctions with other neurons. brane of the receiving neuron. (Once again, do not confuse this
Note in Figure 6.4 that for afferent neurons, both the cell body and use of the term receptor with the sensory receptors at the periph-
the long axon are outside the CNS and only a part of the central eral ends of afferent neurons.)
process enters the brain or spinal cord. Most synapses occur between an axon terminal of one neu-
Efferent neurons have a shape like that shown in Figure 6.1. ron and a dendrite or the cell body of a second neuron. A neuron
Generally, their cell bodies and dendrites are within the CNS, that conducts a signal toward a synapse is called a presynaptic
and the axons extend out to the periphery. There are exceptions, neuron, whereas a neuron conducting signals away from a syn-
however, such as in the enteric nervous system of the gastroin- apse is a postsynaptic neuron. Figure 6.5 shows how, in a multi-
testinal tract described in Chapter 15. Groups of afferent and neuronal pathway, a single neuron can be postsynaptic to one cell
­efferent neuron axons, together with myelin, connective tissue, and presynaptic to another. A postsynaptic neuron may have thou-
and blood vessels, form the nerves of the PNS (Figure 6.4b). sands of synaptic junctions on the surface of its dendrites and cell
Interneurons lie entirely within the CNS. They account body, so that signals from many presynaptic neurons can affect it.
for over 99% of all neurons and have a wide range of physiolog- Interconnected in this way, the many millions of neurons in the
ical properties, shapes, and functions. The number of interneu- nervous system exemplify the general principle of physiology that
rons interposed between specific afferent and efferent neurons information flow between cells, tissues, and organs is an essen-
varies according to the complexity of the action they control. tial feature of homeostasis and allows for complex integration of
The knee-jerk reflex elicited by tapping below the kneecap physiological processes.

Neuronal Signaling and the Structure of the Nervous System 139

(a)

Central nervous system Peripheral nervous system

Cell body

Afferent neuron Afferent terminals

Cell body
Sensory receptor
Axon Axon
(central process) (peripheral process)

Interneurons

Axon
Axon Axon terminal

Muscle, gland, or neuron

Efferent neuron

Blood vessel

Bundle of axons
(b)

Figure 6.4 (a) Three classes of neurons. The arrows

indicate the direction of transmission of neural activity. Afferent
neurons in the PNS generally receive input at sensory receptors
(in some cases, the afferent terminal branches themselves are
Connective modified into a sensory receptor). Efferent components of the
tissue PNS may terminate on muscle, gland, neuron, or other effector
cells. Both afferent and efferent components may consist of two
neurons, not one as shown here. (b) Tranverse section of a nerve
as seen in a light micrograph (magnification approximately 50x).
A nerve is a collection of neuron axons encased in connective
tissue and is located in the peripheral nervous system. ©Jean-Claude
Revy/ISM/Medical Images

Characteristics of Three Classes

TABLE 6.1 of Neurons
6.3 Glial Cells
According to recent analyses, neurons account for only about half
I. Afferent neurons
A. Transmit information into the CNS from receptors at their
of the cells in the human CNS. As mentioned earlier, the remainder
peripheral endings are glial cells (glia, “glue”). Glial cells surround the axon and den-
B. Single process from the cell body splits into a long drites of neurons, and provide them with physical and metabolic
peripheral process (axon) that is in the PNS and a short support. Unlike most neurons, glial cells retain the capacity to
central process (axon) that enters the CNS divide throughout life. Consequently, many CNS tumors actually
originate from glial cells rather than from neurons (see Case D in
II. Efferent neurons
Chapter 19 for an example).
A. Transmit information out of the CNS to effector cells,
There are several different types of glial cells found in the
particularly muscles, glands, neurons, and other cells
B. Cell body with multiple dendrites and a small segment of the CNS (Figure 6.6). One type discussed earlier is the oligodendro-
axon are in the CNS; most of the axon is in the PNS cyte, which forms the myelin sheath of CNS axons.
A second type of CNS glial cell, the astrocyte, helps reg-
III. Interneurons ulate the composition of the extracellular fluid in the CNS by
A. Function as integrators and signal changers removing potassium ions and neurotransmitters around synapses.
B. Integrate groups of afferent and efferent neurons into reflex Another important function of astrocytes is to stimulate the for-
circuits
mation of tight junctions (review Figure 3.9) between the cells that
C. Lie entirely within the CNS
make up the walls of capillaries found in the CNS. This forms the
D. Account for > 99% of all neurons
blood–brain barrier, which is a much more selective filter for
140 Chapter 6
 Presynaptic addition, astrocytes have many neuronlike characteristics. For
example, they have ion channels, receptors for certain neurotrans-
mitters and the enzymes for processing them, and the capability
Postsynaptic
of generating weak electrical responses. Thus, in addition to their
well-defined functions, it is speculated that astrocytes may take
part in information signaling in the brain.
Axon The microglia, a third type of CNS glial cell, are special-
ized, macrophage-like cells that perform immune functions in the
Synapse CNS, and may also contribute to synapse remodeling and plastic-
ity. Lastly, ependymal cells line the fluid-filled cavities within
the brain and spinal cord and regulate the production and flow of
cerebrospinal fluid, which will be described later.
Presynaptic
Schwann cells, the glial cells of the PNS, have most of the
Postsynaptic properties of the CNS glia. As mentioned earlier, Schwann cells
produce the myelin sheath of the axons of the peripheral neurons.

Presynaptic 6.4 Neural Growth and Regeneration

The elaborate networks of neuronal processes that characterize
the nervous system depend upon the outgrowth of specific axons
to specific targets.

Growth and Development of Neurons

Postsynaptic
Development of the nervous system in the embryo begins with a
series of divisions of undifferentiated precursor cells (stem cells)
that can develop into neurons or glia. After the last cell division,
Figure 6.5 A neuron postsynaptic to one cell can be each neuronal daughter cell differentiates, migrates to its final
presynaptic to another. Arrows indicate direction of neural transmission. location, and sends out processes that will become its axon and
dendrites. A specialized enlargement, the growth cone, forms the
exchanged substances than is present between the blood and most tip of each extending axon and is involved in finding the correct
other tissues. Astrocytes also sustain the neurons metabolically— route and final target for the process.
for example, by providing glucose and removing the secreted As the axon grows, it is guided along the surfaces of other
metabolic waste product ammonia. In embryos, astrocytes guide cells, most commonly glial cells. Which route the axon follows
CNS neurons as they migrate to their ultimate destination, and depends largely on attracting, supporting, deflecting, or inhibit-
they stimulate neuronal growth by secreting growth factors. In ing influences exerted by several types of molecules. Some of

Capillary

Neurons

Astrocyte
Oligodendrocyte

Myelinated axons

Myelin (cut)
Ependymal
cells

Cerebrospinal Microglia
fluid

Figure 6.6 Glial cells of the central nervous system.

Neuronal Signaling and the Structure of the Nervous System 141
 these molecules, such as cell adhesion molecules, reside on growth cone, which grows out to the effector organ so that function
the membranes of the glia and embryonic neurons. Others are can be restored. Return of function following a peripheral nerve
­soluble neurotrophic factors (growth factors for neural tissue) injury is delayed because axon regrowth proceeds at a rate of only
in the extracellular fluid surrounding the growth cone or its about 1 mm per day. So, for example, if afferent neurons from your
­distant target. thumb were damaged by an injury in the area of your shoulder, it
Once the target of the advancing growth cone is reached, might take 2 years for sensation in your thumb to be restored.
synapses form. During these early stages of neural ­development– Spinal injuries typically crush rather than cut the tissue,
which occur during all trimesters of pregnancy and into infancy– leaving the axons intact. In this case, a primary problem is self-
alcohol and other drugs, radiation, malnutrition, and viruses can destruction (apoptosis) of the nearby oligodendrocytes. When
exert effects that cause permanent damage to the developing fetal these cells die and their associated axons lose their myelin sheath,
nervous system. For example, some babies of women infected the axons cannot transmit information effectively. Severed axons
with the Zika virus during pregnancy are born with severely within the CNS may grow small new extensions, but no significant
underdeveloped brains, a condition called microcephaly. regeneration of the axon occurs across the damaged site, and there
A surprising aspect of development of the nervous system are no well-documented reports of significant return of function.
occurs after growth and projection of the axons. Many of the Functional regeneration is prevented either by some basic differ-
newly formed neurons and synapses degenerate. In fact, as many ence of CNS neurons or some property of their environment, such
as 50% to 70% of neurons undergo a programmed self-destruction as inhibitory factors associated with nearby glia. Presumably,
called apoptosis in the developing CNS. Exactly why this seem- there was selection pressure during evolution to limit growth of
ingly wasteful process occurs is unknown, although neuroscien- neurons in the mature CNS to minimize the possibility of disrupt-
tists speculate that this refines or fine-tunes connectivity in the ing the precise architecture of the complex neuronal networks that
nervous system. This is a likely reason that humans rarely retain exist throughout the brain.
any memories of events that occur prior to 4 years of age. Researchers are trying a variety of ways to provide an
Throughout the life span, our brain has an amazing ability environment that will support axonal regeneration in the CNS.
to modify its structure and function in response to stimulation or They are creating tubes to support regrowth of the severed axons,
injury, a characteristic known as plasticity. This may involve the redirecting the axons to regions of the spinal cord that lack growth-
generation of new neurons, but particularly involves the remod- inhibiting factors, preventing apoptosis of the oligodendrocytes so
eling of synaptic connections. These events are stimulated by myelin can be maintained, and supplying neurotrophic factors that
exercise and by engaging in cognitively challenging activities. support recovery of the damaged tissue.
The degree of neural plasticity varies with age. For many Medical researchers are also attempting to restore function to
neural systems, the critical time window for development occurs damaged or diseased spinal cords and brains by implanting undiffer-
at a fairly young age. In visual pathways, for example, regions of entiated stem cells that will develop into new neurons and replace
the brain involved in processing visual stimuli are permanently missing neurotransmitters or neurotrophic factors. Initial stem cell
impaired if no visual stimulation is received during a critical time, research focused on the use of embryonic and fetal stem cells, which,
which peaks between 1 and 2 years of age. By contrast, the ability while yielding promising results, raises ethical concerns. Recently,
to learn a language undergoes a slower and more subtle change in however, researchers have developed promising techniques using
plasticity—humans learn languages relatively easily and quickly stem cells isolated from adults, and using adult cells that have been
until adolescence, but learning becomes slower and more difficult induced to revert to a stem-cell-like state.
as we proceed from adolescence through adulthood.
The basic shapes and locations of major neuronal circuits SECTION A SU M M A RY
in the mature CNS do not change once formed. However, the
creation and removal of synaptic contacts begun during fetal Structure and Maintenance of Neurons
development continue throughout life as part of normal growth, I. The nervous system is divided into two parts. The central nervous
learning, and aging. Also, although it was previously thought system (CNS) consists of the brain and spinal cord, and the PNS
that production of new neurons ceases around the time of birth, consists of nerves outside of the CNS.
a growing body of evidence now indicates that the ability to pro- II. The basic unit of the nervous system is the nerve cell, or neuron.
III. The cell body and dendrites receive information from other neurons.
duce new neurons is retained in some brain regions throughout
IV. The axon, which may be covered with sections of myelin separated
life. For example, cognitive stimulation and exercise have both
by nodes of Ranvier, transmits information to other neurons or
been shown to increase the number of neurons in brain regions effector cells.
associated with learning even in adults. In addition, the effec-
tiveness of some antidepressant medications has been shown to Functional Classes of Neurons
I. Neurons are classified in three ways:
depend upon the production of new neurons in regions involved
a. Afferent neurons transmit information into the CNS from
in emotion and motivation (Chapter 8).
receptors at their peripheral endings.
Regeneration of Axons b. Efferent neurons transmit information out of the CNS to
effector cells.
If axons are severed, they can repair themselves and restore sig- c. Interneurons lie entirely within the CNS and form circuits with
nificant function provided that the damage occurs outside the CNS other interneurons or connect afferent and efferent neurons.
and does not affect the neuron’s cell body. After such an injury, the II. Neurotransmitters, which are released by a presynaptic neuron and
axon segment that is separated from the cell body degenerates. The combine with protein receptors on a postsynaptic neuron, transmit
part of the axon still attached to the cell body then gives rise to a information across a synapse.
142 Chapter 6
Glial Cells 6.1 Structure and Maintenance of Neurons
I. The CNS also contains glial cells, which help regulate the anterograde dyneins
extracellular fluid composition, sustain the neurons metabolically, axon initial segment
form myelin and the blood–brain barrier, serve as guides for axon hillock kinesins
developing neurons, provide immune functions, and regulate axon terminal myelin
cerebrospinal fluid. axonal transport nodes of Ranvier
Neural Growth and Regeneration cell body oligodendrocytes
I. Neurons develop from stem cells, migrate to their final locations, collaterals retrograde
and send out processes to their target cells. dendrites Schwann cells
II. Cell division to form new neurons and the plasticity to remodel dendritic spines varicosities
after injury markedly decrease between birth and adulthood. 6.2 Functional Classes of Neurons
III. After degeneration of a severed axon, damaged peripheral afferent neurons postsynaptic neuron
neurons may regrow the axon to their target organ. Functional efferent neurons presynaptic neuron
regeneration of severed CNS axons does not usually occur. interneurons sensory receptors
nerves synapse
SECTION A R EV I EW QU E ST ION S 6.3 Glial Cells
1. Describe the direction of information flow through a neuron in astrocyte ependymal cells
response to input from another neuron. What is the relationship blood–brain barrier microglia
between the presynaptic neuron and the postsynaptic neuron?
6.4 Neural Growth and Regeneration
2. Contrast the two uses of the word receptor.
3. Where are afferent neurons, efferent neurons, and interneurons growth cone plasticity
located in the nervous system? Are there places where all three
could be found? SECTION A CLI N ICA L T ER M S
6.4 Neural Growth and Regeneration
SECTION A K EY T ER M S
microcephaly Zika virus
central nervous system (CNS) neurotransmitters
glial cells peripheral nervous system (PNS)
neuron

SECTION B
Membrane Potentials

6.5 Basic Principles of Electricity by the difference in the amount of charge between two points, a
potential difference (often referred to simply as the potential).
This section provides an excellent demonstration of the general The units of electrical potential are volts. The total charge that
principle of physiology that physiological processes are dic- can be separated in most biological systems is very small, so the
tated by the laws of chemistry and physics, notably those that potential differences are small and are measured in millivolts
determine the net flux of charged molecules. As discussed in (1 mV = 0.001 V).
Chapter 4, the predominant solutes in the extracellular fluid are The movement of electrical charge is called a current. The
sodium and chloride ions. The intracellular fluid contains high electrical potential between charges tends to make them flow, pro-
concentrations of potassium ions and ionized nonpenetrating ducing a current. If the charges are opposite, the current brings
molecules, particularly phosphate compounds and proteins with them toward each other; if the charges are alike, the current
negatively charged side chains. Electrical phenomena resulting increases the separation between them. The amount of charge that
from the distribution of these charged particles occur at the cell’s moves—in other words, the magnitude of the current—depends
plasma membrane and have a significant function in signal inte- on the potential difference between the charges and on the nature
gration and cell-to-cell communication, the two major functions of the material or structure through which they are moving. The
of the neuron. hindrance to electrical charge movement is known as resistance.
A fundamental physical principle is that charges of the same If resistance is high, the current flow will be low. The effect of
type repel each other—positive charge repels positive charge, and voltage V and resistance R on current I is expressed in Ohm’s law:
negative charge repels negative charge. In contrast, oppositely
V
charged substances attract each other and will move toward each I=
other if not separated by some barrier (Figure 6.7). R
Separated electrical charges of opposite sign have the poten- Materials that have a high electrical resistance reduce cur-
tial to do work if they are allowed to come together. This poten- rent flow and are known as insulators. Materials that have a low
tial is called an electrical potential or, because it is determined resistance allow rapid current flow and are called conductors.
Neuronal Signaling and the Structure of the Nervous System 143
 (a) (a) Voltmeter
Electrical forces
0
+ Attraction – +

+ + Repulsion

Intracellular Extracellular
Repulsion (recording) (reference)
microelectrode electrode

+ +
+ +
– ––
+ – – – +
Cell – +
(b)

+ – –
– – +
Force increases with the Force increases as

+ – – – +
quantity of charge distance of separation

+ + +
Extracellular fluid
between charges
+ decreases

+
+ + (b)
+
+ +

Recorded potential (mV)

+
Figure 6.7 (a) Types of electrical interactions. (b) Effects on
electrical forces of quantity and distance between charges.
0 *
Restingmembrane
Resting membranepotential
potential
–70
Water that contains dissolved ions is a relatively good con-
ductor of electricity because the ions can carry the current. As we
have seen, the intracellular and extracellular fluids contain many Time
ions and can therefore carry current. Lipids, however, contain
Figure 6.8 (a) Apparatus for measuring membrane potentials.
very few charged groups and cannot carry current. Therefore, the The voltmeter records the difference between the intracellular and
lipid layers of the plasma membrane are regions of high electrical extracellular electrodes. (b) The potential difference across a plasma
resistance separating the intracellular fluid and the extracellular membrane as measured by an intracellular microelectrode. The asterisk
fluid, two low-resistance aqueous compartments. indicates the moment the electrode entered the cell.

6.6 The Resting Membrane Potential the potential. By definition, a cell under such conditions would no
longer be “resting.”
At rest, neurons have a potential difference across their plasma The resting membrane potential exists because of a tiny
membranes, with the inside of the cell negatively charged with excess of negative ions inside the cell and an excess of positive
respect to the outside (Figure 6.8). This potential is the resting ions outside. The excess negative charges inside are electrically
membrane potential (abbreviated Vm). attracted to the excess positive charges outside the cell, and vice
By convention, extracellular fluid is designated as the volt- versa. Thus, the excess charges (ions) collect in a thin shell tight
age reference point, and the polarity (positive or negative) of the against the inner and outer surfaces of the plasma membrane
membrane potential is stated in terms of the sign of the excess (­Figure 6.9), whereas in the bulk of the intracellular and extracel-
charge on the inside of the cell by comparison. For example, if the lular fluid the number of positive and negative charges is balanced.
inside of a cell has an excess of negative charge and the potential Unlike the diagrammatic representation in Figure 6.9, the number
difference across the membrane has a magnitude of 70 mV, we say of positive and negative charges that have to be separated across a
that the membrane potential is −70 mV (inside relative to outside). membrane to account for the potential is actually an infinitesimal
Keep in mind that volts are a measure of the difference in charge fraction of the total number of charges in the two compartments.
across a membrane; a Vm of −70 mV does not say anything about Table 6.2 lists typical concentrations of sodium, potas-
the absolute number of negative and positive charges that exist on sium, and chloride ions in the extracellular fluid and in the intra-
either side of a membrane. cellular fluid of a representative neuron. Each of these ions has a
10- to 30-fold difference in concentration between the inside and
Nature and Magnitude of the Resting Membrane the outside of the cell. Although this table appears to contradict
Potential our earlier assertion that the bulk of the intracellular and extra-
The magnitude of the resting membrane potential in neurons is cellular fluid has a balance of charges, there are many other ions
generally in the range of −40 to −90 mV. The resting membrane not listed, including Mg2+, Ca2+, H+, HCO3−, HPO42−, SO42−, and
potential holds steady unless changes in electrical current alter ionized organic compounds including amino acids, and proteins.
144 Chapter 6
 + – +
– + – Contribution of Ion Concentration Differences
– + + – + Extracellular
– – + – fluid To understand how concentration differences for Na+ and K+
+ + + + create membrane potentials, first consider what happens when
+
+ + + –
– + + – – – + –
– + the membrane is permeable (has open channels) to only one ion
+
– + –
– – – + –
– + + (Figure 6.10). In this hypothetical situation, assume that the
– – +– –+ +
+ +– – – + – + membrane contains K+ channels but no Na+ or Cl− channels.
+ – + + – +
– Initially, compartment 1 contains 0.15 M NaCl, compartment
+– Cell – +
– + + – – 2 contains 0.15 M KCl, and no ion movement occurs because the
– + +– –– + – + +
+
+ – – + – channels are closed (Figure 6.10a). There is no potential differ-
+
– – +– –
+ – ence across the membrane because the two compartments contain
+ – – + –
– + – – – + – + equal numbers of positive and negative ions. The positive ions are
+ – + +
+ + –+ + + ­different—Na+ versus K+, but the total numbers of positive ions
– – –
– + – +
+
+ +
–
in the two compartments are the same, and each positive ion bal-
+ +
– – + – + – ances a chloride ion.
However, if these K+ channels are opened, K+ will diffuse
Figure 6.9 The excess positive charges outside the cell and the down its concentration gradient from compartment 2 into com-
excess negative charges inside collect in a tight shell against the plasma partment 1 (Figure 6.10b). Sodium ions will not be able to move
membrane. In reality, these excess charges are only an extremely small across the membrane. After a few potassium ions have moved into
fraction of the total number of ions inside and outside the cell. compartment 1, that compartment will have an excess of positive

(a)
When all ions are accounted for, each solution is indeed elec-
Compartment 1 Compartment 2
trically neutral. Of the ions that can flow across the membrane
and affect its electrical potential, Na+, K+, and Cl− are present 0.15 M 0.15 M
in the highest concentrations, and the membrane permeability to
each is independently determined. Na+ and K+ generally make NaCl KCI
the most important contributions in generating the resting mem- (b)
brane potential, but in some cells Cl− is also a factor. Notice that
the Na+ and Cl− concentrations are lower inside the cell than out- + – K+
side, and that the K+ concentration is greater inside the cell. The Na+
concentration differences for Na+ and K+ are established by the
(c)
action of the sodium/potassium-ATPase pump (Na+/K+-ATPase,
Chapter 4) that pumps Na+ out of the cell and K+ into it. The rea-
son for the Cl− distribution varies between cell types, as will be
K+ + – K+
Na+
+ –
described later.
The magnitude of the resting membrane potential depends (d)
mainly on two factors: (1) differences in specific ion concentrations
K+
+ –
in the intracellular and extracellular fluids; and (2) differences in K+ + –
membrane permeabilities to the different ions, which reflect the
number of open channels for the different ions in the plasma mem-
Na+ + –

brane. A third factor, a direct contribution from ion pumps, has a (e)

K+
very minor role. We will examine each of these in detail. +
K+ +
–
–
+ + –
Na + –
Distribution of Major Mobile Ions Across
TABLE 6.2 the Plasma Membrane of a Typical
Neuron Figure 6.10 Generation of a potential across a membrane due
to diffusion of K+ through K+ channels (red). Arrows represent
Concentration (mmol/L) ion movements; as in Figure 4.3, arrow length represents the
magnitude of the flux. See the text for a complete explanation of
Ion Extracellular Intracellular
the steps a–e.
Na+ 145 15
PHYSIOLOG ICAL INQUIRY
Cl− 100 7*
■ In setting up this experiment, 0.15 mole of NaCl was placed in
K +
5 150 compartment 1, 0.15 mole of KCl was placed in compartment
2, and each compartment has a volume of 1 liter. What is the
A more accurate measure of electrical driving force can be obtained using a measurement called approximate total solute concentration in each compartment at
milliequivalents/L (mEq/L), which factors in ion valence. Because all the ions in this table have a valence
of 1, the mEq/L is the same as the mmol/L concentration. equilibrium (that is, in panel e)?
*Intracellular Cl− concentration varies significantly between neurons due to differences in expression of Answer can be found at end of chapter.
membrane transporters and channels.

Neuronal Signaling and the Structure of the Nervous System 145

charge, leaving behind an excess of negative charge in compart- (a)
Compartment 1 Compartment 2
ment 2 (Figure 6.10c). Thus, a potential difference has been cre-
ated across the membrane. 0.15 M 0.15 M
This introduces another major factor that can cause net
movement of ions across a membrane: an electrical potential. As NaCl KCI
compartment 1 becomes increasingly positive and compartment (b)
2 increasingly negative, the membrane potential difference begins
to influence the movement of the potassium ions. The negative Na+ – +
charge of compartment 2 tends to attract them back into their ori-
ginal compartment, and the positive charge of compartment 1
K+
tends to repel them out of compartment 1 (Figure 6.10d). (c)

Na+
In other words, using the terminology introduced in Na+
Chapter 4, there is an electrochemical gradient across the mem- – +
brane for all ions. As long as the flux or movement of ions due – +
K+
to the K+ concentration gradient is greater than the flux due to
(d)
the membrane potential, net flux of K+ will occur from compart-
ment 2 to compartment 1 (see Figure 6.10d) and the membrane Na+ – +
– +
Na+
potential will progressively increase. However, eventually, the
membrane potential will become negative enough to produce a
– +
K+
flux equal but opposite to the flux produced by the concentration (e)
gradient (Figure 6.10e). The membrane potential at which these
two fluxes become equal in magnitude but opposite in direction Na+ –
–
+
+
Na+

is called the equilibrium potential for that ion—in this case, K+.
At the equilibrium potential for an ion, there is no net movement
–
–
+
+ K+
of the ion because the opposing fluxes are equal, and the poten-
tial will undergo no further change. Note from Figure 6.10 that Figure 6.11 Generation of a potential across a membrane due to
diffusion of Na+ through Na+ channels (blue). Arrows represent ion
as long as a concentration gradient was initially present and there
movements; as in Figure 4.3, arrow length indicates the magnitude of the
were open channels for K+, a membrane potential was automatic- flux. So few sodium ions cross the membrane that ion concentrations do
ally generated. It is worth emphasizing that the number of ions not change significantly from step (a) to step (e). See the text for a more
crossing the membrane to establish this equilibrium potential is complete explanation.
insignificant compared to the number originally present in com-
partment 2, so there is no significant change in the K+ concentra- PHYSIOLOG ICAL INQUIRY
tion in either compartment between step (a) and step (e).
The magnitude of the equilibrium potential (in mV) for any ■ In this hypothetical system, what would the concentrations of
type of ion depends on the concentration gradient for that ion across each ion be at equilibrium (panel e) if open channels for both Na+
the membrane. If the concentrations on the two sides were equal, and K+ were present?
the net flux would be zero and the equilibrium potential would Answer can be found at end of chapter.
also be zero. The larger the concentration gradient, the larger the
equilibrium potential because a larger, electrically driven move-
ment of ions will be required to balance the movement due to the
its concentration gradient? How are these two factors mathemati-
concentration difference.
cally related? It turns out that if the concentration gradient for any
Now consider the situation in which the membrane sepa-
ion is known, the equilibrium potential for that ion can be calcu-
rating the two compartments is replaced with one that contains
lated by means of the Nernst equation.
only Na+ channels. A parallel situation will occur (Figure 6.11).
The Nernst equation describes the equilibrium potential for
Sodium ions (Na+) will initially move from compartment 1 to
any ion—that is, the electrical potential necessary to balance a given
compartment 2. When compartment 2 is positive with respect
ionic concentration gradient across a membrane so that the net flux of
to compartment 1, the difference in electrical charge across the
the ion is zero. The Nernst equation is
membrane will begin to drive Na+ from compartment 2 back to
compartment 1 and, eventually, net movement of Na+ will cease. 61 C
Eion = log out
Again, at the equilibrium potential, the movement of ions due Z Cin
to the concentration gradient is equal but opposite to the move-
where
ment due to the electrical gradient, and an insignificant number of
sodium ions actually move in achieving this state. Eion = equilibrium potential for a particular ion, in mV
Thus, the equilibrium potential for one ion can be different Cin = intracellular concentration of the ion
in magnitude and direction from those for other ions, depending Cout = extracellular concentration of the ion
on the concentration gradients between the intracellular and extra- Z = the valence of the ion
cellular compartments for each ion. 61 = a constant value that takes into account the universal gas
Is there a way to predict how much electrical force is constant, the temperature (37°C in all our examples), and
required to exactly balance the tendency of an ion to diffuse down the Faraday electrical constant
146 Chapter 6
 Using the concentration gradients from Table 6.2, the equi- to the equilibrium potential for K+ (Figure 6.12). The value of the
librium potentials for Na+ (ENa) and K+ (EK) are Cl− equilibrium potential is also near the resting membrane poten-
tial in many neurons, but for reasons we will return to shortly, Cl−
61 145
ENa = log = + 60 mV actually has minimal importance in determining neuronal resting
+1 15 membrane potentials compared to K+ and Na+.
61 5 In summary, the resting potential is generated across the
EK = log = − 90 mV
+1 150 plasma membrane largely because of the movement of K+ out of the
cell down its concentration gradient through constitutively open K+
Thus, at these typical concentrations, Na+ flux through open channels (called leak channels, or ungated channels, to distinguish
channels will tend to bring the membrane potential toward +60 mV, them from gated channels). This makes the inside of the cell negative
whereas K+ flux will bring it toward −90 mV. If the concentration with respect to the outside. Even though K+ flux has more impact on
gradients change, the equilibrium potentials will change. the resting membrane potential than does Na+ flux, the resting mem-
The hypothetical situations presented in Figures 6.10 and brane potential is not equal to the K+ equilibrium potential, because
6.11 are useful for understanding how individual permeating ions having a small number of open leak channels for Na+ does pull the
like Na+ and K+ influence membrane potential, but keep in mind membrane potential slightly toward the Na+ equilibrium potential.
that real cells are far more complicated. Many charged molecules Thus, at the resting membrane potential, ion channels allow net
contribute to the overall electrical properties of cell membranes. movement both of Na+ into the cell and K+ out of the cell.
For example, real cells are rarely permeable to only a single ion at Over time, the concentrations of intracellular sodium and
a time, as we see next. potassium ions do not change, however, because of the action of the
Contribution of Different Ion Permeabilities Na+/K+-ATPase pump. In a resting cell, the number of ions the pump
moves equals the number of ions that leak down their electrochemical
When channels for more than one type of ion are open in the mem- gradient. As long as the concentration gradients remain stable and the
brane at the same time, the permeabilities and concentration gradients ion permeabilities of the plasma membrane do not change, the electri-
for all the ions must be considered when accounting for the membrane cal potential across the resting membrane will also remain constant.
potential. For a given concentration gradient, the greater the mem-
brane permeability to one type of ion, the greater the contribution that
(a) (b)
ion will make to the membrane potential. Given the concentration
gradients and relative membrane permeabilities (Pion) for Na+, K+, and
Cl−, the resting membrane potential of a membrane (Vm) can be calcu- Na+ + 60 ENa
lated using the Goldman-Hodgkin-Katz (GHK) equation:
Na+
P [K ] + PNa [Naout] + PCl [Clin]
Vm = 61 log K out
PK [Kin] + PNa [Nain] + PCl [Cl out]

Voltage (mV)
– 70 mV
+ 0
The GHK equation is essentially an expanded version of K
the Nernst equation that takes into account individual ion perme-
abilities. In fact, setting the permeabilities of any two ions to zero
K+
gives the equilibrium potential for the remaining ion. Note that
– 70 Vm at rest
the Cl− concentrations are reversed as compared to Na+ and K+
(the inside concentration is in the numerator and the outside in the
Extracellular fluid – 90 EK
denominator), because Cl− is an anion and its movement has the
opposite effect on the membrane potential. Ion gradients and per-
KEY
meabilities vary widely in different excitable cells of the human
Concentration
body and in other animals, and yet the GHK equation can be used gradient
to determine the resting membrane potential of any cell if the con- Electrical
ditions are known. For example, if the relative permeability val- gradient
ues of a cell were PK = 1, PNa = 0.04, and PCl = 0.45 and the ion
concentrations were equal to those listed in Table 6.2, the resting Figure 6.12 Forces influencing sodium and potassium ions at the
membrane potential would be resting membrane potential (Vm). (a) At a resting membrane potential
of −70 mV, both the concentration and electrical gradients favor
(1)(5) + (.04)(145) + (.45)(7) inward movement of Na+, whereas the K+ concentration and electrical
Vm = 61 log = − 70 mV
(1)(150) + (.04)(15) + (.45)(100) gradients are in opposite directions. (b) The greater permeability of
K+ maintains the resting membrane potential at a value near EK.
The contributions of Na+, K+, and Cl− to the overall mem-
brane potential are thus a function of their concentration gradients
and relative permeabilities. The concentration gradients determine PHYSIOLOG ICAL INQUIRY
their equilibrium potentials, and the relative permeability deter- ■ Would decreasing a neuron’s intracellular fluid [K+] by
mines how strongly the resting membrane potential is influenced 1 mM have the same effect on resting membrane potential as
toward those potentials. In mammalian neurons, the K+ permeabil- raising the extracellular fluid [K+] by 1 mM?
ity may be as much as 100 times greater than that for Na+ and Cl−, Answer can be found at end of chapter.
so neuronal resting membrane potentials are typically fairly close
Neuronal Signaling and the Structure of the Nervous System 147
Contribution of Ion Pumps negative resting potential because with each cycle it moves three
+ +
The leak of Na and K down their electrochemical gradients Na+ out of the cell for every two K+ that it brings in. This unequal
through ion channels is the main factor in determining the resting transport of positive ions makes the inside of the cell more neg-
membrane potential, but the Na+/K+ -ATPase pump is essential ative than it would be from ion diffusion alone. When a pump
to this process because it maintains the concentration gradients. moves net charge across the membrane and contributes directly
In addition, the pump plays a very minor direct role in creating a to the membrane potential, it is known as an electrogenic pump.
In most cells, the electrogenic contribution to the membrane
potential is quite small. Even though the electrogenic contribution
(a)
of the Na+/K+-ATPase pump is small, the pump always makes an

Na+
essential indirect contribution to the membrane potential because
Intracellular fluid Extracellular fluid it maintains the concentration gradients that result in ion diffusion
and charge separation.

Summary of the Development of a Resting

ATP − +
3 Na+
Membrane Potential
When a membrane potential is maintained at a resting value of
Na+ /K+-ATPase +
–70 mV, the inward and outward leak of positive ions must be
− +

K+
2K
pump equal even though there is a greater permeability to K+. How
ADP does this steady state develop? Figure 6.13 summarizes this
process in three conceptual steps. First, the action of the Na+/
K+-ATPase pump sets up the concentration gradients for Na+ and
K+ (­Figure 6.13a). These concentration gradients determine the
equilibrium potentials for the two ions—that is, the value to which
each ion would bring the membrane potential if it were the only
permeating ion. Simultaneously, the pump has a small electrogenic
(b)
effect on the membrane due to the fact that three Na+ are pumped

Na+
out for every two K+ pumped in. The next step shows that initially
– +
Intracellular fluid Extracellular fluid

– +
there is a greater flux of K+ out of the cell than Na+ into the cell
(Figure 6.13b). This is because in a resting membrane there is a
greater permeability (more leak channels) to K+ than there is to Na+.
– +
ATP – +
Because there is greater net efflux than influx of positive ions dur-
3 Na+ ing this step, a significant negative membrane potential develops,
with the value approaching that of the K+ equilibrium potential.
2 K+
In the steady-state resting neuron, the flux of ions across the mem-
– +

K+
ADP – +
brane reaches a dynamic balance in which K+ is highly permeable
but has a small electrochemical gradient and Na+ has low permea-
bility but a large electrochemical gradient. In this state the inward
– +
and outward currents are equal, so the membrane potential rests at
a steady value (Figure 6.13c). Because the membrane potential is

– +
not equal to the equilibrium potential for either ion, there is a small
– +
but steady leak of Na+ into the cell and K+ out of the cell. The con-
centration gradients do not dissipate over time, however, because ion
(c)
movement by the Na+/K+-ATPase pump exactly balances the rate at
which the ions leak in the opposite direction.
– +
Intracellular fluid Extracellular fluid

– +
Now let’s return to the behavior of chloride ions in excitable
cells. The plasma membranes of many cells also have Cl− chan-

– +
Na+ nels but do not contain chloride ion pumps. Therefore, in these
cells, Cl− concentrations simply shift until the equilibrium poten-
ATP – +
3 Na+ tial for Cl− is equal to the resting membrane potential. In other
words, the negative membrane potential determined by Na+ and
2 K+
K+ moves Cl− out of the cell, and the Cl− concentration inside the
– +
ADP – +
cell becomes lower than that outside. This concentration gradient

K+ – + Figure 6.13 Summary of steps explaining the resting membrane

potential. (a) An Na+/K+-ATPase pump establishes concentration gradients and

– +
generates a small negative potential. (b) Greater net movement of K+ than Na+ makes

– +
the membrane potential more negative on the inside. (c) At a steady negative resting
membrane potential, ion fluxes through the channels and pump balance each other.
148 Chapter 6
produces a diffusion of Cl− back into the cell that exactly opposes or chemical stimuli. When a neuron receives a chemical signal
the movement out because of the electrical potential. from a neighboring neuron, for instance, some gated channels will
In contrast, some cells have a nonelectrogenic active- open, allowing greater ionic current across the membrane. The
transport system that moves Cl− out of the cell, generating a strong greater movement of ions down their electrochemical gradient
concentration gradient. In these cells, the Cl− equilibrium poten- alters the membrane potential so that it is either depolarized or
tial is negative to the resting membrane potential, and net Cl− dif- hyperpolarized relative to the resting state. We will see that par-
fusion into the cell contributes to the excess negative charge inside ticular characteristics of these gated ion channels determine the
the cell; that is, net Cl− diffusion makes the membrane potential nature of the electrical signal generated.
more negative than it would be if only Na+ and K+ were involved.
Graded Potentials
Graded potentials are changes in membrane potential that are
6.7 Graded Potentials and Action confined to a relatively small region of the plasma membrane.
They are usually produced when some specific change in the
Potentials cell’s environment acts on a specialized region of the membrane.
You have just learned that all cells have a resting membrane poten- They are called graded potentials simply because the magnitude
tial due to the presence of ion pumps, ion concentration gradients, of the potential change can vary (is “graded”). Graded potentials
and leak channels in the cell membrane. In addition, however, some are given various names related to the location of the potential or
cells have another group of ion channels that can be gated (opened the function they perform—for instance, receptor potential, syn-
or closed) under certain conditions. Such channels give a cell the aptic potential, and pacemaker potential are all different types of
ability to produce electrical signals that can transmit information graded potentials (Table 6.3).
between different regions of the membrane. This property is known
as excitability, and such membranes are called excitable mem-
branes. Cells of this type include all neurons and muscle cells. The A Miniglossary of Terms Describing the
TABLE 6.3 Membrane Potential
electrical signals occur in two forms: graded potentials and action
potentials. Graded potentials are important in signaling over short Potential or potential The voltage difference between two points due
distances, whereas action potentials are long-distance signals that difference to separated electrical charges of opposite sign
are particularly important in neuronal and muscle cell membranes.
The terms depolarize, repolarize, and hyperpolarize are Membrane The voltage difference between the inside
potential and outside of a cell
used to describe the direction of changes in the membrane potential
relative to the resting potential in an excitable cell (­Figure 6.14). Equilibrium The voltage difference across a membrane
The resting membrane potential is “polarized,” simply meaning potential that produces a flux of a given ion species
that the outside and inside of a cell have a different net charge. that is equal but opposite to the flux due to
The membrane is depolarized when its potential becomes less the concentration gradient of that same ion
negative (closer to zero) than the resting level. Overshoot refers to
Resting membrane The steady potential of an unstimulated cell
a reversal of the membrane potential polarity—that is, when the potential
inside of a cell becomes positive relative to the outside. When a
membrane potential that has been depolarized returns to the rest- Graded potential A potential change of variable amplitude and
ing value, it is repolarized. The membrane is hyperpolarized duration that is conducted decrementally; has
when the potential is more negative than the resting level. no threshold or refractory period
The changes in membrane potential that the neuron uses as Action potential A brief all-or-none depolarization of the
signals occur because of changes in the permeability of the cell membrane, which reverses polarity in
membrane to ions. Recall from Chapter 4 that gated ion channels neurons; has a threshold and refractory
in a membrane may be opened or closed by mechanical, electrical, period and is conducted without decrement
+60 Synaptic potential A graded potential change produced in
Overshoot

the postsynaptic neuron in response to

Membrane potential (mV)

the release of a neurotransmitter by a

presynaptic terminal; may be depolarizing
0 (an excitatory postsynaptic potential or
EPSP) or hyperpolarizing (an inhibitory
Repolarizing
Depolarizing

Hyperpolarizing

postsynaptic potential or IPSP)

Receptor potential A graded potential produced at the peripheral

Resting potential
–70 endings of afferent neurons (or in separate
receptor cells) in response to a stimulus
–90
Pacemaker A spontaneously occurring graded potential
Time
potential change that occurs in certain specialized cells
Figure 6.14 Depolarizing, overshoot, repolarizing, and Threshold The membrane potential at which an action
hyperpolarizing changes in membrane potential relative to the
potential potential is initiated
resting potential.
Neuronal Signaling and the Structure of the Nervous System 149
 Whenever a graded potential occurs, charge flows between (a)
0 mV
the place of origin of this potential and adjacent regions of the
plasma membrane, which are still at the resting potential. In Depolarization Hyperpolarization
Figure 6.15, a small region of a membrane has been depolar- –70 mV
ized by transient application of a chemical signal, briefly opening Stimulus Stimulus
membrane cation channels and producing a potential less nega-

Membrane potential (mV)

tive than that of adjacent areas. Positive charges inside the cell
(b)
(mainly K+ ions) will move through the intracellular fluid away 0 mV

from the depolarized region and toward the more negative, rest-
ing regions of the membrane. Simultaneously, outside the cell, –70 mV
positive charge will move from the more positive region of the Weak stimulus Strong stimulus
resting membrane toward the less positive regions the depolar-
ization just created. Note that this local current moves positive
(c) 0 mV
charges toward the depolarization site along the outside of the Measured at Measured 1 mm
membrane and away from the depolarization site along the inside stimulus site from stimulus site
of the membrane. Thus, depolarization spreads to adjacent areas –70 mV
along the membrane. Stimulus Stimulus
Depending upon the initiating event, graded potentials
can occur in either a depolarizing or a hyperpolarizing direction Time (msec)
(Figure 6.16a), and their magnitude is related to the magnitude
of the initiating event (Figure 6.16b). In addition to the move- Figure 6.16 Graded potentials can be recorded under experimental
conditions in which the stimulus strength can vary. Such experiments
ment of ions on the inside and the outside of the cell, charge is lost
show that graded potentials (a) can be depolarizing or hyperpolarizing,
across the membrane because the membrane is permeable to ions (b) can vary in size, and (c) are conducted decrementally. In this
through open leak channels. The result is that the change in mem- example, the resting membrane potential is −70 mV.
brane potential decreases as the distance increases from the initial
site of the potential change (Figure 6.16c). In fact, plasma mem-
branes are so leaky to ions that these currents die out almost com-
pletely within a few millimeters of their point of origin. Because Site of initial depolarization
of this, local current is decremental; that is, the flow of charge Charge Extracellular
decreases as the distance from the site of origin of the graded fluid
potential increases (Figure 6.17).
Because the electrical signal decreases with distance,
graded potentials (and the local current they generate) can func- Axon
tion as signals only over very short distances (a few millimeters).
However, if additional stimuli occur before the graded potential
Direction of current
has died away, these can add to the graded potential from the first
Figure 6.17 Leakage of charge (predominately K+) across the
plasma membrane reduces the local current at sites farther along the
Extracellular fluid Open cation channel membrane from the site of initial depolarization.

+ + + + + + + +
+ + + – – – – – – + + +
+ + – – – – – – –
– – + + + + – stimulus. This process, termed summation, is particularly impor-
Chemical tant for sensation, as Chapter 7 will discuss. Graded potentials are
stimulus the only means of communication used by some neurons, whereas
Area of depolarization
in other neurons, graded potentials initiate a type of signal that
Intracellular fluid travels longer distances, which we describe next.

Figure 6.15 Depolarization and graded potential caused by a Action Potentials

chemical stimulus. Inward positive current through ligand-gated
Action potentials are very different from graded potentials. They
cation channels depolarizes a region of the membrane, and local
are large alterations in the membrane potential; the membrane
currents spread the depolarization to adjacent regions.
potential may change by as much as 100 mV. For example, a cell
might depolarize from −70 to +30 mV, and then repolarize to its
PHYSIOLOG ICAL INQUIRY resting potential. Action potentials are generally very rapid (as
■ If the ligand-gated ion channel allowed only K+ movement, how brief as 1–4 milliseconds) and may repeat at frequencies of several
would this figure be different? hundred per second. The propagation of action potentials down
Answer can be found at end of chapter. the axon is the mechanism the nervous system uses to communi-
cate from cell to cell over long distances.

150 Chapter 6
 What properties of ion channels allow them to generate depolarized, local voltage-gated Na+ channels open before the
these large, rapid changes in membrane potential, and how are voltage-gated K+ channels do, and if the membrane is then repo-
action potentials propagated along an excitable membrane? These larized to negative voltages, the voltage-gated K+ channels are
questions are addressed in the following sections. also slower to close. The second key difference is that voltage-
gated Na+ channels have an extra feature in their structure known
Voltage-Gated Ion Channels As introduced in Chapter 4, as an inactivation gate. This structure, sometimes visualized as
there are many types of ion channels and several different a “ball and chain,” limits the flux of Na+ by blocking the channel
mechanisms that regulate the opening of the different types. shortly after depolarization opens it. When the membrane repo-
Ligand-gated ion channels open in response to the binding of larizes, the channel closes, forcing the inactivation gate back out
signaling molecules (as shown in Figure 6.15), and mechanically of the pore and allowing the channel to return to the closed state.
gated ion channels open in response to physical deformation Integrating these channel properties with the basic principles
(stretching) of the plasma membranes. Whereas these types of governing membrane potentials, we can now explain how action
channels often mediate graded potentials that can serve as the potentials occur.
initiating stimulus for an action potential, it is voltage-gated
ion channels that give a membrane the ability to undergo action Action Potential Mechanism In our previous coverage of
potentials. There are dozens of different types of voltage-gated resting membrane potential and graded potentials, we saw that
ion channels, varying by which ion they conduct (for example, the membrane potential depends upon the concentration gradients
Na+, K+, Ca2+, or Cl−) and in how they behave as the membrane and membrane permeabilities of different ions, particularly Na+
voltage changes. For now, we will focus on the particular types of and K+. This is true of the action potential as well. During an
voltage-gated Na+ and K+ channels that mediate most neuronal action potential, transient changes in membrane permeability
action potentials. allow Na+ and K+ to move down their electrochemical gradients.
Figure 6.18 summarizes the relevant characteristics of these Figure 6.19 illustrates the steps that occur during an action
channels. Na+ and K+ channels are similar in having sequences potential.
of charged amino acid residues in their structure that make the In step 1 of the figure, the resting membrane potential is
channels reversibly change shape in response to changes in mem- close to the K+ equilibrium potential because there are more
brane potential. When the membrane is at a negative potential (for open K+ channels than Na+ channels. Recall that these are
example, at the resting membrane potential), both types of chan- leak channels and that they are distinct from the voltage-gated
nels tend to stay closed, whereas membrane depolarization tends ion channels just described. An action potential begins with a
to open them. Two key differences, however, allow these channels depolarizing stimulus—for example, when a neurotransmitter
to make different contributions to the production of action poten- binds to a specific ligand-gated ion channel and allows Na+ to
tials. First, voltage-gated Na+ channels respond faster to changes enter the cell (review Figure 6.15). This initial depolarization
in membrane voltage. When an area of a membrane is suddenly stimulates the opening of some voltage-gated Na+ channels,
and further entry of Na+ through those channels adds to the
local membrane depolarization. When the membrane reaches a
Ion channel Channel states Rate critical threshold potential (step 2), depolarization becomes a
positive feedback loop. Na+ entry causes depolarization, which
Inactivation Na+ opens more voltage-gated Na+ channels, which causes more
gate depolarization, and so on. This process is represented as a rapid
Open and depolarization of the membrane potential (step 3), and it over-
Sodium inactivate shoots so that the membrane actually becomes positive on the
very rapidly
inside and negative on the outside. In this phase, the membrane
Closed Open Inactivated
approaches but does not quite reach the Na+ equilibrium poten-
tial (+60 mV) because Na+ channels begin to inactivate and K+
channels begin to open.
Open and
As the membrane potential reaches its peak value (step
Potassium close slowly 4), the Na+ permeability abruptly declines as inactivation gates
break the cycle of positive feedback by blocking the open Na+
K+ channels. Meanwhile, the depolarized state of the membrane has
Closed Open
begun to open the relatively sluggish voltage-gated K+ ­channels,
Depolarization and the resulting increased K+ flux out of the cell rapidly
­repolarizes the membrane toward its resting value (step 5). The
return of the membrane to a negative potential causes voltage-
Repolarization
gated Na+ channels to go from their inactivated state back to
Figure 6.18 Behavior of voltage-gated Na+ and K+ the closed state (without opening, as described earlier) and K+
channels. Depolarization of the membrane causes Na+ channels to channels to also return to the closed state. Because voltage-gated
rapidly open, then undergo inactivation followed by the opening of K+ K+ channels close relatively slowly, immediately after an action
channels. When the membrane repolarizes to negative voltages, both potential there is a period when K+ permeability remains above
channels return to the closed state. resting levels and the membrane is transiently hyperpolarized

Neuronal Signaling and the Structure of the Nervous System 151

 (a)
4
+30
1 Steady resting membrane potential is near EK, PK > PNa, due to
leak K+ channels.
Membrane potential (mV)

2 Local membrane is brought to threshold voltage by a depolarizing

0
5
stimulus.
3
3 Current through opening voltage-gated Na+ channels rapidly
depolarizes the membrane, causing more Na+ channels to open.
4 Inactivation of Na+ channels and delayed opening of voltage-gated
K+ channels halt membrane depolarization.
Threshold potential 5 Outward current through open voltage-gated K+ channels repolarizes
2 the membrane back to a negative potential.
7 6 Persistent current through slowly closing voltage-gated K+ channels
–70 hyperpolarizes membrane toward EK; Na+ channels return
1
Resting membrane 6 from inactivated state to closed state (without opening).
potential
7 Closure of voltage-gated K+ channels returns the membrane
Na+ potential to its resting value.
Voltage-gated Na+ channels

Voltage-gated K+ channels

(b) K+ K+
Relative membrane permeability

600

PNa+ Figure 6.19 The changes in (a) membrane potential and

(b) relative membrane permeability (P) to sodium and potassium ions
during an action potential. Steps 1–7 are described in more detail in
300 the text.
PK+
PHYSIOLOG ICAL INQUIRY
100
■ If extracellular [Na+] is elevated, how would the resting potential
and action potential of a neuron change?
0 1 2 3 4
Answer can be found at end of chapter.
Time (msec)

toward the K+ equilibrium potential (step 6). This portion of the earlier, cellular accumulation of Na+ and loss of K+ are prevented
action potential is known as the afterhyperpolarization. Once by the continuous action of the membrane Na+/K+-ATPase pumps.
the voltage-gated K+ channels finally close, however, the resting As explained previously, not all membrane depolarizations
membrane potential is restored (step 7). Whereas voltage-gated in excitable cells trigger the positive feedback process that leads to
Na+ channels operate in a positive feedback mode at the begin- an action potential. Action potentials occur only when the initial
ning of an action potential, voltage-gated K+ channels bring the stimulus plus the current through the Na+ channels it opens are
action potential to an end and induce their own closing through a sufficient to elevate the membrane potential beyond the thresh-
negative feedback process (Figure 6.20). old potential. Stimuli that are just strong enough to depolarize
You may think that large movements of ions across the mem- the membrane to this level are threshold stimuli (Figure 6.21).
brane are required to produce such large changes in membrane The threshold of most excitable membranes is about 15 mV less
potential. Actually, the number of ions that cross the membrane negative than the resting membrane potential. Thus, if the resting
during an action potential is extremely small compared to the total potential of a neuron is −70 mV, the threshold potential may be
number of ions in the cell, producing only infinitesimal changes −55 mV. At depolarizations less than threshold, the positive feed-
in the intracellular ion concentrations. Yet, if this tiny number of back cycle cannot get started. In such cases, the membrane will
additional ions crossing the membrane with repeated action poten- return to its resting level as soon as the stimulus is removed and no
tials were not eventually moved back across the membrane, the action potential will be generated. These weak depolarizations are
concentration gradients of Na+ and K+ would gradually dissipate called subthreshold potentials, and the stimuli that cause them are
and action potentials could no longer be generated. As mentioned subthreshold stimuli.

152 Chapter 6
(a) Action potential
+30
Stop
Opening of Inactivation

Membrane potential (mV)

Depolarizing
voltage-gated of Na+ channels
stimulus
Na+ channels 0
+ Subthreshold
Positive potentials
Depolarization feedback Threshold
of membrane Increased PNa+ potential
potential

Increased flow −70

Resting
of Na+ into
the cell potential
Threshold
stimulus
(b)

Stimulus strength
Depolarization Opening of
of membrane voltage-gated
by Na+ influx K+ channels
0

Subthreshold
Negative
Repolarization stimuli
feedback
of membrane Increased PK+
potential Time

Figure 6.21 Changes in the membrane potential with increasing

Increased flow strength of excitatory stimuli. When the membrane potential reaches
of K+ out of threshold, action potentials are generated. Increasing the stimulus
the cell strength above threshold level does not cause larger action potentials.
(The absolute value of threshold is not indicated because it varies from
Figure 6.20 Feedback control in voltage-gated ion channels. cell to cell.)
(a) Na+ channels exert positive feedback on membrane potential.
(b) K+ channels exert negative feedback.

The generation of action potentials is prevented by local

anesthetics such as procaine (Novocaine) and lidocaine
Stimuli stronger than those required to reach threshold elicit (Xylocaine) because these drugs block voltage-gated Na+ chan-
action potentials, but as can be seen in Figure 6.21, the action nels, preventing them from opening in response to depolarization.
potentials resulting from such stimuli have exactly the same Without action potentials, graded signals generated in sensory
amplitude as those caused by threshold stimuli. This is because neurons—in response to injury, for example—cannot reach the
once threshold is reached, membrane events are no longer depen- brain and give rise to the sensation of pain.
dent upon stimulus strength. Rather, the depolarization generates Some animals produce toxins (poisons) that work by inter-
an action potential because the positive feedback cycle is oper- fering with nerve conduction in the same way that local anes-
ating. Action potentials either occur maximally or they do not thetics do. For example, some organs of the pufferfish produce
occur at all. Another way of saying this is that action potentials an extremely potent toxin, tetrodotoxin, that binds to voltage-
are all-or-none. gated Na+ channels and prevents the Na+ component of the action
The firing of a gun is a mechanical analogy that shows potential. In Japan, chefs who prepare this delicacy are specially
the principle of all-or-none behavior. The magnitude of the trained to completely remove the toxic organs before serving the
explosion and the velocity at which the bullet leaves the gun pufferfish dish called fugu. Individuals who eat improperly pre-
do not depend on how hard the trigger is squeezed. Either the pared fugu may die, even if they ingest only a tiny quantity of
trigger is pulled hard enough to fire the gun, or it is not; it’s all tetrodotoxin.
or none.
Because the amplitude of a single action potential does not Refractory Periods During the action potential, a second
vary in proportion to the amplitude of the stimulus, an action stimulus, no matter how strong, will not produce a second
potential cannot convey information about the magnitude of the action potential (Figure 6.22). That region of the membrane is
stimulus that initiated it. How then do you distinguish between a then said to be in its absolute refractory period. This occurs
loud noise and a whisper, a light touch and a pinch? This informa- during the period when the voltage-gated Na+ channels are
tion, as we will discuss later, depends upon the number and pat- either already open or have proceeded to the inactivated state
terns of action potentials transmitted per unit of time (i.e., their during the first action potential. The inactivation gate that has
frequency) and not upon their magnitude. blocked these channels must be removed by repolarizing the

Neuronal Signaling and the Structure of the Nervous System 153

Membrane potential (mV) The refractory periods limit the number of action poten-
tials an excitable membrane can produce in a given period of
time. Most neurons respond at frequencies of up to 100 action
potentials per second, and some may produce higher frequen-
cies for brief periods. Refractory periods contribute to the sep-
aration of these action potentials so that individual electrical
signals pass down the axon. The refractory periods also are the
key in determining the direction of action potential propaga-
tion, as we see next.

Action Potential Propagation The action potential

Stimulus strength

can only travel the length of a neuron if each point along the
membrane is depolarized to its threshold potential as the
action potential moves down the axon (Figure 6.23). As with
graded potentials (refer back to Figure 6.15), the membrane
Absolute Relative refractory period is depolarized at each point along the way with respect to the
refractory adjacent portions of the membrane, which are still at the resting
period
membrane potential. The difference between the potentials
Time causes current to flow, and this local current depolarizes the
= Threshold stimuli and action potentials at adjacent membrane where it causes the voltage-gated Na+
normal resting membrane potential
channels located there to open. The current entering during an
= Threshold stimuli and action potentials during
relative refractory period
action potential is sufficient to easily depolarize the adjacent
= Stimuli during absolute refractory period
membrane to the threshold potential.
cannot induce a second action potential The new action potential produces local currents of its
own that depolarize the region adjacent to it (Figure 6.23b),
Figure 6.22 Absolute and relative refractory periods of the action producing yet another action potential at the next site, and so
potential determined by a paired-pulse protocol. After a threshold on, to cause action potential propagation along the length of
stimulus that results in an action potential (first stimulus and solid the membrane. Thus, there is a sequential opening and closing
voltage trace), a second stimulus given at various times after the first of voltage-gated Na+ and K+ channels along the membrane. It
can be used to determine refractory periods. All stimuli shown are is like lighting a trail of gunpowder—the action potential does
of the minimum size needed to stimulate an action potential. During
not move, but it “sets off” a new action potential in the region
the absolute refractory period, a second stimulus (black), no matter
how strong, will not produce a second action potential. In the relative
of the axon just ahead of it. Because each regeneration of the
refractory period (stimuli and action potentials shown in red), a second action potential depends on the positive feedback cycle of a new
action potential can be triggered, but a larger stimulus is required to group of Na+ channels where the action potential is occurring,
reach threshold. Action potentials are reduced in size during the relative the action potential arriving at the end of the membrane is virtu-
refractory period, due both to the residual inactivation of some Na+ ally identical in form to the initial one. Thus, action potentials
channels and the persistence of some open K+ channels. are not decremental; they do not decrease in magnitude with dis-
tance like graded potentials.
Because a membrane area that has just undergone an
membrane and closing the pore before the channels can reopen action potential is refractory and cannot immediately undergo
to a second stimulus. another, the only direction of action potential propagation is
Following the absolute refractory period, there is an inter- away from a region of membrane that has recently been active.
val during which a second action potential can be produced— This is again similar to a burning trail of gunpowder—the fire
but only if the stimulus strength is considerably greater than can only spread in the forward direction where the gunpowder
usual. This is the relative refractory period, which can last as is fresh, and not backward where the gunpowder has already
long as 15 msec and coincides roughly with the period of after- burned.
hyperpolarization. During the relative refractory period, some If the membrane through which the action potential must
but not all of the voltage-gated Na+ channels have returned to a travel is not refractory, excitable membranes can conduct action
resting state. With fewer Na+ channels available, the magnitude potentials in either direction, with the direction of propagation
of the action potential is temporarily reduced. In addition, some determined by the stimulus location. For example, the action
of the K+ channels that repolarized the membrane are still open. potentials in skeletal muscle cells are initiated near the middle
Outflow of K+ through these channels opposes some of the of the cells and propagate toward the two ends. In most neurons,
depolarization produced by Na+ entry, making it more difficult however, action potentials are initiated at one end of the cell
to reach threshold unless a stronger stimulus occurs. Thus, dur- and propagate toward the other end, as shown in Figure 6.23.
ing the relative refractory state, it is possible for a new stimulus The propagation ceases when the action potential reaches the
to depolarize the membrane above the threshold potential, but end of an axon.
only if the stimulus is large in magnitude or outlasts the relative The velocity with which an action potential propagates along a
refractory period. membrane depends upon fiber diameter and whether or not the fiber

154 Chapter 6
(a) −70 mV −70 mV −70 mV
Time (msec)
0 1 2 3 4 0 1 2 3 4 0 1 2 3 4

– – – – + + + + + + + +
Local

+ + + + – – – – – – – –
current
from
opening
of ligand- +
gated
channels
Initial site Resting membrane Resting membrane
of action depolarized toward
potential threshold by
local current
1 2 3

(b) −70 mV −70 mV −70 mV

Time (msec)
0 1 2 3 4 0 1 2 3 4 0 1 2 3 4

+ + + + – – – – + + + +
– – – – + + + + – – – –

+ Figure 6.23 One-way

propagation of an action potential. For
simplicity, potentials are shown only on
Membrane is Present site of Resting membrane the upper membrane, local currents are
refractory; local action potential depolarized toward shown only on the inside of the membrane,
current cannot threshold by local and repolarizing currents are not shown.
stimulate a current (a) Local current from the opening of
second action
potential ligand-gated ion channels in the cell body
and dendrites causes an action potential to
1 2 3
be initiated in region 1, and local current
depolarizes region 2. (b) Action potential in
region 2 generates local currents; region 3
is depolarized toward threshold, but region

−70 mV −70 mV −70 mV

(c) 1 is refractory. (c) Action potential in region
3 generates local currents, but region 2 is
Time (msec) refractory.
0 1 2 3 4 0 1 2 3 4 0 1 2 3 4

+ + + + + + + + – – – –
PHYSIOLOG ICAL INQUIRY
– – – – – – – – + + + +
–
■ Striking the ulnar nerve in your elbow
+ against a hard surface (sometimes
called “hitting your funny bone”)
initiates action potentials near the
Resting membrane Membrane is Present site of midpoint of sensory and motor axons
refractory; local action potential traveling in that nerve. In which
current cannot direction will those action potentials
stimulate a
second action propagate?
potential Answer can be found at end of chapter.
1 2 3

is myelinated. The larger the fiber diameter, the faster the action Myelin is an insulator that makes it more difficult for charge
potential propagates. This is because a large (wide) fiber offers less to flow between intracellular and extracellular fluid compart-
internal resistance to local current; more ions will flow in a given ments. Because there is less “leakage” of charge across the myelin,
time, bringing adjacent regions of the membrane to threshold faster. a local current can spread farther along an axon. Moreover, the

Neuronal Signaling and the Structure of the Nervous System 155

 Direction of action potential propagation

Na+ channel

Na+
Myelin + + + + + + + +
− −

+ + − − − − − − − −
Intracellular fluid
+ + – – – – − − − −

− − + + + + + + + +
Na+

Active node Node to which Inactive node

of Ranvier; depolarization at resting
site of action is spreading and membrane
potential regenerating an potential
action potential

Figure 6.24 Myelinization and saltatory conduction of action potentials. K+ channels are not depicted (they are located primarily at the myelin/
node junctions and help to repolarize the neuron). As described in Figure 6.15, positive charges move away from the site of depolarization on the
inside of the cell, and toward it on the outside.

PHYSIOLOG ICAL INQUIRY

■ A general principle of physiology states that homeostasis is essential for health and survival. In what ways might the presence of myelin
contribute to homeostasis?
Answer can be found at end of chapter.

concentration of voltage-gated Na+ channels in the myelinated velocity of 100 m/sec, it only takes about 0.02 sec. Perhaps you’ve
region of axons is low. Therefore, action potentials occur only dropped a heavy object on your toe and noticed that an imme-
at the nodes of Ranvier, where the myelin coating is interrupted diate, sharp pain (carried by large-diameter, myelinated neurons)
and the concentration of voltage-gated Na+ channels is high occurs before the onset of a dull, throbbing ache (transmitted
(Figure 6.24). Action potentials appear to jump from one node along small-diameter, unmyelinated neurons).
to the next as they propagate along a myelinated fiber; for this
reason, such propagation is called saltatory conduction (Latin, Generation of Action Potentials In our description of
saltare, “to leap”). However, it is important to understand that an action potentials thus far, we have spoken of “stimuli” as the
action potential does not, in fact, jump from region to region but initiators of action potentials. These stimuli bring the membrane
rather is regenerated at each node. to the threshold potential, and voltage-gated Na+ channels initiate
Propagation via saltatory conduction is faster than propa- the action potential. How is the threshold potential attained,
gation in nonmyelinated fibers of the same axon diameter. This and how do various types of neurons actually generate action
is because less charge leaks out through the myelin-covered sec- potentials?
tions of the membrane, more charge arrives at the node adjacent In afferent neurons, the initial depolarization to thresh-
to the active node, and an action potential is generated there old is achieved by a graded potential—here called a receptor
sooner than if the myelin were not present. Moreover, because potential. Receptor potentials are generated in the sensory recep-
ions cross the membrane primarily at the nodes of Ranvier, tors at the peripheral ends of the neurons, which are at the ends
the membrane pumps need to restore fewer ions. Myelinated farthest from the CNS. In all other neurons, the depolarization to
axons are therefore metabolically more efficient than unmyelin- threshold is due either to a graded potential generated by synaptic
ated ones. Thus, myelin adds speed, reduces metabolic cost, input to the neuron, known as a synaptic potential, or to a spon-
and saves room in the nervous system because the axons can taneous change in the neuron’s membrane potential, known as a
be thinner. pacemaker potential. The next section will address the produc-
Conduction velocities range from about 0.5 m/sec (1 mi/h) tion of synaptic potentials. Chapter 7 will discuss the production
for small-diameter, unmyelinated fibers to about 100 m/sec of receptor potentials, and Chapters 12, 13, and 15 will consider
(225 mi/h) for large-diameter, myelinated fibers. At 0.5 m/sec, an pacemaker potentials in different organ systems.
action potential would travel the distance from the toe to the spi- The differences between graded potentials and action poten-
nal cord and brain of an average-sized person in about 4 sec; at a tials are summarized in Table 6.4.

156 Chapter 6
 TABLE 6.4 Differences Between Graded Potentials and Action Potentials
Graded Potential Action Potential

Amplitude varies with size of the initiating event. All-or-none. Once membrane is depolarized to threshold, amplitude is
independent of the size of the initiating event.

Can be summed. Cannot be summed.

Has no threshold. Has a threshold that is usually about 15 mV depolarized relative to the
resting potential.

Has no refractory period. Has a refractory period.

Amplitude decreases with distance. Is conducted without decrement; the depolarization is amplified to a
constant value at each point along the membrane.

Duration varies with initiating conditions. Duration is constant for a given cell type under constant conditions.

Can be a depolarization or a hyperpolarization. Is only a depolarization.

Initiated by environmental stimulus (receptor), by neurotransmitter Initiated by a graded potential.

(synapse), or spontaneously.

Mechanism depends on ligand-gated ion channels or other chemical or Mechanism depends on voltage-gated ion channels.
physical changes.

SECTION B SU M M A RY a. APs occur in excitable membranes because these membranes

contain many voltage-gated Na+ channels. These channels
Basic Principles of Electricity open as the membrane depolarizes, causing a positive feedback
I. Separated electrical charges create the potential to do work, as opening of more voltage-gated Na+ channels and moving the
occurs when charged particles produce an electrical current as they membrane potential toward the Na+ equilibrium potential.
flow down a potential gradient. The lipid barrier of the plasma b. The AP ends as the Na+ channels inactivate and K+ channels
membrane is a high-resistance insulator that keeps charged ions open, restoring resting conditions.
separated, whereas ionic current flows readily in the aqueous c. Depolarization of excitable membranes triggers an AP only
intracellular and extracellular fluids. when the membrane potential exceeds a threshold potential.
The Resting Membrane Potential d. Regardless of the size of the stimulus, if the membrane reaches
threshold, the AP generated is the same size.
I. Membrane potentials are generated mainly by the diffusion of ions
e. A membrane is refractory for a brief time following an AP.
and are determined by both the ionic concentration differences
f. APs are propagated without any change in size from one site to
across the membrane and the membrane’s relative permeability to
another along a membrane.
different ions.
g. In myelinated nerve fibers, APs are regenerated at the nodes of
a. Plasma membrane Na+/K+-ATPase pumps maintain low
Ranvier in saltatory conduction.
intracellular Na+ concentration and high intracellular K+
h. APs can be triggered by depolarizing graded potentials in
concentration.
sensory neurons, at synapses, or in some cells by pacemaker
b. In almost all resting cells, the plasma membrane is much more
potentials.
permeable to K+ than to Na+, so the membrane potential is close
to the K+ equilibrium potential—that is, the inside is negative
relative to the outside.
c. The Na+/K+-ATPase pumps directly contribute a small SECTION B R EV I EW QU E ST ION S
component of the potential because they are electrogenic. 1. Describe how negative and positive charges interact.
Graded Potentials and Action Potentials 2. Contrast the abilities of intracellular and extracellular fluids and
I. Neurons signal information by graded potentials and action membrane lipids to conduct electrical current.
potentials (APs). 3. Draw a simple cell; indicate where the concentrations of Na+, K+,
II. Graded potentials are local potentials whose magnitude can vary and Cl− are high and low and the electrical potential difference
and that die out within 1 or 2 mm of their site of origin. across the membrane when the cell is at rest.
III. An AP is a rapid change in the membrane potential during which 4. Explain the conditions that give rise to the resting membrane
the membrane rapidly depolarizes and repolarizes. At the peak, potential. What effect does membrane permeability have on this
the potential reverses and the membrane becomes positive inside. potential? What functions do Na+/K+-ATPase membrane pumps
APs provide long-distance transmission of information through the play in the membrane potential? Are these functions direct or
nervous system. indirect?

Neuronal Signaling and the Structure of the Nervous System 157

 5. Which two factors involving ion diffusion determine the magnitude leak channels resting membrane potential
of the resting membrane potential? Nernst equation
6. Explain why the resting membrane potential is not equal to the K+
6.7 Graded Potentials and Action Potentials
equilibrium potential.
7. Draw a graded potential and an action potential on a graph of absolute refractory period mechanically gated ion channels
membrane potential versus time. Indicate zero membrane potential, action potential propagation overshoot
resting membrane potential, and threshold potential; indicate when action potentials pacemaker potential
the membrane is depolarized, repolarizing, and hyperpolarized. afterhyperpolarization receptor potential
8. List the differences between graded potentials and action potentials. all-or-none relative refractory period
9. Describe how ion movement generates the action potential. decremental repolarized
10. What determines the activity of the voltage-gated Na+ channel? depolarized saltatory conduction
11. Explain threshold and the relative and absolute refractory periods excitability summation
in terms of the ionic basis of the action potential. excitable membranes synaptic potential
12. Describe the propagation of an action potential. Contrast this event graded potentials threshold potential
in myelinated and unmyelinated axons. hyperpolarized threshold stimuli
13. List three ways in which action potentials can be initiated in neurons. inactivation gate voltage-gated ion channels
ligand-gated ion channels

SECTION B K EY T ER M S
SECTION B CLI N ICA L T ER M S
6.5 Basic Principles of Electricity
6.7 Graded Potentials and Action Potentials
current potential difference
electrical potential resistance lidocaine (Xylocaine) procaine (Novocaine)
Ohm’s law local anesthetics tetrodotoxin

6.6 The Resting Membrane Potential

electrogenic pump Goldman-Hodgkin-Katz (GHK)
equilibrium potential equation

SECTION C
Synapses
As defined earlier, a synapse is an anatomically specialized junction 6.8 Functional Anatomy
between two neurons, at which the electrical activity in a presynap-
tic neuron influences the electrical activity of a postsynaptic neuron. of Synapses
Anatomically, synapses include parts of the presynaptic and post- There are two types of synapses: electrical and chemical.
synaptic neurons and the extracellular space between these two cells.
According to recent estimates, there are more than 1014 (100 trillion!) Electrical Synapses
synapses in the CNS. At electrical synapses, the plasma membranes of the presynaptic
Activity at synapses can increase or decrease the likelihood and postsynaptic cells are joined by gap junctions (Figure 6.26a;
that the postsynaptic neuron will fire action potentials by produc- refer also to Figure 3.9). These allow the local currents resulting
ing a brief, graded potential in the postsynaptic membrane. The
membrane potential of a postsynaptic neuron is brought closer to
threshold (depolarized) at an excitatory synapse, and it is either
driven farther from threshold (hyperpolarized) or stabilized at its
resting potential at an inhibitory synapse.
Hundreds or thousands of synapses from many different
presynaptic cells can affect a single postsynaptic cell (conver-
gence), and a single presynaptic cell can send branches to affect
many other postsynaptic cells (divergence, Figure 6.25). Con-
vergence allows information from many sources to influence
a cell’s activity; divergence allows one cell to affect multiple
pathways.
The level of excitability of a postsynaptic cell at any moment
(i.e., how close its membrane potential is to threshold) depends on
the number of synapses active at any one time and the number that Convergence Divergence
are excitatory or inhibitory. If the membrane of the postsynaptic
neuron reaches threshold, it will generate action potentials that are Figure 6.25 Convergence of neural input from many neurons onto a
propagated along its axon to the axon terminals, which in turn single neuron, and divergence of output from a single neuron onto many
influence the excitability of other cells. others. Arrows indicate the direction of transmission of neural activity.
158 Chapter 6
 (a) electrical synapses were rare in the adult mammalian nervous
system. However, they have now been described in widespread
Axon of locations, and it is suspected that they may have more important
presynaptic functions than previously thought. Among the possible functions
cell
are synchronization of electrical activity of neurons clustered in
local CNS networks and communication between glial cells and
Axon neurons. Multiple isoforms of gap-junction proteins have been
terminal
Gap junction described, and the conductance of some of these is modulated
by factors such as membrane voltage, intracellular pH, and Ca2+
concentration. More research will be required to gain a complete
understanding of this modulation and all of the complex roles of
Current flow
electrical synapses in the nervous system. Their function is better
understood in cardiac and smooth muscle tissues, where they are
also numerous (see Chapter 9).

Postsynaptic Chemical Synapses

cell Figure 6.26b shows the basic structure of a typical chemical
synapse. The axon of the presynaptic neuron ends in slight swell-
ings, the axon terminals, which hold the synaptic vesicles that
(b) contain neurotransmitter molecules. The postsynaptic membrane
Direction of action
potential propagation adjacent to an axon terminal has a high density of membrane
proteins that make up a specialized area called the ­postsynaptic
density. A 10 to 20 nm extracellular space, the synaptic cleft,
Terminal of separates the presynaptic and postsynaptic neurons and pre-
presynaptic vents direct propagation of the current from the presynaptic
axon
Mitochondrion neuron to the postsynaptic cell. Instead, signals are transmitted
across the synaptic cleft by means of a chemical messenger—a
neurotransmitter—released from the presynaptic axon termi-
­
nal. Sometimes more than one neurotransmitter may be simul-
Synaptic
vesicle taneously released from an axon, in which case the additional
­neurotransmitter is called a cotransmitter. These neurotransmit-
ters have different receptors on the postsynaptic cell. As we will
Vesicle
docking
see shortly, a major advantage of chemical synapses is that they
site permit integration of multiple signals arriving at a given cell.

6.9 Mechanisms of Neurotransmitter
Synaptic cleft
Release
As shown in detail in Figure 6.27a, neurotransmitters are stored
Postsynaptic Postsynaptic in small vesicles with lipid bilayer membranes. Prior to activation,
density cell many vesicles are docked on the presynaptic membrane at release
regions known as active zones, whereas others are dispersed within
the terminal. Neurotransmitter release is initiated when an action
Figure 6.26 (a) An electrical synapse. Note that there potential reaches the presynaptic terminal membrane. A key feature
is very little space between the two cells, which are connected by of neuron terminals at chemical synapses is that in addition to the
gap junctions through which ions diffuse. (b) Diagram of a chemical Na+ and K+ channels found elsewhere in the neuron, they also pos-
synapse. Vesicles containing chemical neurotransmitters are docked sess voltage-gated Ca2+ channels. Depolarization during the action
at the presynaptic membrane, ready for release. The postsynaptic potential opens these Ca2+ channels, and because the electrochemi-
membrane is distinguished microscopically by the postsynaptic density, cal gradient favors Ca2+ influx, Ca2+ flows into the axon terminal.
which contains neurotransmitter–receptor proteins. Calcium ions activate processes that lead to the fusion
of docked vesicles with the synaptic terminal membrane
(Figure 6.27b). Prior to the arrival of an action potential, vesicles
from arriving action potentials to flow directly across the junction are loosely docked in the active zones by the interaction of a group
through the connecting channels from one neuron to the other. of proteins, some of which are anchored in the vesicle membrane
This depolarizes the membrane of the second neuron to thresh- and others that are found in the membrane of the terminal. These are
old, continuing the propagation of the action potential. One advan- collectively known as SNARE proteins (soluble N-ethylmaleimide-
tage of electrical synapses is that communication between cells sensitive factor attachment protein receptors). Calcium ions
via these synapses is extremely rapid. It was formerly thought that entering during depolarization bind to a separate family of
Neuronal Signaling and the Structure of the Nervous System 159
 (a) 1 Action potential through a G protein and/or a second messenger, a type referred to as­
reaches terminal metabotropic receptors. In either case, the result of the bind-
2 Voltage-gatedCa2+
channels open ing of neurotransmitter to receptor is the opening or closing of
Voltage-gated Axon terminal specific ligand-gated ion channels in the postsynaptic plasma
Ca2+ channel Synaptic membrane, which eventually leads to changes in the membrane
vesicles potential in that neuron.
Because of the sequence of events involved, there is a very
Ca2+
Active brief synaptic delay—about 0.2 msec—between the arrival of
zone
4 Neurotransmitter an action potential at a presynaptic terminal and the membrane
is released and potential changes in the postsynaptic cell.
diffuses into the 3 Calcium enters
cleft
Neurotransmitter binding to the receptor is transient and
axon terminal
reversible. As with any binding site, the bound ligand—in this
Ca2+ case, the neurotransmitter—is in equilibrium with the unbound
form. Thus, if the concentration of unbound neurotransmitter in
6 Neurotransmitter
5 Neurotransmitter binds
removed from the synaptic cleft decreases, the number of occupied receptors will
to postsynaptic receptors decrease. The ion channels in the postsynaptic membrane return to
synaptic cleft
their resting state when the neurotransmitters are no l­ onger bound.
Postsynaptic cell

Removal of Neurotransmitter from the Synapse

Neurotransmitters are usually secreted in large amounts by presyn-
(b) aptic cells, which maximizes the likelihood of binding to a post-
synaptic cell receptor. Unbound neurotransmitters must be removed,
Synaptotagmin
however, to terminate the signal and to prevent diffusion of trans-
mitter out of the synapse where nearby cells might be affected.
+ Ca2+ Unbound neurotransmitters are removed from the syn-
aptic cleft when they (1) are actively transported back into the
presynaptic axon terminal for reuse (in a process called reuptake);
SNAREs (2) are transported into nearby glial cells where they are degraded;
(3) diffuse away from the receptor site; or (4) are enzymatically
Figure 6.27 (a) Mechanisms of signaling at a chemical transformed into inactive substances, some of which are trans-
synapse. (b) Magnified view showing details of neurotransmitter release. ported back into the presynaptic axon terminal for reuse. The
Calcium ions trigger synaptotagmin and SNARE proteins to induce enzymes involved in this last process may be located on the post-
membrane fusion and neurotransmitter release. (SNARE = Soluble synaptic or presynaptic membrane or within the synaptic cleft.
N-ethylmaleimide-sensitive factor attachment protein receptor)

Excitatory Chemical Synapses

proteins associated with the vesicle, synaptotagmins, triggering a The two kinds of chemical synapses—excitatory and inhibitory—
conformational change in the SNARE complex that leads to mem- are differentiated by the effects of the neurotransmitter on the
brane fusion and neurotransmitter release. After fusion, vesicles can postsynaptic cell. Whether the effect is excitatory or inhibitory
undergo at least two possible fates. At some synapses, vesicles com- depends on the type of ion channel influenced by the neurotrans-
pletely fuse with the membrane and are later recycled by endocytosis mitter when it binds to its receptor.
from the membrane at sites outside the active zone (see Figure 4.21). At an excitatory chemical synapse, the postsynaptic
At other synapses, especially those at which action potential fir- response to the neurotransmitter is a depolarization, bringing the
ing frequencies are high, vesicles may fuse only briefly while they membrane potential closer to threshold. The usual effect of the
release their contents and then reseal the pore and withdraw back activated receptor on the postsynaptic membrane at such synapses
into the axon terminal (a mechanism called “kiss-and-run fusion”). is to open nonselective channels that are permeable to Na+ and K+.
These ions then are free to move according to the electrical and
concentration gradients across the membrane.
6.10 Activation of the Postsynaptic Cell Both electrical and concentration gradients drive Na+ into
Once neurotransmitters are released from a presynaptic axon ter- the cell, whereas for K+, the electrical gradient opposes the con-
minal, they diffuse across the cleft. How do they interact with the centration gradient (review Figure 6.12). Opening channels that
postsynaptic cell? are permeable to both ions therefore results in the simultaneous
movement of a relatively small number of potassium ions out of
Binding of Neurotransmitters to Receptors the cell and a larger number of sodium ions into the cell. Thus, the
Neurotransmitters rapidly and reversibly bind to receptors on the net movement of positive ions is into the postsynaptic cell, causing
plasma membrane of the postsynaptic cell. The activated recep- a slight depolarization. This membrane potential change is called
tors themselves may be ion channels, which designates them an excitatory postsynaptic potential (EPSP, Figure 6.28).
as ­ionotropic receptors (review Figure 6.15 for an example). The EPSP is a depolarizing graded potential that decreases in
­Alternatively, the receptors may indirectly influence ion channels ­magnitude as it spreads away from the synapse by local current.
160 Chapter 6
 0 0

Membrane potential (mV)

Membrane potential (mV)

Threshold Threshold
EPSP
−70 −70

IPSP

10 20 10 20
Time (msec) Time (msec)

Figure 6.28 Excitatory postsynaptic potential (EPSP). Stimulation Figure 6.29 Inhibitory postsynaptic potential (IPSP). Stimulation
of the presynaptic neuron is marked by the green arrow. (Drawn of the presynaptic neuron is marked by the red arrow. (This
larger than normal: typical EPSP = 0.5 mV) hyperpolarization is drawn larger than a typical IPSP.)

PHYSIOLOG ICAL INQUIRY

■ Assuming a typical EPSP of 0.5 mV, approximately how many

Membrane potential (mV)

simultaneous EPSPs would be required to bring a typical neuron
to threshold? 0

Answer can be found at end of chapter.

Threshold
Its only function is to bring the membrane potential of the post-
synaptic neuron closer to threshold.
−70

Inhibitory Chemical Synapses

Time
At inhibitory chemical synapses, the potential change in the post-
synaptic neuron is generally a hyperpolarizing graded potential Figure 6.30 Synaptic inhibition of postsynaptic cells where ECl is
called an inhibitory postsynaptic potential (IPSP, Figure 6.29). equal to the resting membrane potential. Stimulation of a presynaptic
Alternatively, there may be no IPSP but rather stabilization of the neuron releasing a neurotransmitter that opens Cl− channels (red
membrane potential at its existing value. In either case, activation arrows) has no direct effect on the postsynaptic membrane potential.
of an inhibitory synapse lessens the likelihood that the postsynaptic However, when an excitatory synapse is simultaneously activated
cell will depolarize to threshold and generate an action potential. (green arrows), Cl− movement into the cell diminishes the EPSP.
At an inhibitory synapse, the activated receptors on the post-
synaptic membrane open Cl− or K+ channels; Na+ permeability PHYSIOLOG ICAL INQUIRY
is not affected. In those cells that actively regulate ­intracellular
■ If a postsynaptic cell has a Cl− equilibrium potential of -65 mV,
Cl− concentrations via active transport out of the cell, the Cl−
will synaptic activity that opens Cl− channels be excitatory or
equilibrium potential is more negative than the resting potential. inhibitory?
Therefore, as Cl− channels open, Cl− enters the cell, producing a
­hyperpolarization—that is, an IPSP. In cells that do not actively Answer can be found at end of chapter.
transport Cl−, the equilibrium potential for Cl− is equal to the
resting membrane potential. Therefore, an increase in Cl− per-
meability does not change the membrane potential but is able to resting membrane potential would be about −90 mV instead of
increase chloride’s influence on the membrane potential. If any −70 mV. Thus, with increased K+ permeability, more potassium
positive charges enter a cell, Cl– ions will also enter and neutralize ions leave the cell and the membrane moves closer to the K+ equi-
their effect. Thus, membrane potential is stabilized near the rest- librium potential, causing a hyperpolarization.
ing value, and it is more difficult for excitatory inputs from other
synapses to change the potential when these chloride channels are
simultaneously open (Figure 6.30).
6.11 Synaptic Integration
Increased K+ permeability, when it occurs in the postsyn- In most neurons, one excitatory synaptic event by itself is not
aptic cell, also produces an IPSP. Earlier, we noted that if a cell enough to reach threshold in the postsynaptic neuron. For exam-
membrane were permeable only to K+, the resting membrane ple, a single EPSP may be only 0.5 mV, whereas changes of about
potential would equal the K+ equilibrium potential; that is, the 15 mV are necessary to depolarize the neuron’s membrane to
Neuronal Signaling and the Structure of the Nervous System 161
threshold. This being the case, an action potential can be initiated neurons also summate in the postsynaptic neuron, resulting in a
only by the combined effects of many excitatory synapses. greater degree of depolarization. Although it clearly is necessary that
Of the thousands of synapses on any one neuron, probably stimulation of A and B occur closely in time for summation to occur,
hundreds are active simultaneously or close enough in time that this is called spatial summation because the two inputs occurred
the effects can add together. The membrane potential of the post- at different locations on the cell. The interaction of multiple EPSPs
synaptic neuron at any moment is, therefore, the result of all the through spatial and temporal summation can increase the inward
synaptic activity affecting it at that moment. A depolarization of flow of positive ions and bring the postsynaptic membrane to thresh-
the membrane toward threshold occurs when excitatory synaptic old so that action potentials are initiated (see part 4 of Figure 6.31).
input predominates, and either a hyperpolarization or stabilization So far, we have tested only the patterns of interaction of
occurs when inhibitory input predominates. excitatory synapses. Because EPSPs and IPSPs are due to oppo-
A simple experiment can demonstrate how EPSPs and sitely directed local currents, they tend to cancel each other, and
IPSPs interact, as shown in Figure 6.31. Assume there are three there is little or no net change in membrane potential when both
synaptic inputs to the postsynaptic cell. The synapses from axons A and C are stimulated (see Figure 6.31, part 5). Inhibitory poten-
A and B are excitatory, and the synapse from axon C is inhibi- tials can also show spatial and temporal summation.
tory. There are stimulators on axons A, B, and C so that each can Depending on the postsynaptic membrane’s resistance and on
be activated individually. An electrode is placed in the cell body the amount of charge moving through the ligand-gated ion chan-
of the postsynaptic neuron that will record the membrane poten- nels, the synaptic potential will spread to a greater or lesser degree
tial. In part 1 of the experiment, we will test the interaction of across the plasma membrane of the cell. The membrane of a large
two EPSPs by stimulating axon A and then, after a short time, area of the cell becomes slightly depolarized during activation of an
stimulating it again. Part 1 of Figure 6.31 shows that no interaction excitatory synapse and slightly hyperpolarized or stabilized during
occurs between the two EPSPs. The reason is that the change in activation of an inhibitory synapse, although these graded potentials
membrane potential associated with an EPSP is fairly short-lived, will decrease with distance from the synaptic junction (Figure 6.32).
as is true of all graded potentials. Within a few milliseconds (by Inputs from more than one synapse can result in summation of the
the time we stimulate axon A for the second time), the postsynap- synaptic potentials, which may then trigger an action potential.
tic cell has returned to its resting condition. In the previous examples, we referred to the threshold of
In part 2, we stimulate axon A for the second time before the postsynaptic neuron as though it were the same for all parts
the first EPSP has died away; the second synaptic potential adds of the cell. However, different parts of the neuron have differ-
to the previous one and creates a greater depolarization than from ent thresholds. In general, the axon hillock has a more negative
one input alone. This is called temporal summation because threshold (i.e., much closer to the resting potential) than the mem-
the input signals arrive from the same presynaptic cell at differ- brane of the cell body and dendrites. This is due to a higher den-
ent times. The potentials summate because an additional influx sity of v­ oltage-gated Na+ channels in this area of the membrane.
of positive ions occurs before ions leaking out through the mem- ­Therefore, the axon hillock is most responsive to small changes in
brane have returned it to the resting potential. the membrane potential that occur in response to synaptic poten-
In part 3 of Figure 6.31, axon B is first stimulated alone to tials on the cell body and dendrites, and is the first region to reach
determine its response, and then axons A and B are stimulated simul- threshold whenever enough EPSPs summate. The resulting action
taneously. The EPSPs resulting from input from the two separate potential is then propagated from this point down the axon.

Recording 1 2 3 4 5
microelectrode
Temporal Spatial
Membrane potential (mV)

+30
Inhibitory summation summation
synapse C
A
Threshold
B

−70

Excitatory Axon
synapses hillock
A A A A B A+B AA B B C A+C
Axon
Time

Figure 6.31 Interaction of EPSPs and IPSPs at the postsynaptic neuron. Presynaptic neurons (A–C) were stimulated at times indicated by the
arrows, and the resulting membrane potential was recorded in the postsynaptic cell by a recording microelectrode.

PHYSIOLOG ICAL INQUIRY

■ How might the traces in part 5 be different if the excitatory synapse (A) was much closer to the axon hillock than the inhibitory synapse (C)?
Answer can be found at end of chapter.

162 Chapter 6
 Presynaptic Mechanisms

Membrane potential
A presynaptic terminal does not release a constant amount of neu-
rotransmitter every time it is activated. One reason for this varia-
+ tion involves Ca2+ concentration. Calcium ions that have entered
+ the terminal during previous action potentials are pumped out
+ ++ +
of the cell or (temporarily) into intracellular organelles. If Ca2+
+ +
Time removal does not keep up with entry, as can occur during high-
+ frequency stimulation, Ca2+ concentration in the terminal, and
+ +
consequently the amount of neurotransmitter released upon sub-
Axon hillock sequent stimulation, will be greater than usual. The greater the
amount of neurotransmitter released, the greater the number of
(a) Excitatory synapse
ion channels opened in the postsynaptic membrane and the larger
the amplitude of the EPSP or IPSP in the postsynaptic cell.

Membrane potential
The neurotransmitter output of some presynaptic terminals is
also altered by activation of membrane receptors on the terminals
themselves. Activation of these presynaptic receptors influences
+
Ca2+ influx into the terminal and thus the number of neurotrans-
+
+ mitter vesicles that release neurotransmitter into the synaptic cleft.
+ These presynaptic receptors may be associated with a second
+ Time
+ synaptic ending known as an axo–axonic synapse, in which an
+
axon terminal of one neuron ends on an axon ­terminal of another.
Axon hillock For example, in Figure 6.33, the neurotransmitter released by A
binds with receptors on B, resulting in a change in the amount
of neurotransmitter released from B in response to action poten-
(b) Inhibitory synapse
tials. Thus, neuron A has no direct effect on neuron C, but it has
an important influence on the ability of B to influence C. Neuron
Figure 6.32 Comparison of excitatory and inhibitory synapses,
A is thus exerting a presynaptic effect on the synapse between B
showing current direction through the postsynaptic cell following
synaptic activation. (a) Current through the postsynaptic cell is away and C. Depending upon the type of presynaptic receptors activated
from the excitatory synapse and may depolarize the axon hillock. by the neurotransmitter from neuron A, the presynaptic effect
(b) Current through the postsynaptic cell is toward the inhibitory may decrease the amount of neurotransmitter released from B
synapse and may hyperpolarize the axon hillock. The arrow on the (­presynaptic inhibition) or increase it (­presynaptic facilitation).
graph indicates moment of stimulus. Axo–axonic synapses such as A in Figure 6.33 can alter
the Ca2+ concentration in axon terminal B or even affect neu-
rotransmitter synthesis there. The mechanisms bringing about
The fact that the axon hillock usually has the lowest thresh-
old explains why the locations of individual synapses on the
postsynaptic cell are important. A synapse located near the axon
hillock will produce a greater voltage change in the axon hillock
than will a synapse on the outermost branch of a dendrite because Presynaptic
it will expose it to a larger local current. In some neurons, how- receptor
ever, signals from dendrites may be boosted by the presence of A
some voltage-gated Na+ channels in parts of those dendrites.
Postsynaptic potentials last much longer than action poten- C
tials. In the event that cumulative EPSPs cause the axon hillock
to still be depolarized to threshold after an action potential has B
been fired and the refractory period is over, a second action poten-
tial will occur. In fact, as long as the membrane is depolarized
to threshold, action potentials will continue to arise. Neuronal
responses almost always occur in bursts of action potentials rather Autoreceptor
than as single, isolated events.

6.12 Synaptic Strength Postsynaptic receptor

Individual synaptic events—whether excitatory or inhibitory—

have been presented as though their effects are constant and repro-
ducible. Actually, enormous variability occurs in the postsynaptic
potentials that follow a presynaptic input. The effectiveness or
strength of a given synapse is influenced by both presynaptic and Figure 6.33 A presynaptic (axo–axonic) synapse between
postsynaptic mechanisms. axon terminal A and axon terminal B. Cell C is postsynaptic to cell B.
Neuronal Signaling and the Structure of the Nervous System 163
these effects vary from synapse to synapse. The receptors on the Recall, too, from Chapter 5 that the number of recep-
axon terminal of neuron B could be ionotropic, in which case tors is not constant, varying with up- and down-regulation, for
the membrane potential of the terminal is rapidly and directly example. Also, the ability of a given receptor to respond to its
affected by neurotransmitter from A. Alternatively, they might neurotransmitter can change. Thus, in some systems, a receptor
be metabotropic, in which case the alteration of synaptic machin- responds normally when first exposed to a neurotransmitter but
ery by second messengers is generally slower in onset and longer then eventually fails to respond despite the continued presence of
in duration. In either case, if the Ca2+ concentration in axon ter- the receptor’s neurotransmitter, a phenomenon known as receptor
minal B increases, the number of vesicles releasing neurotrans- desensitization. This is part of the reason that drug abusers some-
mitter from B increases. Decreased Ca2+ reduces the number of times develop a tolerance to drugs that elevate certain brain neu-
vesicles releasing transmitter. Axo–axonic synapses are impor- rotransmitters, forcing them to take increasing amounts of the
tant because they selectively control one specific input to the drug to get the desired effect (see Chapter 8).
postsynaptic neuron C. This type of synapse is particularly com- Imagine the complexity when a cotransmitter (or several
mon in the modulation of sensory input, for example in the mod- cotransmitters) is released with the neurotransmitter to act upon post-
ulation of pain pathways (discussed in Chapter 7). synaptic receptors and maybe upon presynaptic receptors as well!
Some receptors on the presynaptic terminal are not associ- Clearly, the possible variations in transmission are great at even a
ated with axo–axonic synapses. Instead, they are activated by neu- single synapse, and these provide mechanisms by which synaptic
rotransmitters or other chemical messengers released by nearby strength can be altered in response to changing conditions, part of the
neurons or glia or even by the axon terminal itself. In the last case, phenomenon of plasticity described at the beginning of this chapter.
the receptors are called autoreceptors (see Figure 6.33) and pro-
vide an important feedback mechanism that the neuron can use Modification of Synaptic Transmission by Drugs
to regulate its own neurotransmitter output. In most cases, the and Disease
released neurotransmitter acts on autoreceptors to decrease its The great majority of therapeutic, illicit, and so-called “recreational”
own release, thereby providing negative feedback control. drugs that act on the nervous system do so by altering synaptic
mechanisms and thus synaptic strength. Drugs act by interfering
Postsynaptic Mechanisms with or stimulating normal processes in the neuron involved in neu-
Postsynaptic mechanisms for varying synaptic strength also exist. rotransmitter synthesis, storage, and release, and in receptor activa-
For example, as described in Chapter 5, many types and subtypes tion. The synaptic mechanisms labeled in Figure 6.34 are important
of receptors exist for each kind of neurotransmitter. The differ- to synaptic function and are vulnerable to the effects of drugs.
ent receptor types operate by different signal transduction mecha- Recall from Chapter 5 that ligands that bind to a receptor
nisms and can have different—sometimes even opposite—effects and activate it are called agonists, and those that bind to a recep-
on the postsynaptic mechanisms they influence. A given signal tor and inhibit its activation are antagonists. By occupying the
transduction mechanism may be regulated by multiple neurotrans- receptors, antagonists prevent binding of the normal neurotrans-
mitters, and the various second-messenger systems affecting a mitter at the synapse. Specific agonists and antagonists can affect
channel may interact with each other. receptors on both presynaptic and postsynaptic membranes.

Direction of action potential A drug might

propagation A increase leakage of neurotransmitter
from vesicle to cytoplasm, exposing it
to enzyme breakdown.
Presynaptic B increase transmitter release into cleft.
neuron
C block transmitter release.

Synthesizing D inhibit transmitter synthesis.

enzyme E block transmitter reuptake.
D
Degrading F block cleft or intracellular enzymes that
enzymes Neurotransmitter metabolize transmitter.
C precursors G bind to receptor on postsynaptic
A
membrane to block (antagonist) or
F
Vesicle mimic (agonist) transmitter action.
B
H inhibit or stimulate second-messenger
activity within postsynaptic cell.
E
Reuptake

G
Synaptic
Receptors cleft
Figure 6.34 Possible actions of drugs on a synapse.
H
Postsynaptic neuron

164 Chapter 6
 distinctions between neuromodulators and neurotransmitters are not
TABLE 6.5 Factors That Determine Synaptic Strength
always clear. In fact, certain neuromodulators are often synthesized
I. Presynaptic factors by the presynaptic cell and coreleased with the neurotransmitter. To
A. Availability of neurotransmitter add to the complexity, many hormones, paracrine factors, and mes-
1. Availability of precursor molecules sengers used by the immune system serve as neuromodulators.
2. Amount (or activity) of the rate-limiting enzyme in the Neuromodulators often modify the postsynaptic cell’s
pathway for neurotransmitter synthesis response to specific neurotransmitters, amplifying or dampening
B. Axon terminal membrane potential the effectiveness of ongoing synaptic activity. Alternatively, they
C. Axon terminal Ca2+ may change the presynaptic cell’s synthesis, release, reuptake, or
D. Activation of membrane receptors on presynaptic terminal metabolism of a transmitter. In other words, they alter the effec-
1. Axo–axonic synapses
tiveness of the synapse.
2. Autoreceptors
In general, the receptors for neurotransmitters influence ion
3. Other receptors
E. Certain drugs and diseases, which act via the above channels that directly affect excitation or inhibition of the post­
mechanisms A–D synaptic cell. These mechanisms operate within milliseconds.
Receptors for neuromodulators, on the other hand, more often bring
II. Postsynaptic factors about changes in metabolic processes in neurons, often via G pro-
A. Immediate past history of electrical state of postsynaptic teins coupled to second-messenger systems. Such changes, which
membrane (e.g., excitation or inhibition from temporal or can occur over minutes, hours, or even days, include alterations in
spatial summation) enzyme activity or, through influences on DNA transcription, in pro-
B. Effects of other neurotransmitters or neuromodulators tein synthesis. Thus, neurotransmitters are involved in rapid commu-
acting on postsynaptic neuron nication, whereas neuromodulators tend to be associated with slower
C. Up- or down-regulation and desensitization of receptors
events such as learning, development, and motivational states.
D. Certain drugs and diseases
The number of substances known to act as neurotransmitters
III. General factors or neuromodulators is large and still growing. Table 6.6 provides a
A. Area of synaptic contact framework for categorizing that list. A huge amount of information
B. Enzymatic destruction of neurotransmitter has accumulated concerning the synthesis, metabolism, and mech-
C. Geometry of diffusion path anisms of action of these messengers—material well beyond the
D. Neurotransmitter reuptake scope of this book. The following sections will therefore present

Diseases can also affect synaptic mechanisms. For example, Classes of Some of the Chemicals Known
the neurological disorder tetanus is caused by the bacillus Clostrid- TABLE 6.6 or Presumed to Be Neurotransmitters or
ium tetani, which produces a toxin (tetanus toxin). This toxin is a Neuromodulators
protease that destroys SNARE proteins in the presynaptic terminal
so that fusion of vesicles with the membrane is prevented, inhibiting I. Acetylcholine (ACh)
neurotransmitter release. Tetanus toxin specifically affects inhibi-
tory neurons in the CNS that normally are important in suppress- II. Biogenic amines
ing the neurons that lead to skeletal muscle activation. Therefore, A. Catecholamines
1. Dopamine (DA)
tetanus toxin results in an increase in muscle contraction and a rigid
2. Norepinephrine (NE)
or spastic paralysis. Toxins of the Clostridium botulinum bacilli, 3. Epinephrine (Epi)
which cause botulism, also block neurotransmitter release from syn- B. Serotonin (5-hydroxytryptamine, 5-HT)
aptic vesicles by destroying SNARE proteins. However, they target C. Histamine
the excitatory synapses that activate skeletal muscles; consequently,
botulism is characterized by reduced muscle contraction, or a flac- III. Amino acids
cid paralysis. Low doses of one type of botulinum toxin (Botox) are A. Excitatory amino acids; for example, glutamate
injected therapeutically to treat a number of conditions, including B. Inhibitory amino acids; for example, gamma-aminobutyric
facial wrinkles, severe sweating, uncontrollable blinking, misalign- acid (GABA) and glycine
ment of the eyes, migraine headaches, and others.
IV. Neuropeptides
Table 6.5 summarizes the factors that determine synaptic
strength.    For example, endogenous opioids, oxytocin, tachykinins

V. Gases
6.13 Neurotransmitters   For example, nitric oxide, carbon monoxide, hydrogen sulfide
and Neuromodulators
VI. Purines
We have emphasized the role of neurotransmitters in eliciting EPSPs
   For example, adenosine and ATP
and IPSPs. However, certain chemical messengers elicit complex
responses that cannot be described as simply EPSPs or IPSPs. VII. Lipids
The word modulation is used for these complex responses, and   For example, prostaglandins and endocannabinoids
the messengers that cause them are called neuromodulators. The
Neuronal Signaling and the Structure of the Nervous System 165
only some basic generalizations about a few key ­neurotransmitters. receptors on presynaptic terminals in reward pathways of the brain
For simplicity’s sake, we use the term ­neurotransmitter in a general explains why tobacco products are among the most highly addictive
sense, realizing that sometimes the messenger may be described substances known.
more appropriately as a neuromodulator.
A note on terminology should also be included here. ­Neurons Muscarinic Acetylcholine Receptors The other general
are often referred to using the suffix -ergic; the missing prefix type of cholinergic receptor is stimulated not only by acetylcholine
is the type of neurotransmitter the neuron releases. For example, but by muscarine, a poison contained in some mushrooms;
dopaminergic applies to neurons that release the n­ eurotransmitter therefore, these are called muscarinic receptors. These receptors
dopamine. are metabotropic and couple with G proteins, which then alter the
activity of a number of different enzymes and ion channels. They
Acetylcholine are prevalent at some cholinergic synapses in the brain and at
Acetylcholine (ACh) is a major neurotransmitter in the PNS at the junctions where a major division of the PNS innervates peripheral
neuromuscular junction (where a motor neuron contacts a skeletal glands, tissues, and organs, like salivary glands, smooth muscle
muscle cell; see Chapter 9) and in the brain. Neurons that release cells, and the heart. Atropine is a naturally occuring antagonist of
ACh are called cholinergic neurons. The cell bodies of the brain’s muscarinic receptors with many clinical uses, such as in eyedrops
cholinergic neurons are concentrated in relatively few areas, but that relax the smooth muscles of the iris, thereby dilating the pupils
their axons are widely distributed. for an eye exam.
Acetylcholine is synthesized from choline (a common nutri- Alzheimer’s Disease Many cholinergic neurons in the
ent found in many foods) and acetyl coenzyme A in the cytoplasm brain degenerate in people with Alzheimer’s disease, a brain
of synaptic terminals and stored in synaptic vesicles. After it is disease that is usually age related and is the most common cause
released and activates receptors on the postsynaptic membrane, of declining intellectual function in late life. Alzheimer’s disease
the concentration of ACh at the postsynaptic membrane decreases affects 10% to 15% of people over age 65, and 50% of people over
(thereby stopping receptor activation) due to the action of the age 85. Because of the degeneration of cholinergic neurons, this
enzyme acetylcholinesterase. This enzyme is located on the pre- disease is associated with a decreased amount of ACh in certain
synaptic and postsynaptic membranes and rapidly destroys ACh, areas of the brain and even the loss of the postsynaptic neurons
releasing choline and acetate. The choline is then transported back that would normally respond to it. These defects and those in
into the presynaptic axon terminals where it is reused in the syn- other neurotransmitter systems that are affected in this disease
thesis of new ACh. Some chemical weapons, such as the nerve gas are related to the declining language and cognitive abilities,
Sarin, inhibit acetylcholinesterase, causing a buildup of ACh in the confusion, and memory loss that characterize individuals with
synaptic cleft. This results in overstimulation of postsynaptic ACh Alzheimer’s disease. Several genetic mechanisms have been
receptors, initially causing uncontrolled muscle contractions but identified as potential contributors to increased risk of developing
ultimately leading to receptor desensitization and paralysis. Alzheimer’s disease. One example is a gene on chromosome 19
There are two general types of ACh receptors, and they are that codes for a protein involved in carrying cholesterol in the
distinguished by their responsiveness to two different chemicals. bloodstream. Mutations of genes on chromosomes 1, 14, and 21
Nicotinic Acetylcholine Receptors Recall that although are associated with abnormally increased concentrations of beta-
a receptor is considered specific for a given ligand, such as ACh, amyloid protein, which is associated with neuronal cell death in
most receptors will recognize natural or synthetic compounds that a severe form of the disease that can begin as early as 30 years
exhibit some degree of chemical similarity to that ligand. Some ACh of age. This emerging picture of genetic risk factors is complex,
receptors respond not only to acetylcholine but to the compound and in some cases it appears that multiple genes are simultaneously
nicotine and have therefore come to be known as nicotinic involved. Some research also suggests that lifestyle factors like
receptors. Nicotine is a plant alkaloid compound that constitutes diet, exercise, social engagement, and mental stimulation may
1% to 2% of tobacco products. It is also contained in treatments contribute to whether cholinergic neurons are lost and Alzheimer’s
for smoking cessation, such as nasal sprays, chewing gums, and disease develops. Interestingly, synthetic chemicals that act like
transdermal patches. Nicotine’s hydrophobic structure allows rapid nerve gas but in a nontoxic manner are currently used to help
absorption through lung capillaries, mucous membranes, skin, and slow the progression of Alzheimer’s disease. These drugs do not
the blood–brain barrier. The nicotinic acetylcholine receptor is an restore lost cholinergic cells but help increase the concentration
excellent example of a receptor that contains an ion channel (i.e., of acetylcholine in synapses of remaining cells by inhibiting the
a ligand-gated ion channel). In this case, the channel is permeable activity of acetylcholinesterase.
to both sodium and potassium ions, but because Na+ has the larger
electrochemical driving force, the net effect of opening these Biogenic Amines
channels is depolarization due to Na+ influx. Nicotinic receptors The biogenic amines are small, charged molecules that are syn-
are present at the neuromuscular junction and, as Chapter 9 will thesized from amino acids and contain an amino group (R—NH2).
explain, several nicotinic receptor antagonists are toxins that The most common biogenic amines are dopamine, norepineph-
induce paralysis. Nicotinic receptors in the brain are important rine, serotonin, and histamine. Epinephrine, another biogenic
in cognitive functions and behavior. For example, one cholinergic amine, is not a common neurotransmitter in the CNS but is the
system that employs nicotinic receptors has a major function in major hormone secreted by the adrenal medulla. Norepinephrine
attention, learning, and memory by reinforcing the ability to detect is an important neurotransmitter in both the central and peripheral
and respond to meaningful stimuli. The presence of nicotinic components of the nervous system.
166 Chapter 6
Catecholamines Dopamine (DA), norepinephrine (NE), and commonly used to describe neurons that release norepinephrine
epinephrine all contain a catechol ring (a six-carbon ring with two or epinephrine and also to describe the receptors to which those
adjacent hydroxyl groups) and an amine group, which is why they neurotransmitters bind. There are two major classes of receptors
are called catecholamines. The catecholamines are formed from for norepinephrine and epinephrine: alpha-adrenergic receptors
the amino acid tyrosine and share the same two initial steps in their (alpha-adrenoceptors) and beta-adrenergic receptors
synthetic pathway (Figure 6.35). Synthesis of catecholamines (­beta-adrenoceptors). All catecholamine receptors are metabo-
begins with the uptake of tyrosine by the axon terminals and tropic, and thus use second messengers to transfer a signal from
its conversion to another precursor, L-dihydroxyphenylalanine the surface of the cell to the cytoplasm. Alpha-adrenoceptors exist
(L-dopa) by the rate-limiting enzyme in the pathway, tyrosine in two subclasses, α1 and α2. They act presynaptically to inhibit
hydroxylase. Depending on the enzymes expressed in a given norepinephrine release (α2) or postsynaptically to either stimulate
neuron, any one of the three catecholamines may ultimately be or inhibit the activity of different types of K+ channels (α1). Beta-
released. Autoreceptors on the presynaptic terminals strongly adrenoceptors act via stimulatory G proteins to increase cAMP in
modulate synthesis and release of the catecholamines. the postsynaptic cell. There are three subclasses of beta-receptors,
After activation of the receptors on the postsynaptic cell, the β1, β2, and β3, which function in different ways in different tissues
catecholamine concentration in the synaptic cleft declines, mainly (as will be described in Section D and Table 6.11). The subclasses
because a membrane transporter protein actively transports the of alpha- and beta-receptors are distinguished by the drugs that
catecholamine back into the axon terminal. The catecholamine influence them and their second-messenger systems.
neurotransmitters are also broken down in both the extracellu-
lar fluid and the axon terminal by enzymes such as monoamine Serotonin Serotonin (5-hydroxytryptamine, or 5-HT) is
oxidase (MAO). Drugs known as monoamine oxidase (MAO) produced from tryptophan, an essential amino acid. Its effects
inhibitors increase the amount of norepinephrine and dopamine generally have a slow onset, indicating that it works as a
in a synapse by slowing their metabolic degradation. Among other neuromodulator. Serotonergic neurons innervate virtually every
things, they are used in the treatment of mood disorders such as structure in the brain and spinal cord and operate via at least
some types of depression. 16 different receptor subtypes.
Within the CNS, the cell bodies of the catecholamine- In general, serotonin has an excitatory effect on pathways
releasing neurons lie in the brainstem and hypothalamus. that are involved in the control of muscles, and an inhibitory effect
Although these neurons are relatively few in number, their axons on pathways that mediate sensations. The activity of serotonergic
branch greatly and go to virtually all parts of the brain and spinal neurons is lowest or absent during sleep and highest during states
cord. These neurotransmitters have essential functions in states of of alert wakefulness. In addition to their contributions to motor
consciousness, mood, motivation, directed attention, movement, activity and sleep, serotonergic pathways also function in the reg-
blood pressure regulation, and hormone release, functions that ulation of food intake, reproductive behavior, and emotional states
will be covered in more detail in Chapters 8, 10, 11, and 12. such as mood and anxiety.
Epinephrine and norepinephrine are also synthesized in Selective serotonin reuptake inhibitors such as paroxetine
the adrenal glands. For historical reasons having to do with (Paxil) are thought to aid in the treatment of depression by inac-
nineteenth-century physiologists referring to secretions of the tivating the presynaptic membrane 5-HT transporter, which medi-
adrenal gland as “adrenaline,” the adjective “adrenergic” is ates the reuptake of serotonin into the presynaptic cell. This, in

OH OH OH OH OH
OH OH OH OH

Tyrosine Dopa Dopamine Phenylethanolamine

hydroxylase decarboxylase β-hydroxylase N-methyltransferase
H C H H C H H C H H C OH H C OH

H C COOH H C COOH H C H H C H H C H
NH2 NH2 NH2 NH2 N
H
CH3

Tyrosine L-Dopa Dopamine Norepinephrine Epinephrine

Figure 6.35 Catecholamine biosynthetic pathway. Tyrosine hydroxylase is the rate-limiting enzyme, but which neurotransmitter is ultimately
released from a neuron depends on which of the other three enzymes are present in that cell. The dark-colored box indicates the more common CNS
catecholamine neurotransmitters. Epinephrine is primarily a hormone released by the adrenal glands.
Neuronal Signaling and the Structure of the Nervous System 167
turn, increases the synaptic concentration of the neurotransmit- Glutamate There are a number of excitatory amino acids,
ter. Interestingly, such drugs are often associated with decreased but the most common by far is glutamate, which is estimated to
appetite but paradoxically cause weight gain due to disruption of be the primary neurotransmitter at 50% of excitatory synapses
enzymatic pathways that regulate fuel metabolism. This is one in the CNS. As with other neurotransmitters, pharmacological
example of how the use of reuptake inhibitors for a specific neu- manipulation of the receptors for glutamate has permitted
rotransmitter—one with widespread actions—can cause unwanted identification of specific receptor subtypes by their ability to bind
side effects. Serotonin is found in both neural and nonneural cells, natural and synthetic ligands. Although metabotropic glutamate
with the majority located outside of the CNS. In fact, approximately receptors do exist, the vast majority are ionotropic, with two
90% of the body’s total serotonin is found in the digestive system, important subtypes being found in postsynaptic membranes. They
8% is in blood platelets and immune cells, and only 1% to 2% is are designated as AMPA receptors (identified by their binding
found in the brain. to α-amino-3–hydroxy-5–methyl-4 isoxazolepropionic acid) and
The drug lysergic acid diethylamide (LSD) stimulates the NMDA receptors (which bind N-methyl-D-aspartate).
5-HT2A subtype of serotonin receptor in the brain. Though the Cooperative activity of AMPA and NMDA receptors has been
mechanism is not completely understood, alteration of this recep- implicated in one example of a synaptic modulation p­ rocess called
tor complex produces the intense visual hallucinations that are long-term potentiation (LTP). This mechanism couples frequent
produced by ingestion of LSD. activity across a synapse with lasting changes in the strength of sig-
naling across that synapse and is thus thought to be one of the major
Amino Acid Neurotransmitters cellular processes involved in learning and memory. Figure 6.36
In addition to the neurotransmitters that are synthesized from outlines the mechanism in stepwise fashion. When a presynaptic
amino acids, several amino acids themselves function as neu- neuron fires action potentials (step 1), glutamate is released from
rotransmitters. Although the amino acid neurotransmitters chemi- presynaptic terminals (step 2) and binds to both AMPA and NMDA
cally fit the category of biogenic amines, they are traditionally receptors on postsynaptic membranes (step 3). AMPA receptors
placed into a category of their own. The amino acid neurotrans- function just like the excitatory postsynaptic receptors discussed
mitters are by far the most prevalent neurotransmitters in the earlier—when glutamate binds, the channel becomes permeable to
CNS, and they affect virtually all neurons there. both Na+ and K+, but the larger entry of Na+ creates a depolarizing

1 High-frequency
action potentials Presynaptic cell
in presynaptic
cell

Secretory vesicle
containing glutamate

8 Long-lasting increase
in glutamate synthesis
and release

2 Glutamate
is released

3 Glutamate Figure 6.36 Long-term

AMPA binds to Retrograde
receptor messenger potentiation at glutamatergic synapses.
Na+ both channels
Episodes of intense firing across a synapse
5 Depolarization result in structural and chemical changes
−
− Ca2+ drives Mg2+ that amplify the strength of synaptic
+ − ion out of pore
+ − Mg2+ signaling during subsequent activation. See
4 Na+ entry + text for description of each step; details of
depolarizes + − −
cell by the mechanism linking steps 1 and 2 were
+ +
20–30 mV described in Figure 6.27. Note that both
NMDA AMPA and NMDA receptors are nonspecific
receptor cation channels that also allow K+ flux, but
Postsynaptic cell 6 Ca2+ entry activates 7 Long-lasting increase the net Na+ and Ca2+ fluxes indicated are
second-messenger in glutamate receptors most relevant to the LTP mechanism, as
systems and sensitivity described in the text.
168 Chapter 6
EPSP of the postsynaptic cell (step 4). By contrast, NMDA-­receptor excitatory glutamate synapses, with the overall effect being global
channels also mediate a substantial Ca+ flux, but opening them depression of the electrical activity of the brain. Thus, as a per-
requires more than just glutamate binding. A magnesium ion blocks son’s blood alcohol content increases, there is a progressive reduc-
NMDA channels when the membrane voltage is near the negative tion in overall cognitive ability, along with sensory perception
resting potential, and to drive it out of the way the membrane must inhibition (hearing and balance, in particular), loss of motor coor-
be significantly depolarized by the current through AMPA channels dination, impaired judgment, memory loss, and unconsciousness.
(step 5). This explains why it requires a high frequency of presynap- Very high doses of ethanol are sometimes fatal, due to suppres-
tic action potentials to complete the long-term potentiation mecha- sion of brainstem centers responsible for regulating the circula-
nism. At low frequencies, there is insufficient temporal summation tory and respiratory systems. Dopaminergic and endogenous
of AMPA-receptor EPSPs to provide the 20–30 mV of depolariza- opioid signaling pathways (discussed in the next section) are also
tion needed to move the magnesium ion, and so the NMDA recep- affected by ethanol, which results in short-term mood elevation or
tors do not open. When the depolarization is sufficient, however, euphoria. The involvement of these pathways underlies the devel-
NMDA receptors do open, allowing Ca2+ to enter the postsynaptic opment of long-term alcohol dependence in some people.
cell (step 6). Calcium ions then activate a second-messenger cascade
in the postsynaptic cell that includes persistent activation of multiple Glycine Glycine is the major neurotransmitter released from
different protein kinases, stimulation of gene expression and pro- inhibitory interneurons in the spinal cord and brainstem. It binds
tein synthesis, and ultimately a long-lasting increase in the sensitiv- to ionotropic receptors on postsynaptic cells that allow Cl− to
ity of the postsynaptic neuron to glutamate (step 7). There is some enter, thus preventing them from approaching the threshold for
evidence that this second-messenger system can also activate long- firing action potentials. Normal function of glycinergic neurons
term enhancement of presynaptic glutamate release via retrograde is essential for maintaining a balance of excitatory and inhibitory
signals that have not yet been identified (step 8) but in some cases activity in spinal cord integrating centers that regulate skeletal
LTP may occur without retrograde signals. After LTP has occurred, muscle contraction. This becomes apparent in cases of poisoning
each subsequent action potential arriving along this presynaptic cell with the neurotoxin strychnine, an antagonist of glycine
will cause a greater depolarization of the postsynaptic membrane. receptors sometimes used to kill rodents. Victims experience
Thus, repeatedly and intensely activating a particular pattern of syn- hyperexcitability throughout the nervous system, which leads
aptic firing (as you might when studying for an exam) causes chemi- to convulsions, spastic contraction of skeletal muscles, and
cal and structural changes that facilitate future activity along those ultimately death due to impairment of the muscles of respiration.
same pathways (as might occur when recalling what you learned).
NMDA receptors have also been implicated in mediating Neuropeptides
excitotoxicity. This is a phenomenon in which the injury or death of The neuropeptides are composed of two or more amino acids
some brain cells (due, for example, to blocked or ruptured blood ves- linked together by peptide bonds. About 100 neuropeptides
sels) rapidly spreads to adjacent regions. When glutamate-­containing have been identified, but their physiological functions are not all
cells die and their membranes rupture, the flood of glutamate exces- known. It seems that evolution has favored the same chemical
sively stimulates AMPA and NMDA receptors on nearby neurons. messengers for use in widely differing circumstances, and many
The excessive stimulation of those neurons causes the accumula- of the neuropeptides have been previously identified in nonneural
tion of toxic concentrations of intracellular Ca2+, which in turn kills tissue where they function as hormones or paracrine substances.
those neurons and causes them to rupture, and the wave of damage They generally retain the name they were given when first discov-
progressively spreads. Recent experiments and clinical trials suggest ered in the nonneural tissue.
that administering NMDA receptor antagonists may help minimize The neuropeptides are formed differently than other neu-
the spread of cell death following injuries to the brain. rotransmitters, which are synthesized in the axon terminals by very
few enzyme-mediated steps. The neuropeptides, in contrast, are
GABA GABA (gamma-aminobutyric acid) is the major derived from large precursor proteins, which in themselves have little,
inhibitory neurotransmitter in the brain. Although it is not one if any, inherent biological activity. The synthesis of these precursors,
of the 20 amino acids used to build proteins, it is classified with directed by mRNA, occurs on ribosomes, which exist only in the cell
the amino acid neurotransmitters because it is a modified form body and large dendrites of the neuron, often a considerable distance
of glutamate. With few exceptions, GABA neurons in the brain from axon terminals or varicosities where the peptides are released.
are small interneurons that dampen activity within neural circuits. In the cell body, the precursor protein is packaged into vesicles,
Postsynaptically, GABA may bind to ionotropic or metabotropic which are then moved by axonal transport into the terminals or vari-
receptors. The ionotropic receptor increases Cl− flux into the cosities (review Figure 6.3), where the protein is cleaved by specific
cell, resulting in hyperpolarization (an IPSP) of the postsynaptic peptidases. Many of the precursor proteins contain multiple peptides,
membrane. In addition to the GABA binding site, this receptor has which may be different or be copies of one peptide. Neurons that
several additional binding sites for other compounds, including release one or more of the peptide neurotransmitters are collectively
steroids, barbiturates, and benzodiazepines. Benzodiazepine called peptidergic. In many cases, neuropeptides are cosecreted
drugs such as alprazolam (Xanax) and diazepam (Valium) reduce with another type of neurotransmitter and act as neuromodulators.
anxiety, guard against seizures, and induce sleep by increasing The amount of neuropeptide released from vesicles at synapses
Cl− flux through the GABA receptor. is significantly less than the amount of nonpeptidergic neurotransmit-
Synapses that use GABA are also among the many tar- ters such as catecholamines. In addition, neuropeptides can diffuse
gets of the ethanol (ethyl alcohol) found in alcoholic beverages. away from the synapse and affect other neurons at some distance,
Ethanol stimulates GABA synapses and simultaneously inhibits in which case they are referred to as neuromodulators. The actions
Neuronal Signaling and the Structure of the Nervous System 169
of these neuromodulators are longer lasting (on the order of several endocannabinoids N-arachidonoylethanolamine (anandamide)
hundred milliseconds) than when neuropeptides or other molecules and 2-­arachidonoylglycerol. The endocannabinoids are generated
act as neurotransmitters. After release, neuropeptides can interact in response to Ca2+ entry into some postsynaptic cells and act as ret-
with either ionotropic or metabotropic receptors. They are eventually rograde messengers by binding to specific receptors on presynaptic
broken down by peptidases located in neuronal membranes. terminals. Cannabinoid receptors are found in widespread locations
Endogenous opioids—a group of neuropeptides that throughout the central and peripheral nervous systems in pathways
includes beta-endorphin, the dynorphins, and the enkephalins— regulating a wide range of physiological functions including appetite,
have attracted much interest because their receptors are the sites pain sensation, mood, memory, and locomotor activity. These recep-
of action of opiate drugs such as morphine and codeine. The tors are the principal target of tetrahydrocannabinol (THC), the
opiate drugs are powerful analgesics (that is, they relieve pain principal psychoactive constituent of plants in the Cannabis genus.
without loss of consciousness), and the endogenous opioids
undoubtedly have a function in regulating pain. There is also evi- 6.14 Neuroeffector Communication
dence that the opioids function in regulating eating and drinking
behavior, circulatory system function, and mood and emotion. Thus far, we have described the effects of neurotransmitters
released at synapses between neurons. Many neurons of the PNS
end, however, not at synapses on other neurons but at ­neuroeffector
Gases
junctions on muscle, gland, and other cells. The neurotransmitters
Certain very short-lived gases also serve as neurotransmitters. released by these efferent neurons’ terminals or varicosities pro-
Nitric oxide is the best understood, but recent research indicates vide the link by which electrical activity of the nervous system
that carbon monoxide and hydrogen sulfide are also emitted regulates effector cell activity.
by neurons as signals. Gases are not released by exocytosis of The events that occur at neuroeffector junctions are simi-
presynaptic vesicles, nor do they bind to postsynaptic plasma lar to those at synapses between neurons. The neurotransmitter
membrane receptors. They are produced by enzymes in axon is released from the efferent neuron upon the arrival of an action
terminals (in response to Ca 2+ entry) and simply diffuse from potential at the neuron’s axon terminals or varicosities. The neu-
their sites of origin in one cell into the intracellular fluid of rotransmitter then diffuses to the surface of the effector cell,
other neurons or effector cells, where they bind to and activate where it binds to receptors on that cell’s plasma membrane. The
proteins. For example, nitric oxide released from neurons acti- receptors may be directly under the axon terminal or varicosity,
vates guanylyl cyclase in recipient cells. This enzyme increases or they may be some distance away so that the diffusion path the
the concentration of the second-messenger cyclic GMP, which neurotransmitter follows is long. The receptors on the effector cell
in turn can alter ion channel activity in the postsynaptic cell. may be either ionotropic or metabotropic. The response (such as
Nitric oxide functions in a bewildering array of neurally medi- altered muscle contraction or glandular secretion) of the effec-
ated events—learning, development, drug tolerance, penile and cli- tor cell will be described in later chapters. As we will see in the
toral erection, and sensory and motor modulation, to name a few. next section, the major neurotransmitters released at neuroeffector
Paradoxically, it is also implicated in neural damage that results, for junctions are acetylcholine and norepinephrine.
example, from the stoppage of blood flow to the brain or from a head
injury. In later chapters, we will see that nitric oxide is produced
not only in the central and peripheral nervous systems but also by SECTION C SU M M A RY
a variety of nonneural cells; for example, it has important paracrine I. An excitatory synapse brings the membrane of the postsynaptic cell
functions in the circulatory and immune systems, among others. closer to threshold. An inhibitory synapse prevents the postsynaptic
cell from approaching threshold by hyperpolarizing or stabilizing
Purines the membrane potential.
II. Whether a postsynaptic cell fires action potentials depends on the
Other nontraditional neurotransmitters include the purines, ATP number of synapses that are active and whether they are excitatory
and adenosine, which act principally as neuromodulators. ATP or inhibitory.
is present in all presynaptic vesicles and is coreleased with one III. Neurotransmitters are chemical messengers that pass from one
or more other neurotransmitters in response to Ca2+ influx into neuron to another and modify the electrical or metabolic function
the terminal. Adenosine is derived from ATP via enzyme activity of the recipient cell.
occurring in the extracellular compartment. Both presynaptic and Functional Anatomy of Synapses
postsynaptic receptors have been described for adenosine, and the I. Electrical synapses consist of gap junctions that allow current to
functions these substances have in the nervous system and other flow between adjacent cells.
tissues are active areas of research. II. In chemical synapses, neurotransmitter molecules are stored in
synaptic vesicles in the presynaptic axon terminal, and when released
transmit the signal from a presynaptic to a postsynaptic neuron.
Lipids
Mechanisms of Neurotransmitter Release
A number of membrane phospholipid-derived substances are I. Depolarization of the axon terminal increases the Ca2+
important in synaptic signaling, most commonly acting as neu- concentration within the terminal, which causes the release of
romodulators. Many of these are members of the eicosanoid neurotransmitter into the synaptic cleft.
family of molecules derived from the polyunsaturated fatty II. The neurotransmitter diffuses across the synaptic cleft and binds to
acid arachidonic acid. These include prostaglandins, throm- receptors on the postsynaptic cell; the activated receptors usually
boxanes, and leukotrienes (review Figure 5.12) as well as the open ion channels.
170 Chapter 6
Activation of the Postsynaptic Cell 6.8 Functional Anatomy of Synapses
I. At an excitatory synapse, the electrical response in the postsynaptic chemical synapse synaptic cleft
cell is called an excitatory postsynaptic potential (EPSP). At electrical synapses synaptic vesicles
inhibitory synapses, it is either an inhibitory postsynaptic potential postsynaptic density
(IPSP) or a stabilization of the membrane potential near resting
levels. 6.9 Mechanisms of Neurotransmitter Release
II. Usually at an excitatory synapse, nonspecific cation channels in the active zones synaptotagmins
postsynaptic cell open, but Na+ flux dominates, because it has the SNARE proteins
largest electrochemical gradient. At inhibitory synapses, channels
to Cl− or K+ open. 6.10 Activation of the Postsynaptic Cell
excitatory postsynaptic potential ionotropic receptors
Synaptic Integration (EPSP) metabotropic receptors
I. The postsynaptic cell’s membrane potential is the result of inhibitory postsynaptic potential reuptake
temporal and spatial summation of the EPSPs and IPSPs at the (IPSP)
many active excitatory and inhibitory synapses on the cell.
II. Action potentials are generally initiated by the temporal and spatial 6.11 Synaptic Integration
summation of many EPSPs. spatial summation temporal summation
Synaptic Strength 6.12 Synaptic Strength
I. Synaptic strength is modified by presynaptic and postsynaptic
agonists presynaptic facilitation
events, drugs, and diseases (see Table 6.5).
antagonists presynaptic inhibition
Neurotransmitters and Neuromodulators autoreceptors receptor desensitization
I. In general, neurotransmitters cause EPSPs and IPSPs, and axo–axonic synapse
neuromodulators cause, via second messengers, more complex
6.13 Neurotransmitters and Neuromodulators
metabolic effects in the postsynaptic cell.
II. The actions of neurotransmitters are usually faster than those of acetylcholine (ACh) excitatory amino acids
neuromodulators. acetylcholinesterase excitotoxicity
III. A substance can act as a neurotransmitter at one type of receptor adenosine GABA (gamma-aminobutyric acid)
and as a neuromodulator at another. alpha-adrenergic receptors glutamate
IV. The major classes of known or suspected neurotransmitters and (alpha-adrenoceptors) glycine
neuromodulators are listed in Table 6.6. AMPA receptors hydrogen sulfide
2-arachidonoylglycerol L-dopa
Neuroeffector Communication ATP long-term potentiation (LTP)
I. The synapse between a neuron and an effector cell is called a beta-adrenergic receptors monoamine oxidase (MAO)
neuroeffector junction. (beta-adrenoceptors) muscarinic receptors
II. The events at a neuroeffector junction (release of neurotransmitter beta-endorphin N-arachidonoylethanolamine
into an extracellular space, diffusion of neurotransmitter to the biogenic amines (anandamide)
effector cell, and binding with a receptor on the effector cell) are carbon monoxide neuromodulators
similar to those at synapses between neurons. catecholamines neuropeptides
cholinergic nicotinic receptors
dopamine (DA) nitric oxide
dynorphins NMDA receptors
SECTION C R EV I EW QU E ST ION S endocannabinoids norepininephrine (NE)
1. Describe the structure of presynaptic axon terminals, and the endogenous opioids peptidergic
mechanism of neurotransmitter release. enkephalins serotonin
2. Contrast the postsynaptic mechanisms of excitatory and inhibitory epinephrine
synapses.
3. Explain how synapses allow neurons to act as integrators; include
the concepts of facilitation, temporal and spatial summation, and
convergence in your explanation. SECTION C CLI N ICA L T ER M S
4. List at least eight ways in which the effectiveness of synapses may 6.12 Synaptic Strength
be altered.
Botox tetanus toxin
5. Discuss differences between neurotransmitters and
botulism
neuromodulators.
6. List the major classes of neurotransmitters, and give examples 6.13 Neurotransmitters and Neuromodulators
of each. alprazolam (Xanax) monoamine oxidase (MAO)
7. Detail the mechanism of long-term potentiation, and explain what Alzheimer’s disease inhibitors
function it might have in learning and memory. analgesics morphine
atropine nicotine
beta-amyloid protein paroxetine (Paxil)
SECTION C K EY T ER M S Cannabis Sarin
codeine strychnine
convergence excitatory synapse diazepam (Valium) tetrahydrocannabinol (THC)
divergence inhibitory synapse LSD
Neuronal Signaling and the Structure of the Nervous System 171
SECTION D
Structure of the Nervous System
We now survey the anatomy and broad functions of the major struc- are often clustered together. Groups of neuron cell bodies in the
tures of the central and peripheral nervous systems. Figure 6.37 PNS are called ganglia (singular, ganglion). In the CNS, they
provides a conceptual overview of the organization of the nervous are called nuclei (singular, nucleus), not to be confused with
system for you to refer to as we discuss the various subdivisions in cell nuclei.
this section and in later chapters.
First, we must introduce some important terminology.
Recall that a long extension from a single neuron is called an
6.15 Central Nervous System: Brain
axon and that the term nerve refers to a group of many axons During development, the CNS forms from a long tube. As the
that are traveling together to and from the same general loca- anterior part of the tube, which becomes the brain, folds dur-
tion in the PNS. There are no nerves in the CNS. Rather, a ing its continuing formation, initially three different regions
group of axons traveling together in the CNS is called a path- become apparent, identified as the forebrain, midbrain, and
way, a tract, or, when it links the right and left halves of the hindbrain (Figure 6.38). These regions continue to develop,
brain, a commissure. Two general types of pathways occur in forming subdivisions. The forebrain develops into two major
the CNS. The first are sometimes referred to as long neural subdivisions, the cerebrum and the diencephalon. The mid-
pathways and consist of neurons with relatively long axons that brain remains as a single major division. The hindbrain devel-
carry information directly between the brain and spinal cord or ops into three parts: the pons, medulla oblongata, and the
between large regions of the brain. The second type are multi- cerebellum. The pons, medulla oblongata, and the midbrain
synaptic pathways and include many neurons with branching are heavily interconnected and share many similar functions;
axons and many synaptic connections. Because synapses are for that reason and their anatomical location, they are consid-
the sites where new information can be integrated into neural ered together as the brainstem.
messages, these pathways perform complex neural processing, The brain also contains four interconnected cavities, the
while long neural pathways transmit signals with relatively less cerebral ventricles, which are filled with fluid and which provide
alteration. The cell bodies of neurons with similar functions support for the brain.

Central nervous system Peripheral nervous system

Brain
Somatic sensory

Afferent division Visceral sensory

Special sensory

Figure 6.37 Overview of the

structural and functional organization of
Spinal the nervous system.
cord Somatic motor

Efferent division P H YS I O LO G I C A L I N Q U I RY
Autonomic motor ■ Describe how the central and
peripheral nervous systems illustrate
Sympathetic the general principle of physiology
Parasympathetic that information flow between cells,
Enteric tissues, and organs is an essential
feature of homeostasis and allows
for integration of physiological
processes.
Answer can be found at end of
chapter.

172 Chapter 6
(a) (b)
Frontal lobe Parietal lobe

Forebrain Cerebrum Occipital

Diencephalon lobe

Forebrain

Midbrain
Temporal
Midbrain lobe
Pons
Brainstem
Medulla Cerebellum
oblongata (part of
Hindbrain
hindbrain)
Figure 6.38 Structures of the
human brain. (a) Development of the three
Spinal cord major parts of the brain in a 4-week-old
embryo. (b) The major divisions of the adult
brain shown in sagittal section. The outer
surface of the cerebrum (cortex) is divided into
four lobes as shown.

Overviews of the brain subdivisions are included here and The cerebral hemispheres (Figure 6.39) consist of the
in Table 6.7, but details of their functions are given more fully in cerebral cortex—an outer shell of gray matter composed primar-
Chapters 7, 8, and 10. ily of cell bodies that give the area a gray appearance—and an inner
layer of white matter, composed primarily of tracts of myelinated
Forebrain: The Cerebrum axons. The cerebral cortex in turn overlies cell clusters, which
The larger component of the forebrain, the cerebrum, consists of are also gray matter and are collectively termed the ­subcortical
the right and left cerebral hemispheres as well as some associ- nuclei. The tracts consist of the many axons of neurons that bring
ated structures on the underside of the brain. information into the cerebrum, carry information out, and connect

TABLE 6.7 Summary of Functions of the Major Parts of the Brain

I. Forebrain
A. Cerebrum
1. Contains the cerebral cortex, which participates in perception (Chapter 7); the generation of skilled movements (Chapter 10); reasoning,
learning, and memory (Chapter 8)
2. Contains subcortical nuclei, including the basal nuclei that participate in coordination of skeletal muscle activity (Chapter 10), and the limbic
system, which participates in generation of emotions, emotional behavior, and some aspects of learning (Chapter 8)
3. Contains interconnecting axonal pathways
B. Diencephalon
1. Contains the thalamus, which acts as a synaptic relay station for sensory pathways on their way to the cerebral cortex (Chapter 7);
participates in control of skeletal muscle coordination (Chapter 10); and has a key function in awareness (Chapter 8)
2. Also contains the hypothalamus, which regulates anterior pituitary gland function (Chapter 11); regulates water balance (Chapter 14);
participates in regulation of autonomic nervous system (Chapters 6 and 16); regulates eating and drinking behavior (Chapter 16); regulates
reproductive system (Chapters 11 and 17); reinforces certain behaviors (Chapter 8); generates and regulates circadian rhythms (Chapters 1, 7,
and 16); regulates body temperature (Chapter 16); and participates in generation of emotional behavior (Chapter 8)

II. Cerebellum (Part of Hindbrain)

A. Coordinates movements, including those for posture and balance (Chapter 10)
B. Participates in some forms of learning (Chapter 8)

III. Brainstem (Midbrain, Pons, and Medulla Oblongata)

A. Contains all the axons of neurons passing between the spinal cord, forebrain, and cerebellum
B. Contains the reticular formation and its various integrating centers, including those for cardiovascular and respiratory activity (Chapters 12
and 13)
C. Contains nuclei for cranial nerves III through XII

Neuronal Signaling and the Structure of the Nervous System 173

 Layers

1
2

3
Gray
matter
4
Pyramidal
cells 5
6

White matter

Gyrus
Corpus
callosum
Sulcus

Lateral
Cerebral
ventricle
cortex
Cerebrum
(limbic system
Thalamus Basal nuclei not shown)
Diencephalon
(epithalamus
not visible) Hypothalamus
Third ventricle

Pituitary
gland

Figure 6.39 Frontal section of the cerebral hemispheres showing portions of the cerebrum and underlying diencephalon (thalamus and
hypothalamus; the epithalamus is not visible in this plane of section). The limbic system is shown in Figure 6.40. The corpus callosum is a large bundle
of axons that connects the two hemispheres, which are folded into gyri and sulci. Some of the fluid-filled ventricles of the brain are also indicated, as
is the pituitary gland. The inset shows a simplified depiction of the six-layer organization of the cerebral cortex. Not shown is the extensive degree of
neuronal input into the different layers from cells outside the cerebral cortex.

different areas within a hemisphere. The cortex layers of the left parts of the cortex and to other parts of the CNS. Nonpyrami-
and right cerebral hemispheres, although largely separated by a dal cells are mostly involved in receiving inputs into the cerebral
deep longitudinal division, are connected by a massive bundle of cortex and in local processing of information. This elaboration of
axons in a commissure known as the corpus callosum. the human cerebral cortex into multiple cell layers, like its highly
folded structure, allows for an increase in the number and inte-
Cerebral Cortex The cerebral cortex of each cerebral gration of neurons for signal processing. Such specialization of
hemisphere is divided into four lobes, named after the overlying structural surface area to enhance function in organs throughout
skull bones covering the brain: the frontal, parietal, occipital, and the body affirms the general principle of physiology that struc-
temporal lobes. Although it averages only 3 mm in thickness, the ture and function are related. This is supported by the fact that
cerebral cortex is highly folded. This results in an area containing an increase in the number of cell layers in the cerebral cortex has
cortical neurons that is four times larger than it would be without paralleled the increase in behavioral and cognitive complexity in
folding, yet does not appreciably increase the volume of the brain. vertebrate evolution. For example, reptiles have just three layers
This folding also results in the characteristic external appearance of in the cortex, and dolphins have five. Some regions of the human
the human cerebrum, with its sinuous ridges called gyri (singular, brain with ancient evolutionary origins, such as the olfactory cor-
gyrus) separated by grooves called sulci (singular, sulcus). tex, persist in having only three cell layers.
The neurons of the human cerebral cortex are organized in The cerebral cortex is one of the most complex integrating areas
six distinct layers, composed of varying sizes and numbers of two of the nervous system. It is here that basic afferent information is col-
basic types: pyramidal cells (named for the shape of their cell bod- lected and processed into meaningful perceptual images, and control
ies) and nonpyramidal cells. The pyramidal cells form the major over the systems that govern the movement of the skeletal muscles is
output cells of the cerebral cortex, sending their axons to other refined. Neuronal axons enter the cerebral cortex predominantly from
174 Chapter 6
the diencephalon and areas of the brainstem; there is also extensive different nuclei. These nuclei and their pathways form the master
signaling between areas within the cerebral cortex. Some of the input command center for neural and endocrine coordination. Indeed, the
neurons convey information about specific events in the environment, hypothalamus is the single most important control area for homeo-
whereas others control levels of cortical excitability, determine states static regulation of the internal environment. Behaviors having to
of arousal, and direct attention to specific stimuli. do with preservation of the individual (for example, eating and
drinking) and preservation of the species (reproduction) are among
Basal Nuclei The subcortical nuclei are heterogeneous groups the many functions of the hypothalamus. The hypothalamus lies
of gray matter that lie deep within the cerebral hemispheres. directly above and is connected by a stalk to the pituitary gland,
Predominant among them are the basal nuclei (often, but less an important endocrine structure that the hypothalamus regulates
correctly referred to as basal ganglia), which have an important (Chapter 11). As mentioned earlier, some parts of the hypothalamus
function in controlling movement and posture and in more and thalamus are also considered part of the limbic system.
complex aspects of behavior. The epithalamus is a small mass of tissue that includes
the pineal gland, which participates in the control of circadian
Limbic System Thus far, we have described discrete anatomical rhythms through release of the hormone melatonin.
areas of the forebrain. Some of these forebrain areas, consisting
of both gray and white matter, are also classified together in a
functional system called the limbic system. This interconnected
Hindbrain: The Cerebellum
group of brain structures includes portions of frontal-lobe cortex, The cerebellum consists of an outer layer of cells, the cerebellar
temporal lobe, thalamus, and hypothalamus, as well as the fiber cortex (do not confuse this with the cerebral cortex), and several
pathways that connect them (Figure 6.40). Besides being connected deeper cell clusters. Although the cerebellum does not initiate vol-
with each other, the parts of the limbic system connect with many untary movements, it is an important center for coordinating move-
other parts of the CNS. Structures within the limbic system are ments and for controlling posture and balance. To carry out these
associated with learning, emotional experience and behavior, and functions, the cerebellum receives information from the muscles
a wide variety of visceral and endocrine functions (see Chapter 8). and joints, skin, eyes, vestibular apparatus, viscera, and the parts
of the brain involved in control of movement. Although the cere­
bellum’s function is almost exclusively motor, recent research
Forebrain: The Diencephalon
strongly suggests that it also may be involved in some forms of
The diencephalon, which is divided in two by the narrow third learning. The other components of the hindbrain—the pons and
cerebral ventricle, is the second component of the forebrain. medulla oblongata—are considered together with the midbrain.
It contains the thalamus, hypothalamus, and epithalamus (see
Figure 6.39). The thalamus is a collection of several large nuclei Brainstem: The Midbrain, Pons,
that serve as synaptic relay stations and important integrating and Medulla Oblongata
centers for most inputs to the cortex, and it has a key function
in general arousal (Chapter 8). The thalamus also is involved in All the axons of neurons that relay signals between the forebrain,
focusing attention. For example, it is responsible for filtering out cerebellum, and spinal cord pass through the brainstem. Run-
extraneous sensory information, like when you try to concentrate ning through the core of the brainstem and consisting of loosely
on a private conversation at a loud, crowded party. arranged nuclei intermingled with bundles of axons is the ­reticular
The hypothalamus lies below the thalamus and is on the formation, the one part of the brain absolutely essential for life.
undersurface of the brain; like the thalamus, it contains numerous It receives and integrates input from all regions of the CNS and
processes a great deal of neural information. The reticular forma-
tion is involved in motor functions, cardiovascular and respiratory
control, and the mechanisms that regulate sleep and wakefulness
and that focus attention. Most of the biogenic amine neurotrans-
mitters are released from the axons of cells in the reticular forma-
Septal
tion. Because of the far-reaching projections of these cells, these
nuclei neurotransmitters affect all levels of the nervous system.
The pathways that convey information from the reticular
Frontal lobe
formation to the upper portions of the brain stimulate arousal
Thalamus and wakefulness. They also direct attention to specific events by
Olfactory
bulbs
Hypothalamus selectively stimulating neurons in some areas of the brain while
inhibiting others. The neuronal pathways that descend from the
Hippocampus
reticular formation to the spinal cord influence activity in both
efferent and afferent neurons. Considerable interaction takes place
between the reticular pathways that go up to the forebrain, down
to the spinal cord, and to the cerebellum. For example, all three
components function in controlling muscle activity.
Figure 6.40 Major structures of the limbic system The reticular formation encompasses a large portion of the
(portions enhanced in violet) and their anatomical relation to the brainstem, and many areas within the reticular formation serve
hypothalamus (purple) are shown in this partially transparent view distinct functions. For example, some reticular formation neurons
of the brain. are clustered together, forming brainstem nuclei and integrating
Neuronal Signaling and the Structure of the Nervous System 175
centers. These include the cardiovascular, respiratory, swallowing, root ganglia, contain the cell bodies of these afferent neurons.
and vomiting centers, all of which we will discuss in later chapters. The axons of efferent neurons leave the spinal cord on the ventral
The reticular formation also has nuclei important in eye-movement side via the ventral roots. A short distance from the cord, the
control and the reflexive orientation of the body in space. dorsal and ventral roots from the same level combine to form a
In addition, the brainstem contains nuclei involved in pro- spinal nerve, one on each side of the spinal cord, carrying two-
cessing information for 10 of the 12 pairs of cranial nerves. These way information from afferents and efferents.
are the peripheral nerves that connect directly with the brain and
innervate the muscles, glands, and sensory receptors of the head, 6.17 Peripheral Nervous System
as well as many organs in the thoracic and abdominal cavities.
Neurons in the PNS transmit signals between the CNS and
receptors and effectors in all other parts of the body. As noted
6.16 Central Nervous System: Spinal earlier, the axons are grouped into bundles called nerves. The
Cord PNS has 43 pairs of nerves: 12 pairs of cranial nerves and
31 pairs of spinal nerves that connect with the spinal cord.
The spinal cord lies within the bony vertebral column
Table 6.8 lists the cranial nerves and summarizes the informa-
(Figure 6.41). It is a slender cylinder of soft tissue about as big
tion they transmit. The 31 pairs of spinal nerves are designated
around as your little finger. The central butterfly-shaped area (in
by the vertebral levels from which they exit: cervical, thoracic,
cross section) of gray matter is composed of interneurons, the cell
lumbar, sacral, and coccygeal (Figure 6.42). Neurons in the
bodies and dendrites of efferent neurons, the entering axons of
spinal nerves at each level generally communicate with nearby
afferent neurons, and glial cells. The regions of gray matter pro-
structures, controlling muscles and glands as well as receiv-
jecting toward the back of the body are called the dorsal horns,
ing sensory input. The eight pairs of cervical nerves innervate
whereas those oriented toward the front are the ventral horns.
the neck, shoulders, arms, and hands. The 12 pairs of thoracic
The gray matter is surrounded by white matter, which con-
nerves are associated with the chest and upper abdomen. The
sists of groups of myelinated axons. These tracts run longitudinally
five pairs of lumbar nerves are associated with the lower abdo-
through the cord, some descending to relay information from the
men, hips, and legs; the five pairs of sacral nerves are associ-
brain to the spinal cord, others ascending to transmit information
ated with the genitals and lower digestive tract. A single pair of
to the brain. Pathways also transmit information between different
coccygeal nerves associated with the skin over the region of the
levels of the spinal cord.
tailbone brings the total to 31 pairs.
Groups of afferent neuron axons that enter the spinal cord
These peripheral nerves can contain axons of neurons
from the peripheral nerves enter on the dorsal side of the cord
belonging to the efferent or the afferent division of the PNS
via the dorsal roots. Small bumps on the dorsal roots, the dorsal
(refer back to ­Figure 6.37). All the spinal nerves contain both
afferent and efferent fibers, whereas some of the cranial nerves
Gray matter contain only afferent fibers (the optic nerves from the eyes, for
Ventral Dorsal example) or only efferent fibers (the hypoglossal nerve to mus-
horn horn cles of the tongue, for example).
Dorsal
White matter
root As noted earlier, afferent neurons convey information from
Dorsal sensory receptors at their peripheral endings to the CNS. The long
root part of their axon is outside the CNS and is part of the PNS. Afferent
ganglion neurons are sometimes called primary afferents or first-order neu-
Spinal cord rons because they are the first cells entering the CNS in the synapti-
Spinal cally linked chains of neurons that handle incoming information.
Ventral
nerve root Efferent neurons carry signals out from the CNS to muscles,
glands, and other tissues. The efferent division of the PNS is more
complicated than the afferent, being subdivided into a somatic
nervous system and an autonomic nervous system. These terms
are somewhat misleading because they suggest the presence of
additional nervous systems distinct from the central and periph-
eral systems. Keep in mind that these terms together make up the
efferent division of the PNS.
The simplest distinction between the somatic and autonomic
systems is that the neurons of the somatic division innervate skel-
Vertebra etal muscle, whereas the autonomic neurons innervate smooth
and cardiac muscle, glands, neurons in the gastrointestinal tract,
and other tissues. Other differences are listed in Table 6.9.
The somatic portion of the efferent division of the PNS is
made up of all the axons of neurons going from the CNS to skel-
etal muscle cells. The cell bodies of these neurons are located in
Figure 6.41 Section of the spinal cord, ventral view. The groups in the brainstem or the ventral horn of the spinal cord. Their
arrows indicate the direction of transmission of neural activity. large-diameter, myelinated axons leave the CNS and pass without
176 Chapter 6
 TABLE 6.8 The Cranial Nerves
Name Fibers Comments

I. Olfactory Afferent Carries input from receptors in olfactory (smell) neuroepithelium*

   II. Optic Afferent Carries input from receptors in eye*

III. Oculomotor Efferent Innervates skeletal muscles that move eyeball up, down, and medially, and
raise upper eyelid; innervates smooth muscles that constrict pupil and alter
lens shape for near and far vision
Afferent Transmits information from receptors in muscles

IV. Trochlear Efferent Innervates skeletal muscles that move eyeball downward and laterally

Afferent Transmits information from receptors in muscles

V. Trigeminal Efferent Innervates skeletal muscles used for chewing

Afferent Transmits information from receptors in skin; skeletal muscles of face,

nose, and mouth; and teeth sockets

VI. Abducens Efferent Innervates skeletal muscles that move eyeball laterally

Afferent Transmits hearing and balance information from receptors in muscles

VII. Facial Efferent Innervates skeletal muscles of facial expression and swallowing; innervates
nose, palate, and lacrimal and salivary glands
Afferent Transmits information from taste buds in front of tongue and mouth

VIII. Vestibulocochlear Afferent Transmits hearing and balance information from receptors in inner ear

IX. Glossopharyngeal Efferent Innervates skeletal muscles involved in swallowing and parotid salivary
gland
Afferent Transmits information from taste buds at back of tongue and receptors
in auditory-tube skin; also transmits information from carotid artery
baroreceptors (blood pressure receptors) and from chemoreceptors that
detect changes in blood gas levels

X. Vagus Efferent Innervates skeletal muscles of pharynx and larynx and smooth muscle and
glands of thorax and abdomen
Afferent Transmits information from receptors in thorax and abdomen

XI. Accessory Efferent Innervates sternocleidomastoid and trapezius muscles in the neck

XII. Hypoglossal Efferent Innervates skeletal muscles of tongue

*The olfactory and optic pathways are CNS structures so are not technically “nerves.”

any synapses to skeletal muscle cells. The neurotransmitter these neuronal network in the wall of the tract. This network is called the
neurons release is acetylcholine. Because activity in the somatic enteric nervous system, and although often classified as a subdi-
neurons leads to contraction of the innervated skeletal muscle cells, vision of the autonomic efferent nervous system, it also includes
these neurons are called motor neurons. Excitation of motor neu- sensory neurons and interneurons. Chapter 15 will describe this
rons leads only to the contraction of skeletal muscle cells; there are network in more detail in the context of gastrointestinal physiology.
no somatic neurons that inhibit skeletal muscles. Muscle relaxation In contrast to the somatic nervous system, the autonomic
involves the inhibition of the motor neurons in the spinal cord. nervous system is made up of two neurons in series that connect
the CNS and the effector cells (Figure 6.43). The first neuron has
its cell body in the CNS. The synapse between the two neurons is
6.18 Autonomic Nervous System outside the CNS in a cell cluster called an autonomic ganglion.
The efferent innervation of tissues other than skeletal muscle is The neurons passing between the CNS and the ganglia are called
by way of the autonomic nervous system. A special case occurs preganglionic neurons; those passing between the ganglia and
in the gastrointestinal tract, where autonomic neurons innervate a the effector cells are postganglionic neurons.
Neuronal Signaling and the Structure of the Nervous System 177
 Peripheral Nervous System: Somatic and
TABLE 6.9 Autonomic Divisions
Skull
Somatic
C1
Consists of a single neuron between CNS and skeletal muscle cells

Innervates skeletal muscle cells

Dorsal root
ganglion
Can lead only to muscle cell excitation

C8 Autonomic
T1
Has two-neuron chain (connected by a synapse) between CNS and
effector organ

Innervates smooth and cardiac muscle, glands, GI neurons, but not

skeletal muscle cells
Scapula

Can be either excitatory or inhibitory

CNS Somatic nervous system Effector organ

Ribs
Skeletal
muscle

CNS Autonomic nervous system

Smooth or
cardiac
muscles,
Preganglionic Postganglionic glands, or
T12 other cells
neuron Ganglion neuron
L1 12th rib
Figure 6.43 Efferent division of the PNS, including an overall plan
of the somatic and autonomic nervous systems.
Cutaway of
vertebra

Anatomical and physiological differences within the

autonomic nervous system are the basis for its further subdivi-
sion into sympathetic and parasympathetic divisions (review
Figure 6.37). The neurons of the sympathetic and parasympa-
L5
thetic divisions leave the CNS at different levels—the s­ ympathetic
­neurons from the thoracic and lumbar regions of the spinal cord,
S1
Pelvis and the ­parasympathetic neurons from the brainstem and the
sacral portion of the spinal cord (Figure 6.44). Therefore, the
sympathetic division is also called the thoracolumbar division, and
the parasympathetic division is called the craniosacral division.
S5
The two divisions also differ in the location of ganglia. Most
CO1
of the sympathetic ganglia lie close to the spinal cord and form
the two chains of ganglia—one on each side of the cord—known
Sacrum as the sympathetic trunks (see Figure 6.44 and Figure 6.45).
Other sympathetic ganglia, called collateral ganglia—the celiac,
Coccyx superior mesenteric, and inferior mesenteric ganglia—are in the
(tailbone)

Figure 6.42 Dorsal view of the spinal cord and spinal nerves. Parts of the skull and vertebrae have been cut away; the ventral roots of
the spinal nerves are not visible. In general, the eight cervical (C) nerves control the muscles and glands and receive sensory input from the neck,
shoulders, arms, and hands. The 12 thoracic (T) nerves are associated with the shoulders, chest, and upper abdomen. The five lumbar nerves (L) are
associated with the lower abdomen, hips, and legs; and the five sacral (S) nerves are associated with the genitals and lower digestive tract. The single
coccygeal (CO1) nerve innervates the skin region around the tailbone. Source: Redrawn from Fundamental Neuroanatomy by Walle J. H. Nauta and Michael Fiertag.

178 Chapter 6
 Parasympathetic preganglionic neurons
Parasympathetic postganglionic neurons
Sympathetic preganglionic neurons
Sympathetic postganglionic neurons
Midbrain
Pons Lacrimal
III gland
Superior
Brainstem VII cervical
IX ganglion
X
Eye
C1
Olfactory
Medulla glands
Cervical

Vagus Middle
nerve cervical
ganglion
Salivary
glands
Inferior C8
cervical T1
ganglion

Sympathetic trunk
Sympathetic
ganglia

Heart
Thoracic
Spinal cord

Lungs Celiac
ganglion

Spleen Superior T12

mesenteric L1
Stomach ganglion
Lumbar

Adrenal
gland L5
Large intestine S1
Kidney
Sacral

Inferior S5
Urinary Small mesenteric
bladder intestine ganglion

Figure 6.44 The parasympathetic (at left) and sympathetic (at right) divisions of the autonomic nervous system. Although single nerves
are shown exiting the brainstem and spinal cord, all represent paired (left and right) nerves. Only one sympathetic trunk is indicated, although there
are two, one on each side of the spinal cord. The celiac, superior mesenteric, and inferior mesenteric ganglia are collateral ganglia. Not shown are the
neurons innervating the liver, blood vessels, genitalia, and skin glands.

abdominal cavity, closer to the innervated organs (see Figure 6.44). whereas sympathetic trunks extend the entire length of the cord,
In contrast, the parasympathetic ganglia lie within, or very close from the cervical levels high in the neck down to the sacral levels.
to, the organs that the postganglionic neurons innervate. The ganglia in the extra lengths of sympathetic trunks receive pre-
Preganglionic sympathetic neurons leave the spinal cord ganglionic neurons from the thoracolumbar regions because some
only between the first thoracic and second lumbar segments, of the preganglionic neurons, once in the sympathetic trunks, turn
Neuronal Signaling and the Structure of the Nervous System 179
 Sympathetic trunk to travel upward or downward for several segments before forming
(chain of sympathetic ganglia) synapses with postganglionic neurons (see Figure 6.45, numbers 1
and 4). Other possible paths the sympathetic fibers might take are
shown in Figure 6.45, numbers 2, 3, and 5.
The overall activation pattern within the sympathetic and
parasympathetic systems tends to be different. In the sympathetic
division, although small segments are occasionally activated inde-
Spinal cord pendently, it is more typical for increased sympathetic activity to
1 (dorsal side) occur body-wide when circumstances warrant activation. The para-
sympathetic system, in contrast, tends to activate specific organs in a
pattern finely tailored to each given physiological situation.
2 In both the sympathetic and parasympathetic divisions,
acetylcholine is the neurotransmitter released between pre- and
postganglionic neurons in autonomic ganglia, and the postgangli-
onic cells have predominantly nicotinic acetylcholine receptors
3
(Figure 6.46). In the parasympathetic division, acetylcholine is
also the neurotransmitter between the postganglionic neuron and
the effector cell. In the sympathetic division, norepinephrine is
To 4 usually the transmitter between the postganglionic neuron and the
collateral effector cell. We say “usually” because a few sympathetic post-
ganglion ganglionic endings release acetylcholine (e.g., sympathetic path-
ways that regulate sweating).
In addition to the classical autonomic neurotransmitters just
5 Gray matter
described, there is a widespread network of postganglionic neu-
White matter
rons recognized as nonadrenergic and noncholinergic. These neu-
rons use nitric oxide and other neurotransmitters to mediate some
Preganglionic forms of blood vessel dilation and to regulate various gastrointes-
neuron Sympathetic
ganglion tinal, respiratory, urinary, and reproductive functions.
Many of the drugs that stimulate or inhibit various compo-
Postganglionic nents of the autonomic nervous system affect receptors for acetyl-
neuron
choline and norepinephrine. Recall that there are several types of
receptors for each neurotransmitter. A great majority of acetylcho-
Figure 6.45 Relationship between a sympathetic trunk and line receptors in the autonomic ganglia are nicotinic receptors. In
spinal nerves (1 through 5) with the various courses that preganglionic
sympathetic neurons (solid lines) take through the sympathetic trunk.
Dashed lines represent postganglionic neurons. A mirror image of this
exists on the opposite side of the spinal cord.
Figure 6.46 Transmitters used in the
various components of the peripheral
SOMATIC NS CNS N-AChR efferent nervous system. Notice that the
ACh
first neuron exiting the CNS—whether
Skeletal
muscles in the somatic or the autonomic nervous
system—releases acetylcholine. In a very
few cases, postganglionic sympathetic
neurons may release a transmitter
AUTONOMIC NS CNS Ganglion N-AChR M-AChR other than norepinephrine. (ACh,
Parasympathetic acetylcholine; NE, norepinephrine;
division Epi, epinephrine; N-AChR, nicotinic
acetylcholine receptor; M-AChR,
ACh muscarinic acetylcholine receptor)
Smooth
Smooth
or
or cardiac
cardiac
Ganglion muscles,
muscles, P H YS I O LO G I C A L I N Q U I RY
NE glands,
glands,
Sympathetic ororGIother ■ How would the effects differ between
division cells
neurons a drug that blocks muscarinic
Adrenergic acetylcholine receptors and one
ACh N-AChR receptors
that blocks nicotinic acetylcholine
via bloodstream receptors?
Answer can be found at end of
Adrenal Epi chapter.
medulla

180 Chapter 6
contrast, the acetylcholine receptors on cellular targets of postgan- accelerator (sympathetic) will slow the car. Dual innervation by
glionic autonomic neurons are muscarinic receptors (Table 6.10). neurons that cause opposite responses provides a very fine degree
(The cholinergic receptors on skeletal muscle fibers, innervated of control over the effector organ; this is perhaps one of the most
by the somatic motor neurons, not autonomic neurons, are nico- obvious examples of the general principle of physiology that most
tinic receptors.) physiological functions are controlled by multiple regulatory sys-
One set of postganglionic neurons in the sympathetic divi- tems, often working in opposition.
sion never develops axons. Instead, these neurons form part of an A useful generalization is that the sympathetic system
endocrine gland, the adrenal medulla (see Figure 6.46). Upon increases its activity under conditions of physical or psychologi-
activation by preganglionic sympathetic axons, cells of the adre- cal stress. Indeed, a generalized activation of the sympathetic
nal medulla release a mixture of about 80% epinephrine and 20% system is called the fight-or-flight response, describing the
norepinephrine into the blood. These catecholamines, properly situation of an animal forced to either challenge an attacker or
called hormones rather than neurotransmitters in this circum- run from it. All resources for physical exertion are activated:
stance because they are released into the blood, are transported via Heart rate and blood pressure increase; blood flow increases to
the blood to effector cells having receptors sensitive to them. The the skeletal muscles, heart, and brain; the liver releases glucose;
receptors may be the same adrenergic receptors that are located and the pupils dilate. Simultaneously, the activity of the gastro-
near the release sites of sympathetic postganglionic ­neurons and intestinal tract and blood flow to it are inhibited by sympathetic
are normally activated by the norepinephrine released from these firing. In contrast, when the parasympathetic system is activated,
neurons. In other cases, the receptors may be located in places a person is in a rest-or-digest state in which most of the above
that are not near the neurons and are therefore activated only by processes are reversed or not activated.
the circulating epinephrine or norepinephrine. The overall effect The two divisions of the autonomic nervous system rarely
of these two catecholamines is slightly different due to the fact operate independently, and autonomic responses generally repre-
that some adrenergic receptor subtypes have a higher affinity for sent the regulated interplay of both divisions.
epinephrine (e.g., β2), whereas others have a higher affinity for
norepinephrine (e.g., α1).
Table 6.11 is a reference list of the effects of autonomic 6.19 Protective Elements Associated
nervous system activity, which will be described in later chap- with the Brain
ters. Note that the heart and many glands and smooth muscles
are innervated by both sympathetic and parasympathetic fibers; As mentioned earlier, the brain lies within the skull, and the spinal
that is, they receive dual innervation. Whatever effect one divi- cord lies within the vertebral column. How is tissue of the CNS
sion has on the effector cells, the other division usually has the protected from these surfaces, and how are cells of the CNS pro-
opposite effect. (Several exceptions to this rule are indicated in tected from potentially damaging substances in the blood?
Table 6.11.) Moreover, the two divisions are usually activated
reciprocally; that is, as the activity of one division increases, the Meninges and Cerebrospinal Fluid
activity of the other decreases. Think of this like a person driving Between the soft neural tissues and the bones that house them are
a car with one foot on the brake and the other on the accelera- three types of membranous coverings called meninges: the thick
tor. Either depressing the brake (parasympathetic) or relaxing the dura mater next to the bone, the arachnoid mater in the middle,
and the thin pia mater next to the nervous tissue (Figure 6.47).
The subarachnoid space between the arachnoid mater and pia
Locations of Receptors for Acetylcholine, mater is filled with cerebrospinal fluid (CSF). The meninges and
TABLE 6.10 Norepinephrine, and Epinephrine their specialized parts protect and support the CNS, and they cir-
culate and absorb the cerebrospinal fluid. Meningitis is an infec-
I. Receptors for acetylcholine tion of the meninges that occurs in the CSF of the subarachnoid
A. Nicotinic receptors space that can result in increased intracranial pressure, seizures,
1. On postganglionic neurons in the autonomic ganglia and loss of consciousness.
2. At neuromuscular junctions of skeletal muscle Ependymal cells make up a specialized epithelial structure
3. On some CNS neurons
called the choroid plexus, which produces CSF at a rate that com-
B. Muscarinic receptors
pletely replenishes it about three times per day. The black arrows
1. On smooth muscle
2. On cardiac muscle in Figure 6.47 show the flow of CSF. It circulates through the
3. On gland cells brain’s interconnected ventricular system to the brainstem, where
4. On some CNS neurons it passes through small openings out to the subarachnoid space
5. On some neurons of autonomic ganglia (although the great surrounding the brain and spinal cord. Aided by circulatory, respi-
majority of receptors at this site are nicotinic) ratory, and postural pressure changes, the fluid ultimately flows to
the top of the outer surface of the brain, where most of it enters the
II. Receptors for norepinephrine and epinephrine bloodstream through one-way valves in large veins. CSF can pro-
A. On smooth muscle vide important diagnostic information for diseases of the nervous
B. On cardiac muscle system, including meningitis. CSF samples are generally obtained
C. On gland cells
by inserting a large needle into the spinal canal below the level
D. On other tissue cells (e.g., adipose, bone, renal tubules)
of the second lumbar vertebra, where the spinal cord ends (see
E. On some CNS neurons
Figure 6.42).
Neuronal Signaling and the Structure of the Nervous System 181
 TABLE 6.11 Some Effects of Autonomic Nervous System Activity
Sympathetic Nervous System Effect Parasympathetic Nervous System Effect
Effector Organ and Receptor Types* (All M-ACh Receptors)
Eyes
Iris muscle Contracts radial muscle (widens pupil), α1 Contracts sphincter muscle (makes pupil smaller)
Ciliary muscle Relaxes (flattens lens for far vision), β2 Contracts (allows lens to become more convex for near vision)
Heart
SA node Increases heart rate, β1 Decreases heart rate
Atria Increases contractility, β1, β2 Decreases contractility
AV node Increases conduction velocity, β1, β2 Decreases conduction velocity
Ventricles Increases contractility, β1, β2 Decreases contractility slightly
Arterioles
Coronary Constricts, α1, α2 —†
Dilates, β2
Skin Constricts, α1, α2 —
Skeletal muscle Constricts, α1 —
Dilates, β2
Abdominal viscera Constricts, α1 —
Kidneys Constricts, α1 —
Salivary glands Constricts, α1, α2 Dilates
Veins Constricts, α1, α2 —
Dilates, β2
Lungs
Bronchial muscle Relaxes, β2 Contracts
Salivary glands Stimulates secretion, α1 Stimulates watery secretion
Stimulates enzyme secretion, β1
Stomach
Motility, tone Decreases, α1, α2, β2 Increases
Sphincters Contracts, α1 Relaxes
Secretion Inhibits (?) Stimulates
Intestine
Motility Decreases, α1, α2, β1, β2 Increases
Sphincters Contracts (usually), α1 Relaxes (usually)
Secretion Inhibits, xα2 Stimulates
Gallbladder Relaxes, β2 Contracts
Liver Glycogenolysis and gluconeogenesis, α1, β2 —
Pancreas Inhibits secretion, α Stimulates secretion
Exocrine glands Inhibits secretion, α2 —
Endocrine glands Stimulates secretion, β2
Adipose cells Increases fat breakdown, α2, β3 —
Kidneys Increases renin secretion, β1 —
Urinary bladder
Bladder wall Relaxes, β2 Contracts
Sphincter Contracts, α1 Relaxes
Uterus Contracts in pregnancy, α1 Variable
Relaxes, β2
Reproductive tract (male) Ejaculation, α1 Erection
Skin
 Muscles causing hair Contracts, α1 —
erection —
Sweat glands Secretion from hands, feet, and armpits, α1 —
Generalized abundant, dilute secretion, M-AChR
Lacrimal glands Minor secretion, α1 Major secretion
 Nasopharyngeal glands — Secretion
*Note that many effector organs contain both alpha-adrenergic and beta-adrenergic receptors. Activation of these receptors may produce either the same or opposing effects. For simplicity, except for the arterioles and a few
other cases, only the dominant sympathetic effect is given when the two receptors oppose each other.
†
A dash means these cells are not innervated by this branch of the autonomic nervous system or that these nerves do not have a significant physiological function.
Source: Brunton, Laurence L., Lazo, John S., Parker, Keith L. Parker, eds., Goodman and Gilman’s The Pharmacological Basis of Therapeutics,11th ed., New York, NY: The McGraw-Hill Companies, Inc., 2006.

182 Chapter 6
 Scalp
Skull bone
Dura mater
Venous blood
Arachnoid mater

Subarachnoid
space of brain
Subarachnoid
Pia mater
space of brain
Brain (cerebrum)
Venous
blood
Cerebrum
Vein
Cerebrospinal fluid

Pia mater
Arachnoid
mater Meninges
Dura mater

Lateral
ventricle Choroid plexus
of third ventricle

Right lateral
Cerebellum ventricle

Central canal Third ventricle

Fourth ventricle
Spinal cord
Choroid plexus of
fourth ventricle

Figure 6.47 The meningeal membranes and flow pattern of cerebrospinal fluid through the four interconnected ventricles of the brain.
The lateral ventricles form the first two. The choroid plexus forms the cerebrospinal fluid (CSF), which flows out of the ventricular system at the
brainstem (arrows).

Thus, the CNS literally floats in a cushion of cerebro- the only substrate metabolized by the brain to supply its energy
spinal fluid. Because the brain and spinal cord are soft, deli- requirements, and most of the energy from the oxidative break-
cate tissues, they are somewhat protected from sudden and down of glucose is transferred to ATP. The brain’s glycogen stores
jarring movements by this shock-absorbing fluid. If the out- are negligible, so it depends upon a continuous blood supply of
flow is obstructed, cerebrospinal fluid accumulates, causing glucose and oxygen. In fact, the most common form of brain
hydrocephalus (“water on the brain”). In severe, untreated damage is caused by a decreased blood supply to a region of the
cases, the resulting elevation of pressure in the ventricles causes brain. When neurons in the region are without a blood supply and
compression of the brain’s blood vessels, which may lead to deprived of glucose and oxygen for even a few minutes, they cease
inadequate blood flow to the neurons, neuronal damage, and to function and die. This neuronal death, when it results from vas-
cognitive dysfunction. cular disease, is called a stroke.
Although evidence exists that CSF may have some nutri- Although the adult brain makes up only 2% of the body
tive functions for the brain, the brain—like all tissues—receives weight, it receives 12% to 15% of the total blood supply, which
its nutrients from the blood. Under normal conditions, glucose is supports its high oxygen utilization. If the blood flow to a

Neuronal Signaling and the Structure of the Nervous System 183

region of the brain is reduced to 10% to 25% of its normal level, SECTION D SU M M A RY
energy-dependent membrane ion pumps begin to fail, mem-
brane ion gradients decrease, extracellular K+ concentration Central Nervous System: Brain
increases, and neuronal membrane potentials become abnor- I. The brain consists of the cerebrum, diencephalon, midbrain, pons,
mally depolarized. medulla oblongata, and cerebellum.
II. The cerebrum, made up of right and left cerebral hemispheres,
and the diencephalon together form the forebrain. The cerebral
The Blood–Brain Barrier cortex forms the outer shell of the cerebrum and is divided into the
The exchange of substances between blood and extracellular parietal, frontal, occipital, and temporal lobes.
III. The diencephalon contains the thalamus, epithalamus, and
fluid in the CNS is different from the more-or-less unrestricted
hypothalamus.
diffusion of nonprotein substances from blood to extracel-
IV. The limbic system is a set of deep forebrain structures associated
lular fluid in the other organs of the body. A complex group with learning and emotion; it is considered part of the cerebrum but
of blood–brain barrier mechanisms closely controls both the includes parts of the thalamus and hypothalamus.
kinds of substances that enter the extracellular fluid of the brain V. The cerebellum functions in posture, movement, and some kinds of
and the rates at which they enter. These mechanisms minimize memory.
the ability of many harmful substances to reach the neurons, but VI. The midbrain, pons, and medulla oblongata form the brainstem,
they also reduce the access of some potentially helpful therapeu- which contains the reticular formation.
tic drugs. Central Nervous System: Spinal Cord
The blood–brain barrier is formed by the cells that line the I. The spinal cord is divided into two areas: central gray matter, which
smallest blood vessels in the brain. It has anatomical structures, contains nerve cell bodies and dendrites; and white matter, which
such as tight junctions, and physiological transport systems that surrounds the gray matter and contains myelinated axons organized
handle different classes of substances in different ways. Sub- into ascending or descending tracts.
stances that dissolve readily in the lipid components of the plasma II. The axons of the afferent and efferent neurons form the spinal nerves.
membranes enter the brain quickly. Therefore, the extracellular Peripheral Nervous System
fluid of the brain and spinal cord is a product of—but chemically I. The PNS consists of 43 paired nerves—12 pairs of cranial nerves
different from—the blood. and 31 pairs of spinal nerves, as well as neurons found in the
The blood–brain barrier accounts for some drug actions, gastrointestinal tract wall. Most nerves contain the axons of both
too, as we can see from the following scenario. Morphine differs afferent and efferent neurons.
chemically from heroin only slightly: Morphine has two hydroxyl II. The efferent division of the PNS is divided into somatic and
groups, whereas heroin has two acetyl groups (—COCH3). This autonomic parts. The somatic fibers innervate skeletal muscle cells
difference renders heroin more lipid-soluble and able to cross the and release the neurotransmitter acetylcholine.
blood–brain barrier more readily than morphine. As soon as her-
Autonomic Nervous System
oin enters the brain, however, enzymes remove the acetyl groups
I. The autonomic nervous system innervates cardiac and smooth muscle,
and change it to morphine. The morphine, less soluble in lipid, is glands, gastrointestinal tract neurons, and other tissue cells. Each
then effectively trapped in the brain, where it may have prolonged autonomic pathway consists of a preganglionic neuron with its cell
effects. Other drugs that have rapid effects in the CNS because of body in the CNS and a postganglionic neuron with its cell body in an
their high lipid solubility are barbiturates, nicotine, caffeine, and autonomic ganglion outside the CNS.
alcohol. II. The autonomic nervous system is divided into sympathetic and
Many substances that do not dissolve readily in lipids, parasympathetic components. Enteric neurons within the walls
such as glucose and other important substrates of brain metab- of the GI tract are also sometimes considered as a separate
olism, nonetheless enter the brain quite rapidly, facilitated by subcategory of the autonomic system. Preganglionic neurons
membrane transport proteins in the cells that line the small- in both the sympathetic and parasympathetic divisions release
acetylcholine; the postganglionic parasympathetic neurons release
est blood vessels of the brain. Similar transport systems also
mainly acetylcholine; and the postganglionic sympathetic neurons
move substances out of the brain and into the blood, prevent-
release mainly norepinephrine.
ing the buildup of molecules that could interfere with brain III. The adrenal medulla is a hormone-secreting part of the
function. sympathetic nervous system and secretes mainly epinephrine.
A barrier is also present between the blood in the capillaries IV. Many effector organs that the autonomic nervous system innervates
of the choroid plexuses and the CSF, and CSF is thus a selective receive dual innervation from the sympathetic and parasympathetic
secretion. For example, K+ and Ca2+ concentrations are slightly divisions of the autonomic nervous system.
lower in CSF than in plasma, whereas the Na+ and Cl− concen-
trations are slightly higher. The choroid plexus vessel walls also Protective Elements Associated with the Brain
I. Inside the skull and vertebral column, the brain and spinal cord are
have limited permeability to toxic heavy metals such as lead, thus
enclosed in and protected by the meninges.
affording a degree of protection to the brain.
II. Brain tissue depends on a continuous supply of glucose and oxygen
The CSF and the extracellular fluid of the CNS are, over for metabolism.
time, in diffusion equilibrium. Thus, the restrictive, selective bar- III. The brain ventricles and the space within the meninges are filled with
rier mechanisms in the capillaries and choroid plexuses regulate cerebrospinal fluid, which is formed in the ventricles.
the extracellular environment of the neurons of the brain and IV. The blood–brain barrier closely regulates the chemical composition
­spinal cord. of the extracellular fluid of the CNS.

184 Chapter 6
 SECTION D R EV I EW QU E ST ION S gray matter pineal gland
gyrus pituitary gland
1. Make an organizational chart showing the CNS, PNS, brain, spinal hindbrain pons
cord, spinal nerves, cranial nerves, forebrain, brainstem, cerebrum, hypothalamus reticular formation
diencephalon, midbrain, pons, medulla oblongata, and cerebellum. limbic system subcortical nuclei
2. Draw a cross section of the spinal cord showing the gray and white medulla oblongata sulcus
matter, dorsal and ventral roots, dorsal root ganglion, and spinal midbrain temporal lobe
nerve. Indicate the general locations of pathways. occipital lobe thalamus
3. List two functions of the thalamus. parietal lobe white matter
4. List the functions of the hypothalamus, and discuss how they relate
to homeostatic control. 6.16 Central Nervous System: Spinal Cord
5. Make a PNS chart indicating the relationships among afferent and dorsal horns spinal nerve
efferent divisions, somatic and autonomic nervous systems, and dorsal root ganglia ventral horns
sympathetic and parasympathetic divisions. dorsal roots ventral roots
6. Contrast the somatic and autonomic divisions of the efferent
nervous system; mention at least three characteristics of each. 6.17 Peripheral Nervous System
7. Name the neurotransmitter released at each synapse or afferent division motor neurons
neuroeffector junction in the somatic and autonomic systems. autonomic nervous system somatic nervous system
8. Contrast the sympathetic and parasympathetic components of the efferent division
autonomic nervous system; mention at least four characteristics of each.
9. Explain how the adrenal medulla can affect receptors on various 6.18 Autonomic Nervous System
effector organs despite the fact that its cells have no axons. adrenal medulla postganglionic neurons
10. The chemical composition of the CNS extracellular fluid is different autonomic ganglion preganglionic neurons
from that of blood. Explain how this difference is achieved. dual innervation rest-or-digest state
enteric nervous system sympathetic division
fight-or-flight response sympathetic trunks
SECTION D K EY T ER M S
parasympathetic division
commissure pathway
6.19 Protective Elements Associated with the Brain
ganglion tract
nucleus arachnoid mater dura mater
blood–brain barrier meninges
6.15 Central Nervous System: Brain cerebrospinal fluid (CSF) pia mater
basal ganglia cerebrum choroid plexus subarachnoid space
basal nuclei corpus callosum
brainstem cranial nerves SECTION D CLI N ICA L T ER M S
cerebellum diencephalon
cerebral cortex epithalamus 6.19 Protective Elements Associated with the Brain
cerebral hemispheres forebrain hydrocephalus stroke
cerebral ventricles frontal lobe meningitis

CHAPTER 6 Clinical Case Study: A Woman Develops Pain, Visual Problems, and
Tingling in Her Legs
A 37-year-old woman visited her doc- by lumbar puncture showed the presence of an abnormally
tor because of back pain and numb- high concentration of the disease-fighting proteins called anti­
ness and tingling in her legs. Sensory bodies (see Chapter 18), which suggested excess immune sys-
tests also showed reduced ability to tem activity within her CNS. Magnetic resonance imaging (MRI)
sense light touch and to feel a pinprick was used to visualize her nervous system tissues, and several
on both legs. X-ray images showed no abnormal spots, or lesions, were noted in her mid-thoracic spinal
abnormalities of the vertebrae or her cord, in her brainstem, and near the ventricles of her brain (see
spinal canal that might obstruct or dam- Figure 19.6 for an explanation of MRI).
©Comstock Images/Getty Images age nerve pathways. She was prescribed
anti-inflammatory medications and sent Reflect and Review #1
home, and her symptoms gradually sub- ■ What critical functions are controlled by the brainstem?
sided. Three months later, she came back to the clinic because
her symptoms had returned. In addition to back pain and sensory Her condition was tentatively diagnosed as multiple sclerosis,
disturbances in her legs, however, she now also reported expe- which was confirmed when a follow-up MRI performed 4 months
riencing double vision when she looked to one side, and per- later showed an increase in the number and size of lesions in her
sistent dizziness. A sample of her cerebrospinal fluid obtained nervous system.
—Continued next page

Neuronal Signaling and the Structure of the Nervous System 185

—Continued failed action potential conduction in the motor, sensory, and visual
In the disease multiple sclerosis (MS), a loss of myelin systems. Cerebrospinal fluid analysis can reveal the presence of an
occurs at one or several places in the nervous system. Multiple abnormal immune reaction against myelin. The most definitive evi-
sclerosis ranks second only to trauma as a cause of neurological dence, however, is usually the visualization by MRI of multiple, pro-
disability arising in young and middle-aged adults. It most com- gressive, scarred (sclerotic) areas within the brain and spinal cord,
monly strikes between the ages of 20 and 50 and twice as often from which this disease derives its name (Figure 6.48).
in females as in males. It currently affects approximately 400,000 The cause of multiple sclerosis is not known, but it appears to
Americans and as many as 3 million people worldwide. Multiple result from a combination of genetic and environmental factors. It
sclerosis is an autoimmune condition in which the myelin sheaths tends to run in families and is more common among Caucasians than
surrounding axons in the CNS are attacked and destroyed by anti- in other racial groups. The involvement of environmental triggers is
bodies and cells of the immune system, leaving behind areas of suggested by occasional geographic clusters of disease outbreaks
scarring. and also by the observation that the prevalence of MS in people
of Japanese descent increases significantly when they move to the
Reflect and Review #2 United States. Among the suspects for the environmental trigger is
■ What are the functions of myelin? infection early in life with a virus, such as those that cause measles,
cold sores, chicken pox, or influenza. There is presently no cure for
The loss of insulating myelin sheaths results in increased multiple sclerosis, but anti-inflammatory agents and drugs that sup-
leak of K+ through newly exposed channels. This results in hyper- press the immune response have been proven to reduce the sever-
polarization and failure of action potential conduction of neurons ity and slow the progression of the disease.
in the brain and spinal cord. Depending upon the location of the
affected neurons, symptoms can include muscle weakness, fatigue, Clinical term: multiple sclerosis (MS)
decreased motor coordination, slurred speech, blurred or hazy
vision, bladder dysfunction, pain or other sensory disturbances, and
cognitive dysfunction. In many patients, the symptoms are mark-
edly worsened when body temperature is elevated, for example, by
exercise, a hot shower, or hot weather.
The severity and rate of progression of MS vary enormously
among individuals, ranging from isolated, episodic attacks with
complete recovery in between to steadily progressing neurological
disability. In the latter case, MS can ultimately be fatal as brainstem
centers responsible for respiratory and cardiovascular function are
destroyed. Because of the variability in presentation, diagnosing MS
can be difficult. A person having several of these symptoms on two
or more occasions separated by more than a month is a candidate Figure 6.48 MRI images of a patient with multiple sclerosis, showing
for further testing. Nerve-conduction tests can detect slowed or several lesions (white areas). ©Living Art Enterprises, LLC/Science Source

See Chapter 19 for complete, integrative case studies.

CHAPTER 6 T E ST QU E ST ION S Recall and Comprehend Answers appear in Appendix A.

These questions test your recall of important details covered in this chapter. They also help prepare you for the type of questions
encountered in standardized exams. Many additional questions of this type are available on Connect and LearnSmart.

1. Which best describes an afferent neuron? c. oligodendrocytes; formation of myelin sheaths on axons in the PNS
a. The cell body is in the CNS and the peripheral axon terminal is in the d. ependymal cells; regulation of production of cerebrospinal fluid
skin. e. astrocytes; removal of potassium ions and neurotransmitters from the
b. The cell body is in the dorsal root ganglion and the central axon brain’s extracellular fluid
terminal is in the spinal cord. 3. If the extracellular Cl− concentration is 110 mmol/L and a particular neuron
c. The cell body is in the ventral horn of the spinal cord and the axon ends maintains an intracellular Cl− concentration of 4 mmol/L, at what membrane
on skeletal muscle. potential would Cl− be closest to electrochemical equilibrium in that cell?
d. The afferent terminals are in the PNS and the axon terminal is in the a. +80 mV
dorsal root. b. +60 mV
e. All parts of the cell are within the CNS. c. 0 mV
2. Which incorrectly pairs a glial cell type with an associated function? d. −86 mV
a. astrocytes; formation of the blood–brain barrier e. −100 mV
b. microglia; performance of immune function in the CNS

186 Chapter 6
 4. Consider the following five experiments in which the concentration gradient c. Open voltage-gated K+ channels cause afterhyperpolarization.
for Na+ was varied. In which case(s) would Na+ tend to leak out of the cell if d. The sizable leak through voltage-gated K+ channels determines the
the membrane potential was experimentally held at +42 mV? value of the resting membrane potential.
e. Opening of voltage-gated Cl− channels is the main factor causing rapid
Extracellular Na+ Intracellular Na+ repolarization of the membrane at the end of an action potential.
Experiment (mmol/L) (mmol/L)
8. Two neurons, A and B, synapse onto a third neuron, C. If neurotransmitter
A 50 15 from A opens ligand-gated ion channels permeable to Na+ and K+ and
B 60 15 neurotransmitter from B opens ligand-gated Cl− channels, which of the
following statements is true?
C 70 15
a. An action potential in neuron A causes a depolarizing EPSP in
D 80 15 neuron B.
E 90 15 b. An action potential in neuron B causes a depolarizing EPSP in neuron C.
c. Simultaneous action potentials in A and B will cause hyperpolarization
a. A only d. A, B, and C of neuron C.
b. B only e. D and E d. Simultaneous action potentials in A and B will cause less
c. C only depolarization of neuron C than if only neuron A fired an action
5. Which is a true statement about the resting membrane potential in a typical potential.
neuron? e. An action potential in neuron B will bring neuron C closer to its action
a. The resting membrane potential is closer to the Na+ equilibrium potential threshold than would an action potential in neuron A.
potential than to the K+ equilibrium potential. 9. Which correctly associates a neurotransmitter with one of its
b. The Cl− permeability is higher than that for Na+ or K+. characteristics?
c. The resting membrane potential is at the equilibrium potential for K+. a. Dopamine is a catecholamine synthesized from the amino acid
d. There is no ion movement at the steady resting membrane potential. tyrosine.
e. Ion movement by the Na+/K+-ATPase pump is equal and opposite to b. Glutamate is released by most inhibitory interneurons in the spinal
the leak of ions through Na+ and K+ channels. cord.
6. If a ligand-gated ion channel equally permeable to both Na+ and K+ was c. Serotonin is an endogenous opioid associated with “runner’s high.”
briefly opened at a specific location on the membrane of a typical resting d. GABA is the neurotransmitter that mediates long-term potentiation.
neuron, what would result? e. Neuropeptides are synthesized in the axon terminals of the neurons that
a. Local currents on the inside of the membrane would flow away from release them.
that region. 10. Which of these synapses does not have acetylcholine as its primary
b. Local currents on the outside of the membrane would flow away from neurotransmitter?
that region. a. synapse of a postganglionic parasympathetic neuron onto a heart cell
c. Local currents would travel without decrement all along the cell’s length. b. synapse of a postganglionic sympathetic neuron onto a smooth muscle
d. A brief local hyperpolarization of the membrane would result. cell
e. Fluxes of Na+ and K+ would be equal, so no local currents would flow. c. synapse of a preganglionic sympathetic neuron onto a postganglionic
7. Which ion channel state correctly describes the phase of the action potential neuron
it is associated with? d. synapse of a somatic efferent neuron onto a skeletal muscle cell
a. Voltage-gated Na+ channels are inactivated in a resting neuronal e. synapse of a preganglionic sympathetic neuron onto adrenal medullary
membrane. cells
b. Open voltage-gated K+ channels cause the depolarizing upstroke of the
action potential.

CHAPTER 6 T E ST QU E ST IONS Apply, Analyze, and Evaluate Answers appear in Appendix A.

These questions, which are designed to be challenging, require you to integrate concepts covered in the chapter to draw your own
conclusions. See if you can first answer the questions without using the hints that are provided; then, if you are having difficulty, refer
back to the figures or sections indicated in the hints.

1. Neurons are treated with a drug that instantly and permanently stops the 5. Some cells are treated with a drug that blocks Cl− channels, and the
Na+/K+-ATPase pumps. Assume for this question that the pumps are not membrane potential of these cells becomes slightly depolarized (less
electrogenic. What happens to the resting membrane potential immediately negative). From these facts, predict whether the plasma membrane of these
and over time? Hint: See Figure 6.13, and think how concentration gradients cells actively transports Cl− and, if so, in what direction. Hint: Remember,
are maintained. Cl− carries a negative charge. Also, see Section 6.10.
2. Extracellular K+ concentration in a person is increased with no change in 6. If the enzyme acetylcholinesterase was blocked with a drug, what
intracellular K+ concentration. What happens to the resting potential and malfunctions would occur in the heart and skeletal muscle? Hint: See
the action potential? Hint: Recall the relationship between concentration Figure 6.46 and Table 6.11 for help.
gradients and diffusion. 7. The compound tetraethylammonium (TEA) blocks the voltage-gated changes
3. A person has received a severe blow to the head but appears to be all right. in K+ permeability that occur during an action potential. After experimental
Over the next week, however, he develops loss of appetite, thirst, and loss treatment of neurons with TEA, what changes would you expect in the
of sexual capacity but no loss in sensory or motor function. What part of action potential? In the afterhyperpolarization? Hint: Refer to Figure 6.19a
the brain do you think may have been damaged? Hint: See Table 6.7 for a and imagine the shape of the action potential without the increase in K+
review of the function of brain structures. permeability shown in Figure 6.19b.
4. A person is taking a drug that causes, among other things, dryness of the 8. A resting neuron has a membrane potential of −80 mV (determined by Na+
mouth and speeding of the heart rate but no impairment of the ability to use and K+ gradients), there are no Cl− pumps, the cell is slightly permeable to Cl−,
the skeletal muscles. What type of receptor does this drug probably block? and ECF [Cl−] is 100 mM. What is the intracellular [Cl−]? Hint: If there are no
Hint: Table 6.11 will help you answer this. pumps for an ion, how would that ion distribute itself across a membrane?
Neuronal Signaling and the Structure of the Nervous System 187
 CHAPTER 6 T E ST QU E ST ION S General Principles Assessment Answers appear in Appendix A.

These questions reinforce the key theme first introduced in Chapter 1, that general principles of physiology can be applied across all
levels of organization and across all organ systems.

1. One of the general principles of physiology introduced in Chapter 1 is: Most 3. Another general principle of physiology states: Structure is a determinant
physiological functions are controlled by multiple regulatory systems, often of—and has coevolved with—function. A common theme in humans and
working in opposition. How do the structure and function of the autonomic other organisms is elaboration of surface area of a structure to maximize
nervous system demonstrate this principle? its ability to perform some function. What structures of the human nervous
2. What general principles of physiology are demonstrated by the mechanisms system demonstrate this principle?
underlying neuronal resting membrane potentials?

CHAPTER 6 A N SWE R S TO P H YS IOLOGICAL INQUIRY QUESTIONS

Figure 6.10 NaCl and KCl ionize in solution virtually completely, so initially fast motor reflexes may help prevent injury by removing a part of the
each compartment would have a total solute concentration of approximately body (such as your hand) from danger, such as a sharp or burning object.
0.3 osmols per liter (see Chapter 4 to review the difference between If your hand did not quickly pull away from such harmful objects, much
moles and osmols). Because an insignificant number of potassium ions more severe injury would occur. Myelin also decreases the metabolic cost
actually move in establishing the equilibrium potential, the final solute of sending electrical signals along axons, thereby saving energy for other
concentrations of the compartments would not be significantly different. homeostatic processes.
Figure 6.11 Na+ and K+ would move down their concentration gradients Figure 6.28 In a typical neuron, the threshold potential is about 15 mV
in opposite directions, each canceling the charge carried by the other. more positive than the resting membrane potential, so it would take about
Thus, at equilibrium, there would be no membrane potential and both 30 simultaneous EPSPs of 0.5 mV to reach threshold.
compartments would have 0.15 M Cl−, 0.075 M Na+, and 0.075 M K+. Figure 6.30 When synaptic Cl– channels open in this case, Cl– would move out
Figure 6.12 No. Changing the ECF [K+] has a greater effect on EK (and thus of the cell and the membrane would depolarize from –70 mV toward –65 mV.
the resting membrane potential). This is because the ratio of external to This would actually be an inhibitory synapse, however, because the open Cl–
internal K+ is changed more when ECF concentration goes from 5 to 6 mM (a channels would tend to keep the membrane near –65 mV and thus prevent it
20% increase) than when ICF concentration is decreased from 150 to 149 mM from depolarizing any further toward the threshold voltage of –55 mV.
(a 0.7% decrease). You can confirm this with the Nernst equation. Inserting Figure 6.31 The greater the distance between the synapse and the axon
typical values, when [Kout] = 5 mM and [Kin] = 150 mM, the calculated value hillock (the location of the electrode), the greater the decrement of a
of EK = −90.1 mV. If you change [Kin] to 149 mM, the calculated value of graded potential. Therefore, if synapse A were closer to the axon hillock
EK = −89.9 mV, which is not very different. By comparison, changing [Kout] than synapse C, summing the two would most likely result in a small
to 6 mM causes a greater change, with the resulting EK = −85.3 mV. depolarizing potential. The farther from the hillock synapse C is, the more
Figure 6.15 K+ would exit from the cell and make the inside of the cell closely the depolarization would come to resemble the trace occurring in
more negative in the area of the channel, and thus positive current would response to synapse A firing alone.
flow toward the channel’s location on the inside of the cell and away from Figure 6.37 Information in the form of electrical signals moves in both
the channel on the outside. directions between the CNS and PNS. In this way, the CNS can be
Figure 6.19 The value of the resting potential would change very little informed of changes in the periphery, such as sensory inputs. In turn,
because the permeability of resting membranes to Na+ is very low. information flow from the CNS to the periphery can direct motor functions
However, during an action potential, the membrane voltage would rise more that provide an appropriate response to sensory inputs from the PNS. The
steeply and reach a more positive value due to the larger electrochemical coordination of sensory and motor inputs and outputs is a key way in which
gradient for Na+ entry through open voltage-gated ion channels. homeostasis is achieved and maintained in the body. A summary of many
Figure 6.23 In all of the affected neurons, action potentials will propagate of these types of coordination can be found in Figure 6.44.
in both directions from the elbow—up the arm toward the spinal cord Figure 6.46 The muscarinic receptor blocker would only inhibit
and down the arm toward the hand. Action potentials traveling upward parasympathetic pathways, where acetylcholine released from
along afferent pathways will continue through synapses into the CNS to postganglionic neurons binds to muscarinic receptors on target organs.
be perceived as pain, tingling, vibration, and other sensations of the lower This would reduce the ability to stimulate “rest-or-digest” processes and
arm. In contrast, action potentials traveling backward up motor axons will leave the sympathetic “fight-or-flight” response intact. On the other hand,
die out once they reach the cell bodies because synapses found there are a nicotinic acetylcholine receptor blocker would inhibit all autonomic
“one way” in the opposite direction. control of target organs because those receptors are found at the ganglion
Figure 6.24 Myelin increases conduction speed along an axon, which is in both parasympathetic and sympathetic pathways.
important for rapid signaling and reflexes. As just one common example,

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188 Chapter 6