Download THE PHYSICAL BASIS FUNCTION OF NEURONAL

THE PHYSICAL BASIS
OF NEURONAL FUNCTION
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A
nimal activity depends on the precisely coordinated
~erformance of many individual cells. Perhaps the
most tmportant cells for producing this coordination are
nerve cells, called neurons, which communicate information using a combination of electrical and chemical signals.
The membranes of most neurons are electrically excitable;
that is, signals are generated in and transmitted along
them without decrement as the result of the movement of
charged particles (ions). The properties of electrical signals
allow neurons to carry information rapidly and accurately
to coordinate actions involving many parts, or even all, of
an animal's body. All of the neurons in an organism's body,
along with supporting cells called glial cells (or neuroglia),
make up the nervous system, which collects and processes
information, analyzes it, and generates coordinated output
to control complex behaviors.
Although the complete patterns of neuronal activity
that underlie behavior are understood only for some very
small and relatively simple circuits (see Chapter 11), neurons themselves are among the most thoroughly studied of
all cell types for several reasons. First, neurons transmit information electrically, which allows scientists to monitor
the activity of individual neurons by using various instruments originally developed for the physical sciences. These
measurement techniques, some of which are described in
Chapter 2, have facilitated research on neurons and enormously increased the information available about them.
Second, recordings of electrical activity in neurons have revealed that the properties of individual neurons from nearly
aU animals are very similar. In other words, the mechanisms
involved in transmitting information along and between
neurons is essentially the same whether the neurons come
from an ant or from an anteater. Finally, neurons process
information in a highly sophisticated manner; but in doing
so they rely on a surprisingly small number of physical and
chemical processes, making it possible to formulate general
principles about their function. In this chapter, we introduce the physical and mo lecular mechanisms that alJow
neurons to function so effectively in acquiring and transmittmg info rmation.
OVERVIEW OF NEURONAL STRUCTURE,
FUNCTION, AND ORGANIZATION
Neurons have evolved specialized properties that allow
them to receive information, process it, and transmit it to
other cells. These functions, which are reflected in the overall shape and size of neurons, are performed by identifiable
and anatomically distinct regions of the cell, characterized
by specializations within the membrane and in the subcellular architecture. Although neurons vary greatly in
shape and size, every neuron typically has a soma, or cell
body, which is responsible for metabolic maintenance of
the cell and from which emanate several thin processes
(Figure 5-1). There are two main types of processes:
dendrites and axons. Most neurons possess multiple dendrites and a single axon.
Dendrites generally are branched, extend from the cell
body, and serve as the receptive surface that brings signals
from other neurons toward the cell body. Information from
other neurons is usually transmitted to the dendrites and
soma of a neuron, so neurons with an extensive and complex dendritic tree typically receive many inputs. The location and branching pattern of dendrites can reveal from
where each neuron gets its information.
Axons (also called nerve fibers) are specialized processes that conduct signals away from the cell body. Although many neurons have relatively short axons, the
axons of some nerve cells extend surprisingly long distances. Axons have evolved mechanisms that allow them to
carry information for long distances with high fidelity and
without loss. In a whale, for example, the axon of a single
motor neuron (or motoneuron), which carries information
from the nervous system out to muscle fibers, may extend
many meters from the base of the spine to the muscles that
it controls in the tail fin. (Notice that bundles of axons running through the tissues of an animal's body are called
nerves.) At its termination, each axon may divide into numerous branches, allowing its signals to be sent simultaneously to many other neurons, to glands, or to muscle fiber ·
(see Figure 5-1).
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PHYS IOLOGI CAL PROCESSES . . . • • •. • • • · ' ' . •••
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complex, but most neurons h~~~ f
·
''ndiJdiC-er
tain 'd
1 entt'fi•a ble regtons,
Dendrite
dendrites, a soma, and an ~- ~
t i ce that there is little CO«el atiort bt
tween phylogeny and the COrnpl~ ·
#~
nerve net
figure 5-1 The general ~ _
of neurons varies from simp~ to
.·-""~Jr
•
Cell from coelenterate
............. . .......
of neuronal st~re. Althou~ si~
animals have stmple neurons (e.g.,"'coelenterate neuron), some lleut0f1$
in h igher animals also have a ~
Bipolar cell trom
vertebrate retina
Motor neuron from
yertebrat• spinal cord
structure (e.g ., the vertebrate retinil
bipolar cell). Higher animals also have
neurons with a very complexs~
1
(e.g ., the Purkinje cell from the l'llal'l\malian cerebellum), but so do i~~sects
and other simpler animals. In SOmt
neurons (e.g., cerebellar Purkinje Q!ll$
and vertebrate motor neurons), tile
dendrites and the axon are easily distinguished. In other neurons(e.g., retinal bipolar cells and mammalian association cells}, no morphologic features
readily d isti nguish the axon from the
dendrites.
Soma
Two different Insect neurons
Association cell from
Purklnje cell from mammalian cerebellum
During the embryonic development of each neuron,
dendrites and the axon grow out from the soma. Throughout the life of the cell, the maintenance of processes depends on the slow, but steady, flow down the processes of
proteins and other constituents that are synthesized in the
soma. If an axon in an adult organism is badly damaged or
severed, it typically degenerates within a few days or weeks.
In mammals, regeneration or regrowth of axons is limited
to nerves in the periphery of the body, whereas in coldblooded vertebrates, some regeneration also may occur
within the central nervous system (i.e., the brain and spinal
cord). Damaged neurons in some invertebrates readily regenerate and reinnervate their original targets.
Transmission of Signals in a Single Neuron
A rypical vertebrate spinal motor neuron, which has its
soma in the spinal cord and carries signals to skeletal mus-
mammalian thalamus
de fibers, displays the structural and functional features
that characterize many neurons (Figure 5-2). The surface
membrane of motor-neuron dendrites and the membrane
of the soma receive signals from, or are innervated by, the
terminals of other nerve cells. Typically, but not always, the
soma integrates (sums) messages from the many input neu·
rons to determine whether the neuron will initiate its own
response, an action potential (AP), also called a nen:e im·
pulse. The axon carries an AP from its point of origin, the
spike-initiating zone, to the axon terminals, which contact
. th·
skeletal muscle cells in the case of motor neurons. Typ!C3 ·
the spike-initiating zone is located near the axon bill~,
the junction of the axon and cell body, although 10
many neurons the spike-initiating zone lies elstwhe_re.
Many axons are surrounded by supporting cells, whtch
provide an insulating layer called the myelin sheath (se<
Chapter 6).
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Dendrites
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THE PHYSICAL BAS IS O F NE URONAL FUNCTIO N
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Presynaptic terminals
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INTEGRATION
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------1-----SPIKE
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INITIATION
Axon
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Vo ltage-gated ion channel\ allow ron~ to move across
the cdlmemhrane in response to change~ 10 the d(· trical
fie!~ ncro:.s the membrane. Neurons po~~s~ vanous types
~f '_on ch~nnc:ls, each pcrmmmg pa. age of a particular
10mc specres. The different types of ion channels found in
neurons a re not distributed uniformly over 1hc surface of
the cell. Instead, they a rc localized in different regions that
have specialized signaling functions. For example, the axonal membrane is specialized for the conduction of APs by
virtue of its fast-acting, voltage-gated ion channels that selectively allow Na+ and K • to cross the membrane. In addition, the membrane of nxon terminals contains voltagegated Ca 2 + channels and other specializations that allow
neurons to transmit signals to other cells when APs invade
the terminals.
hillock
IMPULSE
CONDUCTION
----- ------ ~ ------
TRANSMITIER
SECRETION
-----------' -----Figure S-2 A vertebrat e spinal motor neuron exemplifies the functionally specialized regions of a typical neuron. The flow of information is indicated by small black arrows. Information is received and integrated by
the membrane of the dendrites. In some neurons the soma also receives
information and contributes to integration. In spinal motor neurons. action potentials are initiated at the spike-initiating zone, in or near the axon
hillock, and then travel along th e axon to the axon term inals, where a
chemical neurotransmitter is released to carry the signal on to another
cell. In other types of neurons. the spike-initiating zone may have a different location. The axon and surrounding myelin sheath cells are shown
in longitudinal section.
The physiological behavior of a neuron depends on the
propenies of its surface membrane. All entities that can
carry electrical signals, including wires a nd cell membranes,
possess passive electrical properties such as capacitance and
resistance. Unlike wires, the membranes of neurons also
possess active electrical properties that allow these cells to
conduct electrical signals without decrement. The active
electrical re ·ponscs of neurons and other excitable cells depend on the pre~nce o f specialized proteins, known as
voltage-gated ion channels. rn the cell membrane.
Transmission of Signals between Neurons
Information processing by any nervous system begins when
sensory neurons collect information and send it to other
neurons. The axon of an information-gathering neuron is
called an afferent fiber. Sensory neurons pass information
on to other neurons, and the signal is transferred from neuron to neuron in the animal's nervous system. Interneurons
lie entirely within the central nervous system and carry information between other neurons. Information is passed
between neurons, or between neurons and other target
cells, at specialized locations called synapses. Eventually, if
the animal is to respond in a ny way to the sensory information, signals must activate neurons that control effector
organs, such as muscles or glands. Neurons that carry information out to effectors are called efferent neurons. Together the afferent neurons and efferent neurons, along
with any interneurons that participate in processing the information, make up a neuronal circuit (Figure 5-3}.
A cell that carries information toward a particular neuron is said to be presynaptic to that neuron, while a cell that
receives information tra nsmitted across a synapse from a
particular neuron is said to be postsynaptic to that neuron.
Synaptic transmission affects the postsyna ptic neuron via
mechanisms discussed in Chapter 6. Briefly, most synaptic
transmission is carried by neurotransmitters, which are specific molecules released by the axon terminals of the presynaptic neuron in response to APs in the axon. The membrane of the postsynaptic neuron's dendrites and soma, the
part of the postsynaptic cell that typically receives synaptic signals, contains ligand-gated ion channels, which bind
neurotransmitters and react to them. The postsynaptic effects of a neuron's numerous synaptic inputs are integrated
to produce a net postsynaptic potential in the dendrites,
soma, and axon hillock. As indicated in Figur(• 5-4, infor·
mation is carried in neuronal circuits via aJte matin~ gr.tded
and all-or-none electrical si~nals.
Organizat ion of t he Nervous System
The nervous system is compo ed of two ha.,ic cell<; typc.' s:
neurons and s upport ing gli<tl cell . As we h.tve seen. llcttrons are cia s if-ied functiona lly into tlm.'C.' rypel!:
PHYSIOLOGICAL PROCESSES . . • .
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FI"'Unt 5-3 In a simple neuronal circu· •
.,.
.
It, ar il
ferent neuron carnes sensory informatio.o ·
·nterneurons in the central nervous
t,_.
I
SJS'!l.and an efferent neuron carries the prn.-.'· '
""""~•
information to e ffector organs. Th1s fig
uret,~
the p osterior ~f a ~~oach illustrates
neuronal cirCUit cons1st1ng of wind-rec ~
. th
'I ·
eplcr
(afferent) neurons 1n e ta1 • g1ant int er~...
rons in the central nervous system, and ~
(efferent) neurons controlling the musctesci
the legs. The wind-receptor neurons COn
the giant intemeurons at synapses in the!oct
minal ganglion of the nervous system, and~
g iant intemeuro~s contact th~ leg motor 1'\eu.
rons at synapses 1n the thorac1c ganglia. St~m.
ulation of the wind-receptor neurons <:au
ses
the cockroach to run away from the stimulus
Leg motor
neuron (efferent)
• Sensory neurons, which transmit information collected
from external stimuli (e.g., sound, light, pressure, and
chemical signals) or respond to stimuli inside the body
(e.g., the blood oxygen level, the position of a joint, or
the orientation of the head)
• Interneurons, which connect other neurons within the
central nervous system
• Mo~r neurons, which carry signals to effector organs,
causmg contraction of muscles or secretion by gland cells
The essential function of sensory neurons is to transform
the physical energy available in a stimulus into the electrical signals used by the nervous system. Networks of intemeurons, which are the most numerous type of neuron
exchange information and perform most of the com 1 '
. tha
p9
~mputattons
t produce behavior. Motor neurons consntute
the output
portion of a neuronal circuit, carrymg
·
:c. •
.
specmc ~structlons to muscles or to other effector organs
that they mnervate. (Neurons that innervate gland cells and
other effector targets are also called "motor" ll
th gh
ce s, even
ou they do not control bodily movement.)
~eurons are grouped into clusters in almost all ph I
Typ1cally, the cell bodies of many-even most
y a.
· d · h'
-neurons
are contame Wit m the central nervous syste (CNS
though the cell bodies of some neurons a 1m d . ), al. h J
.
re ocate m the
penp ery. n most arumals, the CNS consists of b .
cated in the head, and a nerve cord wh'1 h a ram, lo. 1y a1ong the midline of the animal
' M' extends
postenor
.
Lbr
·
L~•
any mvertebr
nave a am ruu~ted in the h~d and collect'
f
ates
Ions o ncuronal
cell bodies, called ganglia, distributed along the nerve cor ;
these control local regions of the animal (Figure 5-5). Ve·tebrates also have ganglia, consisting of peripheral neuronal cell bodies, outside the CNS. In vertebrates the nent
cord, called the spinal cord, is located along the dorsal mi,.
line, whereas in many invertebrates (e.g., insects, cru
taceans, and annelids), the major nerve cord lies along t~·
ventral midline. Many neurons that have cell bodies in rh
CNS send processes into the rest of the body (the peripl:
ery) to collect sensory information or to deliver motor in·
formation to control the activity of muscles or glands.
The other main cell type in the nervous system, glia
ce~s, fills all of the space between neurons, except for a ve~
thin extracellular space (about 20 nm wide) that separate
t~e glia~ and neuronal membranes. In general, more com·
P ex anunals have a larger number of glial cells relative 10
neurons than d0 1ess complex animals. The vertebrare
central nervo
·o
.
us system, for instance contains 10tJmes more gl'1a1ce11s t h an neurons and' these cells occup~.
a bo ut half the
1
'
Th
· f
vo ume of the nervous system. ~
ratiO o glial 11
in m .
ce s to neurons is considerably small~r
ost mvenebrates
h •
Glial cells pr 1
metabor
ov e mnmate structural and per 3 ~
f Jc, .support for neurons. Several ' different cdl
ty n.os
r~ unctiOn as gl'131
k
oligodendr
.
ce1Is. In vertebrates, for examr ·
riphery Ocytes 10 the CNS and Schwann cdls in the rt'"
wrap each
·
.
.
. h h.
which contr'b
axon m an msulatmg mydtn s e.lt
1
sion of AP5 ute~ to assuring reliable and rapid trJ" ' "11'
(~ Ftgure 5-2).
·d . .
PHYSIOLOG ICAL PROCESSfS
132
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.•. · · · · · · ' ' ' ' • . ' • . . . • •.. . • • • .. '
ftgute ·s -6 Potent••I dff
• •~•"'"' ,.,...11\1.,._
1
aoOts eellrMmbtane5 "'• tyl"'~ltl~<l\pl,lltO
and dlipl~d ut•ng one of two t'~ oil!!
A
tr.al tnstNrnenU•tion. W M osc:.11ov4 ,..:,
pllfltl liOd plott IN l<'f'IPI•tude of 11<1 ~N..ari
••9"•1•n the verucal d•splecemem of • t.t.,,
of electront emrtted by a e.thod. r~ty ~~~
the pa,,.ge of time" i~ ~ 1tle ~~v'
itontalaxis. TM beam of electron& IS dc,,e.
from left to right by a time base 96ne<ao~
cathode
and it• posttion is visuahzed a~ it · wrilt\• ~
the phosphof screen. lM, the size of a~
fed into the OKilloscope is plotted on 0..
screen as a function of time. (I) A digital~
Original
signal
Data storage
8
Control of
experiment
puter " " be used to simulate the tss.ot, 11
functions of an oscilloscope with the advbn.
tage that data can be digitized and stoftd do.
rectly 15 they are record6d. An analog "9"41
sensed by electrodes placed across a etll
membrane is converted to digital information
by sampling the signal at discrete time inter.
vals that are sufficiently short to capture all the
necessary information. Once the data are
stored in the computer, they can be readily
displayed or processed a& required. Cornput.
ers also can be used to control many aspects
of an experiment, including the pattern of
stimulation to cells.
Computer
Data analysis
J'..-:.
Original
signal
Signal
amplifier
excitable tissues has a long history, which is reviewed in
Spotlight 5-1. To understand both the basis for this excitability and its consequences for how a neuron functions,
we need to be able to measure the details of the electrical
changes across the membrane as a function of time.
Measuring Membrane Potentials
Electric currents are generated in living tissues whenever
there is a net flux ofcharged particles across the membrane.
Such currents can be detected directly by using two electrodes to measure the change in electrical potential that is
caused by current flow across the ceU membrane. One sensing electrode is placed in electrical contact with the fluid
jn.sid( the cell, and the other is placed in contact with the
extracellular medium, so the two electrodes indicate the
voltage, or potential difference, between the cytosol and the
6tracellular fluid. The potential difference measured
across the cell membrane (the membrane potential, Vml is
electronically amplified and displayed on a recording in·
strument. Until recendy, recordings of membrane potentials
were typically visualized using an oscilloscope, bur re·
searchers now rely extensively on digital computers to con·
trol equipment and display data during experiments, as
well as to analyze and store data later (Figure 5-6}.
Much of what we know about how APs are generated
rests on experiments carried out by A. L. Hodgkin and
A. F. Huxley in the 1940s and 1950s. They recorded mem·
brane potentials from squid axons, which arc large enough
that a silver wire can be inserted and run longitudinall}
down the inside of this cylindrical process (Hodgkin and
Huxley, 1952). The electrical activity of neurons that are
smaller than the squid giant axon has been studied u mg
glass capillary rnicr~lectrodes, which are described 10
Chapter 2. A cell is not damaged when it is impaled b ' '1
.
T
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133
TH E PHYSICAL BASIS OF NEURONAL FUNCTION
•
rnicroelectrode because the lipid bilayer of th .
·
.
c membrane
.
.,.,Js itself aroun d t h e pipette tip after rv•netrat·
"'""'"
d . h
..-~
Jon. 1nsertJon
the
plasma
memb
.
·
of the electro e up. t rough
. .
rane mto the
II mtenor mto electrical cont· .
.h
ceubrings the ce
·
·
InUit)' Wit the
voltage-recordmg amplifier. By convention• th e mem b rane
.
potential is always taken as the.intracellular p o t enna
1re1
arive to the extracellular potential. In other wo d h
. I . b.
r s, t e extracellular potentia
.
bIS ar ttrarily defined as zero. In practice the a mph 6er su tra~ts the extracellular potential from
the intracellular potenttal to give the potential difference.
~ s.imple ar~an~ement for me~suring membrane potential JS shown m Ftgure 5-7. In thts experiment, the neuron is immersed in a physiological saline solution that is in
contact with a reference electrode. Before the tip of the
recording microe/ectrode enters the cell, the microelectrode
and the reference electrode are both in the saline solution
and are therefore at the same electrical potential; the potential difference recorded between the two electrodes is
zero (see Figure 5-7A). As the tip of the microelectrode penetrates the cell membrane and enters the cytosol, a downward shift of the voltage trace suddenly appears, indicating
that the electrode has entered the cell and is now measuring the potential difference across the cell membrane (see
Figure 5-7B). By electrophysiological convention, insidenegative potentials are shown as downward displacements
of the oscilloscope trace. T he steady inside-negative potential recorded by the electrode tip after it enters the cytosol
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is the resting potential, V,.,.,, of the cell membrane and is
most conveniently expressed in millivo lts (mV, or thousandths of a volt). This re~ting potential is the membrane
po tential measured when no activt- evcmo; or post~ynaptic
events are occurring. Virtually all cells that have been investigated have a negative resting potential with a value between - 20 mV and - 100 mV.
The potential sensed by the intracellular electrode does
not change a s the tip is advanced further into the cell, because in the steady state the interior of the cell has the same
potential everywhere. Thus, the entire potential difference
between the cell's interior and exterior is localized across
the surface membrane and in the regions immediately ad·
jacent to the inner and outer surfaces of the membrane.
This potential difference constitutes an electrical gradient
that is available as an energy source to move ions across
the membrane. The electric field, E, equals the voltage in
volts divided by the distance, d, in meters (E = Vld). Since
d, the thickness of the membrane, is approximately 5 nm
(5 X to- ~ m), the actual electric field across cell membranes is very large.
Distinguishing Passive and Active Membrane
Electrical Properties
As noted earlier, the membranes of neurons and other excitable cells display both passive and active electrical properties. To understand the basis of electrical integration and
Amplifier
A
'
Recording
---~~ Reference
0 m V I - - - - - --
electrode
+
saline
bath
-80 mV L - - - - - - Time__....
B
Recording
OmVI---.
r....----
1~=~:
-SOmVL-----------Time__....
cell mem~
- d ff
t A \ N o potenb~. ~re IS a shrft '"the recorded potential I erence. or-t
the
·I diflere:u:e IS recorded between the reference electr~de and eu
'e:.ord "9 'l'lleroe,ectrode when both are'" the sahne bath•ng ~en m'" (8) A:. soon ctS the mcoelectrode 'P penetrates the neurons me -
F~gUre 5-7 V/h.., a m 1cro<>l..ctrode penetrates
a neurons'
brane, the electrode records an abrupt shift in the negative directiOn,
which is shown as a downward deflection on the osCilloscope screen or
the computer monitor. This deflect1on corresponds to the resting poten·
ual across the membrane.
134
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,.HYSIOLOGICAL PROCESSES
~
,.
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~
· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · . ~essandto Volta. a physicist at Pwa. lt~ly: took up ~ •.,,.,
SPOTLIGHT 5 · 1
.
In 1 ?92hePf~analtematN$explana'"'-· 'e~u·nents.
......,l 'Vr
..
.-ults
He wgg~ted that the
electrical Sttmuh.J~ c...U\
Ga
vam
s
r....
·
.•
I
THE DISCOVERY OF
-~•e to contract in Galvan• s expenments was 9t:r
~
'de the tissue by the COntact between dtUJm1f3f rrv''-L
ate d outst
·- ...,
aline fluids of the tissue. It took several years fcc Vo~t.
and the s
th I
I '
. .
to demonstrate unequivocally e e ectro yttc ongtn of e~ectii<al
.
1ngthemu.,.,.
"ANIMAL ELECTRICITY"
Electrical excitability is a fundamental property of neurons and
muscles. Today we understand this phenomenon in great detail,
but electrically excitable animal tissues have been studied for
centuries. Both the study of • animal electricityHand the origin of
electrochemical theory can be traced to observations made late
in the 18th century by Luigi Galvani, a professor of anatomy at
Bologna, Italy. Working with a nerve-muscle preparation dis·
sected out of a frog leg, Galvani noticed that the muscles con·
tracted if the nerve and muscle were touched by metal rods in a
particular way. The two rods had to be made of different metals
(e.g., one of copper and the other of zinc). In Galvani's experi·
mental setup, one rod contacted the muscle and the other con·
ru,._ . .
current from d ·15s·1milar metals, because. at that time no ,...
..~
.mstrumentwas ...
--ailable that was suffioently sensitive to de•~
~
th e weak currents. Indeed. the nerve-muscle preparation frOO'I
leg was probably the most sensitive indicator of
th~frog
e~q:l(
current available at that time and for many years afterward.
In his search for a method to produce stronger electrical CIJr.
rents, Volta found that he could increase the amount of electrJ<..
ity produced electrolytically by placing metal-and-saline cells.n
series. The fruit of his labor was the so-<:alled voltaic pile, a stact<
of alternating silver and zinc plates separated by saline-soakeo
papers. This first "wet-cell " battery produced higher voltages
tacted the nerve to that muscle; when the two rods were brought
than can be produced by a single silver-zinc cell, and the dest9!'
together, the muscle contracted, as illustrated in diagram A.
Galvani and his nephew Giovanni Aldini, a physicist, ascribed this
is still commonly used in today's batteries.
Although Galvani's original experiments did not really pro-,o
response to a di.scharge of" animal electricity" that was stored in
the muscle and delivered by the nerves. They hypothesized that
the existence of " animal electricity, they did demonstrate tt c.•
H
some living tissues can respond to minute electric currents '
an "electrical fluidH passed from the muscle through the metal
1840, Carlo Matteucci advanced the study of electricity in tlss..·
and back into the nerve, and that the discharge of electricity from
by using the electrical activity of a contracting muscle to stirr
the muscle triggered the contraction. We now understand that
this creative interpretation, which was published in 1791, is
iment was the first recorded demonstration that excitable t1ss
late a s~cond nerve-muscle preparation (diagram B). His exp<-·
largely incorrect. Nevertheless, this work stimulated many in-
actually produces electric current. Since the 19th century, 1t h. •
quisitive amateur and professional scientists of the t ime to in-
become evident that the production of signals in the nerve
vestigate two new and important areas of science: the physiology of excitation in nerve and muscle and the chemical origin of
system and in other excitable tissues depends on the electn "
properties of cell membranes.
electricity.
A
B
Zinc
Electric current
now between Injured
Contracted
Muscle
and active portions
of muscle 1 stimulates
nerve to muscle 2
In Galvani's experiments W, a muscle and its nerve were contacted by
rods of two cflfferent metals, such as copper and zinc. When the two rods
were touched together. the muscle contracted. (B) Matteucci elaborated
on Galvani's experiment by connecting one muscle-nerve preparation (1)
to a second one (2). When muscle 1 was stimulated by making the dissimtlar metal rods contact each other, the electrical activity of muscle 1
stimulated the nerve to mYsde 2, causing it to contract. In this experiment, muscle 1 had to be injured at the point of contact with the nerve
from muscle 2 in Ol'der fOI' the ionic currents flowing in the fibers of mus-
0. 1 to st•mulate the ~•
.. ... . ...................... . . . . . . . . . . . . . . . . . . . . .
. . ..
.. .
135
THE PHYSICAL BASIS OF NE URO NAL FUNCTION
. . . . .. ...... ......... . . .
. .. . . . . . .. .
signaling in neurons, both their passive and active electrical
rties must be measured.
prope
I
. I
.
The passive e ectrtca properties of the cell membrane
an be measured by passing a pulse of current across
~be membrane to. produce a ~light perturbation of the
membrane potenttal. To d~ thts, two ~1icroelecrrodes are
inserted into one cell, as Illustrated m Figure 5-8. One,
he current electrode, delivers a c urrent that can be made
; 0 flow across the membrane in either the inward (bathto-cytosol) or the outward (cytosol-to-bath) direction,
depending on the polarity (direction) of the electric current delivered from t.he electrode. The other electrode, the
recording electrode, records the effect of this current
upon Vm. Note that all ~h~ current carried in solution
and across the membrane ts m the form of migrating ions.
By convention, the flow of ionic current is from a region
of relative positivity to one of relative negativity and
corresponds to the direction of cation migration. Thus,
if the electrode is made positive, this current will, by
definition, flow directly from the current electrode into
the cell and out of the cell through its membrane. Conversely, if t.he electrode is made negative, it will draw
positive charge out of the cell and cause current flow into
the ceU across the membrane; this situation is depicted in
Figure 5-8A.
Voltage
pulse
•
•
•
•••
•
••
•
•
••
•
•
•
•
•
•
0
•
• • • • • • • • • •
•••
••••
When a current pulse removes positive charge from
inside the cell through the current electrode (i.e., when the
current electrode is made more negative), the negative
interior of the cell becomes still more negative; this increase in the potential difference across the cell membrane
is called hyperpolarization. For example, the magnitude
of the intracellular potential may change from a resting
potential of - 60 mV to a new hyperpolarized potential
of -70 mV. Neuronal membranes generally respond
passively to hyperpolarization, producing no response
other than the change in potential caused by the applied
current (Figure 5-9, traces 1 and 2). As discussed in the
next section, the change in membrane potential that
accompanies the passage of an applied current is given
by Ohm's law (equation 5-1), which relates the potential
(in volts) to the magnitude of the current (in amperes)
flowing across the membrane and to the membrane's resistance (in ohms). Thus the passive electrical properties
of the membrane can be represented by conventional electrical circuit elements.
When a current pulse adds positive charge to the
interior of the cell through the current electrode, the additional positive charges will diminish the potential difference across the membrane, causing depolarization of the
membrane (Figure S-9, trace 3). That is, the intracellular
Amplifier
Voltage
display
.,-
_____
,__---
~
-
...,.
..
B
F9n $-1 1-npal•ng a cell With two microelectrodes allows the passive
eoeatQ) Pl'ocertles of the membfane to be measured. (A) Diagram of an
tl-.'ef1~1 ~to mealure pass1ve membrane properties. Current
I!"Jws"' 'Cll'OJ!t WO'Jgh the wires. bath•"9 r.altne, resistor, OJrrent elec·
"odt ir.d ce' me-b-ane To ma nt.wl constancy of the stimulattng cur..._ "'res.-~ •J ~.C to ha-...e a !ar greater rescstance that'! the other
~¢1
r "9 OtCUit The record.n9 amplfier has a very hogh
Saline bath
Glass capillary electrodes
filled with electrolyte
solution (e.g., 3M K+ acetate)
inserted through surface
membrane.
Tip diameter of electrode is about 0.5 ~tm
input resistance, preventing any appreciable current from leaving the cell
through the recording electrode. (B) Magnified view of the glass capillary
microelectrodes inserted through the membrane of the cell. The elec·
trode at the left is used to pass current into, or out of, the cell The cur·
rent changes the membrane potential. V,, as rt crosses the plnma
membrane
136
••
•
PH YSIOLO GI CA L PROCESSES
•
• • • • • • • • • • • •
••
••
•
•
••••
••
••
•
0
•
•
•
••
•••
••
•
••
•
"
0
•••
••
••
••
•
••
•
•
•
••
••
••••
•
0
0
••
0
F"1$1UN 5-9 SotNr ~IJI'nl.l~~ e-10'-e only pan-.e mer--.
brane '~·ether sttmull t"NrJ e IOice act~",.. re.
!.p<>n".An
------------
20
J4
f3
I
I
I
I
12
~
.s
E
0
CD
....
:;
0
II)
:I
"5
11
.5
00
2ms
as well 5hov"' here are"""'"' reccrd$ lrOtn
an e.(pe11ment il'l wh.eh different amo-.snb of ~!tent
are p~ into en e,crtable cell usong the e~,.
ment.al setup deptcted .n Fogure S-8. The trac~ e>l
the stomulvs currents (bottom) and the corr~
-20
potential becomes less negative (e.g., it may shift from
-60 mV to -50 mV). As the amount of applied current is
increased, the degree of depolarization will also increase.
Depolarizing a neuron causes membrane channels that are
selectively permeable to sodium ions (Na+) to begin opening. When electrically excitable cells become sufficiently depolarized to open some critical number of Na +-selective
channels, an AP is triggered (Figure 5-9, trace 4a). The
value of the membrane potential that triggers production
of an AP is called the threshold potential. The opening of
voltage-gated Na+ channels in response to depolarization,
and the resulting flow of Na + ions into the cell, is one example of membrane excitation. The opening of Na+-selective channels reduces the electrical resistance across the
membrane (or increases the conductance), which can allow
more current to flow. The mechanisms responsible for the
AP and other instances of membrane excitation are discussed in more detaiJ later in this chapter.
Role of Jon Channels
Table 5-1 summarizes the properties of some ion channels
that function in the passive and active electrical responses
of neurons. The passive change in Vm that occurs in response to hyperpolarization or depolarization does not de~nd on opening or closing of ion-selective channels.
Rather, the ionic current that produces passive electrical responses flows primarily through K +-selective channels that
are alway o~n . These resting potassium channels are
largely responsible for maintaining the resting potential,
V a r<~ the cell membrane. These channels typically are
ldl '
untformly d1 tributed over the entire membrane of ex·
Jt.tble dis.
ing changes in the membrane potentoal (top) ilfe on.
dtcated by small numerals. If the introduced current
causes the membrane potential to become fi'IOfe
negatiVe with respect to the outside of the cell. It ;~
called hyperpolarizong (ttaces 1 and 2} If the introduced curre nt causes the membrane potential to
become more positive with respect to the OU!$ode of
the cell, it is .;ailed depolarizing (tri!c~ 3 and 4). Hy.
perpolariz.i ng currents and small depolarizing currents produce passive shifts in V.., (traces 1- 3). Wrth
suffocient depolarizat100. an additional OJrreot enters
the cell. producing a sudden active electrical response, the AP (trace 4a). Note that the size of the
passive responses is more or less linearly proportional to the stimulus current, whereas in the active
response the change in membrane potential is much
larger than would be expected for a linear response.
At threshold. some stimuli will produce APs, whereas
other stimuli of the same magnitude will produce
only a passive response {trace 4b).
The active change in V m that occurs in excitable cells
depends on the opening or closing (gating) of numerous
ion-selective channels typically in response to depolarization of the membrane. The opening (or closing) of a population of ion channels controls the flow of an ionic current
that is driven from one side of the membrane to the other
by the electrochemical gradient for the ionic species permeating the channels. This gating of ion channels is the immediate cause for nearly all active electrical signals in living
tissue. The simultaneous opening of many ion channels
generates the currents that are measured across cell membranes. The voltage-gated ion channels that mediate active
electrical responses may be localized to particular areas
(e.g., the axonal membrane in neurons).
Most membrane channels allow one or a few species of
ions to pass much more readily than all other ions; that is,
they exhibit some degree of ion selectivity. The ion channels
that make cell membranes excitable are named for the ionic
species that normally moves through them. For example,
Na + is the ion that normally moves through the fast-acting,
voltage-gated sodium channels, which open in response to
membrane depolarization, but certain other ions (e.g.,
lithium ions) also can pass through these channels. In ad·
clition to voltage-gated channels, which respond to changes
in V m, other ion channels are gated when messenger molecules (e.g., neurotransmitters) bind to receptor protejns on
the cell surface. These ligand-gated channels are discussed
in Chapter 6. Still other ion channels, found in ensory rt·
ceptor cells, arc gated by specific stimulus energies uch-'
light (photoreceptors), chemicals (taste buds and (llfactor)'
neurons), or mechanical strain (mechanorecept.ors). ~
channels arc discussed in Chapter 7.