-

THE PHYSICAL BASIS FUNCTION OF NEURONAL

...... . ........ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Animal 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 molecular mechanisms that alJow neurons to function so effectively in acquiring and trans­mittmg information.

127

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).

I ----

128 PHYS IOLOGICAL PROCESSES . ..•• •. • • • · ' ' . ••• . . .. •• • • 0 • • •

... .... . .. . 0

#~ Cell from coelenterate

nerve net

Dendrite

. . . . . . . . ............. . ....... . . . .

figure 5-1 The general~_ of neurons varies from simp~ to .·-""~Jr

•tr complex, but most neurons h~~~ f

'd 'fi bl · ' C-er tain 1 entt •a e regtons, 'ndiJdi

Bipolar cell trom vertebrate retina Motor neuron from

yertebrat• spinal cord

dendrites, a soma, and an ~-~ t i ce that there is little CO«elatiort bt tween phylogeny and the COrnpl~ · of neuronal st~re. Althou~ si~ animals have stmple neurons (e.g.,"'­coelenterate neuron), some lleut0f1$

in h igher animals also have a ~ 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 asso­

ciation cells}, no morphologic features

readily d istinguish the axon from the dendrites.

Soma Two different Insect neurons

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-

Association cell from 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. T yp!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).

. . . . . . . . . . . . . . . . . . . . . . . . . . THE PHYSICAL BAS IS O F NEURONAL FUNCTION .... . .. 129 • • 0 •• 0 0 •• • • • •• 0 • ••

• • • 0

• • •••• • • • 0 ••• 0 • • ••••• • ••

Dendrites

Axon hillock

Presynaptic terminals

_________ 1 _____ _

INTEGRATION

----------, ------1------SPIKE INITIATION _____________ t _____ _

IMPULSE CONDUCTION

----- ------~------

TRANSMITIER SECRETION

-----------' ------Figure S-2 A vertebrate spinal motor neuron exemplifies the function­

ally specialized regions of a typical neuron. The flow of information is in­

dicated 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. ac­

tion potentials are initiated at the spike-initiating zone, in or near the axon

hillock, and then travel along the axon to the axon terminals, 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 dif­

ferent 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 and 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.

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 are not distributed uniformly over 1hc surface of the cell. Instead, they arc 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 a llow Na+ and K • to cross the membrane. In ad­dition, the membrane of nxon terminals contains voltage­gated Ca2

+ channels and other specializations that allow neurons to transmit signals to other cells when APs invade the terminals.

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 any 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 transmitted across a synapse from a particular neuron is said to be postsynaptic to that neuron. Synaptic transmission affects the postsynaptic 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 aJtematin~ gr.tded and all-or-none electrical si~nals.

Organizat ion of the Nervous System

The nervous system is compo ed of two ha.,ic cell<; typc.'s: neurons and support ing gli<tl cell . As we h.tve seen. llctt­

rons are cia s if-ied functiona lly into tlm.'C.' rypel!:

130 PHYSIOLOGICAL PROCESSES ..•. . ... ..... . . . . . . . .. . . .

• 0 • ••• 0 •• • • 0

; , , ,

, , ,'

, , ~t•llfii'.:JI' ',,

' '

. ..

' ' ,,

. . . . . . . . . . . . . ........... .; ..... . 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.-.'· '

ff """"~ information to e ector organs. Th1s fig • uret,~

the posterior ~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~

,,' , , , Metathoracic ',,, ganglion ',

(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~ giant intemeuro~s contact th~ leg motor 1'\eu. rons at synapses 1n the thorac1c ganglia. St~m. ulation of the wind-receptor neurons <:au

, / , ,

, , , , ,

, , , ,

,''Synapse

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 con-sntute the output portion of a neuronal circuit c ·

:c. • . , arrymg 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 1 m 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' h a ram, lo-. 1 1 ' 1' extends po nor y a ong the midline of the animal M . ste-

L- br · 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 d 1 b 0 ess complex animals. The verte rare central nervo ·o . us system, for instance contains 10-tJmes more gl' 1 11 h ' . bo

1a ce s t an neurons and these cells occup~ a 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 Glial cells pr ·d . . h •

metabor ov1 e mnmate structural and per 3~ tyn.os f Jc, . support for neurons. Several ' different cdl r~ unctiOn as gl' 1 1 k

oligodendr . 13 ce Is. 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 sion of AP

1 ute~ to assuring reliable and rapid trJ" ' "11' 5 (~ Ftgure 5-2).

132 PHYSIOLOG ICAL PROCESSfS .•. · · · · · · ' ' ' ' • . ' • ... • •.. . • • • .. ' .. ' • . • . . P I dff . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ftgute ·s-6 otent•• • •~•"'"' ,.,...11\1.,._

1 aoOts eellrMmbtane5 "'• tyl"'~ltl~<l\pl,lltO and dlipl~d ut•ng one of two t'~ oil!! 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.,,

8

A

cathode

Original signal

Control of experiment

J'..-:. Original signal

Computer

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 of charged 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

Data storage

Data analysis

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~ 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~ 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.

across the cell membrane (the membrane potential, V ml 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 19 50s. 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

!

t '

•••••••••• • •• 0 •••• . . . . . . .. . . . . . . . . . . . . rnicroelectrode because the lipid bilayer of th .

d h · . c membrane .,.,Js itself aroun t e pipette tip after rv•netrat· 1 . "'""'" d . h ..-~ Jon. nsertJon of the electro e up t rough the plasma memb . ·

h II . . . rane mto the ceu brings t e ce mtenor mto electrical cont· . . h

· · InUit)' Wit the voltage-recordmg amplifier. By convention th b • e mem rane potential is always taken as the intracellular p t . 1 1 . o enna re-arive to the extracellular potential. In other wo d h . I . b. r s, t e ex-tracellular potentia IS ar ttrarily defined as zero I .

6 b . n prac-

tice the a mph er 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 5-7 A). 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

TH E PHYSICAL BASIS OF NEURONAL FUNCTION 133 • ... ... . . ... 0 0 ••• • • • • • ••••• • ••• • •• ••• • • •

is the resting potential, V,.,.,, of the cell membrane and is most conveniently expressed in millivolts (mV, or thou­sandths of a volt). This re~ting potential is the membrane potential 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 as 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

A Amplifier

Recording

---~~ Reference 0 mVI-------

electrode

B

+ saline bath

' cell mem­F~gUre 5-7 V/h .. , a m1cro<>l .. ctrode penetrates a neurons ~ - - d ff t A \ No poten-

b~. ~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 -

-80 mV L------­Time__....

Recording

OmVI---.

r....-----SOmVL-----------­

Time__....

1~=~: 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 pot en·

ual across the membrane.

134 ,.HYSIOLOGICAL PROCESSES . . . . . . . . . . . . . ~ ,. . . ~ . . . . . . ... . .. · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · . ~essandto Volta. a physicist at Pwa. lt~ly: took up~ • .,,.,

SPOTLIGHT 5 · 1 . In 1 ?92hePf~analtematN$explana'"'-· '-

THE DISCOVERY OF

"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 electricityH and 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·

tacted the nerve to that muscle; when the two rods were brought

together, the muscle contracted, as illustrated in diagram A. Galvani and his nephew Giovanni Aldini, a physicist, ascribed this

response to a di.scharge of" animal electricity" that was stored in

the muscle and delivered by the nerves. They hypothesized that

an "electrical fluidH passed from the muscle through the metal

and back into the nerve, and that the discharge of electricity from

the muscle triggered the contraction. We now understand that

this creative interpretation, which was published in 1791, is

largely incorrect. Nevertheless, this work stimulated many in­

quisitive amateur and professional scientists of the t ime to in­

vestigate two new and important areas of science: the physiol­

ogy of excitation in nerve and muscle and the chemical origin of

electricity.

A

Contracted Muscle

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 ~• .. ... . ......................

B

e~u·nents. ......,l 'Vr

I .. .-ults He wgg~ted that the electrical Sttmuh.J~ c... Ga vam s r.... · .• U\

. -~•e to contract in Galvan• s expenments was 9t:r 1ngthemu.,.,. ~

d 'de the tissue by the COntact between dtUJm1f3f rrv''-L ate outst ·- ... ,

d the aline fluids of the tissue. It took several years fcc Vo~t. an s th I I ' . . to demonstrate unequivocally e e ectro yttc ongtn of e~ectii<al

f d·15s·1milar metals, because at that time no ru,._ . . current rom . ,... .. ~ . twas --ailable that was suffioently sensitive to de•~ mstrumen ... ~

th e weak currents. Indeed. the nerve-muscle preparation frOO'I th~frog leg was probably the most sensitive indicator of 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

than can be produced by a single silver-zinc cell, and the dest9!' is still commonly used in today's batteries.

Although Galvani's original experiments did not really pro-,o

the existence of "animal electricity, H they did demonstrate tt c.•

some living tissues can respond to minute electric currents '

1840, Carlo Matteucci advanced the study of electricity in tlss..· by using the electrical activity of a contracting muscle to stirr

late a s~cond nerve-muscle preparation (diagram B). His exp<-·

iment was the first recorded demonstration that excitable t1ss

actually produces electric current. Since the 19th century, 1t h. • become evident that the production of signals in the nerve

system and in other excitable tissues depends on the electn "

properties of cell membranes.

Zinc

Electric current now between Injured and active portions

of muscle 1 stimulates nerve to muscle 2

. . . . . . . . . . . . . . . . . .. .. . . . . . . .

THE PHYSICAL BASIS OF NE URO NAL FUNCTION 135 .. ...... ......... . . . . . . . . .. . . . . . .. . • • • ••• • •• • • •• • • • • • • 0 • •••••••••• ••• ••••

signaling in neurons, both their passive and active electrical

perties must be measured. pro 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 current 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.

B

Voltage pulse

.,-,__--­_____ ...,. ~ - ..

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

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

Voltage Amplifier display

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 YSIOLOGI CA L PROCESSES •• • • •••••••••••• •• •• • • •••• •• •• • 0 • • • •• ••• •• • •• • " 0 ••• •• •• •• • •• • • • •• •• •••• • 0 0 •• 0

------------

20

I J4 I f3 I 12

0

I 11

2ms -20

potential becomes less negative (e.g., it may shift from -60 m V to -50 m V). 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 V m 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.

~ .s E CD .... :; 0 II) :I "5 .5 00

F"1$1UN 5-9 SotNr ~IJI'nl.l~~ e-10'-e only pan-.e mer--. brane '~·ether sttmull t"NrJ e IOice act~",.. re. !.p<>n".An as well 5hov"' here are"""'" ' reccrd$ 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~ 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.ing 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.