2 Neurophysiology The Generation, Transmission, and Integration of Neural Signals
Grab the Bull by the Brains Perhaps the most dramatic neuroscience demonstration in history occurred in 1964 when Yale professor José Delgado strolled into an arena in Spain to face an enraged bull trained to attack humans. Armed only with a remote control, Delgado watched the massive bull paw the earth, lower its head, and charge right at him. Just before the bull reached him, Delgado pressed a button on the remote control that caused a wire, called an electrode, in the bull's brain to deliver a tiny trickle of electricity. The bull stopped cold. When Delgado electrically stimulated another part of the bull's brain, the animal turned to the right and calmly trotted away. Repeated stimulations rendered the bull docile for several minutes (Marzullo, 2017). Other bulls responded differently to brain stimulation, depending on the brain region targeted. One animal produced a single "moo" for every button press--a hundred times in a row. Delgado also electrically stimulated electrodes in the brains of people, in an attempt
to pinpoint the cause of a neurological disorder. Depending on which part of the brain was stimulated, patients might suddenly become anxious or angry (Delgado, 1969). In this #MeToo era, probably the creepiest response elicited by one brain stimulation site was in women who suddenly became romantically interested in the man interviewing them. Yet as soon as the electrical stimulation of their brains stopped, the women returned to their usual reserved behavior. Why does a tiny bit of electrical stimulation in the brain produce such profound changes in mood and behavior? The reason is that neurons normally use electrical signals to sum up vast amounts of information. When Delgado electrically stimulated the brain, he was triggering those normal electrical signals in a very abnormal way, with sometimes startling results. To understand how even a tiny electrical charge to the brain can so dramatically affect the mind, we need to understand how electrical signaling works in the brain.
Neurophysiology is the study of the specialized life processes that allow neurons to use chemical and electrical signals to process and transmit information. In this chapter we'll study the electrical processes at work within a neuron; in Chapter 3 we'll look at the chemical signals that pass between neurons. We'll see that brain function is an alternating series of electrical signals within neurons and of chemical signals between neurons. For example, a doctor may use a small rubber mallet to strike just below your knee and watch your leg kick upward in what is known as the knee-jerk reflex. Simple as it appears, a lot happens during this test. First, sensory neurons in the muscle detect the hammer tap and send a rapid electrical signal along their axons to your spinal cord. That rapid electrical signal along the axons from knee to spinal cord is called an action potential, which is a major topic in this chapter. When the action potential reaches the axon terminals, they release a chemical, called a neurotransmitter, to stimulate spinal motor neurons.
See Video 2.1: Electrical Stimulation of the Brain
Courtesy of the Delgado estate and José Carlos Delgado
In response to the neurotransmitter, the motor neurons send
action potentials down their own axons to release yet another neu-
rotransmitter onto muscles. In response to that neurotransmitter,
the muscles contract, kicking your foot into the air. Problems in
electrical or chemical signaling in this circuit might cause the kick
to be stronger or weaker, faster or slower, than it should be.
So this "simple" behavior involves several rounds of signaling:
first electrical (along sensory neuron axons), then chemical (sen-
sory neurons to motor neurons), then electrical again (along motor
neuron axons), and finally chemical again (motor neurons to mus-
cle). This is the classic pattern of neural function: information flows
within a neuron via electrical signals (action potentials) and passes
between neurons through chemical signals (neurotransmitters).
This sequence also reflects the organization of this chapter. First
we explain how neurons produce action potentials and send them
along their axons. Then we describe how the action potential causes
Hold It Right There! Dr. José Delgado stops a bull in the
axon terminals to release neurotransmitter into the synapse. Next
middle of a charge, using the remote control in his hand.
we discuss how the neurotransmitter affects the electrical state of
the neuron on the other side of the synapse. And we conclude the
chapter by discussing how electrical probing of the brain revealed
that the brain's surface reflects a map of the body. All this will prepare us for Chapter 3,
where we will learn more details about the chemical signals between neurons.
View Animation 2.2: Brain Explorer neurophysiology The study of the life processes of neurons. ion An atom or molecule that has acquired an electrical charge by gaining or losing one or more electrons. anion A negatively charged ion, such as a protein or a chloride ion. cation A positively charged ion, such as a potassium or sodium ion. intracellular fluid Also called cytoplasm. The watery solution found within cells. extracellular fluid Also called interstitial fluid. The fluid in the spaces between cells. cell membrane The lipid bilayer that encloses a cell. microelectrode An especially small electrode used to record electrical potentials inside living cells.
2.1Electrical Signals Are the Vocabulary of the Nervous System
The first section of this chapter explains how neurons use electrical forces to process information. Reading this material should enable you to: Identify the two physical forces that make neurons more negatively charged inside than outside. Understand the changes in a neuron's membrane that produce a large electrical signal called an action potential. Explain the changes in channels and movement of ions that underlie the action potential. Understand how the action potential spreads along the length of an axon. Understand how each neuron uses these electrical signals to integrate information from other neurons.
Like all living cells, neurons are more negative on the inside than on the outside, so we say they are polarized, meaning there is a difference in electrical charge between the inside and outside of the cell. Let's consider a neuron at rest, neither perturbed by other neurons nor producing its own signals. Of the many ions (electrically charged molecules) that a neuron contains, a majority are anions ("ANN-eye-ons"; negatively charged ions), especially large protein anions that cannot exit the cell. The rest are cations ("CAT-eye-ons"; positively charged ions). (It may help you to remember that the letter t, which occurs in the word cation, is shaped a bit like a plus sign, +.) All of these ions are dissolved in the intracellular fluid inside the cell and the extracellular fluid outside the cell membrane. If we insert a fine microelectrode into the interior of a neuron and place another electrode in the extracellular fluid and take a reading (as in FIGURE 2.1), we find that the inside of the neuron is more negative than the fluid around it. Specifically, a
Outside axon ++++++++++++++++ ----------------- - -In-sid-e-a-xo-n - - - - - - - - - - ++++++++++++++++
Recording microelectrode There is zero potential difference between the two electrodes when both are in the bath...
Outside axon ++++++++++++++++ ----------------- - -In-sid-e-a-xo-n - - - - - - - - - - ++++++++++++++++
...but when the microelectrode enters the axon, it records a negative potential (the inside of the axon is more negative than the outside).
0 -30 -65 Time Microelectrode enters cell 0 -30 -65 Time
FIGURE 2.1 Measuring the Resting Potential
View Activity 2.1: Distribution of Ions resting potential The difference in electrical potential across the membrane of a nerve cell at rest. millivolt (mV) A thousandth of a volt. ion channel A pore in the cell membrane that permits the passage of certain ions through the membrane when the channel is open. potassium ion (K+) A potassium atom that carries a positive charge.
neuron at rest exhibits a characteristic resting potential (an electrical difference across the membrane) of about -50 to -80 thousandths of a volt, or millivolts (mV) (the negative sign indicates that the cell's interior is more negative than the outside). To understand how this negative membrane potential comes about, we have to consider some special properties of the cell membrane, as well as two forces that drive ions across it. The cell membrane is a double layer of fatty molecules studded with many sWorattssoonf/Bspreeecdilaovliezed proteins. One impTohretManintdt'syMpeacohfinme embrane-spanning pFrooutnediantioinss tohf BeraioinnancdhBaehnanveiolr, 4ae tube- Dragon y Media Group lMikMe 4peo_0re2.0t1h.aait allow01s/i1o0n/2s0o20f a specific type to pass through the membrane (FIGURE 2.2). As we'll see later, some types of ion channels are gated: they can open and close rapidly in response to various influences. But some ion channels stay open all the time, and the cell membrane of a neuron contains many such channels that selectively allow potassium ions (K+) to cross the
Outside cell Inside cell Outside Most sodium ions (Na+), chloride ions (Cl-), and calcium ions (Ca2+) are in the extracellular space.
These ions are exchanged through - specialized channels in the cell membrane. The large, negatively charged protein molecules stay inside the neuron.
FIGURE 2.2 The Distribution of Ions Inside and Outside a Neuron
Particles move from areas of high concentration to areas of low concentration. That is, they move down their concentration gradient.
(B) Diffusion through semipermeable membranes Cell membranes permit some substances to pass through, but not others.
FIGURE 2.3 Ionic Forces Underlying Electrical Signaling in Neurons
(C) Electrostatic forces Like charges repel each other.
Opposite charges are attracted to each other.
membrane, but not sodium ions (Na+). Because it is studded with these K+ channels,
we say that the cell membrane of a neuron exhibits selective permeability, allowing
some things to pass through, but not others. The membrane allows K+ ions, but not
Na+ ions, to enter or exit the cell fairly freely.
The resting potential of the neuron reflects a balancing act between two opposing
processes that drive K+ ions in and out of the neuron. The first of these is diffusion
(FIGURE 2.3A), which is the tendency for molecules of a substance to spread from re-
gions of high concentration to regions of low concentration. For example, when placed
in a glass of water, the molecules in a drop of ink will tend to spread from the drop out
into the rest of the water, where they are less concentrated. So we say that molecules
tend to "move down their concentration gradient" until they are evenly distributed. If
a selectively permeable membrane divides the fluid, particles that can pass through
the membrane, such as K+, will diffuse across until they are equally concentrated on
both sides. Other ions, unable to cross the membrane, will remain concentrated on
The second force at work is electrostatic pressure, which arises from the distribu-
tion of electrical charges rather than the distribution of molecules. Charged particles
exert electrical force on one another: like charges repel, and opposite charges attract
sodium ion (Na+) A sodiWumatasotonm/Btrheaetdlove (FIGURE 2.3C). Positively charged cations like K+ are thus attracted to the negatively carries a positive charge. The Mind's Machine charged interior of the cell; conversely, anions are repelled by the cell interior and so Foundations of Brain and Behavior 4e selective permeability TDhreagpornopyerMtyeodfia Grouptend to exit to the extracellular fluid.
a membrane that allows somMeMs4ueb_s0t2a.0n3c.eais to pass through, but not others.
05/6/N20o2w0 let's consider the situation across a neuron's cell membrane. Much of the energy consumed by a neuron goes into operating specialized membrane proteins called
diffusion The spontaneous spread of molecules from an area of high concentration to an area of low concentration. electrostatic pressure The propensity of charged molecules or ions to move toward areas with the opposite charge. sodium-potassium pump The energetically expensive mechanism that pushes sodium ions out of a cell,
sodium-potassium pumps that pump three Na+ ions out of the cell for every two K+ ions pumped in (FIGURE 2.4A). This action results in a buildup of K+ ions inside the cell (and reduces Na+ inside the cell), but as we explained earlier, the membrane is selectively permeable to K+ ions (but not Na+ ions). Therefore, K+ ions can leave the inte- rior, moving down their concentration gradient and causing a net buildup of negative charges inside the cell (FIGURE 2.4B). As negative charge builds up inside the cell, it begins to exert electrostatic pressure to pull positively charged K+ ions back inside. Eventually the opposing forces exerted by the K+ concentration gradient and by electrostatic
pressure reach the equilibrium potential, the electrical charge that exactly balances the
Cells contain many large, negatively charged molecules, such as proteins, that do not cross the membrane.
The sodium-potassium (Na+-K+) pump continually pushes Na+ ions out and pulls K+ ions in. This ion pump requires considerable energy.
FIGURE 2.4 The Ionic Basis of the Resting Potential
(C) Equilibrium potential Cations like Na+ push against the membrane's exterior, attracted to the negative interior. Likewise, anions coat the interior of the cell membrane, attracted to cations on the other side. Most of the cell's potential difference is due to these charges immediately surrounding the membrane.
The membrane is permeable to K+ ions, which pass back out again through channels down their concentration gradient. The departure of K+ ions leaves the inside of the cell more negative than the outside. Na+ ions cannot pass back inside.
departed to bring the membrane potential to -65 mV or so, the electrical attraction pulling K+ in is exactly balanced by the concentration gradient pushing K+ out. This is the K+ equilibrium potential,
approximately the cell's resting potential.
concentration gradient: any further movement of K+ ions into the cell (drawn by electrostatic attraction) is matched by the flow of K+ ions out of the cell (moving down their concentration gradient). This point approximates the cell's resting potential of about -65 mV (values may range between -50 and -80 mV), as FIGURE 2.4C depicts. The resting potential of a neuron provides a baseline level of polarization found in all cells. But unlike most other cells, neurons routinely undergo a brief but radical change in polarization, sending an electrical signal from one end of the neuron to the other, as we'll discuss next. A threshold amount of depolarization triggers an action potential Action potentials are very brief but large changes in neuronal polarization that arise in the initial segment of the axon, just after the axon hillock (the cone-shaped region where the axon emerges from the cell body; see Figure 1.4A), and then move rapidly down the axon. The information that a neuron sends to other cells is encoded in patterns of these action potentials, so we need to understand their properties--where they come from, how they race down the axon, and how they send information across synapses to other cells. Let's turn first to the creation of the action potential. Two concepts are central to understanding how action potentials are triggered. Hyperpolarization is an increase in membrane potential (i.e., the neuron becomes even more negative on the inside, relative to the outside). So if the neuron already has a resting potential of, say, -65 mV, hyperpolarization makes it even farther from zero, maybe -70 mV. Depolarization is the reverse, referring to a decrease in membrane potential. TWheatsdoenp/oBlraeerdizloavteion of a neuron from a resting potential of -65 mV to, say, -50 mV mTahkeeMsitnhde'siMnsaicdheinoef the neuron more like the outside. In other words, depolarization of aFnoeuundroantiobnrsionfgBsraitisn manedmBebhraavnioerp4oetential closer to zero. Dragon y Media Group MML4eet_'s02u.0s4e.aai n app0a2r/a2t1u/s2t0o20apply hyperpolarizing and depolarizing stimuli to a neuron, via electrodes. (Later we'll talk about how synapses produce similar hyperpolarizations and depolarizations.) Applying a hyperpolarizing stimulus to the membrane
View Animation 2.3: The Resting Membrane Potential equilibrium potential The point at which the movement of ions across the cell membrane is balanced, as the electrostatic pressure pulling ions in one direction is offset by the diffusion force pushing them in the opposite direction. axon hillock The cone-shaped area on the cell body from which the axon originates. hyperpolarization An increase in membrane potential (the interior of the neuron becomes even more negative). depolarization A decrease in membrane potential (the interior of the neuron becomes less negative).
FIGURE 2.5 The Effects of Hyperpolarizing and Depolarizing Stimuli on a Neuron
Time Increasing the strength of hyperpolarizing stimuli (above) leads to greater hyperpolarization of the neuron (below).
Responses Farther from the stimulating electrode, hyperpolarization occurs almost simultaneously but is diminished.
Time Increasing the strength of depolarizing stimuli leads to increasing depolarization of the neuron until the threshold is reached and an action potential is generated. Responses
Responses Very strong stimulation Responses
local potential An electrical potential that is initiated by stimulation at a specific site, is a graded response that spreads passively across the cell membrane, and decreases in strength with time and distance. Watson/Breedlove thrTehsehMolidnd 'sTMheacshtiimneulus intensity that is jusFt oaudnedqautaiotnestooftBrigragineraannd Baechtiaovniopro4teential in aDnraagxoonn.y Media Group actMioMn4pe_o0t2e.0n5t.iaail Also05c/a6l/le2d02s0pike. A rapid reversal of the membrane potential that momentarily makes the inside of a neuron positive with respect to the outside.
produces an immediate response that passively mirrors the stimulus pulse (FIGURES 2.5A and B). The greater the stimulus, the greater the response, so these changes in the neuron's potential are graded responses. If we measured the membrane response at locations farther and farther away from the stimulus location, we would see another way in which the membrane response seems passive. Like the ripples spreading from a pebble dropped in a pond, these graded local potentials across the membrane get smaller as they spread away from the point of stimulation (see Figure 2.5B bottom). Up to a point, the application of depolarizing pulses to the membrane follows the same pattern as for hyperpolarizing stimuli, producing local, graded responses. However, the situation changes suddenly if the stimulus depolarizes the axon to -40 mV or so (the exact value varies slightly among neurons). At this point, known as the threshold, a sudden and brief (0.5- to 2.0-millisecond) response--the action potential, sometimes referred to as a spike because of its shape--is provoked (FIGURE 2.5C). An action potential is a rapid reversal of the membrane potential that momentarily makes
the inside of the neuron positive with respect to the outside. Unlike the passive graded potentials that we have been discussing, the action potential is actively reproduced (or propagated) down the axon, through mechanisms that we'll discuss shortly. Applying strong stimuli to produce depolarizations that far exceed the neuron's threshold reveals another important property of action potentials: larger depolarizations do not produce larger action potentials. In other words, the size (or amplitude) of the action potential is independent of stimulus size. This characteristic is referred to as the all-or-none property of the action potential: either it fires at its full amplitude, or it doesn't fire at all. It turns out that neurons encode information by changes in the number of action potentials rather than in their amplitude. With stronger stimuli, more action potentials are produced, but the size of each action potential remains the same. A closer look at the form of the action potential shows that the return to baseline membrane potential is not simple. Many axons exhibit small potential changes immediately following the spike; these changes are called afterpotentials (see Figure 2.5C), and they are also related to the movement of ions in and out of the cell, which we take up next. Ionic mechanisms underlie the action potential What events explain the action potential? The action potential is created by the sudden movement of Na+ ions into the axon (Hodgkin and Katz, 1949). At its peak, the action potential reaches about +40 mV, approaching the equilibrium potential for Na+, when the concentration gradient pushing Na+ ions into the cell would be exactly balanced by the positive charge pushing them out. The action potential thus involves a rapid shift in membrane properties, switching suddenly from the potassium-dependent resting state to a primarily sodium-dependent active state and then swiftly returning to the resting state. This shift is accomplished through the actions of a very special kind of ion channel: the voltage-gated Na+ channel. Like other ion channels, this channel is a tubular, membrane-spanning protein, but its central Na+-selective pore is gated. The gate is ordinarily closed. But if we electrically stimulate the neuron, or if synapses affect the neuron in ways we'll describe later, then the axon may be depolarized. If the axon is depolarized enough to reach threshold levels, the channel's shape changes, opening the "gate" to allow Na+ ions through for a short while. This tiny protein molecule, the voltage-gated Na+ channel, is really a quite complicated machine. It monitors the axon's membrane potential, and at threshold the channel changes its shape to open the pore, shutting down again just a millisecond later. The channel then "remembers" that it was recently open and refuses to open again for a short time. These properties of the voltage-gated Na+ channel are responsible for the characteristics of the action potential. You might wonder whether the repeated inrush of Na+ ions would allow them to build up, affecting the cell's resting potential. In fact, relatively few Na+ ions need to enter to change the membrane potential, and the K+ ions quickly restore the resting potential. In the long run, the sodium-potassium pump enforces the concentrations of ions that maintain the resting potential. Consider what happens when a patch of axonal membrane depolarizes. As long as the depolarization is below threshold, Na+ channels remain closed. But when the depolarization reaches threshold, a few Na+ channels open at first, allowing a few ions to start entering the neuron. The positive charges of those ions depolarize the membrane even further, opening still more Na+ channels. Thus, the process accelerates until the barriers are removed and Na+ ions rush in (FIGURE 2.6). The voltage-gated Na+ channels stay open for a little less than a millisecond, and then they automatically close again. By this time, the membrane potential has shot up to about +40 mV. Positive charges inside the nerve cell start to push K+ ions out, aided by the opening of additional voltage-gated K+ channels that let lots of K+ ions rush out quickly, restoring the resting potential.
View Animation 2.4: The Action Potential all-or-none property The condition that the size (amplitude) of the action potential is independent of the size of the stimulus. afterpotential The positive or negative change in membrane potential that may follow an action potential. voltage-gated Na+ channel A Na+-selective channel that opens or closes in response to changes in the voltage of the local membrane potential. It mediates the action potential.
Suf cient depolarization 30 of the axon results in an action potential.
The membrane potential at any given time depends on how many and which channels are open.
1 Open K+ channels create the resting potential.
2 Any depolarizing force will bring the membrane potential closer to threshold.
FIGURE 2.6 Voltage-Gated Sodium Channels Produce the Action Potential
3 At threshold, voltage-gated Na+ channels open, causing a rapid change of polarity-- the action potential.
4 Na+ channels automatically close again; gated K+ channels open, repolarizing and even hyperpolarizing the cell (afterpotential).
5 All gated channels close. The cell returns to its resting potential.
reWfraatscotno/rByreeTdelmovpeorarily unresponsive orThineaMctiinvadt'esdM. achine
aFbosuonlduatteiornesfroaf cBtroairnyapnhdaBseehaviAorb4reief
period of complete insensitivity to stimuli.
Applying very strong stimuli reveals another important property of axonal membranes. As we bombard the axon with ever-stronger stimuli, an upper limit to the frequency of action potentials becomes apparent at about 1,200 spikes per second. (Many neurons have even slower maximum rates of response.) Similarly, applying pairs of stimuli that are spaced closer and closer together reveals a related phenomenon: beyond a certain point, only the first stimulus is able to elicit an action potential. The axonal membrane is said to be refractory (unresponsive) to the second stimulus. Refractoriness has two phases: During the absolute refractory phase, a brief period immediately following the production of an action potential, no amount of stimulation can induce another action potential, because the voltage-gated Na+ channels can't respond (in Figure 2.6, see the brackets above the graph, as well as step 4). The absolute phase is followed by a period of reduced sensitivity, the relative refractory phase, during which only strong stimulation can depolarize the axon to threshold to produce another action potential. The neuron is relatively refractory because K+ ions are still flowing out, so the cell is temporarily hyperpolarized after firing an action potential (see Figure 2.6, step 4). The overall duration of the refractory phase is what determines a neuron's maximal rate of firing. In general, the transmission of action potentials is limited to axons. Cell bodies and dendrites usually have few voltage-gated Na+ channels, so they do not conduct action potentials. The ion channels on the cell body and dendrites are stimulated chemically
at synapses, as we'll discuss later in this chapter. Because the axon has many such channels, an action potential that occurs at the origin of the axon regenerates itself down the length of the axon, as we discuss next.
1. What does it mean if a neuron is depolarized or hyperpolarized, and which action brings the cell closer to threshold? 2. Describe how the polarity of a neuron changes during the phases of an action potential. 3. How does the flow of ions account for that sequence of changes in electrical potential? 4. What mechanisms underlie the two phases of the refractory period? Action potentials are actively propagated along the axon Now that we've explored how voltage-gated channels underlie action potentials, we can turn to the question of how action potentials spread down the axon--another function for which voltage-gated channels are crucial. Consider an experimental setup like the one pictured in FIGURE 2.7: recording electrodes are positioned along the length of the axon, allowing us to record an action potential at various points on the axon. Recordings like this show that an action potential begun at the axon hillock spreads in a sort of chain reaction down the length of the axon. How does the action potential travel? It is important to understand that the action potential is regenerated along the length of the axon. Remember, the action potential is a spike of depolarizing electrical activity (with a peak of about +40 mV), so it strongly
FIGURE 2.7 Propagation of the Action Potential -65
Neurophysiology63 View Animation 2.5: Action Potential Propagation The farther the recording electrode is from the site of stimulation, the later the action potential reaches it. However, the size of the action potential is the same at each point along the axon.
FIGURE 2.8 Conduction along Unmyelinated versus Myelinated Axons
(A) Continuous conduction along unmyelinated axon
(B) Rapid saltatory conduction along myelinated axon
The inrush of Na+ ions depolarizes the neighboring region of axon, opening up Na+ channels there. The successive opening of neighboring Na+ channels continues down every branch of the axon.
Na+ channels open, generating an action potential. Na+
Myelin channels the depolarization down the axon interior.
Depolarization spreads within the axon very rapidly, like electricity through a wire.
The depolarized Na+ channels open, re-creating the action Na+ potential at the new node...
...and so on, hopping down the nodes in saltatory conduction.
depolarizes the next adjacent axon segment. Because this adjacent axon segment is similarly covered with voltage-gated Na+ channels, the depolarization immediately creates a new action potential, which in turn depolarizes the next patch of membrane, which generates yet another action potential, and so on all down the length of the axon (FIGURE 2.8A). An analogy is the spread of fire along a row of closely spaced match heads in a matchbook. When one match is lit, its heat is enough to ignite the next match, and so on along the row. Voltage-gated Na+ channels open when the axon is depolarized to threshold. In turn, the influx of Na+ ions--the movement of positive charges into the axon--depolarizes the adjacent segment of axonal membrane and therefore opens new gates for the movement of Na+ ions.
BOX 2.1 How Is an Axon Like a Toilet?
It might help you to remember basic facts about action potentials if you consider how much they resemble a flushing toilet. For example, if you gently push the lever on a toilet, nothing much happens. As you gradually increase the force you apply to the lever, you will eventually find the threshold--the amount of force that is just enough to trigger a flush (step 1 of the figure). Likewise, the neuron has a threshold--the amount of depolarization that is just enough to trigger an action potential at the start of an axon. Once you're past the threshold, it doesn't matter how hard you pushed the (traditional style) toilet lever; the flush will always be the same. Similarly, once the neuron is pushed past threshold, the action potential will be the same. This is the all-or-none property of action potentials (step 2). After a toilet has flushed, it takes a while (about a minute) before it can flush again (step 3). Likewise, after a neuron fires, it takes a while (about a millisecond) before it can fire again. This is the neuron's refractory period. Why do neurons have a refractory period for action potentials? As you may remember, the voltage-gated sodium channels always slam shut for a while after they've opened, no matter what the membrane potential is. Until that time is up, the sodium channels won't open again. If the situation is urgent, we can flush our toilet about 60 times per hour or fire our neurons about 1,000 times per second. (If things are really urgent, we might do both.)
1 A toilet ush is similar to an action potential.
2 All-or-none property Pushing the toilet lever harder does not produce
To view the animation The Action Potential,
neuron past threshold 3e.mindsmachine.com/av3.4 does not increase the size
3 Refractory phase Until the tank is full, the toilet will not ush again. Until the Na+ channels recover, the neuron cannot produce another action potential.
4 Direction Like water in a properly operating toilet, an action potential always travels in one direction only.
Also notice that when a properly working toilet flushes, the water always goes in the same direction (no one wants a toilet that sometimes flushes backward!) (step 4). Likewise, the neuron's action potential goes in only one direction down the axon, from the end attached to the cell body to the axon terminals. Of course, neurons are different from toilets in many ways. The outflow of a toilet goes only to the single sewer line leaving a house, but an action potential may flow down many axon branches, to
communicate with hundreds of other neurons. Voltage-gated sodium channels on the axon branches ensure that the action potential is just as large in each branch, so it's not diminished by spreading out among branches. A toilet has only one lever, but each neuron has hundreds or thousands of synapses, and by producing different sorts of local, graded potentials, some synapses make the neuron more likely to reach threshold, while others make it less likely.
The axon normally conducts action potentials in only one direction--from the
axon hillock toward the axon terminals--because, as it progresses along the axon, the
action potential leaves in its wake a stretch of refractory membrane (see Figure 2.8A).
The action potential does not spread back over the axon hillock and the cell body and
dendrites, because the membranes there have too few voltage-gated Na+ channels to
Many of the characteristics of action potentFioaulsndhaatvioensboefeBnrawinhainmdsBicehaallvyiolrik4eened to
the action of a toilet, as BOX 2.1 explores.
If we record the speed of action potentials aMloMn4ge_aBxooxn_s02t.h01a.taidiffer 0in1/d13ia/m202e0ter, we
see that conduction velocity varies with the diameter of the axon. Larger axons allow
the depolarization to spread faster through the interior. In mammals, the conduction
velocity in large fibers may be as fast as 150 meters per second. (We will discuss axon
conduction velocity The speed at which an action potential is propagated along the length of an axon.
myelin The fatty insulation around an axon, formed by glial cells. The myelin sheath boosts the speed at which action potentials are conducted. node of Ranvier A gap between successive segments of the myelin sheath where the axon membrane is exposed. saltatory conduction The form of conduction that is characteristic of myelinated axons, in which the action potential jumps from one node of Ranvier to the next. multiple sclerosis (MS) Literally "many scars." A disorder characterized by the widespread degeneration of myelin.
diameter and conduction velocity again in Chapter 5.) Although not as fast as the speed of light (as was once believed), neural conduction can nevertheless be very fast: over 300 miles per hour. This relatively high rate of conduction ensures rapid sensory and motor processing. The fastest conduction velocities require more than just large axons. Myelin sheathing also greatly speeds conduction. As we described in Chapter 1, the myelin sheath is provided by glial cells. This sheath surrounding the axon is interrupted by nodes of Ranvier, small gaps spaced about every millimeter along the axon (see Figure 1.5A). Because the myelin insulation resists the flow of ions across the membrane, the action potential "jumps" from node to node. This process is called saltatory conduction (from the Latin saltare, "to jump") (FIGURE 2.8B). The evolution of rapid saltatory conduction in vertebrates has given them a major behavioral advantage over the invertebrates, whose axons are unmyelinated and thus slower in conduction. Multiple sclerosis (MS) is a disease in which myelin is compromised, with highly variable effects on brain function, as described in Signs & Symptoms next.
SIGNS & SYMPTOMS Multiple Sclerosis Most cases of multiple sclerosis (MS) are due to the body's immune system generating antibodies that attack one or more molecules in myelin. If the myelin is damaged enough, then saltatory conduction of axon potentials is disrupted, throwing off the brain's timing in coordinating behavior and interpreting sensory input (FIGURE 2.9). MS can present with a bewildering variety of motor and/ or sensory symptoms, depending on where, exactly, myelin damage occurs. For many people, the first symptoms they notice are blurred vision or poor color perception. For others, the first symptoms are unexpected tingling sensations, or a difficulty coordinating their walking, with the feeling of stiff legs. Eventually, almost all MS patients experience fatigue. The various symptoms wax and wane for reasons no one understands. While MS symptoms generally worsen over time, the rate of change varies a great deal across patients, making it impossible to predict how the disease might progress. There is currently no cure for MS, but there are medicines to manage the
Signal from brain is blocked because of damaged myelin.
FIGURE 2.9 MS Impairs Axonal Conduction
symptoms, mostly by interfering with the immune system to curtail myelin damage. It's also important to get physical therapy to learn how to maintain normal activity despite the symptoms. Smoking increases the risk of MS. It is also more common in women than in men. Symptoms tend
to be reduced during pregnancy when estrogen levels are high (Voskuhl and Momtazee, 2017), so there is growing interest in whether hormones might offer an effective treatment.
1. How is the action potential propagated along the axon? 2. What factor causes saltatory conduction, and why does it speed propagation of the action potential? 3. Why do action potentials move only away from the cell body? 4. What is the underlying cause of multiple sclerosis, and what are some symptoms of the disease? Synapses cause local changes in the postsynaptic membrane potential At the beginning of the chapter, we told you that when the action potential reaches the end of an axon, it causes the axon to release a chemical, called a neurotransmitter (or transmitter), into the synapse. We will discuss the many different types of transmitters in detail in Chapter 4. For now, what you need to know is that when an axon releases neurotransmitter molecules into a synapse, they briefly alter the membrane potential of the other cell. Because information is moving from the axon to the target cell on the other side of the synapse, we say the axon is from the presynaptic cell, and the target neuron on the other side of the synapse is the postsynaptic cell. The brief changes in the membrane potential of the postsynaptic cell in response to neurotransmitter are called, naturally enough, postsynaptic potentials. A given neuron, receiving synapses from many other cells, is subject to hundreds or thousands of postsynaptic potentials. When added together, this massive array of local potentials determines whether the axon hillock's membrane potential will reach threshold and therefore trigger an action potential. The nervous system employs electrical synapses too (see A STEP FURTHER 2.1, on the website), but the vast majority of synapses use neurotransmitters to produce postsynaptic potentials. We can study postsynaptic potentials with a setup like that shown in FIGURE 2.10. This setup allows us to compare the effects of activity of excitatory versus inhibitory
In this schematic model, when an excitatory presynaptic neuron (dashed) res, it shows a normal action potential and causes depolarization (EPSP) in the postsynaptic neuron (solid). + -
40 Presynaptic neuron 0 EPSP -65 Postsynaptic neuron 0 12345 Time (ms) 40 Presynaptic neuron
neurotransmitter Also called simply transmitter, synaptic transmitter, or chemical transmitter. The chemical released from the presynaptic axon terminal that serves as the basis of communication between neurons. presynaptic Located on the "transmitting" side of a synapse. postsynaptic Referring to the region of a synapse that receives and responds to neurotransmitter. postsynaptic potential A local potential that is initiated by stimulation at a synapse, can vary in amplitude, and spreads passively across the cell membrane, decreasing in strength with time and distance.
FIGURE 2.10 Recording Postsynaptic Potentials
When an inhibitory presynaptic neuron (dotted) res, it also shows a normal action potential, but it causes hyperpolarization (IPSP) in the postsynaptic neuron (solid).
-65 IPSP Postsynaptic neuron 01234 5 Time (ms)
68CHAPTER2 excitatory postsynaptic potential (EPSP) A depolarizing potential in a neuron that is normally caused by synaptic excitation. EPSPs increase the probability that the postsynaptic neuron will fire an action potential. inhibitory postsynaptic potential (IPSP) A hyperpolarizing potential in a neuron. IPSPs decrease the probability that the postsynaptic neuron will fire an action potential. chloride ion (Cl-) A chlorine atom that carries a negative charge. View Animation 2.6: Spatial Summation
synapses on the local membrane potential of a postsynaptic cell. The responses of the presynaptic and postsynaptic cells are shown on similar graphs in Figure 2.10 for easy comparison of their timing. It is important to remember that excitatory and inhibitory neurons get their names from their actions on postsynaptic neurons, not from their effects on behavior. Stimulation of the excitatory presynaptic neuron (red in Figure 2.10) causes it to produce an all-or-none action potential that spreads to the end of the axon, releasing transmitter. After a brief delay, the postsynaptic cell (yellow) displays a small local depolarization, as Na+ channels open to let the positive ions in. This postsynaptic membrane depolarization is known as an excitatory postsynaptic potential (EPSP) because it pushes the postsynaptic cell a little closer to the threshold for an action potential. The action potential of the inhibitory presynaptic neuron (blue in Figure 2.10) looks exactly like that of the excitatory presynaptic neuron; all neurons use the same kind of action potential. But the effect on the postsynaptic side is quite different. When the inhibitory presynaptic neuron is activated, the postsynaptic membrane potential becomes even more negative, or hyperpolarized. This hyperpolarization moves the cell membrane potential away from threshold--it decreases the probability that the neuron will fire an action potential--so it is called an inhibitory postsynaptic potential (IPSP). Usually IPSPs result from the opening of channels that permit chloride ions (Cl-) to enter the cell. Because Cl- ions are much more concentrated outside the cell than inside (see Figure 2.2), they rush into the cell, making its membrane potential more negative. What determines whether a synapse excites or inhibits the postsynaptic cell? One factor is the particular neurotransmitter released by the presynaptic cell. Some transmitters typically generate an EPSP in the postsynaptic cells; others typically generate an IPSP. Sometimes the same neurotransmitter can be excitatory at one synapse and inhibitory at another, depending on what sort of receptor the postsynaptic cell possesses. So in the end, whether a neuron fires an action potential at any given moment is decided by the balance between the number of excitatory and the number of inhibitory signals that it is receiving, and it receives many signals of both types at all times. Now that you know more about the parts of neurons and how they communicate, we summarize the differences between axons (which send information via action potentials) and dendrites (which receive information from synapses) in TABLE 2.1. Spatial summation and temporal summation integrate synaptic inputs Synaptic transmission is an impressive process, but complex behavior requires more than the simple arrival of signals across synapses. Neurons must also be able to integrate the messages they receive. In other words, they perform information processing-- by using a sort of neural algebra, in which each nerve cell adds and subtracts the many inputs it receives from other neurons. As we'll see next, this is possible because of the characteristics of synaptic inputs, the way in which the neuron integrates the postsynaptic potentials, and the trigger mechanism that determines whether a neuron will fire an action potential.
TABLE 2.1 Comparing Axons and Dendrites
Voltage changes All-or-none Graded, variable
We've seen that postsynaptic potentials are caused by transmitter chemicals that can be either depolarizing (excitatory) or hyperpolarizing (inhibitory). From their points of origin on the dendrites and cell body, these graded EPSPs and IPSPs spread passively over the postsynaptic neuron, decreasing in strength over time and distance. Whether the postsynaptic neuron will fire depends on whether a depolarization exceeding threshold reaches the axon hillock, triggering an action potential. If many EPSPs are received, the axon may reach threshold and fire. But if both EPSPs and IPSPs arrive at the axon hillock, they partially cancel each other. Thus, the net effect is the difference between the two: the neuron subtracts the IPSPs from the EPSPs. Simple arithmetic, right? Well, yes, summed EPSPs and IPSPs do tend to cancel each other out. But because postsynaptic potentials spread passively and dissipate as they cross the cell membrane, the resulting sum is also influenced by distance. For example, EPSPs from synapses close to the axon hillock will produce a larger effect there than will EPSPs from farther away. The summation of potentials originating from different physical locations across the cell body is called spatial summation. Only if the overall sum of all the potentials--both EPSPs and IPSPs--is sufficient to depolarize the cell to threshold at the axon hillock is an action potential triggered (FIGURE 2.11A). Usually it takes excitatory messages from many presynaptic neurons to cause a postsynaptic neuron to fire an action potential. Postsynaptic effects that are not absolutely simultaneous can also be summed, because the postsynaptic potentials last a few milliseconds before fading away. The closer they are in time, the greater is the overlap and the more complete is the summation, which in this case is called temporal summation. Temporal summation is easily understood if you imagine a neuron with only one input. If EPSPs arrive one right after the other, they sum, and the postsynaptic cell eventually reaches threshold and produces an action potential (FIGURE 2.11B). But these graded potentials fade quickly, so if too much time passes between successive EPSPs, they will never sum and no action potentials will be triggered.
spatial summation The summation of postsynaptic potentials that reach the axon hillock from different locations across the cell body. If this summation reaches threshold, an action potential is triggered. temporal summation The summation of postsynaptic potentials that reach the axon hillock at different times. The closer in time the potentials occur, the greater the summation.
If three EPSPs arrive at three different parts of the dendrite, that may be enough to push the postsynaptic cell to threshold, triggering an action potential. Any IPSPs that might arrive (not shown) would counteract the EPSPs.
FIGURE 2.11 Spatial versus Temporal Summation
Even a single synapse may push the postsynaptic cell to threshold if many action potentials arrive in quick succession, providing overlapping EPSPs.
TABLE 2.2 Characteristics of Electrical Signals of Nerve Cells
Excitatory postsynaptic potential (EPSP) Inhibitory postsynaptic potential (IPSP)
Transmission between neurons Transmission between neurons
Depolarizing, from less than 1 to more than 20 mV Hyperpolarizing, from less than 1 to about 15 mV
Mode of propagation Actively propagated, regenerative Local, passive spread Local, passive spread
Ion channel opening First Na+, then K+, in different channels Na+, K+ Cl-, K+
Channel sensitive to: Voltage (depolarization) Chemical (neurotransmitter) Chemical (neurotransmitter)
TABLE 2.2 summarizes the many properties of action potentials, EPSPs, and IPSPs, noting the similarities and differences among the three kinds of neural potentials.
It should now be clear that although action potentials are all-or-none phenomena, the postsynaptic effect they produce is graded in size and determined by the processing of many inputs occurring close together in time. The membrane potential at the axon hillock thus reflects the moment-to-moment integration of all the neuron's inputs, which the axon hillock encodes into action potentials. Dendrites add to the story of neuronal integration. A vast number of synaptic inputs, arrayed across the dendrites and cell body, can induce postsynaptic potentials. So dendrites expand the receptive surface of the neuron and increase the amount of input the neuron can handle. All other things being equal, the farther out on a dendrite a potential occurs, the less effect it should have at the axon, because the potential decreases in size as it passively spreads. When the potential arises at a dendritic spine (see Figure 1.4), its effect is even smaller because it has to spread down the shaft of the spine. Thus, information arriving at various parts of the neuron is weighted, in terms of the distance to the axon hillock and the path resistance along the way.
View Animation 2.7: Synaptic Transmission
1. What are EPSPs and IPSPs? 2. Compare and contrast spatial summation versus temporal summation. 3. Discuss the electrical properties of a neuron that allow it to process information. 4. Where does information enter a neuron, and how does a neuron send information to other cells?
2.2Synaptic Transmission Requires a Sequence of Events
This portion of the chapter explains how neurons release chemicals to signal one another. After reading this material, you should be able to: Identify the sequence of steps that take place when one neuron releases a chemical signal to affect another. Understand how a variety of chemical signals enables a diversity of neuronal responses to other neurons. Identify the interactions between neurons and muscles that underlie a simple reflex.
1 The action potential is propagated over the presynaptic membrane.
2 Depolarization of the presynaptic terminal leads to in ux of Ca2+.
3 Ca2+ promotes exocytosis, the fusion of vesicles with the presynaptic membrane, which releases transmitter into the cleft.
4 The binding of transmitter to receptor molecules in the postsynaptic membrane opens channels, permitting ion ow and initiating an excitatory or inhibitory postsynaptic potential.
5 Excitatory or inhibitory postsynaptic potentials spread passively over dendrites and the cell body to the axon hillock.
Enzymes and precursors for synthesis of transmitter and vesicle wall are continually transported to the axon terminals.
66aa. Enzyme present in the extracellular space breaks down excess transmitter.
6b Reuptake of transmitter slows synaptic action and recycles transmitter for subsequent transmission.
7 Transmitter binds to autoreceptors in the presynaptic membrane informing the presynaptic cell about transmitter levels.
The steps that take place during chemical synaptic transmission are summarized in FIGURE 2.12: 1. The action potential arrives at the presynaptic axon terminal. 2. Voltage-gated calcium channels in the membrane of the axon terminal open, allowing calcium ions (Ca2+) to enter. W3.atCsoan2/+Bcraeeudsleosvesynaptic vesicles filled with neurotransmitter to fuse with the ThepMreinsdy'ns aMpatcihcinmeembrane and rupture, releasing the transmitter molecules into Foundations of Brain and Behavior 4e Dragthone syyMnaepditaicGcrloeufpt. M4.MT4rea_n02s.m12i.attier mo0le1/cu13l/e2s0b2i0nd to special receptor molecules in the postsynaptic membrane, leading--directly or indirectly--to the opening of ion channels in the postsynaptic membrane. The resulting flow of ions creates a local EPSP or IPSP in the postsynaptic neuron.
FIGURE 2.12 Steps in Transmission at a Chemical Synapse
5. The IPSPs and EPSPs in the postsynaptic cell spread toward the axon hillock.
(If the sum of all the EPSPs and IPSPs ultimately depolarizes the axon hillock
enough to reach threshold, an action potential will arise.)
structure that contains molecules of neurotransmitter.
6. Synaptic transmission is rapidly stopped, so the message is brief and accurately reflects the activity of the presynaptic cell.
synaptic cleft The space between the presynaptic and postsynaptic cells at a synapse. This gap measures about 20-40
7. Synaptic transmitter may also activate presynaptic receptors, resulting in a decrease in transmitter release.
nanometers. calcium ion (Ca2+) A calcium atom that
Let's look at these seven steps in a little more detail.
Action potentials cause the release of transmitter molecules
tween the arrival of an action potential at the axon terminal and the creation of a postsynaptic potential. ligand A substance that binds to receptor molecules, such as a neurotransmitter or drug that binds to postsynaptic receptors.
When an action potential reaches a presynaptic terminal, it causes hundreds of synap- tic vesicles near the presynaptic membrane to fuse with the membrane and discharge their contents--molecules of neurotransmitter--into the synaptic cleft (the space be- tween the presynaptic and postsynaptic membranes). The key event in this process is an influx of calcium ions (Ca2+), rather than K+ or Na+, into the axon terminal. These ions enter through voltage-gated Ca2+ channels opening in response to the arrival of
an action potential. Synaptic delay is the time needed for Ca2+ to enter the terminal,
for the vesicles to fuse with the membrane, for the transmitter to diffuse across the
parasympathetic postganglionic neurons, by motor neurons, and by many neurons in the brain. neurotransmitter receptor Also called simply receptor. A specialized protein, embedded in the cell membrane, that selectively senses and reacts to molecules
synaptic cleft, and for transmitter molecules to interact with their receptors before the postsynaptic cell responds. The presynaptic terminal normally produces and stores enough transmitter to ensure that it is ready for activity. Intense activity of the neuron reduces the number of available vesicles, but soon more vesicles are produced to replace those that were discharged. Neurons differ in their ability to keep pace with a rapid rate of incoming
action potentials. Furthermore, the rate of making the transmitter is regulated by en-
zymes that are manufactured in the neuronal
cell body and transported down the axons to
When ACh molecules occupy both binding sites, the sodium channel opens...
Receptor molecules recognize transmitters The action of a key in a lock is a good analogy for the action of a transmitter on a receptor protein. Just as a particular key can open a door, a mol-
ecule of the correct shape, called a ligand (see
Chapter 3), can fit into a receptor protein and
activate or block it. So, for example, at synapses
where the transmitter is acetylcholine (ACh),
the ACh fits into areas called ligand-binding sites
in neurotransmitter receptor molecules located
...allowing sodium ions to enter the cell. This results in a local depolarization.
in the postsynaptic membrane (FIGURE 2.13). The nature of the postsynaptic receptors at a synapse determines the action of the trans-
mitter (see Chapter 3). For example, ACh can
function as either an inhibitory or an excitatory
The binding sites normally bind ACh molecules, but they also bind nicotine and other drugs.
neurotransmitter, at different synapses. At ex- citatory synapses, binding of ACh to one type of receptor opens channels for Na+ and K+ ions. At inhibitory synapses, ACh may act on anoth- er type of receptor to open channels that allow Cl- ions to enter, thereby hyperpolarizing the
membrane (i.e., making it more negative and so
FIGURE 2.13 A Nicotinic Acetylcholine Receptor
less likely to create an action potential).
The lock-and-key analogy is strengthened by the observation that various chemicals can fit onto receptor proteins and block the entrance of the key. Some of the preparations used in this research sound like the ingredients for a witches' brew. As an example, consider some potent poisons that block ACh receptors: curare and bungarotoxin. Curare is an arrowhead poison used by native South Americans. Extracted from a plant, it greatly increases the efficiency of hunting: if the hunter hits any part of the prey, the arrow's poison soon blocks ACh receptors on muscles, paralyzing the animal. Bungarotoxin, another blocker of ACh receptors, is found in the venom of the manybanded krait (Bungarus multicinctus), a snake native to China and Southeast Asia. The chemical nicotine, found in tobacco products, mimics the action of ACh at some synapses, increasing alertness and heart rate. Molecules such as nicotine that act like transmitters at a receptor are called agonists (from the Greek agon, "contest" or "struggle") of that transmitter. Conversely, molecules that interfere with or prevent the action of a transmitter, like curare, are called antagonists. Just as there are master keys that fit many different locks, there are submaster keys that fit a certain group of locks, as well as keys that each fit only a single lock. Similarly, each chemical transmitter binds to several different receptor molecules. ACh acts on at least four subtypes of cholinergic receptors. Nicotinic cholinergic receptors--yes, the subtype on which nicotine exerts its effects--are found at synapses on muscles and in autonomic ganglia; it is the blockade of these receptors that causes paralysis brought on by curare and bungarotoxin. Most nicotinic sites are excitatory, but there are also inhibitory nicotinic synapses. The many "flavors" of receptors for each transmitter have evolved to enable a variety of actions in the nervous system. The nicotinic ACh receptor resembles a lopsided dumbbell with a tube running down its central axis (see Figure 2.13). The handle of the dumbbell spans the cell membrane, with two sites on the outside that fit ACh molecules (Karlin, 2002). For the channel to open, both of the ACh-binding sites must be occupied. Receptors for some of the synaptic transmitter molecules that we will consider in later chapters, such as gamma-aminobutyric acid (GABA), glycine, and glutamate, are similar. In Chapter 3, we'll learn about another common type of neurotransmitter receptor that alters the internal chemistry of the postsynaptic cell to either open separate ion channels or trigger longer-lasting changes (see Figure 3.2). The coordination of different transmitter systems of the brain is incredibly complex. Each subtype of neurotransmitter receptor has a unique pattern of distribution within the brain. Different receptor systems become active at different times in fetal life. The number of any given type of receptor remains plastic in adulthood: not only are there seasonal variations, but many kinds of receptors show a regular daily variation of 50% or more in number, affecting the sensitivity of cells to that particular transmitter. Similarly, the numbers of some receptors have been found to vary with the use of drugs. We'll learn more about these properties of neurotransmitter receptors in Chapter 3. The action of synaptic transmitters is stopped rapidly When a chemical transmitter such as ACh is released into the synaptic cleft, its postsynaptic action is not only prompt but usually very brief as well. It is important that each activation of the synapse be brief in order to maximize how much information can be transmitted. Think of it this way: the worst doorbell in the world is one that, when the button is pushed, rings forever. Such a doorbell would be able to transmit only one piece of information, and only once. But a doorbell that could ring as fast as a thousand times per minute would be able to send a lot of information--Morse code maybe. Likewise, a synapse can signal over a thousand times per second, potentially sending a lot of information (but not by Morse code). Two processes bring transmitter effects to a prompt halt: 1. Degradation Transmitter molecules can be rapidly broken down and thus inactivated by special enzymes--a process known as degradation (step 6a in Figure 2.12).
curare A neurotoxin that causes paralysis by blocking acetylcholine receptors in muscle. bungarotoxin A neurotoxin, isolated from the venom of the many-banded krait, that selectively blocks acetylcholine receptors. agonist A substance that mimics or boosts the actions of a transmitter or other signaling molecule. antagonist A substance that blocks or reduces the actions of a transmitter or other signaling molecule. cholinergic Referring to cells that use acetylcholine as their synaptic transmitter. degradation The chemical breakdown of a neurotransmitter into inactive metabolites.
acetylcholinesterase (AChE) An enzyme that inactivates the transmitter acetylcholine. reuptake The process by which released synaptic transmitter molecules are taken up and reused by the presynaptic neuron, thus stopping synaptic activity. transporter A specialized membrane component that returns transmitter molecules to the presynaptic neuron for reuse. axo-dendritic synapse A synapse at which a presynaptic axon terminal synapses onto a dendrite of the postsynaptic neuron, either via a dendritic spine or directly onto the dendrite itself. axo-somatic synapse A synapse at which a presynaptic axon terminal synapses onto the cell body (soma) of the postsynaptic neuron. axo-axonic synapse A synapse at which a presynaptic axon terminal synapses onto the axon terminal of another neuron. dendro-dendritic synapse A synapse at which a synaptic connection forms between the dendrites of two neurons. knee-jerk reflex A variant of the stretch reflex in which stretching of the tendon beneath the knee leads to an upward kick of the leg.
For example, the enzyme that inactivates ACh is acetylcholinesterase (AChE). AChE breaks down ACh very rapidly into products that are recycled (at least in part) to make more ACh in the axon terminal. 2. Reuptake Alternatively, transmitter molecules may be swiftly cleared from the synaptic cleft by being absorbed back into the axon terminal that released them--a process known as reuptake (step 6b in Figure 2.12). Norepinephrine, dopamine, and serotonin are examples of transmitters whose activity is terminated mainly by reuptake. In these cases, special receptors for the transmitter, called transporters, are located on the presynaptic axon terminal and bring the transmitter back inside. Once taken up into the presynaptic terminal, transmitter molecules may be repackaged into newly formed synaptic vesicles to await rerelease, conserving the resources that would be needed to make new transmitter molecules. Malfunction of reuptake mechanisms is suspected as the cause of some kinds of mental illness, such as depression (see Chapter 12). Neural circuits underlie reflexes For simplicity, so far we have focused on the classic axo-dendritic synapses (from axon to dendrite) and axo-somatic synapses (from axon to cell body, or soma). But many nonclassic forms of chemical synapses exist in the nervous system. As the name implies, axo-axonic synapses form on axons, often near the axon terminal, allowing the presynaptic neuron to strongly facilitate or inhibit the activity of the postsynaptic axon terminal. Similarly, neurons may form dendro-dendritic synapses, allowing coordination of their activities (FIGURE 2.14). Now that we know more about the electrical signaling that takes place within each neuron and the neurotransmitter signaling that goes on between neurons, we can revisit the knee-jerk reflex that we discussed at the start of the chapter (FIGURE 2.15). Note that this reflex is extremely fast: only about 40 milliseconds elapse between the hammer tap and the start of the kick. Several factors account for this speed: (1) both the sensory and
Axon Dendrite Soma Most synapses are formed by an axon stimulating a dendrite, but axons also sometimes synapse on cell bodies or even other axons... FIGURE 2.14 Different Types of Synaptic Connections In reality, neurons typically summate input from hundreds or even thousands of synapses.
...and in some instances, specialized dendrites synapse on other dendrites.
Tap on patellar tendon stimulates stretch receptor in quadriceps muscle and starts chain of events. Stimulus
Muscle stretch receptor Initial segment of sensory neuron
Action potentials are triggered when the stretch receptor reaches threshold and speed along large sensory axons at about 100 m/s. Sensory neuron releases the neurotransmitter glutamate. About 0.5 ms later, excitatory postsynaptic potential (EPSP) appears in motor neuron. EPSP spreads passively to axon hillock, where it triggers action potentials.
the motor axons involved are myelinated and of large diameter, so they conduct action
potentials rapidly; (2) the sensory cells synapse directly on the motor neurons; and (3)
both the central synapse and the neuromuscular junction are fast synapses. We discuss
other aspects of neural circuits in A STEP FURTHER 2.2, on the website.
We offered this reflex at the start of the chapter as an example of neural process-
ing--electrical signaling within each neuron alternating with chemical signaling
between neurons. Chapter 3 will explain how drugs can interfere with the chemical Watson/Breedlove siTghneaMliinndg'sbMetawceheinneneurons. For the final part of this chapter, let's see how scientists
exFopulonidtatthioenes loefcBtraicinalansidgBneahlainvigorw4eithin neurons to learn more about brain function. Dragon y Media Group
1. Recount the seven steps in synaptic transmission, including processes that end the signal. 2. What ion must enter the axon terminal to trigger neurotransmitter release? 3. What are agonists and antagonists? 4. Describe how information is processed within neurons by electrical signals yet communicated to other neurons by chemical signals.
Action potentials reach neuromuscular junctions. ACh is released as the neurotransmitter. Neuromuscular junction potential starts about 0.5 ms after arrival of presynaptic action potential. Action potentials generated in muscle bers cause contractions that kick the leg out about 40 ms after the tap.
FIGURE 2.15 The Knee-Jerk Reflex
2.3EEGs Measure Gross Electrical Activity of the Human Brain
electroencephalogram (EEG) A recording of gross electrical activity of the brain via large electrodes placed on the scalp. event-related potential (ERP) Also called evoked potential. Averaged EEG recordings measuring brain responses to repeated presentations of a stimulus. Components of the ERP tend to be reliable because the background noise of the cortex has been averaged out. epilepsy A brain disorder marked by major, sudden changes in the electrophysiological state of the brain that are referred to as seizures. seizure A wave of abnormally synchronous electrical activity in the brain. tonic-clonic seizure Also called grand mal seizure. A type of generalized epileptic seizure in which nerve cells fire in high-frequency bursts, usually accompanied by involuntary rhythmic contractions of the body. simple partial seizure Also called absence attack. A seizure that is characterized by a spike-and-wave EEG and often involves a loss of awareness and inability to recall events surrounding the seizure.
The final section of the chapter explains how we can exploit electrical signals to monitor and understand brain function. Reading this section should allow you to: Understand how electroencephalograms (EEGs) work. Explain the logic of event-related potentials. Understand the electrical activity underlying the brain disorder called epilepsy. Appreciate how neurosurgeons discovered important "maps" by electrically stimulating the brain.
The electrical activity of millions of cells working together combines to produce electrical potentials large enough that we can detect them with electrodes applied to the surface of the scalp. Recordings of these spontaneous brain potentials (or brain waves), called electroencephalograms (EEGs) (FIGURE 2.16A), can provide useful information about the activity of brain regions during behavioral processes (Jackson and Bolger, 2014). As we will see in Chapter 10, EEG recordings can distinguish whether a person is asleep or awake. In many countries, EEG activity determines whether someone is legally dead. Event-related potentials (ERPs) are EEG responses to a single stimulus, such as a flash of light or a loud sound. Typically, many ERP responses to the same stimulus are averaged to obtain a reliable estimate of brain activity (FIGURE 2.16B). ERPs have very distinctive characteristics of wave shape and time delay (or latency) that reflect the type of stimulus, the state of the participant, and the site of recording (Luck, 2005). ERPs can also be used to detect hearing problems in babies, evident as reduced or absent ERPs in response to sounds. In Chapter 14 we'll learn how ERPs are used to study subtler psychological processes, such as attention. EEG recordings can also provide vital information for diagnosing seizure disorders, as we discuss next. Electrical storms in the brain can cause seizures Since the dawn of civilization, people have pondered the causes of epilepsy, a disorder in which seizures lasting for a few seconds or minutes may produce dramatic behavioral changes such as alterations or loss of consciousness and rhythmic convulsions of the body. Worldwide, about 30 million people suffer from epilepsy, which we now know to be a disorder of electrical potentials in the brain. In the normal, active brain, electrical activity tends to be desynchronized; that is, different brain regions carry on their functions more or less independently. In contrast, during a seizure there is widespread synchronization of electrical activity: broad stretches of the brain start firing in simultaneous waves, which are evident in the EEGs as an abnormal "spike-and-wave" pattern of brain activity. Many factors, such as trauma, injury, or metabolic problems, can predispose brain tissue to produce such synchronized activity, which, once begun, may readily spread from one brain region to others. There are several major categories of seizure disorders. The most severe, with loss of consciousness and rhythmic convulsions, are called tonic-clonic seizures (formerly known as grand mal seizures) and are accompanied by abnormal EEG activity all over the brain (FIGURE 2.17A). In the more subtle simple partial seizures (or absence attacks, formerly known as petit mal seizures), the characteristic spike-and-wave EEG activity is evident for 5-15 seconds at a time (FIGURE 2.17B), sometimes occurring
(A) Multichannel EEG recording Electrode array for EEG recording.
Each electrode can be assigned a letter on a map of the scalp.
Left hemisphere AC CG GK KO DH HL 200 µV 1 s
Typical EEG recordings showing potential measured between various points on the scalp.
(B) Event-related potentials (average of many stimulus presentations) Negative N1 N0 N Na Nb N1
Early components P3 (labeled I-VI) are associated with P2 brainstem activity...
...followed by largeamplitude negative- and positive-voltage events (labeled N0-N2 and P0-P3) associated with cognitive processing in the cortex.
FIGURE 2.16 Gross Potentials of the Human Nervous System (B after M. Kutas and S. A. Hillyard, 1984. Handbook of Cognitive
Neuroscience. Plenum Press: New York, NY.)
Following stimulus presentation, a xed sequence of processingrelated potentials is generated.
many times per day. The person is unaware of the environment during these periods and later cannot recall events that occurred during the episodes. Behaviorally, people experiencing simple partial seizures show no unusual muscle activity; they just stop what they're doing and seem to stare into space. Complex partial seizures do not involve the entire brain and thus can produce a wide variety of symptoms, often preceded by an unusual sensation, or aura. In one eWxaamtsopnle/,Bareewdolomvean felt an unusual sensation in the abdomen, a sense of foreboding, aTnhdetMiningdli'ns Mg ianchbinoeth hands before the seizure spread. At the height of the episode, she Foundations of Brain and Behavior 4e wDarsaguonnreysMpoednisaiGveroaunpd rocked her body back and forth while speaking nonsensically, twMiMst4ien_g02h.1e6r.alieft arm01,/a1n3/d2l0o2o0king toward the right. Of course, her seemingly random
complex partial seizure A type of seizure that doesn't involve the entire brain and therefore can cause a wide variety of symptoms. aura In epilepsy, the unusual sensations or premonition that may precede the beginning of a seizure.
Courtesy of Hal Blumenfeld, Rik Stokking, Susan Spencer, and George Zubal, Yale School of Medicine
(A) EEG recordings taken from six different parts of the brain all show the same storm of activity during a tonic-clonic seizure.
FIGURE 2.17 Seizure Disorders
(B) In an absence attack, the level of activity is less intense, but it has still invaded the entire cortex.
LT RT LF RF LO RO LF - left frontal LT - left temporal LO - left occipital
RF - right frontal RT - right temporal RO - right occipital
set of behavioral symptoms actually reflected the functions of the particular brain regions activated by the seizure (FIGURE 2.17C); others experiencing seizures would produce a completely different set of behaviors. In some individuals, complex partial seizures may be provoked by stimuli like loud noises or flashing lights. Many seizure disorders can be effectively controlled with the aid of antiepileptic drugs. Although these drugs have a wide variety of neural targets, they tend to selectively reduce the excitability of neurons (Park et al., 2019). There is anticipation that cannabis products such as cannabidiol may control seizures, but so far there have been few controlled trials to determine whether it actually works (Samanta, 2019). For now, about a third of cases of epilepsy are not controlled by medication. If the seizures are severe, or happen very often, they may be life-threatening. Individuals suffering from such severe epilepsy may resort to the drastic step of having parts of the brain removed, as we'll see next.
Surgical probing of the brain revealed a map of the body
Usually the electrical activity causing seizures begins in one part of the brain and then spreads to others. So in the twentieth century, neurosurgeons began taking drastic measures to help people with Wastesovne/reBreepedilelopvsey that did not respond to Thme Medinicda'stioMna:cshuinregical removal of the part Foounf dthaetiobnrsaionf BwrhaeinreanthdeBesheaizvuiorre4sebegin. Dragon y Media Group MMTh4ee_t0r2ic.1k7,.aoif cours0e8,/i2s1/to20r2e0move the part of the brain where the seizures begin, and only that part. Otherwise the patient might take the risks of surgery and still suffer from seizures, or might suffer impairment of a vital function, such as verbal or memory skills, if healthy tissue is removed. One way to locate the origin of the seizures is to compare EEG readings from different places on the skull (see Figure 2.17). But this approach gives only a rough idea of where the seizures
begin, and it is problematic because the recording must be made when a seizure is actually starting. To improve the success rate of such surgeries, Canadian neurosurgeon Wilder Penfield developed a procedure that, nearly a century later, is still compelling (Foerster and Penfield, 1930). Using only local anesthesia to deaden the pain of cutting the scalp and opening up the skull, Penfield had patients remain awake and alert as he exposed the brain. Then he used electrodes to provide a tiny electrical stimulation to the surface of the cortex, asking the patient to report the results. One strategy for people whose epileptic seizures were preceded by an aura was to try to find the point where stimulation recreated the aura.
In one famous case of a woman whose seizures were preceded by the smell of burnt toast, Penfield was able to find a spot where stimulation caused her to smell burnt toast and, presuming that region was the origin of the seizures, surgically removed it. (The brain itself has no pain receptors, so cutting the cortex didn't hurt.) Using this refined technique, Penfield was able to cure about half of his patients, and seizures were reduced in another 25%. Later, José Delgado also stimulated patients' brains to seek the origin of seizures, as we discussed at the start of the chapter. Delgado altered the technique by implanting several electrodes temporarily, so the patient could walk around while doctors electrically stimulated different brain regions and observed the results. In Chapter 5 and
Chapter 12 we'll learn that today electrodes are sometimes implanted in the brain as a treatment for other disorders. In his pioneering work, Penfield did more than help his patients. He also made major discoveries about the organization of the human cortex (FIGURE 2.18). By carefully recording the effects of stimulating different regions of the brain, he found that stimulation of occipital cortex often caused the patient to "see" flashes of light. Stimulating another region might cause the person's thumb to tingle, while stimulation elsewhere might cause the patient's leg to move. Through these studies, Penfield confirmed that each side of the cortex receives information from, and sends commands to, the opposite side of the body. He found that stimulating the postcentral gyrus of the parietal cortex caused patients to experience sensations on various parts of the body in a way that was consistent from one person
to another (see Figure 5.9). Just across the central sulcus from each site, in the precentral gyrus, stimulations caused that same part of the body to move (see Figure 5.22). These "maps" of how the various parts of the body are laid out on the cortex (Jasper and Penfield, 1954) have been reproduced in countless textbooks, providing the basis of what is called the homunculus, the "little man" drawn on the surface of the cortex to depict Penfield's maps, as we will discuss further in Chapter 5. These groundbreaking observations taught us that brain function is organized in a map that reproduces body parts. We also learned that the map is distorted, in the sense that parts of the body that are especially sensitive to touch, such as the lips or fingers, are monitored by a relatively large area of cortex compared with, say, the backs of the legs. Penfield's studies also stimulated a rich store of speculation about the
relationship between the workings of the brain and the mind. In a small minority of patients, electrical stimulation in some sites would sometimes elicit a memory of, for example, sitting on the porch step and hearing a relative's voice, or hearing a snatch of music. As we saw at the start of this chapter, other researchers would find that electrical stimulation of the brain could make people think they loved their examiner or could make an angry, murderous bull peaceful and calm. In another case, electrical stimulation of one part of her brain caused a young woman to find whatever was happening around her to be humorous (Fried et al., 1998). These startling observations--showing that electrical stimulation of the brain triggers mental processes--remain a cornerstone of neuroscience, and a tantalizing demonstration that our mind is a result of physical processes at work in the machine we call the brain.
Hypothesis Sensory information from the body arrives in an organized fashion in the cortex.
Experiment Electrically stimulate the surface of the cortex in alert patients, carefully recording the patient's experience with stimulation at each site. Compare these maps in various patients.
Result Each side of the brain receives sensory information from the opposite side of the body, organized along the postcentral gyrus of the parietal lobe. Across the central sulcus, in the precentral gyrus, cortical regions control movement of that same part of the body so that sensory and motor regions are aligned. Conclusion The maps of sensory cortex and motor cortex are remarkably consistent from one person to another.
FIGURE 2.18 Mapping the Human Brain
Trunk Neck Head Shoulder Arm Elbow Forearm
Hand Digit 5 4 3 2 Thumb Eyes Nose Face Upper lip Lower lip Chin
Reproduced by permission of the Oster Library of the History of Medicine, McGill University
Brain Stimulation Surgeon Wilder Penfield electrically stimulating the surface of the exposed brain in an awake patient.
1. What are EEGs and ERPs? How have these techniques been useful? 2. What are the three main categories of epileptic seizures, and what are the main characteristics of each type? 3. Describe Penfield's surgical procedure and what it revealed about organization of the brain. Recommended Reading Kandel, E. R., Schwartz, J. H., Jessell, T. M., Siegelbaum, S. A., et al. (2013). Principles of Neural Science (5th ed.). New York, NY: McGraw-Hill. Nicholls, J. G., Martin, A. R., Fuchs, P. A., Brown, D. A., et al. (2021). From Neuron to Brain (6th ed.). Sunderland, MA: Oxford University Press/Sinauer. Purves, D., Augustine, G. J., Fitzpatrick, D., Hall, W. C., et al. (2017). Neuroscience (6th ed.). Sunderland, MA: Oxford University Press/Sinauer. Sapolsky, R. M. (2018). Behave: The Biology of Humans at Our Best and Worst. New York, NY: Penguin Books. Valenstein, E. S. (2005). The War of the Soups and the Sparks: The Discovery of Neurotransmitters and the Dispute over How Neurons Communicate. New York, NY: Columbia University Press.
You should be able to relate each summary to the adjacent illustration, including structures and processes. The online version of this Visual Summary includes links to figures, animations, and activities that will help you consolidate the material.
1 Chemical signals transmit information between neurons; electrical signals transmit information within a neuron. The resting potential is a small electrical potential across the neuron's membrane. Review Figure 2.1, Animation 2.2 3 Depolarizing the axon (reducing its resting potential) until it reaches a threshold value opens voltage-gated Na+ channels, making the membrane permeable to Na+. The sodium ions (Na+) rush in, and the axon becomes briefly more positive inside than outside. This event is called an action potential. Review Figure 2.5, Animation 2.4
++++++++++++++++ ----------------- ----------------- ++++++++++++++++ ++++++++++++++++ ----------------- ----------------- ++++++++++++++++
Time Responses Action potential 0 Threshold - 65
2 Different concentrations of ions inside
and outside the neuron--especially potassium ions (K+), to which the resting
account for the resting potential. At the
K+ equilibrium potential, the electrostatic
pressure pulling K+ ions into the neuron is balanced by the diffusion pushing them out. Review Figures 2.2-2.4, Activity 2.1, Animation 2.3 4 Following the action potential,
5 The action potential strongly depolarizes the adjacent patch of axonal membrane, causing it to generate its own action potential, propagating down the axon. Saltatory conduction of the action potential along the nodes of + Ranvier between myelin sheaths + speeds propagation along the axon. Review Figures 2.7-2.9, Animation 2.5
7 Neurons process information by integrating the postsynaptic potentials through both spatial summation (summing Threshold potentials from different locations) and temporal summation (summing potentials across time). Review Figure 2.11, Animation 2.6
9 Synaptic transmission occurs when a chemical neurotransmitter diffuses across the synaptic cleft and binds to neurotransmitter receptors in the postsynaptic membrane. Review Figures 2.12 and 2.13, Box 2.1, Animation 2.7
Transmitter molecules Synaptic vesicle Transporter
Autoreceptor EPSP or IPSP Across cell membrane
-65 IPSP Postsynaptic neuron 01234 5 Time (ms)
synaptic potentials (EPSPs) are depolarizing (they decrease the
stimulus; it is absolutely refractory. For a few milliseconds afterward, the neuron is relatively refractory, requiring
a stronger stimulation than usual in order to fire. Review Figure 2.6
10 Summing electrical activity over millions of
nerve cells as detected by electrodes on the scalp, electroencephalograms (EEGs) can reveal rapid changes in brain function--for example, in response to a brief, controlled stimulus that evokes an event-related potential (ERP). They can also reveal a seizure in someone with epilepsy. Review Figures 2.16-2.18
The Mind's Machine digital resources include additional videos, flashcards, and other study tools.