Module 1
Nervous System
a. The Cells That Make Us Who We Are
To understand how the brain works, you must first have at least a basic
understanding of the two categories of cells that carry messages back and forth in the
brain and throughout the rest of the body. Neurons convey sensory information into
the brain; carry out the operations involved in thought, feeling, and action; and
transmit commands out to the body to control muscles and organs. It is estimated that
there are about 86 billion neurons in the human brain. This means that there are more
neurons in your brain than stars in our galaxy. But as numerous and as important as
they are, neurons make up only half of the brain’s cells.
Neurons are responsible for all the things we do—our movements, our
thoughts, our memories, and our emotions. It is difficult to believe that anything so
simple as a cell can measure up to this task, and the burden is on the neuroscientist to
demonstrate that this is true. As you will see, the neuron is deceptively simple in its
action but impressively complex in its function.
First, let’s look inside a neuron, because we want to show you that the neuron
is a cell, very much like other cells in the body. The cell body is filled with a liquid
called cytoplasm and contains a number of organelles. The largest of these y g g
organelles is the nucleus, which contains the cell’s chromosomes. Other organelles are
responsible for converting nutrients into fuel for the cell, constructing proteins and
lipids, and removing waste materials. So far, this could be the description of any cell;
now, let’s look at the neuron’s specializations that enable it to carry out its unique
role. We use “typical” guardedly here, because there are three major kinds of neurons
and many variations within those types. It is particularly useful for demonstrating the
structure and functions that all neurons have in common.
Dendrites are extensions that branch out from the cell body to receive
information from other neurons. Their branching structure allows them to collect
information from many neurons. The axon extends like a tail from the cell body and
carries information to other locations, sometimes across great distances. The myelin
sheath that wraps around the axon supports the axon and provides other benefits that
we will consider later. Branches at the end of the axon culminate in swellings called
axon terminals. The terminals contain chemical neurotransmitters, which the neuron
releases to communicate with a muscle, an organ, or the next neuron in a chain. In our
examples, we will talk as if neurons form a simple chain, with one cell sending
messages to a single other neuron, and so on; in actuality, a single neuron receives
input from many neurons and sends its output to many others. Neurons are usually so
small that they can be seen only with the aid of a microscope. The cell body is the
largest part of the neuron, ranging from 0.005 to 0.1 millimeter (mm) in diameter in
mammals. (In case you are unfamiliar with metric measurements, a millimeter is
about the thickness of a dime.) Even the giant neurons of the squid, favored by
researchers for their conveniently large size, have axons that are only 1 mm in
diameter. Typical axons are smaller; in mammals, they range from 0.002 to 0.02 mm
in diameter. Axons may be as short as 0.1 mm or as long as 30 m in the blue whale
(D. H. Smith, 2009).
The second type of neuron is the sensory neuron. Sensory neurons carry
information from the body and the outside world into the brain and spinal cord. Motor
and sensory neurons have the same components, but they are configured differently. A
motor neuron’s axon and dendrites extend in several directions from the cell body,
which is why it is called a multipolar neuron. Sensory neurons can be either unipolar
or bipolar. (In the pseudounipolar subtype, both connections to the cell body are
axons; that’s because its sensory information must travel over a longer distance, from
the periphery of the body to the spinal cord and the brain.) Bipolar neurons have an
axon on one side of the cell body and a dendritic process on the other. Motor and
sensory neurons are specialized for transmission over long distances; their lengths are
not shown here in the same scale as the rest of the cell.
The third type is neither motor nor sensory. Interneurons connect one neuron
to another in the same part of the brain or spinal cord. Because interneurons make
connections over very short distances, they do not need the long axons that
characterize their motor and sensory counterparts. In the spinal cord, interneurons
bridge sensory neurons and motor neurons to produce a reflex. In the brain, they
connect adjacent neurons to carry out the complex processing that the brain is noted
for. Considering the major roles they play, it should come as no surprise that
interneurons are by far the most numerous neurons.
The most critical factor in the neuron’s ability to communicate is the
membrane that encloses the cell. The membrane is exceptionally thin—only about 4
nanometers (billionths of a meter) thick—and is made up of lipid (fat) and protein.
Each lipid molecule has a “head” end and a “tail” end. The heads of the molecules are
water soluble, so they are attracted to the seawater-like fluid around and inside cells.
The tails are water insoluble, so they are repelled by the fluid. Therefore, as the heads
orient toward the fluid and the tails orient away from the fluid, the molecules turn
their tails toward each other and form a double-layer membrane.
The membrane not only holds a cell together but also controls the environment
within and around the cell. Some molecules, such as water, oxygen, and most gases,
can diffuse through the membrane freely. Many other substances are barred from
crossing the membrane. Still others are allowed limited passage through protein
channels (shown in the figure in green) that open and close under specific
circumstances. This selective permeability contributes to the most fundamental
characteristic of neurons, polarization, which means that there is a difference in
electrical charge between the inside and outside of the neuron. A difference in
electrical charge between two points, such as the poles of a battery or between the
inside and outside of a neuron, is also called a voltage.
The Resting Potential. Just as you can measure the voltage of a battery, you
can measure a neuron’s voltage. By arbitrary convention, the voltage is expressed as a
comparison of the inside of the neuron with the outside. The difference in charge
between the inside and outside of the membrane of a neuron at rest is called the
resting potential. This voltage is negative and varies anywhere from –40 to –80
millivolts (mV) in different neurons but is typically around –70 mV. You should
understand that neither the inside of the neuron nor the outside has a voltage, because
a voltage is a difference and is meaningful only in comparison with another location.
Note that this voltage is quite small—the voltage of a standard 1.5-V battery is 25
times greater. No matter; we’re moving information, and very little power is required.
The resting potential is due to the unequal distribution of electrical charges on
the two sides of the membrane. The charges come from ions, atoms that have lost or
gained one or more electrons. Sodium ions (Na + ) and potassium ions (K + ) are
positively charged. Chloride ions (Cl− ) are negative, as are certain proteins and
amino acids that make up the organic anions (A − ). The fluid outside the neuron
contains mostly Na + and Cl− ions, and the ions inside the neuron are mostly K + and
A. The inside of the neuron has more negative ions than positive ions, whereas the
ions on the outside are mostly positive, and this makes the resting potential negative.
Ions on the outside are mostly Na + (red) and CL – (green) ions; inside, the
ions are mostly K + ions (blue) and organic anions (dark green). In the middle of the
membrane is an ion channel, which is closed and not allowing ions through; on the
left, a sodiumpotassium pump is discharging three Na + ions outside the neuron,
while on the right, an identical pump is returning two K + ions to the inside.
If you remember from grade-school science that molecules tend to diffuse
from an area of high concentration to one of low concentration, then you are probably
wondering how this imbalance in ion distribution can continue to exist. In fact, two
forces do work to balance the location of the ions. Because of the force of diffusion,
ions tend to move through the membrane to the side where they are less concentrated.
And as a result of electrostatic pressure, ions are repelled from the side that is
similarly charged and attracted to the side that is oppositely charged.
In spite of these two forces, a variety of other influences keep the membrane
polarized. Both forces would move the organic anions out, but they are too large to
pass through the membrane. Their negative charge then repels the chloride ions, so the
force of diffusion is unable to move those ions inside. As a result, the “real player”
then becomes the potassium ions. Potassium’s force of diffusion is stronger than its
electrostatic pressure, and although the potassium and sodium channels are both
closed during resting, potassium can slip through the membrane itself more readily
than the other ions.
Another significant contributor to polarity is the sodium-potassium pump,
which consists of large protein molecules that move sodium ions through the cell
membrane to the outside and potassium ions back inside. It moves three sodium ions
out for every two potassium ions it moves inside, which helps keep the inside of the
membrane more negative than the outside. The pump’s operation is a metabolic
process, which means that it uses energy; in fact, it accounts for an estimated 40% of
the neuron’s energy expenditure. But you will soon see that this energy is well spent,
because the resting potential stores the energy to power the action potential, the major
signal in the nervous system.
Ion Channels and Local Potentials. Before we move on, we need a better
understanding of how the ion channels work. These are pores in the membrane
formed by proteins, and they gate the flow of ions between the extracellular and
intracellular fluids. Chemically gated channels can be opened by ligands
(neurotransmitters or hormones), and electrically gated channels are opened by a
change in the electrical potential of the membrane.
A neuron is usually stimulated by inputs that arrive on the neuron’s dendrites
and/or cell body from another neuron or from a sensory receptor. The effect may be
excitatory or inhibitory, depending on the ligand and the characteristics of the
receptors. An excitatory signal causes a slight partial depolarization, which means that
the polarity in a small area of the membrane is shifted toward zero. This partial
depolarization disturbs the ion balance in the adjacent membrane, so the disturbance
flows down the dendrites and across the cell membrane. This looks at first like the
way the neuron might communicate its messages through the nervous system;
however, because a partial depolarization is decremental—it dies out over distance—
it is effective over only very short distances. For this reason, the partial depolarization
is often called the local potential. The ion channels in the axon are electrically gated,
and they have unique physical properties. If the local potential exceeds the threshold
for activating those channels, typically about 10 mV more positive than the resting
potential, it will initiate an action potential.
The action potential is an abrupt depolarization of the membrane that allows
the neuron to communicate over long distances. The voltage across the resting neuron
membrane is stored energy, just as the term resting potential implies. Imagine
countless sodium ions being held outside the neuron against the combined forces of
diffusion and electrostatic pressure. A stimulus that partially depolarizes a segment of
membrane causes voltage-gated sodium ion channels to open; this allows nearby
sodium ions to rush into the axon at a rate 500 times greater than normal. They are
propelled into the cell’s interior so rapidly that the movement is often described as
explosive. A small area inside the membrane becomes fully depolarized to zero; the
potential even overshoots to around +30 or +40 mV, making the interior at that
location temporarily positive.
Just as abruptly as the neuron “fires,” it begins to recover its resting potential.
At the peak of the action potential, voltage sensors in the sodium channels detect the
depolarization and close a gate, inactivating the channel and preventing further
sodium ion influx (Catterall, 2010). The depolarization also causes voltage-gated
potassium ion channels to open; the positive charge and the higher concentration of
potassium ions inside the membrane combine to force potassium ions out. This
outward flow of positive potassium ions lowers the axon voltage to its resting
potential and sometimes a bit beyond. In total, the action potential lasts about 1
millisecond (one thousandth of a second); the actual duration varies among individual
neurons. (Obviously, these channels are what make the neuron operate; A Further
Look (page 28) describes how they are exploited by nature and in research and
medicine.)
The Japanese delicacy fugu, or puffer fish, produces an exciting tingling
sensation in the diner’s mouth; improperly prepared, it causes numbness and
weakness and, in some cases, a paralysis of the respiratory muscles that has claimed
the lives of hundreds of culinary risk takers. The fish’s natural poison, tetrodotoxin
(TTX), blocks sodium channels and prevents neurons from firing. Researchers are
examining TTX as a potential replacement for opiate painkillers, so this dangerous
toxin might lead to new treatments for chronic pain. Other neurotoxins (neuron
poisons) are found in snake venoms, which block sodium, potassium, or calcium
channels, and scorpion venom, which keeps sodium channels open, prolonging the
action potential.
Interfering with neuron functioning can be useful, though; for example, most
local anesthetics prevent neuron firing by blocking sodium channels (Ragsdale,
McPhee, Scheuer, & Catterall, 1994), and some general anesthetics hyperpolarize the
neuron by opening potassium channels and allowing the potassium ions to leak out
(Nicoll & Madison, 1982; A. J. Patel et al., 1999). The cone snail of the South Seas
can penetrate a wet suit with its proboscis and inject toxins that will kill a human in
half an hour, but the various species’ thousands of toxins that target sodium,
potassium, or calcium channels or block neurotransmitter receptors are in demand by
researchers developing pain relievers and drugs for preventing heart attacks and
epilepsy.
An exciting new research strategy known as optogenetics allows researchers to
create light-responsive channels (as well as receptors) in neurons so that they can be
controlled by light. Different types of channels are triggered by different wavelengths
of light, which allows the researcher either to accelerate or to inhibit firing. The
procedure is being used to understand the circuitry in a variety of behaviors and brain
processes and is showing potential for use in therapeutic procedures. Only a relatively
few ions very near the two sides of the membrane have participated in the action
potential; these dislocated ions quickly diffuse into the surrounding fluid, and the
membrane potential returns to its resting level. Eventually, though, the ions must be
returned to their original locations, or the neuron cannot continue firing; the sodium-
potassium pump takes care of this. (Perhaps you can see now why Jim was in such a
bad way after his bout with chlordane.)
The depolarization that occurs during the action potential triggers nearby
sodium channels to open as well. Thus, a new action potential is triggered right next
to the first one. That action potential in turn triggers another farther along, creating a
chain reaction of action potentials that move through the axon; thus, a signal flows
from one end of the neuron to the other. Nothing physically moves down the axon.
Instead, a series of events occurs in succession along the axon’s length, much as a line
of dominoes standing on end knock each other over when you tip the first one. When
the action potential reaches the terminals, they pass the signal on to the next neuron in
the chain (or to an organ or a muscle). The transmission of signals from neuron to
neuron is covered later; for now, the action potential needs to be examined a bit
further.
The action potential differs in two important ways from the local potential that
initiates it. First, the local potential is a graded potential, which means that it varies in
magnitude with the strength of the stimulus that produced it. The action potential, by
contrast, is ungraded; it operates according to the all-or-none law, which means that it
occurs at full strength or it does not occur at all. A larger graded potential does not
produce a larger action potential; like the fuse of a firecracker, the action potential
depends on the energy stored in the neuron, in this case, due to the difference in ion
concentrations between the two sides of the membrane. A second difference is that the
action potential is nondecremental; it travels down the axon without any decrease in
size, propagated anew and at full strength at each successive point along the way. The
action potential thus makes it possible for the neuron to conduct information over
long distances.
If you remember a few paragraphs back, we stated that the flow of an action
potential down the axon was like knocking down a line of dominoes. And just as you
must go through and reset the dominoes so that they can fall again, the ion channels
must be reset before the neuron can fire again. During the action potential and initial
recovery, the sodium ion channels are open and unresponsive to further stimulation,
no matter how intense; this time is referred to as the absolute refractory period. This
delay in responsiveness has two important effects. First, the 1- to 2-millisecond
duration of the absolute refractory period limits how fast the neuron can generate new
action potentials; a study of cortical fast-spiking neurons found maximal rates of 453
per second in humans, 611 in monkeys, and 342 in mice (B. Wang et al., 2016).
Second, because the ion channels behind the action potential are still recovering, the
impulse can propagate only down the axon toward the dendrites, not back toward the
cell body. This makes neural transmission unidirectional, which has the secondary
effect of preventing the neuron from “locking up.” If recovery were immediate,
activity would self-propagate in both directions from an ongoing action potential; this
would result in impulses moving repeatedly back and forth along the axon, which
would block the ability to respond to newly arriving messages.
At the end of the absolute refractory period, the sodium channels have closed,
so the neuron is able to fire again. But the potassium channels remain open for an
additional 3 or 4 milliseconds, and as potassium ions continue to exit the neuron, the
polarity is driven slightly more negative than the resting potential. During the
resulting relative refractory period, another action potential can be generated but only
by a stronger-than-threshold stimulus. A stimulus that is slightly greater than this
temporarily higher threshold will cause the neuron to fire again before the end of the
relative refractory period; with progressively stronger stimuli, the neuron will fire
increasingly earlier and, therefore, at a higher rate. Thus, the axon encodes stimulus
intensity not in the size of its action potential but in its firing rate, an effect called the
rate law.
Survival depends in part on how rapidly messages can move through the
nervous system, enabling the organism to pounce on its prey, outrun a predator, or
process language quickly. The speed with which the fastest neurons conduct their
impulses approaches 120 meters (m) per second (s), or about 270 miles per hour (435
km/hr). This seems fast, but the speed of electricity flowing through a wire, the
analogy sometimes used to describe neural conduction, is up to 690 times faster.
Because conduction speed is so critical to survival, strategies have evolved for
increasing it. One way is to develop larger-diameter axons, which provide less
resistance to the flow of electrical potentials. By evolving motor neurons with 0.5-
mm-thick axons, the squid has achieved conduction speeds of 30 m/s, compared with
1 m/s in the smallest neurons.
However, conduction speed increases not in direct proportion to axon size but
closer to the square of the diameter (W. A. H. Rushton, 1951). To reach our four-
timesgreater maximum conduction speed of 120 m/s, our axons would have to be 4 2
= 16 times larger than the squid axon, or 8 mm in diameter (the size of a large pea)!
Obviously, your brain would be larger than you could carry around. In other words, if
axon size were the only way to achieve fast conduction speed, you would not exist.
Vertebrates (animals with backbones) have developed another solution, myelination.
Two types of glial cells produce myelin, a fatty tissue that wraps around the axon (like
a jellyroll) to insulate it from the surrounding fluid and from other neurons. Only the
axon is covered, not the cell body. Myelin is produced in the brain and spinal cord by
glial cells called oligodendrocytes and in the rest of the nervous system by Schwann.
Because there are very few sodium channels under the myelin sheath, action
potentials cannot occur there; conduction under myelinated areas is by local graded
potential (Waxman & Ritchie, 1985). However, myelin appears in segments about 1
mm long, with a gap of one or two thousandths of a millimeter between segments;
these gaps in the myelin sheath are called nodes of Ranvier. At each node of Ranvier,
where the membrane is exposed and there are plenty of sodium channels, the graded
potential triggers an action potential. Action potentials thus appear to jump from node
to node in a form of transmission called saltatory conduction. This arrangement has
three benefits. First, the insulating effect of myelin reduces an electrical effect of the
membrane called capacitance. Because capacitance slows the movement of ions down
the axon, the graded potential gets a big boost in speed.
The overall effect of myelination is the equivalent of increasing the axon
diameter 100 times (Koester & Siegelbaum, 2013). Second, the breaks in the
myelination mean that the signal is regenerated by an action potential at every node of
Ranvier. Third, myelinated neurons use much less energy because there is less work
for the sodium-potassium pump to do. Some diseases, such as multiple sclerosis,
destroy myelin. As myelin is lost, the capacitance rises, reducing the distance that
graded potentials can travel before dying out. The individual is worse off than if the
neurons had never been myelinated; because there are few voltage-sensitive sodium
channels under the myelin sheath (Ritchie & Rogart, 1977), action potentials may not
be generated in the previously myelinated area. Therefore, conduction slows or stops
in affected neurons.
There are several types of glial cells, and they make numerous contributions to
neural functioning. During fetal development, radial glia form scaffolds that guide
new neurons to their destinations. Later on, microglia provide energy to neurons and
respond to injury and disease by removing cellular debris. Neurons form seven times
as many connections in the presence of the type of glia called astrocytes, and they
start to lose their synapses if astrocytes are removed from the culture dish.
b. How Neurons Communicate With Each Other
Before the late 1800s, microscopic examination suggested that the brain
consisted of a continuous web called a reticulum. At that point, however, Camillo
Golgi developed a new tissue-staining method that helped anatomists see individual
neurons by randomly staining some entire cells without staining others With this
technique, the Spanish anatomist Santiago Ramón y Cajal (1937/1989) was able to
see that each neuron is a separate cell. The connection between two neurons is called
a synapse, a term derived from the Latin word that means “to grasp.” The neurons are
not in direct physical contact at the synapse but are separated by a small gap called the
synaptic cleft. Two terms will be useful to us in the following discussion: The neuron
that is transmitting to another is called the presynaptic neuron; the receiving neuron is
the postsynaptic neuron.
Until the 1920s, physiologists weren’t sure whether neurons communicated at
the synapse by an electrical current or by releasing a chemical. The German
physiologist Otto Loewi believed that synaptic transmission was chemical, but he did
not know how to test his hypothesis. One night, Loewi awoke from sleep with the
solution to his problem (Loewi, 1953). He wrote his idea down so that he would not
forget it, but the next morning, he could not read his own writing. He recalled that day
as the most “desperate of my whole scientific life” (p. 33). But the following night, he
awoke again with the same idea; taking no chances, he rushed to his laboratory. There
he dissected out the beating hearts of two frogs and bathed them in a salt solution. He
applied electrical stimulation to the vagus nerve attached to one of the hearts, which
slowed the heartbeat. Then he extracted some of the salt solution, which he assumed
would have captured any chemical that might have been released. When he applied
this salt solution to the second heart, that heart slowed, too, just as Loewi predicted.
Then he stimulated the accelerator nerve of the first heart, which caused the heart to
beat faster. When he transferred the solution from the first heart to the second, this
time it sped up. So Loewi demonstrated for the first time that transmission at the
synapse is chemical and that neurons release at least two different chemicals with
opposite effects.
It turned out later that some neurons do communicate electrically by passing
ions through channels that connect one neuron to the next; their main function appears
to be synchronizing activity in nearby neurons (M. V. L. Bennett & Zukin, 2004). In
addition, some neurons release a gas transmitter. Still, Loewi was essentially correct
because the majority of synapses are chemical. (By the way, if this example suggests
to you that the best way to solve a problem is to “sleep on it, ” keep in mind that such
insight occurs only when people have paid their dues in hard work beforehand!) At
chemical synapses, neurotransmitters are stored in the terminals in membraneenclosed
bubbles called vesicles; the term means, appropriately, “little bladders.” When the
action potential arrives at the terminals, it opens channels that allow calcium ions to
enter the terminals from the extracellular fluid. The calcium ions cause the vesicles
clustered nearest the membrane to fuse with the membrane. The membrane opens
there, and the transmitter spills out and diffuses into the cleft in a process called
exocytosis.
On the postsynaptic neuron, the neurotransmitter docks with specialized
protein receptors that match the molecular shape of the transmitter molecules like a
key in a lock. Activation of these receptors opens the ion channels, allowing ions to
flow across the membrane. Ionotropic receptors form the ion channel and open
quickly to produce the immediate reactions required for muscle activity and sensory
processing. Metabotropic receptors open channels indirectly through a second
messenger; they act slowly and produce longer-lasting effects. Opening the channels
is what sets off the graded potential that initiates the action potential. You will see in
the next section that the effect this has on the postsynaptic neuron depends on which
receptors are activated. The chemical jump across the synapse takes a couple of
milliseconds; that is a significant slowing compared with transmission down the axon.
In a system that places a premium on speed, inserting gaps in the neural pathway that
slow down transmission must have some compensating benefit. As you will see in the
following sections, synapses add important complexity to the simple all-or-none
response in the axon.
Opening ion channels on the dendrites and cell body has one of two effects: It
can cause the local membrane potential to shift in a positive direction toward zero,
partially depolarizing the membrane, or it can shift the potential farther in the negative
direction. Partial depolarization is excitatory and facilitates the occurrence of an
action potential; increased polarization, or hyperpolarization, is inhibitory and makes
an action potential less likely to occur. The value of excitation is obvious, but
inhibition can communicate just as much information as excitation does. Also, the
message becomes more complex because input from one source can partially or
completely negate input from another. In addition, inhibition helps prevent runaway
excitation; one cause of the uncontrolled neural storms that sweep across the brain
during an epileptic seizure is a deficiency in receptors for the inhibitory transmitter
GABA (Baulac et al., 2001). Lithium, which is used to reduce manic symptoms of
bipolar disorder, decreases excitatory neurotransmitters while increasing GABA
transmission.
In 2018, two teams of researchers collaborated to publish a description of a
new neuron type that so far has been found only in humans (Boldog et al., 2018). It is
a very small, compact neuron, with a bushy set of dendrites; the term rosehip was
chosen because its appearance resembles a rose after it has lost its petals. Found in the
outermost layer of the cortex (Layer 1), the neurons connect with a type of neuron in
Layer 3 called pyramidal cells because of the conical shape of their cell body. When
human pyramidal neurons fire, they also send excitatory output from their dendrites.
The rosehip neurons appear to be exclusively inhibitory, and they produce dense
synaptic connections on the pyramidal cell dendrites; the researchers suggest that the
rosehip neurons’ role may be to regulate this dendritic excitation. When the research
teams looked for rosehip neurons in rodents, they could not find them, which may
make them one of the very few uniquely human aspects of the nervous system.
Interestingly, pyramidal cells in mice lack the excitatory “backpropagation” that
characterizes human pyramidal cells, which may explain why humans have rosehip
neurons and mice apparently do not. The researchers also found patterns of gene
expression in the rosehip neurons that have been implicated in neuropsychiatric
disease, so one of their next steps is to see if the neurons are involved in these
disorders.
What determines whether the effect on the postsynaptic neuron is exciting or
inhibiting? It depends on a combination of which transmitter is released and the type
of receptors on the postsynaptic neuron. A particular transmitter can have an
excitatory effect at one location in the nervous system and an inhibitory effect at
another; however, some transmitters typically produce excitation, and others most
often produce inhibition. If the receptors open sodium channels, this produces a
partial depolarization of the dendrites and cell body, which acts as an excitatory
postsynaptic potential (EPSP). Other receptors open potassium channels, chloride
channels, or both; as potassium moves out of the cell or chloride moves in, it produces
a hyperpolarization of the dendrites and cell body, or an inhibitory postsynaptic
potential (IPSP). At this point, there is only a graded local potential. This potential
spreads down the dendrites and across the cell body to the axon hillock (where the
axon joins the cell body). Here, a positive graded potential that surpasses threshold
will produce an action potential; a negative graded potential will make it less likely to
be generated. Most neurons have a baseline rate of spontaneous action potential
generation; EPSPs will increase this rate, while IPSPs will decrease the rate of firing.
So now another form of complexity has been added at the synapse: The message to
the postsynaptic neuron can modulate the rate of firing, not just turn it on or off.
You should not assume that excitation of neurons always corresponds to
activation of behavior or that inhibition necessarily suppresses behavior. An EPSP
may activate a neuron that has an inhibitory effect on other neurons, and an IPSP may
reduce activity in a neuron that has an inhibitory effect on other neurons, increasing
their activity. An example of this paradox at the behavioral level is the effect of
Ritalin. Ritalin and many other medications used to treat
attention-deficit/hyperactivity disorder (ADHD) in children are in a class of drugs
called stimulants, which increase activity in the nervous system. Yet in low doses,
they calm hyperactive individuals and improve their ability to concentrate and focus
attention. They do this by increasing stimulating neurotransmitters in frontal areas of
the brain that normally restrain behavior, where activity has been found to be
abnormally low in people with ADHD.
The output of a single neuron is not enough by itself to cause a postsynaptic
neuron to fire or to prevent it from firing. In fact, an excitatory neuron may depolarize
the membrane of the postsynaptic neuron by as little as 0.2 to 0.4 mV; remember that
it takes an approximately 10-mV depolarization to trigger an action potential.
However, a typical neuron receives input from approximately 1,000 other neurons;
because each neuron has numerous terminals, this amounts to as many as 10,000
synaptic connections in most parts of the brain and up to 100,000 in the cerebellum.
Because a single neuron has a relatively small effect, the postsynaptic neuron
must combine potentials from many neurons to fire. This requirement is actually
advantageous: It ensures that a neuron will not be fired by the spontaneous activity of
a single presynaptic neuron, and it allows the neuron to combine multiple inputs into a
more complex message. These potentials are combined at the axon hillock in two
ways. Spatial summation combines potentials occurring simultaneously at different
locations on the dendrites and cell body. Temporal summation combines potentials
arriving a short time apart, from either the same or separate inputs. Temporal
summation is possible because a local potential persists for a few milliseconds.
Spatial summation and temporal summation occur differently, but they have the same
result..
Usually, the transmitter must be inactivated; otherwise, it will continue to
stimulate postsynaptic receptors or leak over to other synapses and interfere with their
functions. Typically, transmitters are taken back into the terminals by membrane
proteins called transporters in a process called reuptake; they are repackaged in
vesicles to be used again. At some synapses, the transmitter in the cleft is absorbed by
nearby astrocytes. In others, transmitters are partially broken down through a process
called inactivation. The neurotransmitter acetylcholine, for example, is inactivated by
the enzyme acetylcholinesterase, which splits the molecule into its components of
choline and acetate. Choline is then taken back into the terminals and used to make
more acetylcholine. Controlling how much neurotransmitter remains in the synapse is
one way to vary behavior, and many drugs capitalize on this mechanism. Cocaine
blocks the reuptake of dopamine; some antidepressant medications block the reuptake
of serotonin, norepinephrine, or both, whereas others (MAO inhibitors) prevent the
enzyme monoamine oxidase from inactivating those transmitters as well as dopamine
and epinephrine; and drugs for treating the muscular disorder myasthenia gravis
increase acetylcholine availability by inhibiting the action of acetylcholinesterase.
The previous description has been of a linear system that amounts to “neuron
A stimulates neuron B, neuron B stimulates neuron C, ” and so on. However, such a
simple system cannot transmit the complex information required to solve a math
equation, write a symphony, or care for a newborn. Not only that, but as messages
flow from neuron to neuron, activity would soon drift out of control; some activity
would fade out, while other activity would escalate until it engulfed an entire area of
the brain. A nervous system that controls complex behavior must have several ways to
regulate its activity. The synapses described so far are referred to as axodendritic and
axosomatic synapses, because their terminals connect to dendrites and cell bodies. At
axoaxonic synapses, a third neuron releases transmitter onto the terminals of the
presynaptic neuron. The result is presynaptic excitation or presynaptic inhibition,
which increases or decreases, respectively, the presynaptic neuron’s release of
neurotransmitter onto the postsynaptic neuron. One way an axoaxonic synapse can
adjust a presynaptic terminal’s activity is by regulating the amount of calcium
entering the terminal, which, you will remember, triggers neurotransmitter release.
Neurons also regulate their own synaptic activity in two ways. Autoreceptors
on the presynaptic terminals sense the amount of transmitter in the cleft; if the amount
is excessive, the presynaptic neuron reduces its output. Postsynaptic neurons
participate in regulation of synaptic activity as well. When there are unusual increases
or decreases in neurotransmitter release, postsynaptic receptors change their
sensitivity or even their numbers to compensate. Glial cells also contribute to the
regulation of synaptic activity. They surround the synapse and prevent
neurotransmitter from spreading to other synapses, but some also remove
neurotransmitter from the synaptic cleft and recycle it for the neuron’s reuse. By
varying the amount of transmitter they remove, glial cells influence postsynaptic
excitability. They can even respond to the neurotransmitter level in the synapse by
releasing transmitters of their own. These gliotransmitters regulate transmitter release
from the presynaptic neuron or directly stimulate the postsynaptic neuron to excite or
inhibit it. Thus, rather than simply being neural “glue” as the name implies, glia
should be considered active partners in neural transmission.
Having a variety of neurotransmitters multiplies the effects that can be
produced at synapses; the fact that there are different subtypes of the receptors adds
even more. For example, two types of receptors detect acetylcholine: the nicotinic
receptor, so called because it is also activated by nicotine, and the muscarinic
receptor, named for the mushroom derivative that can stimulate it. Nicotinic receptors
are excitatory; they are found in muscles and, in lesser numbers, in the brain.
Muscarinic receptors are more frequent in the brain, where they have an excitatory
effect at some locations and an inhibitory one at others. Other transmitters have many
more receptor subtypes than acetylcholine does.
Neurotransmitters are not the only substances that affect the nervous system.
The many drugs and other compounds that mimic or increase the effect of a
neurotransmitter are called agonists. Any substance that reduces the effect of a
neurotransmitter is called an antagonist. Practically all drugs that have a psychological
effect interact with a neurotransmitter system in the brain, and many of them do so by
mimicking or by blocking the effect of neurotransmitters (S. H. Snyder, 1984). You
have already seen that the effect of acetylcholine (ACh) is duplicated by nicotine and
muscarine at the two kinds of acetylcholine receptors (nicotinic-ACh and muscarinic-
ACh, respectively). Opioid drugs such as heroin and morphine also act as agonists,
stimulating receptors for opiate-like transmitters in the body. The drugs naloxone and
naltrexone act as antagonists to opiates, occupying the receptor sites without
activating them; consequently, naloxone and naltrexone can be used to counteract an
overdose. The plant toxin curare blocks nicotinic acetylcholine receptors at the
muscle, causing paralysis (A. Trautmann, 1983). Indigenous tribes of Central and
South America put curare on the tips of their darts and arrows to disable their game. A
synthetic version of curare was used as a muscle relaxant during surgery before safer
and more effective drugs were found (M. Goldberg & Rosenberg, 1987). It was even
used occasionally in the past to treat the muscle spasms of tetanus (lockjaw), which,
ironically, is caused by another neurotoxin.
Underlying this discussion has been the assumption that we can explain
behavior by understanding what neurons do. But we cannot make good on that
promise as long as we talk as if neural communication is limited to single chains of
neurons that either fire or don’t fire. In fact, neurons are capable of generating
complex messages, which they send across intricate networks.
Neurons don’t just produce a train of equally spaced impulses: They vary the
intervals between spikes, they produce bursts of varying lengths, and the bursts can be
separated by different intervals (Cariani, 2004). But do these temporal (time-related)
variations in firing pattern form a code that the brain can use, or are they just “noise”
in the system? The best way to answer this question is to look at sensory processes,
because the researcher can correlate firing patterns with sensory input on one end and
behavior on the other. A good example is an early study done by Patricia Di Lorenzo
and her colleague Gerald Hecht (1993). First, they recorded the firing patterns in
individual taste neurons of rats during stimulation with a sucrose (sugar) solution and
quinine (the flavoring in tonic water)
Individual neurons cannot carry enough information to determine the taste of a
bite of food or the color of an object. Color processing, for example, depends on four
“labeled lines” carrying information about red, green, blue, and yellow light; we can
distinguish millions of colors by comparing the relative activity in these four
pathways. This kind of analysis requires complex interactions among a network of
neurons. Neural networks are groups of neurons that function together to carry out a
process; they are where the most complex neural processing—the “computing” work
of the brain—occurs. Sometimes these networks involve a relatively small number of
neurons in a single area, such as groups of neurons in a part of the brain called the
hippocampus. When rats navigate a maze, these networks store their preceding
choices and calculate their next choice. The networks perform so reliably that the
researcher can use their activity to predict which way the rat will turn after a delay.
c. The Central Nervous System
The nervous system is divided into two subsystems. The central nervous
system (CNS) includes the brain and the spinal cord. Before we go any further, we
need to be sure you understand a couple of terms correctly. As we talk about the
nervous system, be careful not to confuse nerve and neuron. A neuron is a single
neural cell; a nerve is a bundle of axons (the long processes extending from neurons’
cell bodies) running together like a multiwire cable. However, the term nerve is used
only in the peripheral nervous system; inside the CNS, bundles of axons are called
tracts. Most of the neurons’ cell bodies are also clustered in groups; a group of cell
bodies is called a nucleus in the CNS and a ganglion in the PNS.
Each ridge is called a gyrus ; the groove or space between two gyri is called a
sulcus or, if it is large, a fissure. The outer surface is the cortex (literally, “bark”),
which is made up mostly of the cell bodies of neurons; because cell bodies lack
myelin, the cortex looks grayish in color, which is why it is referred to as gray matter.
Remember that neural processing occurs where neurons synapse onto other neurons,
which indicates why the cortex is so important. The cortex is only 1.5 to 4 millimeters
(mm) thick, but the convolutions increase the amount of cortex by tripling the surface
area. The convolutions also provide the axons with easier access to the cell bodies
than if the developing cortex thickened instead of wrinkling. The axons come together
in the central core of each gyrus, where their myelination gives the area a whitish
appearance. Notice how the white matter of each gyrus joins with the white matter of
the next gyrus, creating the large bands of axons that serve as communication routes,
both within each hemisphere and between the two hemispheres.
You’ve overslept, and now you find yourself running to your early morning
test, fretting about being late while rehearsing answers to the questions you expect on
the exam. You interrupt your thoughts only when you have to dodge a bicyclist; your
heart rate increases even further with your anger at the student for riding on the
sidewalk. Do you ever wonder how your brain pulls all this off? It will take the rest of
this text to start answering that question, but this is a good time to mention two ways
the brain’s organization helps it be more efficient. First, the cortex in humans and
most mammals is arranged in layers; the number of layers is usually six, though a
particular layer may be absent in some areas. The layers stand out from each other
because they are separated by fibers that serve the cell bodies, but they also differ in
appearance: They vary in type and size of cells and in the concentration of cell bodies
versus axons. There are differences in function as well. Some researchers have
concluded that Layer I is inhibitory, II and III are associational, IV is sensory, and V
and VI have motor functions.
Second, the cells of the cortex are organized into groups of 80 to 100
interconnected neurons, which are arranged in columns running perpendicular to the
cortical surface. They provide a vertical unification of the cortex’s horizontal layers,
which contributes to their role as the primary information-processing unit in the
cortex. The cells in a column have a similar function; for example, they may receive
input from the same area on the skin’s surface, while surrounding columns serve
adjacent locations. In the visual cortex, the cells in a column may detect object edges
at a particular orientation, while surrounding columns respond to edges at a slightly
different orientation. Having similar functions grouped close together in well-
connected columns helps the brain work quickly and efficiently. Students often ask
whether intelligent people have bigger brains. Bischoff, the leading European
anatomist in the 19th century, argued that the greater average weight of men’s brains
was infallible proof of their intellectual superiority over women. When he died, his
brain was removed and added to his extensive collection, as his will had specified;
ironically, it weighed only 1,245 grams (g), less than the average of about 1,250 g for
women, but the relationship is small and highly variable. What this means is that
factors other than brain size are more important; otherwise, women would be less
intelligent than men, as Bischoff claimed, but we know from research that this is not
the case.
When we look across species, brain size is more related to body size than to
intelligence; the brains of elephants and sperm whales are five to six times larger than
ours. It is a brain’s complexity, not its size, that determines its intellectual power. You
can see two features that distinguish more complex, more highly evolved brains from
less complex ones. One is that the higher brains have more gyri, which means more
surface area and, therefore, more cortex. The other is that the cerebral hemispheres are
larger in proportion to the rest of the brain. It is no accident that the cerebral
hemispheres are perched atop the rest of the brain and the spinal cord. The CNS is
arranged in a hierarchy; as you ascend from the spinal cord through the hindbrain and
midbrain to the forebrain, the neural structures become more complex, and so do the
behaviors they control.
Each of the lobes contains association areas, which carry out further
processing beyond what the primary area does, often combining information from
other senses. Parietal lobe association areas, for example, receive input from the body
senses and from vision; they help the person identify objects by touch, determine the
location of the limbs, and locate objects in space. Damage to the posterior parietal
cortex may produce neglect, a disorder in which the person ignores objects, people,
and activity on the side opposite the damage. This occurs much more frequently when
the damage is in the right parietal lobe. The person may fail to shave or apply makeup
on the left side of the face. In some cases, a stroke patient with a paralyzed arm or leg
will deny that anything is wrong and even claim that the affected limb belongs to
someone else. The lateral fissure separates the temporal lobe from the frontal and
parietal lobes. The temporal lobes contain the auditory projection area, visual and
auditory association areas, an additional language area, and structures important in
learning and memory. The auditory cortex, which receives sound information from the
ears, lies on the superior (uppermost) gyrus of the temporal lobe, mostly hidden from
view within the lateral fissure. Just posterior to the auditory cortex is Wernicke’s area,
an association area that interprets language input arriving from the nearby auditory
and visual areas; it also generates spoken language through Broca’s area and written
language by way of the motor cortex. When Wernicke’s area is damaged, the person
has trouble understanding speech or writing; the person can still speak, but the speech
is mostly meaningless. Like Broca’s area, this structure is found in the left hemisphere
in most people.
The inferior temporal cortex, in the lower part of the lobe, as the name
implies, plays a major role in the visual identification of objects. People with damage
in this area have difficulty recognizing familiar objects by sight, even though they can
give detailed descriptions of the objects. They have no difficulty identifying the same
items by touch. They may also fail to recognize the faces of friends and family
members, though they can identify people by their voices. The neurologist Oliver
Sacks (1990) described a patient who talked to parking meters, thinking they were
children. Considering his strange behavior, it seems remarkable that he was
unimpaired intellectually. As you read about cases like this one and hear of patients
who do things like denying ownership of their paralyzed leg, you may begin to
understand that human capabilities are somewhat independent of each other because
they depend on different parts of the brain. When the neurosurgeon Wilder Penfield
(1955) stimulated patients’ temporal lobes, he often elicited what appeared to be
memories of visual and auditory experiences. Penfield was doing surgery to remove
malfunctioning tissue that was causing epileptic seizures. Before the surgery, Penfield
would stimulate the area with a weak electrical current and observe the effect; this
allowed him to distinguish healthy tissue and important functional areas from the
diseased tissue he wished to remove.
Deep within the brain, the thalamus lies just below the lateral ventricles, where
it receives information from all the sensory systems except olfaction (smell) and
relays it to the respective cortical projection areas. Many other neurons from the
thalamus project more diffusely throughout the cortex and help arouse the cortex
when appropriate. There are actually two thalami, a right and a left, lying side by side.
The hypothalamus, a smaller structure just inferior to the thalamus, plays a
major role in controlling emotion and motivated behaviors, such as eating, drinking,
and sexual activity. The hypothalamus exerts this influence largely through its control
of the autonomic nervous system, which we will consider shortly. The hypothalamus
also influences the body’s hormonal environment through its control over the pituitary
gland. The pituitary is known as the master gland because its hormones control other
glands in the body. The hypothalamus, which, like the thalamus, is paired, contains
perhaps the largest concentration of nuclei important to behavior in the entire brain.
If you were to look inside the longitudinal fissure between the two cerebral
hemispheres, you would see that the hemispheres are distinctly separate from each
other. A couple of inches below the brain’s surface, the longitudinal fissure ends in the
corpus callosum, a dense band of fibers that carry information between the
hemispheres. You know that the two hemispheres carry out somewhat different
functions, so you can imagine that they must communicate with each other constantly
to integrate their activities. In addition, incoming information is often directed to one
hemisphere—visual information appearing to one side of your field of view goes to
the hemisphere on the opposite side, just as information from one side of your body
does. This information is “shared” with the other hemisphere through the crossing
fibers, especially the corpus callosum; the car that is too close on your left is
registered in your right hemisphere, but if you are steering with your right hand, it is
your left hemisphere that must react.
Occasionally, surgeons have to sever the corpus callosum in patients with
incapacitating epileptic seizures that cannot be controlled by drugs or other
treatments. The surgery prevents the out-of-control neural activity in one hemisphere
from engulfing the other hemisphere as well. The patient is then able to maintain
consciousness during seizures and to lead a more normal life. These patients have
been very useful for studying differences in the functions of the two hemispheres,
because a stimulus can be presented to one hemisphere and the information will not
be shared with the other hemisphere. Studies of these individuals have helped
establish, for example, that the left hemisphere is more specialized for language than
the right hemisphere and that the right hemisphere is better at spatial tasks and
recognizing faces.
d. The Peripheral Nervous System
The peripheral nervous system (PNS) is made up of the cranial nerves, which
enter and leave the underside of the brain, and the spinal nerves, which connect to the
sides of the spinal cord at each vertebra. From a functional perspective, the PNS can
be divided into the somatic nervous system and the autonomic nervous system. The
somatic nervous system includes the motor neurons that operate the skeletal muscles
—that is, the ones that move the body—and the sensory neurons that bring
information into the CNS from the body and the outside world. The autonomic
nervous system (ANS) controls smooth muscle (stomach, blood vessels, etc.), the
glands, and the heart and other organs. We dealt with the spinal nerves when we
discussed the spinal cord, and we have said all we need to for now about the somatic
system, so we will give the rest of our attention to the cranial nerves and the ANS.
The cranial nerves enter and exit from the ventral side of the brain. Whereas
the spinal nerves are concerned exclusively with sensory and motor activities within
and on the surface of the body, some of the cranial nerves convey sensory information
to the brain from the outside world. Two of these, the olfactory nerves and the optic
nerves, are often considered part of the brain. One reason for this special status is the
brainlike complexity of the olfactory bulb and of the retina at the back of the eye;
another is that their receptor cells originate in the brain during development and
migrate to their final locations. As a consequence, the olfactory and optic nerves are
sometimes referred to as tracts.
The functions of the ANS are primarily motor; its sensory pathways provide
internal information for regulating its own operations. The ANS is composed of two
branches. The sympathetic nervous system activates the body in ways that help it cope
with demands such as emotional stress and physical emergencies. Your most recent
emergency may have been when you overslept on the morning of a big exam. As you
raced to class, your heart and breathing sped up to provide your body the resources it
needed. Your blood pressure increased as your peripheral blood vessels constricted,
shifting blood supply to the internal organs and your brain. Your muscles tensed to
help you act, and your sweat glands started releasing sweat to cool your suddenly
overheating body. All this activity was just the sympathetic nervous system at work.
The parasympathetic nervous system, on the other hand, slows the activity of most
organs to conserve energy but also activates digestion to renew energy. These two
systems act like a seesaw; when one increases in activity, the other decreases.
e. Development and Change in the Nervous System
Nothing rivals the human brain in complexity, which makes the development
of the brain the most remarkable construction project that you or we can imagine.
During development, its 100 billion neurons must find their way to destinations
throughout the brain and the spinal cord; then they must make precise connections to
an average of 1,000 target cells each. How this is accomplished is one of the most
intriguing mysteries of neurology, but it is a mystery that is being solved a little at a
time.
You already know that the nervous system begins as a hollow tube that later
becomes the brain and the spinal cord. The nervous system begins development when
the surface of the embryo forms a neural groove. The edges of this groove curl
upward until they meet, turning the groove into a neural tube. Development of the
nervous system then proceeds in four distinct stages: cell proliferation, migration,
circuit formation, and circuit pruning.
During proliferation, the cells that will become neurons divide and multiply at
the rate of 250,000 new cells every minute. Proliferation occurs in the ventricular
zone, the area surrounding the hollow tube that will later become the ventricles and
the central canal. During migration, these newly formed neurons move from the
ventricular zone to their final location; most of them move perpendicularly from the
ventricular surface using specialized radial glial cells. An overabundance of neurons
migrating into the cortical layers beginning around Week 11 of development causes it
to start wrinkling and developing the characteristic sulci and gyri seen in the adult
brain. This is where development went awry in her brain. The neurons that would
have formed her cortex failed to migrate properly and got off their radial glial cell
scaffolds too early (J. W. Fox et al., 1998). How neurons move had been unclear until
recent efforts (described in A Further Look) revealed a fascinating mechanism.
During circuit formation, the axons of developing neurons grow toward their
target cells and form functional connections. For example, axons of motor neurons
grow toward the spinal cord, and cells in the retina of the eye send their axons to the
thalamus, where they form synapses with other neurons. To find their way, axons
form growth cones at their tip, which sample the environment for directional cues.
Chemical and molecular signposts attract or repel the advancing axon, coaxing it
along the way. By pushing, pulling, and hemming neurons in from the side, the
chemical and molecular forces guide the neurons to intermediate stations and past
inappropriate targets until they reach their final destinations.
The path to the developing axon’s destination is not necessarily direct, but
thanks to changing genetic control, it is able to make direction changes along the way.
This is most strongly illustrated by an axon whose destination is on the opposite side
of the midline. Ordinarily, a migrating axon will grow parallel to the midline without
crossing over, because it is repelled by a midline chemical that is under the control of
the gene Robo1. But at the appropriate location, the gene Robo3 becomes active; the
axon is then attracted to the midline and turns and enters it. At that point, Robo3 is
downregulated; the axon is repelled again and, continuing in the same direction, exits
the midline and will not recross.
The brain produces extra neurons, apparently as a means of compensating for
the errors that occur in reaching targets. This overproduction is not trivial: The
monkey’s visual cortex contains 35% more neurons at the time of birth than in
adulthood, and the number of axons crossing the corpus callosum is four times what it
will be later in life. The next stage of neural development, circuit pruning, involves
the elimination of excess neurons and synapses. Neurons die if they are unsuccessful
in finding a place on a target cell, are crowded off by a more active neuron, or arrive
late; the monkey’s corpus callosum alone loses 8 million neurons per day during the
first 3 weeks after birth. In a second step of circuit pruning, the nervous system
refines its organization and continues to correct errors by eliminating large numbers
of excessive synapses. For example, in mature mammals, neurons from the left and
right eyes project to alternating columns of cells in the visual cortex, but the
connections made during development are indiscriminate. Synapses are strengthened
or weakened depending on whether the presynaptic neuron and the postsynaptic
neuron fire together, which increases the acuity of the visual system. Because a single
neuron cannot by itself cause another neuron to fire, this is likely to happen when
neighboring neurons are also firing and adding summating inputs through overlapping
terminals. If a neuron is not firing at the same time as its neighbors, it has probably
made its connection in the wrong neighborhood. It is thought that the postsynaptic
neuron sends feedback to the presynaptic terminals in the form of neurotrophins,
chemicals that enhance the development and survival of neurons.
