Science Brain and Behavior contiuned 18

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HOW DO NEURONS COMMUNICATE AND ADAPT? ! 171
The Case of the Frozen Addict
Focus on Disorders
Patient 1: During the first 4 days of July 1982, a 42-
year-old man used 41/2 grams of a “new synthetic
heroin.” The substance was injected intravenously
three or four times daily and caused a burning sensation
at the site of injection. The immediate effects
were different from heroin, producing an unusual
“spacey” high as well as transient visual distortions
and hallucinations. Two days after the final injection,
he awoke to find that he was “frozen” and
could move only in “slow motion.” He had to
“think through each movement” to carry it out. He
was described as stiff, slow, nearly mute, and catatonic
during repeated emergency room visits from
July 9 to July 11. He was admitted to a psychiatric
service on July 15, 1982, with a diagnosis of “catatonic
schizophrenia” and was transferred to our
neurobehavioral unit the next day. (Ballard et al.,
1985, p. 949)
This patient was one of seven young adults hospitalized at
about the same time in California. All showed symptoms of
severe Parkinson’s disease that appeared very suddenly after
drug injection and are extremely unusual in people their
age. All reportedly injected a synthetic heroin that was being
sold on the streets in the summer of 1982.
An investigation by J. William Langston and his colleagues
(Bjorklund, Lindvall, & Langston, 1992) found that the
heroin contained a contaminant called MPTP (1-methyl-4-
phenyl-1,2,3,6-tetrahydropyridine) resulting from poor preparation
during its synthesis. The results of experimental studies
in rodents showed that MPTP was not itself responsible for
the patients’ symptoms but was metabolized into MPP!
(1-methyl-4-phenylpyridinium), a neurotoxin.
In one autopsy of a suspected case of MPTP poisoning,
the victim suffered a selective loss of dopamine neurons in
the substantia nigra. The rest of the brain was normal. Injection
of MPTP into monkeys produced similar symptoms
and a similar selective loss of DA neurons in the substantia
nigra. Thus, the combined clinical and experimental
evidence indicates that Parkinson’s disease can be
induced by a toxin that selectively kills dopamine neurons
in the brainstem.
In 1988, Patient 1 received an experimental treatment
at University Hospital in Lund, Sweden. Dopamine neurons
taken from human fetal brains at autopsy were implanted
into the caudate and putamen. Extensive work with
rodents and nonhuman primates in a number of laboratories
had demonstrated that fetal neurons, which have
not yet developed dendrites and axons, can survive transplantation
and grow into mature neurons that can secrete
neurotransmitters.
Patient 1 had no serious postoperative complications
and was much improved 24 months after the surgery. He
could dress and feed himself, visit the bathroom with help,
and make trips outside his home. He also responded much
better to medication. The transplantation of fetal neurons to
treat Parkinson’s disease continues to be an area of active research
worldwide.
Positron emission tomographic (PET) images of Patient 1’s brain
before the implantation of fetal dopamine neurons (left) and 12
months after this operation (right). The increased area of red
and gold shows that the transplanted neurons are producing
DA. From “Bilateral Fetal Mesencephalic Grafting in Two Patients with
Parkinsonism Induced by 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyradine (MPTP),”
by H. Widner, J. Tetrud, S. Rehngrona, B. Snow, P. Brundin, B. Gustavii, A.
Bjorklund, O. Lindvall, and J. W. Langston, 1992, New England Journal of
Medicine, 327, p. 151.
Dr. Hakan Widner, M.D., PhD.,
Lord University, Sweden
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NORADRENERGIC SYSTEM
The term noradrenergic is derived from adrenaline, the Latin name for epinephrine.
Norepinephrine (noradrenalin) may play a role in learning by stimulating neurons to
change their structure. It may also facilitate normal development of the brain and play
a role in organizing movements.
In the main, behaviors and disorders related to the noradrenergic system concern
the emotions and have been difficult to identify. Some symptoms of depression may be
related to decreases in the activity of noradrenergic neurons, whereas some of the
symptoms of mania (excessive excitability) may be related to increases in the activity
of these same neurons.
SEROTONERGIC SYSTEM
The serotonergic system is active in maintaining a waking EEG in the forebrain when
we move and thus plays a role in wakefulness, as does the cholinergic system. Serotonin
also plays a role in learning, as described in the next section. Some symptoms
of depression may be related to decreases in the activity of serotonin neurons, and
drugs commonly used to treat depression act on serotonin neurons. Consequently, two
forms of depression may exist, one related to norepinephrine and another related to
serotonin.
The results of some research suggest that some symptoms of schizophrenia also
may be related to increases in serotonin activity, which implies that there may be different
forms of schizophrenia as well. Increased serotonergic activity is also related to
symptoms observed in obsessive-compulsive disorder (OCD), a condition in which a
person compulsively repeats acts (such as hand washing) and has repetitive and often
unpleasant thoughts (obsessions).
ROLE OF SYNAPSES IN LEARNING AND MEMORY
Experience actually alters the synapse, because not only are synapses versatile in structure
and function, they are also adaptable, or plastic: they can change. The synapse,
therefore, provides a potential site for the neural basis of learning, a relatively permanent
change in behavior that results from experience. Structural changes in synapses underlie
the three simple learning behaviors examined in this section. In Chapter 13, we
take up learning and memory again. And Experiments and Focus boxes throughout the
In Review .
Although neurons can synthesize more than one neurotransmitter, they are usually identified
by the principal neurotransmitter in their axon terminals. Although there is no oneto-
one relation between any neurotransmitter and any behavior, some neurotransmitters
take part in specific behaviors that may occur only periodically, such as acting as hormones
to stimulate reproduction. Other CNS neurotransmitters continuously monitor vegetative
behaviors. Neural activating systems modulate aspects of behavior. Acetylcholine
produces muscular contractions in the SNS, and acetylcholine and norepinephrine regulate
the complementary divisions of the ANS. The CNS contains not only widely dispersed
glutamate (excitatory) and GABA (inhibitory) neurons but also activating systems of acetylcholine,
norepinephrine, dopamine, and serotonin. These neuromodulatory systems are
associated both with specific aspects of behavior and with specific neurological disorders.
172 ! CHAPTER 5
Noradrenergic neuron. From
adrenaline, Latin for epinephrine; a
neuron containing norepinephrine.
Obsessive-compulsive disorder
(OCD). Behavioral disorder characterized
by compulsively repeated acts (such as
hand washing) and repetitive, often
unpleasant, thoughts (obsessions).
Learning. Relatively permanent change
in behavior that results from experience.
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book often revisit neuroplasticity, the nervous system’s adaptability
and potential for self-repair.
Donald O.Hebb (1949) was not the first to suggest that learning is
mediated by structural changes in synapses. But the change that he envisioned
in his book titled The Organization of Behavior was novel half
a century ago.Hebb theorized: “When an axon of cell A is near enough
to excite a cell B and repeatedly or persistently takes part in firing it,
some growth process or metabolic change takes place in one or both
cells such that A’s efficiency, as one of the cells firing B, is increased” (Hebb, 1949, p. 62).
Hebb’s proposal was untestable when he developed it but has been supported
through the succeeding decades as research methods have advanced. Eric Kandel
(1976) and many other neuroscientists have demonstrated that learning does often require
the joint firing of two neurons, which increases the efficiency of their synapses.
A synapse that physically adapts in this way is called a Hebb synapse today.
Increased efficiency at the Hebb synapse is the structural basis for new behavior,
or learning. To explain the neurological basis of simple kinds of learning, Kandel and
others have studied an animal with a relatively simple nervous system. Their subject,
the marine snail Aplysia californica shown in Figure 5-18, is an ideal subject for learning
experiments. Slightly larger than a softball and lacking a shell, Aplysia has roughly
20,000 neurons, some of which are quite accessible to researchers, who can isolate and
study circuits having very few synapses.
When threatened,Aplysia defensively withdraws its more vulnerable body parts—
the gill (through which it extracts oxygen from the water to breathe) and the siphon (a
spout above the gill that excretes seawater and waste). By touching or shocking the
snail’s appendages, researchers can produce enduring changes in its defensive behaviors.
These behavioral responses can then be used to study underlying changes in the
snail’s nervous system.
At the microscopic level, the physical structure of synapses adapts as a response to
learning. The learned responses that we will now describe—habituation, sensitization,
and associative learning—employ neural mechanisms of which you already know.
Learned responses also underlie behaviors that you will recognize.
Habituation Response
In habituation, the response to a stimulus weakens with repeated presentations of that
stimulus. If you are accustomed to living in the country and then move to a city, you might
at first find the sounds of traffic and people extremely loud and annoying. With time,
however, you stop noticing most of the noise most of the time.You have habituated to it.
Habituation develops with all our senses.When you first put on a shoe, you “feel”
it on your foot, but very shortly it is as if the shoe is no longer there. You have not become
insensitive to sensations, however.When people talk to you, you still hear them;
when someone steps on your foot, you still feel the pressure. Your brain has habituated
to the customary, “background” sensations.
Aplysia habituates to waves in the shallow tidal zone where it lives. These snails are
constantly buffeted by the flow of waves against their bodies, and they learn that waves
are just the background “noise” of daily life. They do not flinch and withdraw every
time a wave passes over them. They habituate to this stimulus.
A sea snail that is habituated to waves remains sensitive to other touch sensations.
Prodded with a novel object, it responds by withdrawing its siphon and gill. The
animal’s reaction to repeated presentations of the same novel stimulus forms the basis
for Experiment 5-2, studying its habituation response.
HOW DO NEURONS COMMUNICATE AND ADAPT? ! 173
Neuroplasticity. The nervous
system’s potential for neurophysical or
neurochemical change that enhances its
adaptability to environmental change and
its ability to compensate for injury.
Habituation. Learning behavior in
which a response to a stimulus weakens
with repeated stimulus Donald O. Hebb presentations.
(1904–1985)
Figure 5-18
Aplysia Californica
Jeff Rotman
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174 ! CHAPTER 5
NEURAL BASIS OF HABITUATION
The Procedure section of Experiment 5-2 shows the setup for studying what happens
to the withdrawal response of Aplysia’s gill after repeated stimulation. A gentle jet of
water is sprayed on the siphon while movement of the gill is recorded. If the jet of water
is presented to Aplysia’s siphon as many as 10 times, the gill-withdrawal response is
weaker some minutes later when the animal is again tested with the water jet. The
decrement in the strength of the withdrawal is habituation, which can last as long as
30 min.
The Results section of Experiment 5-2 starts by showing a simple representation
of the pathway that mediates Aplysia’s gill-withdrawal response. For purposes of illustration,
only one sensory neuron, one motor neuron, and one synapse are shown, even
though, in actuality, about 300 neurons may take part in this response. The jet of water
stimulates the sensory neuron, which in turn stimulates the motor neuron responsible
for the gill withdrawal. But exactly where do the changes associated with habituation
take place? In the sensory neuron? In the motor neuron? Or in the synapse between
the two?
Habituation does not result from an inability of either the sensory or the motor
neuron to produce action potentials. In response to direct electrical stimulation, both
the sensory neuron and the motor neuron retain the ability to generate action potentials
even after habituation. Electrical recordings from the motor neuron show that, accompanying
the development of habituation, the excitatory postsynaptic potentials in
the motor neuron become smaller.
The most likely way in which these EPSPs decrease in size is that the motor neuron
is receiving less neurotransmitter from the sensory neuron across the synapse.And,
if less neurotransmitter is being received, then the changes accompanying habituation
must be taking place in the presynaptic axon terminal of the sensory neuron.
Presynaptic
membrane
Postsynaptic membrane
Ca2+
Ca2+
1
…resulting in less
neurotransmitter
released at the
presynaptic
membrane...
2
…and less depolarization
of the postsynaptic
membrane.
3
Withdrawal response weakens with repeated presentation
of water jet (habituation) owing to decreased Ca2+ influx
and subsequently less neurotransmitter release.
Conclusion
Question: What happens to gill response after repeated stimulation?
EXPERIMENT 5-2
The sensory neuron stimulates
the motor neuron to produce gill
withdrawal before habituation.
Skin of
siphon
Sensory neuron
Motor neuron
Gill
muscle
Procedure
Results
Siphon
Water jet
After
repeated
stimulation
Gill withdraws
from water jet.
1
Gill no longer
withdraws
from water jet,
demonstrating
habituation.
2
With habituation, the influx
of calcium ions in response to an
action potential decreases,…
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HOW DO NEURONS COMMUNICATE AND ADAPT? ! 175
CALCIUM CHANNELS HABITUATE
Kandel and his coworkers measured neurotransmitter output from a sensory neuron
and verified that less neurotransmitter is in fact released from a habituated neuron than
from a nonhabituated one. Recall that the release of a neurotransmitter in response to
an action potential requires an influx of calcium ions across the presynaptic membrane.
As habituation takes place, that calcium ion influx decreases in response to the
voltage changes associated with an action potential. Presumably,with repeated use, calcium
channels become less responsive to voltage changes and more resistant to the passage
of calcium ions.
Why this happens is not yet known.At any rate, the neural basis of habituation lies
in the presynaptic response. Its mechanism, which is summarized in the right-hand
closeup of Experiment 5-2, is a reduced sensitivity of calcium channels and a consequent
decrease in the release of a neurotransmitter. This reduced sensitivity of calcium
channels in response to voltage changes produces habituation, as summarized in the
Conclusion section of the experiment.
Sensitization Response
A sprinter crouched in her starting blocks is often hyperresponsive to the starter’s gun;
its firing triggers in her a very rapid reaction. The stressful, competitive context in
which the race takes place helps to sensitize her to this sound. Sensitization, an enhanced
response to some stimulus, is the opposite of habituation. The organism becomes
hyperresponsive to a stimulus rather than accustomed to it.
Sensitization occurs within a context. Sudden, novel stimulation heightens our
general awareness and often results in larger-than-normal responses to all kinds of
stimulation. If you are suddenly startled by a loud noise, you become much more responsive
to other stimuli in your surroundings, including some to which you had been
previously habituated.
The same thing happens to Aplysia. Sudden, novel stimuli can heighten a snail’s
responsiveness to familiar stimulation.When attacked by a predator, for example, the
snail becomes acutely aware of other changes in its environment and hyperresponds to
them. In the laboratory, a small electric shock to Aplysia’s tail mimics a predatory attack
and effects sensitization, as illustrated in the Procedure section of Experiment 5-3.
A single electric shock to the tail of Aplysia enhances its gill-withdrawal response for a
period that lasts from minutes to hours.
NEURAL BASIS OF SENSITIZATION
The neural circuits participating in sensitization are a little more complex than those
that take part in a habituation response. To simplify the picture, the Results section of
Experiment 5-3 shows only one of each kind of neuron: the sensory and motor neurons
already described that produce the gill-withdrawal response and an interneuron
that is responsible for sensitization.
An interneuron that receives input from a sensory neuron in the tail (and so carries
information about the shock) makes an axoaxonic synapse with a siphon sensory neuron.
The interneuron’s axon terminal contains serotonin. Consequently, in response to
a tail shock, the tail sensory neuron activates the interneuron, which in turn releases
serotonin onto the axon of the siphon sensory neuron. Information from the siphon still
comes through the siphon sensory neuron to activate the motor neuron leading to the
gill muscle, but the gill-withdrawal response is amplified by the action of the interneuron
in releasing serotonin onto the presynaptic membrane of the sensory neuron.
Sensitization. Learning behavior in
which the response to a stimulus
strengthens with repeated presentations of
that stimulus because the stimulus is
novel or because the stimulus is stronger
than normal—for example, after
habituation has occurred.
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176 ! CHAPTER 5
At the molecular level, the serotonin released from the interneuron binds to a
metabotropic serotonin receptor on the axon of the siphon sensory neuron. This binding
activates second messengers in the sensory neuron. Specifically, the serotonin receptor
is coupled through its G protein to the enzyme adenyl cyclase. This enzyme
increases the concentration of the second messenger cyclic adenosine monophosphate
(cAMP) in the presynaptic membrane of the siphon sensory neuron.
Through a number of chemical reactions, cAMP attaches a phosphate molecule
(PO4) to potassium (K!) channels, and the phosphate renders the K! channels less responsive.
The closeup on the right side of the Results section in Experiment 5-3 sums
it up. In response to an action potential traveling down the axon of the siphon sensory
neuron (such as one generated by a touch to the siphon), the K! channels on that neuron
are slower to open. Consequently, potassium ions cannot repolarize the membrane
as quickly as is normal, and so the action potential lasts a little longer than it usually
would.
POTASSIUM CHANNELS SENSITIZE
The longer-lasting action potential prolongs the inflow of Ca2! into the membrane. The
increased concentration of Ca2! in turn results in more neurotransmitter being released
from the sensory synapse onto the motor neuron that leads to the gill muscle. This increased
release of neurotransmitter produces a larger-than-normal gill-withdrawal response.
The gill withdrawal may also be enhanced by the fact that the second messenger
cAMP may mobilize more synaptic vesicles, making more neurotransmitter ready for
release into the sensory–motor synapse.
Sensitization, then, is the opposite of habituation at the synaptic level as well as at
the behavioral level. In sensitization, more calcium influx results in more transmitter
Ca2+
3
2
1
Serotonin reduces K+ efflux through
potassium channels, prolonging an action
potential on the siphon sensory neuron.
…causing greater
depolarization of
the postsynaptic
membrane after
sensitization.
The prolonged
action potential
results in more
Ca2+ influx and
increased
transmitter
release,...
K+
Interneuron
Serotonin Motor
neuron
Sensory
neuron
Second
messenger
Gill withdrawal
Water jet
Enhancement of the withdrawal response after a shock is due to increased
Ca2+ influx and subsequently more neurotransmitter release.
Conclusion
Shock
Skin of
siphon
Sensory
neuron
Interneuron
Motor
neuron Gill
muscle
An interneuron receives input from a “shocked”
sensory neuron in the tail and releases serotonin
onto the axon of a siphon sensory neuron.
A single shock to the tail
enhances the gill-withdrawal
response (sensitization).
Question: What happens to gill response in sensitization?
EXPERIMENT 5-3
Procedure
Results
-
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HOW DO NEURONS COMMUNICATE AND ADAPT? ! 177
being released, whereas, in habituation, less calcium influx results in less neurotransmitter
being released. The structural basis of cellular memory in these two forms of
learning is different, however. In sensitization, the change takes place in potassium
channels, whereas, in habituation, the change takes place in calcium channels.
Long-Term Potentiation and
Associative Learning
The findings from studies of habituation and sensitization in Aplysia show that physical
changes in synapses do underlie simple forms of learning. In this section, we look
at experiments that demonstrate how adaptive synapses participate in learning in the
mammalian brain. Such associative learning, a response elicited by linking unrelated
stimuli together—by learning that A goes with B—is very common.
Associating a telephone number with a person, an odor with a food, or a sound
with a musical instrument are everyday examples of associative learning.Your learning
that learning takes place at synapses is another example. The phenomenon that underlies
associative learning entails a neural change in which an excitatory signal crossing
a synapse is enhanced long after use.
NEURAL BASIS OF ASSOCIATIVE LEARNING
We begin in the forebrain structure called the hippocampus (see Figure 2-20). The limbic
cortex of the mammalian hippocampus has only three layers, rather than the six
layers in the neocortex. The neurons in one of these limbic layers are packed closely together,
which aligns their dendrites and cell bodies. This arrangement allows summed
EPSPs from many of these neurons—sums known as field potentials—to be recorded
quite easily with extracellular electrodes.
Both the relatively simple circuitry of the hippocampus and the ease of recording
large field potentials there make it an ideal structure for studying the neural basis of
learning. In 1973, Timothy Bliss and Terje Lømø demonstrated that repeated electrical
stimulation of the perforant pathway entering the hippocampus produces a progressive
increase in field-potential size recorded from hippocampal cells. This enhancement in
the size of the field potentials lasts for a number of hours to weeks or even longer. Bliss
and Lømø called it long-term potentiation (LTP).
The fact that LTP lasts for some time after stimulation suggests two things:
1. At the synapse, a change must take place that allows the field potential to become
larger and remain larger.
2. The change at the synapse might be related to everyday learning experiences.
Long-term potentiation can be recorded at many synapses in the nervous system,
but the hippocampus, because of its simple structure, continues to be a favorite location
for study. Figure 5-19A illustrates the experimental procedure for a typical synapse. The
presynaptic neuron is stimulated electrically while the electrical activity produced by the
stimulation is recorded from the postsynaptic neuron. The inset in Figure 5-19A shows
the EPSP produced by a single pulse of electrical stimulation.
In a typical experiment, a number of test stimuli are given to estimate the size of
the induced EPSP.Then a strong burst of stimulation, consisting of a few hundred pulses
of electrical current per second, is administered. Then the test pulse is given again. Figure
5-19B illustrates that the increased amplitude of the EPSP remains larger for as long
as 90 min after the high-frequency burst of stimulation.
Associative learning. Linkage of two
or more unrelated stimuli to elicit a
behavioral response.
Long-term potentiation (LTP). In
response to stimulation at a synapse,
changed amplitude of an excitatory
postsynaptic potential that lasts for hours
to days or longer and plays a part in
associative learning.
0.0
0.4
Time (min)
0 30 60 90 120
Amplitude of EPSP
Record
Postsynaptic
neuron
Presynaptic
neuron
Stimulate
Burst of
strong stimulation
0.2
(B)
(A)
Each dot represents
the amplitude of the
EPSP in response to one
weak test stimulation.
Postsynaptic
EPSP
Figure 5-19
Recording Long-Term Potentiation
(A) In this experimental setup, the
presynaptic neuron is stimulated with a
test pulse and the EPSP is recorded from
the postsynaptic neuron. (B) After a
period of intense stimulation, the
amplitude of the EPSP produced by the
test pulse increases.
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178 ! CHAPTER 5
The high burst of stimulation has produced a long-lasting change in the response
of the postsynaptic neuron: LTP has occurred. For the EPSP to increase in size, either
more neurotransmitter must be released from the presynaptic membrane or the postsynaptic
membrane must become more sensitive to the same amount of transmitter.
So the question is,What mechanism enables this change?
NEUROCHEMISTRY OF LTP
To examine the possible synaptic changes underlying LTP, we turn to the results of
some experiments concerning glutamate at the terminals of hippocampal neurons.
Glutamate acts on two different types of receptors on the postsynaptic membrane,
NMDA (N-methyl-D-aspartate) and AMPA (alpha-amino-3-hydroxy-5-methylisoazole-
4-proprionic acid) receptors. As Figure 5-20A shows, AMPA receptors ordinarily
mediate the responses produced when glutamate is released from a presynaptic membrane.
NMDA receptors usually do not respond to glutamate, because their pores are
blocked by magnesium ions (Mg2!).
However, NMDA receptors are doubly gated channels that can open to allow the
passage of calcium ions if two events take place at approximately the same time:
1. The postsynaptic membrane is depolarized by strong electrical stimulation, displacing
the magnesium ion from the NMDA pore (Figure 5-20B).
2. NMDA receptors are activated by glutamate from the presynaptic membrane (Figure
5-20C).
With the doubly gated NMDA channels open, calcium ions enter the postsynaptic
neuron and act through second messengers to initiate the cascade of events associated
with LTP. These events include increased responsiveness of AMPA receptors to glutamate,
formation of new AMPA receptors, and even retrograde messages to the presynaptic
terminal to enhance glutamate release.
Hippocampal NMDA receptors thus mediate a change that in every way meets the
criteria for a Hebb synapse. The synapse changes with use. The familiar part of the
story is that calcium ions take part, just as in learning in Aplysia. The NMDA receptor
change is associative in that two different stimuli—the initial strong electrical stimula-
Because the NMDA receptor pore is
blocked by a magnesium ion, release of
glutamate by a weak electrical
stimulation activates only the AMPA
receptor.
A strong electrical stimulation can
depolarize the postsynaptic membrane
sufficiently that the magnesium ion is
removed from the NMDA receptor pore.
Now glutamate, released by weak
stimulation, can activate the NMDA
receptor to allow Ca2+ influx, which,
through a second messenger, increases
the function or number of AMPA
receptors or both.
Magnesium ion
Glutamate Calcium ions
NMDA receptor
Presynaptic
neuron
Postsynaptic
neuron
AMPA receptor AMPA
receptor
NMDA
receptor
AMPA
receptor
NMDA receptor
Calcium ions
(A) Weak electrical stimulus (B) Strong electrical stimulus (depolarizing EPSP) (C) Weak electrical stimulus
Second
messenger
New AMPA
receptor
Figure 5-20
Glutamate’s Lasting Effects Enhanced
glutamate prompts a neurochemical
cascade that underlies synaptic change
and LTP.
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HOW DO NEURONS COMMUNICATE AND ADAPT? ! 179
tion and the weaker test stimulus—activating two different mechanisms are linked. Remember
that the NMDA receptor is doubly gated. In order for calcium ions to pass
through its pore, the magnesium block must be removed by depolarization of the
membrane, and then glutamate must bind to the receptor.
The demonstration of LTP occurring at a synapse when a weak stimulus is paired
with a stronger one provides a model that underlies real-life associative learning. Normally,
the strong stimulation comes from an interesting feature of the action potentials
produced by certain neurons.When these neurons fire, the nerve impulse travels from
the axon hillock not only down the axon but also back up the dendritic tree (in many
other neurons, the action potential travels only down the axon). This dendritic action
potential creates a depolarization of the postsynaptic membrane that is adequate to remove
the Mg2! block in NMDA receptors.
When the Mg2! blocks are removed, the release of glutamate into any synapse on
the dendrite can activate NMDA receptors and thus produce LTP. The real-life corollary
of weak stimulation may be an environmental event that triggers glutamate-releasing
activity into a synapse at the same time as the postsynaptic membrane is being
depolarized. Thus, if one behavioral event causes the hippocampal cells to discharge at
the same time as some other event causes the release of glutamate onto the dendrites
of those cells, LTP would occur. A specific example will help you see how this process
relates to associative learning in mammals.
Suppose that, as a rat walks around, a hippocampal cell fires when the rat reaches
a certain location. The stimulus that produces this firing may be the sight of a particular
object, such as a light. The neural signal about the light will be carried by the visual
system to the neocortex and then from the visual neocortex to memory storage in
the hippocampal cell, the putative site of learning.
Now suppose that, during an excursion to this place where the light is located, the
rat encounters a tasty piece of food. Input concerning that food can be carried from
the taste area of the neocortex to the same hippocampal cell that fires in response to
the light. As a result, the taste and odor input associated with the food arrives at the
cell at the time that it is firing in response to the light.
Because the cell is firing, the Mg2! block is removed, and so LTP can take place.
Subsequently, the sight of the light will fire this hippocampal cell, but so will the odor
of this particular food. The hippocampal cell, in other words, stores an association between
the food and the light. If the rat were to smell the odor of this food on the snout
of another rat that had eaten it, the hippocampal cell would discharge. Because the discharge
of this cell is also associated with a particular light and location in the environment,
would the rat go to that location, expecting once again to find food there?
Bennett Galef and his coworkers (1990) in fact demonstrated that a rat that smells
the odor of a particular food on the breath of a demonstrator rat will go to the appropriate
location to obtain the food. This social transmission of food-related information
is an excellent example of associative learning. Although the behavior can be
disrupted by lesions in the hippocampus, it has not yet been demonstrated that learning
this food-and-place association is mediated by LTP in synapses, because it is technically
difficult to locate the appropriate synapses and record from them in a freely
moving animal.
Long-term potentiation is not the only change in a neuron that can underlie learning.
Learning can also be mediated by a neuron that becomes less active in response to
repeated stimulation. This process is called long-term depression or LTD. The neural
basis of LTD may be quite similar to that of LTP in that both require NMDA receptors.
In neurons that display LTD, the influx of Ca2! may result not in increased responsiveness
or increased numbers of AMPA receptors but rather in decreased responsiveness
or decreased numbers of AMPA receptors.
For more information about the role
of long-term potentiation in learning, visit
the Chapter 5 Web links on the Brain and
Behavior Web site (www.worth
publishers.com/kolb).
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180 ! CHAPTER 5
A mechanism through which these processes can take place begins with calcium
ions that mobilize second messengers to send instructions to nuclear DNA. The
transcription and translation of nuclear DNA, in turn, initiate structural changes at
synapses. “Dendritic Spines, Small but Mighty” summarizes experimental evidence
about structural changes in dendritic spines. The second messenger cAMP probably
plays an important role in carrying instructions regarding these structural changes to
nuclear DNA. The evidence for cAMP’s involvement comes from studies of fruit flies.
In the fruit fly, Drosophila, two genetic mutations can produce the same learning
deficiency. Both render the second messenger cAMP inoperative, but in opposite ways.
One mutation, called dunce, lacks the enzymes needed to degrade cAMP, and so the
fruit fly has abnormally high levels. The other mutation, called rutabaga, reduces levels
of cAMP below the normal range for Drosophila neurons.
Significantly, fruit flies with either of these mutations are impaired in acquiring habituated
and sensitized responses because their levels of cAMP cannot be regulated.
New synapses seem to be required for learning to take place, and the second messenger
cAMP seems to be needed to carry instructions to form them. Figure 5-22 summarizes
these research findings.
Experiment 5-4 asks whether neural stimulation that produces LTP causes structural
changes in neurons. To investigate this question, German researchers Florian Engert
and Tobias Bonhoeffer (1999) took slices of the hippocampus from the brains of
rats and maintained them in a culture where they subjected the neurons to stimulation.
Learning at the Synapse
The neural changes associated with learning must be long-lasting enough to account
for a relatively permanent change in an organism’s behavior. The changes at synapses
described in the preceding sections develop quite quickly, but they do not last indefinitely,
as memories often do. How, then, can synapses be responsible for the relatively
long term changes in learning and memory?
Repeated stimulation produces habituation and sensitization or associative behaviors
that can persist for months. Brief training produces short-term learning, whereas
longer training periods produce more enduring learning. If you cram for an exam the
night before, you usually forget the material quickly, but, if you study a little each day
for a week, your learning tends to endure.What underlies this more persistent form of
learning? It would seem to be more than just a change in the release of glutamate, and,
whatever the change is, it must be long-lasting.
Craig Bailey and Mary Chen (1989) found that the number and size of sensory
synapses change in well-trained, habituated, and sensitized Aplysia. Relative to a control
neuron, the number and size of synapses decrease in habituated animals and increase in
sensitized animals, as represented in Figure 5-21.Apparently, synaptic events associated
with habituation and sensitization can also trigger processes in the sensory cell that result
in the loss or formation of new synapses.
Motor
neuron
Sensory
neuron
Control Habituated Sensitized
Figure 5-21
Physical Basis of Memory Relative to a
control neural connection (left), the number of
synapses between Aplysia’s sensory neuron and a
motor neuron decline as a result of habituation
(center) and increase as a result of sensitization
(right). Such structural changes may underlie
enduring memories.
Craig Bailey
Mary Chen
cAMP
High levels
Low levels
Normal levels
dunce
No mutation
rutabaga
No learning
No learning
Learning
Drosophila
Figure 5-22
Genetic Disruption of Learning Two
mutations in the fruit fly, Drosophila,
inactivate the second messenger cAMP
by moving its level above or below the
concentration range at which it can be
regulated.
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HOW DO NEURONS COMMUNICATE AND ADAPT? ! 181
Recording
electrode
Stimulating
electrode
Presynaptic
cell
AP5
…and washed off where
one presynaptic axon meets
one postsynaptic dendrite.
Stimulation
Time (min)
9
7
5
3
Voltage (mV)
1
–20 –10 0 10
LTP
20 30 40 50 60 70
Postsynaptic
cell
The presynaptic cell
was stimulated.
Procedure
AP5, a chemical that blocks NMDA receptors on the postsynaptic
neuron, was added to the hippocampal neurons…
After a strong burst
of stimulation,
the EPSP from the
postsynaptic cell was
recorded in response
to weak test
stimulation. LTP had
resulted.
Dendrite before stimulation
Dendrite 30 minutes after stimulation
…two new spines
appeared on the
dendrite in the
area where the AP5
was washed off.
About 30 minutes
after stimulation,...
Results
New dendritic spines can grow in conjunction with LTP.
Conclusion
Question: Can neural stimulation that produces LTP cause structural changes in neurons?
EXPERIMENT 5-4
Dendritic Spines, Small but Mighty
Focus on New Research
Dendritic spines, illustrated in Experiment 5-4, contain an
astounding variety of protein molecules. Research now suggests
that spines are the paramount example of biological
nanotechnology (Tashiro & Yuste, 2003).
To mediate learning, each spine must be able to act independently,
undergoing changes that its neighbors do not
undergo. Spines may appear and disappear on a dendrite in
a matter of seconds, and they may even extend or move
along a dendrite to search out and contact a presynaptic
axon terminal. When forming part of a synapse, they can
change in size and shape and even divide.
Dendritic spines are from about 1 to 3 lm long and
less than 1 lm in diameter and protrude from the dendrite
shaft. Each neuron may have many thousands of spines,
and the human cerebral cortex may contain a total of 1014
dendritic spines. Characteristically, spines have an expanded
head connected to a narrow shaft, but they may
take an array of shapes. The heads of spines serve as biochemical
compartments and can generate huge electrical
potentials.
The mechanisms that allow spines to appear and change
in shape include a number of different cytoskeletal filaments
linked to the membrane receptors. The influx of calcium or
other actions of the dendritic receptors can lead to the assembly
of larger filaments; some can change the length of the
spine, others can change its width, and still others can cause
it to divide.
The activation of receptors can induce mRNA within the
spine to produce more of these structural proteins. In addition,
second messengers within the spine can carry signals to
the cell’s D NA to send more mRNA addressed to just the signaling
spine. Understanding the workings of spines will eventually
assist in understanding learning and adaptation at the
neural level.
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182 ! CHAPTER 5
In their setup, illustrated in the Procedure section of Experiment 5-4,
they injected the fluorescent molecule calcein through the recording
electrode into the postsynaptic cell to color it green and allow them to
view it through a microscope. Then they stimulated the presynaptic hippocampal
neuron sufficiently to depolarize the cell membrane and remove
the Mg2! block from NMDA receptors.
Except for the part being stimulated, the presynaptic neuron was
washed with AP5, a drug that blocks NMDA receptors. A second microelectrode
was inserted into the axons of other neurons that had
synapsed with the first cell. The axons were then stimulated electrically,
and the EPSPs produced by that stimulation were recorded from the
postsynaptic cell.
The graph at the center of Experiment 5-4 shows the amplitude
changes in EPSPs recorded from the postsynaptic neuron. Each dot
represents the size of an EPSP in response to a single test stimulus. Left
of zero on the time scale, a number of weak test stimuli are given to
determine the sizes of the EPSPs, followed by an intense 10-min burst
of electrical stimulation. Then, in response to the stimulation, EPSPs
with larger amplitudes are recorded, indicating that LTP has occurred.
Using a confocal microscope (similar to a light microscope except
that the light comes from a laser), the experimenters observed the
changes to the dendrite. The Results section of Experiment 5-4 sketches
these changes. About 30 min after stimulation, two new spines appeared
on the dendrite.No spines appeared on other parts of the neuron that were still
subjected to the AP5 block. This experiment concludes that new dendritic spines can
grow in conjunction with LTP. The implication is that they adapt to support long-term
interneural communication and may provide the neural basis for brain plasticity and
learning.
In this experiment, the axon terminals could not be seen, but presumably new terminals
arose to connect the stimulated axons to the new dendritic spines, thus forming
new synapses. Note that the new spines appeared about 30 min after LTP, and so
these new connections were not required for LTP. The new synapses, however, are probably
required for LTP to endure.
In Review .
The neural basis for learning and memory resides at the synapse. Aplysia’s synaptic function
mediates two forms of learning: habituation and sensitization. Presynaptic voltagesensitive
calcium channels mediate habituation by growing less sensitive with use.
Metabotropic serotonin receptors on a sensory neuron can change the sensitivity of presynaptic
potassium channels and so increase Ca2! influx to mediate sensitization. At the
same time, these receptors can produce fewer or more synapses to provide a structural,
physical basis for long-term habituation and sensitization and for changes in behavior.
Mammals also demonstrate structural synaptic changes related to associative learning.
Clearly, many changes in the synapses of neurons can mediate learning, but associative
learning takes place only if requisite events take place at nearly the same time and thus
become linked. Because associative learning has a neural basis, measurements of synaptic
structure and neurochemistry may suggest relations between synaptic change, experience,
and behavior. Figure 5-23 summarizes synaptic structures that can be measured
and related to learning and behavior.
Increased axonal
transport
Increase in protein
transport for spine
construction
Increase in density
of contact zones
Increase in number
of synaptic vesicles
Change in stem
length and width
Increase in size
or area of spine
Increase in size or
area of terminal
Change in size
of synaptic cleft
Learn more about the confocal
microscope in the research methods
section of your Foundations CD. You’ll
see a diagram of the apparatus as well
as video clips of cells taken with a
confocal microscope.
Figure 5-23
Neural Bases of Learning Locations
on a synapse where structural changes
may subserve learning
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HOW DO NEURONS COMMUNICATE AND ADAPT? ! 183
SUMMARY
What early experiments provided the key to understanding how neurons communicate
with one another? In the 1920s, Otto Loewi suspected that nerves to the heart secrete a
chemical that regulates its rate of beating. His subsequent experiments with frogs
showed that acetylcholine slows heart rate, whereas epinephrine increases it. This observation
provided the key to understanding the basis of chemical neurotransmission.
What is the basic structure of a synapse that passes information from one neuron to another
neuron? A synapse consists of the first neuron’s axon terminal (surrounded by a
presynaptic membrane), a synaptic cleft (a tiny gap between the two neurons), and a
postsynaptic membrane on the second neuron. Systems for the chemical synthesis of
excitatory or inhibitory neurotransmitters are located in the presynaptic neuron’s axon
terminal or soma, whereas systems for storing the neurotransmitter are in its axon terminal.
Receptor systems on which that neurotransmitter acts are located on the postsynaptic
membrane.
What are the major stages in the function of a neurotransmitter? The four major stages
in neurotransmitter function are (1) synthesis and storage, (2) release from the axon
terminal, (3) action on postsynaptic receptors, and (4) inactivation.After synthesis, the
neurotransmitter is wrapped in a membrane to form synaptic vesicles in the axon terminal.
When an action potential is propagated on the presynaptic membrane, voltage
changes set in motion the attachment of vesicles to the presynaptic membrane and the
release of neurotransmitter by exocytosis. One synaptic vesicle releases a quantum of
neurotransmitter into the synaptic cleft, producing a miniature potential on the postsynaptic
membrane. To generate an action potential on the postsynaptic cell requires
the simultaneous release of many quanta of transmitter. After a transmitter has done
its work, it is inactivated by such processes as diffusion out of the synaptic cleft, breakdown
by enzymes, and reuptake of the transmitter or its components into the axon terminal
(or sometimes uptake into glial cells).
What are the three major varieties of neurotransmitters, and in what kinds of synapses
do they participate? Small-molecule transmitters, neuropeptides, and transmitter gases
are broad classes of the perhaps 100 neurotransmitters. Neurons containing these
transmitters make a variety of connections with various parts of other neurons, as well
as with muscles, blood vessels, and extracellular fluid. Functionally, neurons can be
both excitatory and inhibitory, and they can participate in local circuits or in general
brain systems. Excitatory synapses, known as Type I, are usually located on a dendritic
tree, whereas inhibitory synapses, known as Type II, are usually located on a cell body.
What are the two general classes of receptors for neurotransmitters? Each neurotransmitter
may be associated with both ionotropic and metabotropic receptors. An ionotropic
receptor quickly and directly produces voltage changes on the postsynaptic cell
membrane as its pore opens or closes to regulate the flow of ions through the cell membrane.
Slower-acting, metabotropic receptors activate second messengers to indirectly
produce changes in the function and structure of the cell.
How are the principal neurotransmitter systems related to behavior? Because neurotransmitters
are multifunctional, scientists find it impossible to isolate single-neurotransmitter–
single-behavior relations. Rather, systems of neurons that employ the
same principal neurotransmitter influence various general aspects of behavior. For instance,
acetylcholine, the main neurotransmitter in the somatic motor system, controls
movement of the skeletal muscles, whereas, in the autonomic system, acetylcholine
and norepinephrine are the main transmitters controlling the body’s internal organs.
The central nervous system contains not only widely dispersed glutamate and GABA
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184 ! CHAPTER 5
neurons but also neural activating systems that employ acetylcholine, norepinephrine,
dopamine, or serotonin as their main neurotransmitter. All these systems ensure that
wide areas of the brain act in concert, and each is associated with various classes of behaviors
and disorders.
How do changes in synapses effect learning? Changes in synapses underlie learning
and memory. In habituation, a form of learning in which a response weakens as a result
of repeated stimulation, calcium channels become less responsive to an action potential
and, consequently, less neurotransmitter is released when an action potential is
propagated. In sensitization, a form of learning in which a response strengthens as a
result of stimulation, changes in potassium channels prolong the duration of the action
potential, resulting in an increased influx of calcium ions and, consequently, release
of more neurotransmitter.With repeated training, new synapses can develop, and
both these kinds of learning can become relatively permanent. In associative learning,
when two events take place together, the formation of new synapses can record their
relation for the long term.
What structural changes in synapses may be related to learning? In Aplysia, the number
of synapses connecting sensory neurons and motor neurons decreases in response
to repeated sessions of habituation. Similarly, in response to repeated sessions of sensitization,
the number of synapses connecting the sensory and the motor neurons increases.
Presumably, these changes in synapse number are related to long-term learning.
The results of experiments on the mammalian hippocampus show that the number of
synapses can change rapidly in cultured preparations.About 30 min after long-term potentiation
has been induced, new dendritic spines appear, suggesting that new synapses
are formed during LTP. Possibly the formation of new synapses can similarly be responsible
for new learning.
KEY TERMS
REVIEW QUESTIONS
1. Explain how neurotransmitters are synthesized, stored, released, and broken down.
2. How many kinds of neurotransmitters are there? Describe the problem in
proving that a chemical found in a neuron is a neurotransmitter.
activating system, p. 168
Alzheimer’s disease, p. 170
associative learning, p. 177
autoreceptor, p. 155
carbon monoxide (CO),
p. 164
chemical synapse, p. 153
cholinergic neuron, p. 167
dopamine (DA), p. 153
electrical synapse, p. 153
epinephrine (EP), p. 150
gamma-aminobutyric acid
(GABA), p. 162
glutamate, p. 162
G protein, p. 164
habituation, p. 173
ionotropic receptor, p. 164
learning, p. 172
long-term potentiation
(LTP), p. 177
metabotropic receptor,
p. 164
neuropeptides, p. 167
neuroplasticity, p. 173
neurotransmitter, p. 150
nicotinic ACh receptor
(nAChr), p. 167
nitric oxide (NO), p. 164
noradrenergic neuron,
p. 172
norepinephrine (NE),
p. 150
obsessive-compulsive
disorder (OCD), p. 172
postsynaptic membrane,
p. 153
presynaptic membrane,
p. 153
quantum (pl. quanta),
p. 155
rate-limiting factor, p. 162
reuptake, p. 156
schizophrenia, p. 170
second messenger, p. 166
sensitization, p. 175
small-molecule
transmitters, p. 156
storage granule, p. 153
synaptic cleft, p. 153
synaptic vesicle, p. 153
transmitter-activated
receptor, p. 155
transporter, p. 153
neuroscience interact ive
There are many resources available for
expanding your learning online:
www.worthpublishers.com/kolb
Try the Chapter 5 quizzes and
flashcards to test your mastery of the
chapter material. You’ll also be able to
link to other sites that will reinforce
what you’ve learned.
www.pdf.org
Link to this site to learn more about
Parkinson’s disease and current research
to find a cure.
On your Foundations CD-ROM, you’ll
find that the module on Neural
Communication provides important
reinforcement of what you’ve learned.
In addition, the Research Methods
module contains coverage of some of
the technological techniques referred to
in this chapter, including the confocal
microscope.
CH05.qxd 1/28/05 10:11 AM Page 184

3. What are the two main kinds of transmitter-activated receptors and how do they
differ in function?
4. Choose a neurotransmitter-activating system and describe its organization.
5. Which mechanisms are the same and which are different in the various kinds of
learning discussed in this chapter?
FOR FURTHER THOUGHT
Speculate about how the origins of synaptic systems in the brain parallel the evolution
of species.Why are such potential relations important?
RECOMMENDED READING
Cooper, J. R., Bloom, F. E., & Roth, R. H. (2002). The biochemical basis of neuropharmacology.
New York: Oxford University Press. This readable and up-to-date account of the
chemical systems in the brain is a good reference. The book describes the various kinds
of brain neurotransmitters and the kinds of synapses and chemical systems in which
they are found.
HOW DO NEURONS COMMUNICATE AND ADAPT? ! 185
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Focus on Comparative Biology: Metamorphosis
Perspectives on Brain Development
Mr. Higgins Builds a House
Linking Brain and Behavioral Development
Neurobiology of Development
Gross Development of the Human Nervous System
Origins of Neurons and Glia
Growth and Development of Neurons
Focus on Disorders: Cerebral Palsy
Glial Development
Correlating Behavior with
Brain Development
Motor Behaviors
Language Development
Development of Problem-Solving Ability
A Caution about Linking Correlation to Causation
Brain Development and the
Environment
Experience and Cortical Organization
Experience and Neural Connectivity
Critical Periods for Experience and
Brain Development
Abnormal Experience and Brain Development
Focus on Disorders: Romanian Orphans
Hormones and Brain Development
Focus on New Research: Hormones and the Range
of a Behavior
Injury and Brain Development
Drugs and Brain Development
Other Kinds of Abnormal Brain Development
Focus on Disorders: Schizophrenia
Mental Retardation
How Do Any of Us Develop
a Normal Brain?
186 !
C H A P T E R 6
How Does the Brain Develop
and Adapt?
Left: Oliver Meckes/Ottawa/Photo Researchers. Middle: Photodisc.
Right: R. E. Steiner/Photo Researchers.
CH06.qxd 1/28/05 10:13 AM Page 186

able to fend for ourselves. Human offspring are virtually
helpless for an extended time after birth. The behavioral demands
on the brain of a newborn include relatively simple
actions such as searching for a nipple from
which to feed and recognizing it and signaling
hunger or discomfort to caregivers
by crying out.
Soon a human infant develops a variety
of new behaviors such as crawling and,
later, walking, eating solid foods, using
tools, and learning a language. At school
age, the child’s brain becomes able to formulate
increasingly complex ideas, solve
challenging problems, and remember large
quantities of information. Not a metamorphosis
but clearly a transformation.
Brain maturation does not end at college
graduation but continues well into the
20s. As the adult brain begins to age, it
starts to lose cells and grows fewer new
ones. Eventually the cumulative loss forces
the middle-aged brain to reconfigure some
of its parts to forestall the effects of aging.
In old age, the progressive loss of neurons
and connections can be delayed, or
even prevented, by keeping the brain active.
If new connections are being formed
by life-long learning and cognitive stimulation,
there is a reduction in synaptic loss—
a “use it or lose it” scenario. In fact, even if neurons are lost
in aging, at least some neuron loss may be compensated by
increasing synapses on the remaining neurons.
Brain development, then, is lifelong, a continuous
process central to human functioning. Changes in the brain
allow us to adapt to the environment throughout our life cycle.
Behavioral development depends on brain development.
Metamorphosis
Focus on Comparative Biology
A fertilized monarch butterfly egg first develops through
a larval stage to begin life as a caterpillar. After a time,
the caterpillar spins itself a cocoon. Inside, as a seemingly
inert pupa, it undergoes a transformation,
emerging from the cocoon as an adult
butterfly. These rigidly demarked stages of
development, collectively called metamorphosis,
are noted on the accompanying
sketch.
Consider how formidable metamorphosis
is. The developing larva fashions a
caterpillar’s body, including a nervous system
that produces crawly, caterpillar-like
movements and controls a feeding apparatus
designed for munching leaves. During
metamorphosis, this original nervous system
is reconstructed to control the flight,
feeding, and reproductive behaviors of a
butterfly.
The addition of flying is remarkable
because this behavior requires entirely different
muscles from those used in crawling.
And where the caterpillar’s main
challenge is to find food as it inches slowly
around in a limited area, adult monarch
butterflies fly hundreds to thousands of
miles in their annual migration and must
navigate to a specific geographical location.
A caterpillar would seem to need a
major brain overhaul to control the completely reconfigured
body and new behaviors that go with being a butterfly.
We humans do not metamorphose into a different life
form in the course of our development, but we do “morph”
through a variety of stages nonetheless. Like the monarch,
we begin life as a fertilized egg that develops a body and a
nervous system. When we are born, however, we are not
Larva
Caterpillar
Cocoon
Adult
butterfly
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How did the brain evolve from a small and simple organ into a large and highly
complex one? When we consider the many kinds of neurons and glia located
in specific nuclei, cortical layers, and so on, we wonder, How is this complicated
architecture accomplished? Considering how many influences on brain development
there are, how do the vast majority of people end up normal?
PERSPECTIVES ON BRAIN DEVELOPMENT
We can shed light on nervous system development by viewing its architecture from different
vantage points—structural, functional, and environmental. In this chapter, we
consider the neurobiology of development first, explore the behavioral correlates of developing
brain functions next, and then explore how experiences and environments influence
neuroplasticity over the life span.
To understand how scientists go about studying the interconnected processes of
brain and behavioral development, think about all the architectural parallels between
how the brain is constructed and how a house is built.
Mr. Higgins Builds a House
Mr. Higgins finds a picture of his dream house in a magazine and decides to build it
himself. He orders a blueprint that outlines the structure so that everyone who works
on its construction is building the same house. Mr. Higgins quickly discovers that
houses, like brains, go through several stages of development.
The construction phase begins with the laying of a concrete foundation. At this
point, however, Mr. Higgins starts to realize that the blueprint is not as detailed as it
first appeared. It specifies where the walls, pipes, and electrical outlets will be, but
it does not always say exactly what materials to use where. Thus, the choice of a particular
kind of plywood or a particular type of nail or screw is often more or less random
within limits. Similarly, the blueprint specifies connections between certain
circuits in the power box and certain fixtures or outlets, but it does not detail the precise
route that the connecting wires should take.
Mr. Higgins also finds that the blueprint does not specify the precise order in
which tasks should be done. He knows that the foundation has to be finished first, the
subfloor next, and the walls framed after that. But what comes then is largely left to his
discretion.
Given the number of options open to him,Mr. Higgins realizes that his home will
undoubtedly be unique, different from anyone else’s conception of the blueprint. He
also discovers that outside events can influence how his house will turn out. A severe
storm may cause damage or delay the process. Changes in the quality of construction
materials will change the quality of the building, for better or worse.
Neuropsychologists recognize much the same process at work in “building” a
brain. Like a house, a brain is constructed in levels, each one with a different function
(Figure 6-1).Whereas house plans are drawn in the form of a blueprint, the plans for
a brain are encoded in genes.
As Mr.Higgins learned, architects do not specify every detail in a blueprint; nor do
genes include every instruction for how a brain is assembled and wired. The brain is
just too complex to be encoded entirely and precisely in genes. For this reason, the fate
of billions of brain cells is left partly open, especially in regard to the massive undertaking
of forming appropriate connections between cells.
If the structure and fate of each brain cell are not specified in advance, what controls
brain development? Many factors are at work, including special molecules, such
188 ! CHAPTER 6
Prosencephalon
(forebrain)
Mesencephalon
(midbrain)
Rhombencephalon
(hindbrain)
Spinal cord
Figure 6-1
Three-Chambered Architecture Recall
from Figure 2-14 that the human brain
evolved from the expansion of the
three-chambered vertebrate nervous
system shown here—hindbrain,
midbrain, forebrain—to a fivechambered
mammalian brain.
CH06.qxd 1/28/05 10:13 AM Page 188

as hormones. Like house building, brain development is influenced by events in the environment
in the construction phase and by the quality of the materials used.
Experiences both in the womb and after birth can change the way in which the
brain develops. Similary, if the brain is injured or affected by poisons or drugs, brain
development may be compromised because the building materials are compromised.
We return to enviornmental influences later, after examining the major stages in brain
development and the interconnected processes of brain and behavioral development.
Linking Brain and Behavioral Development
Brain and behavior develop apace. Scientists thus reason that these two lines of development
are closely linked. Events that alter behavioral development should similarly
alter the brain’s structural development and vice versa.
As the brain develops, neurons become more and more intricately connected, and
these increasingly complex interconnections underlie increasingly complex behavior.
These observations enable neuroscientists to study the relation between brain and behavioral
development from three different perspectives:
1. Structural development can be studied and correlated with the emergence of
behavior.
2. Behavioral development can be analyzed and predictions can be made about what
underlying circuitry must be emerging.
3. Factors that influence both brain structure and behavioral development, such as
language or injury, can be studied.
PREDICTING BEHAVIOR FROM BRAIN STRUCTURE
We can look at the structural development of the nervous system and correlate it with
the emergence of specific behaviors. For example, we can link the development of certain
brain structures to motor development of, say, grasping or crawling in infants. As
brain structures mature, their functions emerge and develop, manifested in behaviors
that we can observe.
Neural structures that develop quickly—the visual system, for instance—
exhibit their functions sooner than structures that develop more slowly, as do
those for speech. Because the human brain continues to develop well past adolescence,
you should not be surprised that some abilities emerge or mature
rather late. Certain cognitive behaviors controlled by the frontal lobes, for example,
are among the last to develop.
Perhaps the best example is the ability to understand the nuances of social
interaction, which is a function of the frontal lobes. One way to test a person’s
understanding of social interaction is illustrated in Figure 6-2. The person looks
at a cartoon scene and is asked to mimic the facial expression appropriate for the
face that is blank.
This ability does not emerge until midadolescence, and so adults have no
difficulty with this task, but children are very poor at producing the correct expression.
Not that children have trouble producing facial expressions; they do so
spontaneously at a very early age.What they lack is an adultlike ability to interpret
expressions, because brain structures that play an important role in this ability
are late to mature. Children therefore may make social gaffes and are often
unable to grasp all the nuances of a social situation or interaction.
Behaviors that seem simple to us adults, such as a wink or a flirtatious look,
are incomprehensible to children. Children, then, are not miniature adults who
HOW DOES THE BRAIN DEVELOP AND ADAPT? ! 189
Figure 6-2
Testing Social Development Until
midadolescence, the nuances of social
perception present children with great
difficulty. In this test, the task is to mimic
the facial expression that is socially
appropriate for the blank face in the
drawing. Adapted from “Developmental
Changes in the Recognition and Comprehensional
Expression: Implications for Frontal Lobe
Function,” by B. Kolb, B. Wilson, and L. Taylor,
1992, Brain and Cognition, 20, p. 77.
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simply need to learn the “rules” of adult behavior. The brain of a child is very different
from that of an adult, and the brains of children at different ages are really not comparable
either.
CORRELATING BRAIN STRUCTURE AND BEHAVIOR
We can turn our sequence of observations around, scrutinizing behavior for the emergence
of new abilities, and then inferring underlying neural maturation. For example, as
language emerges in the young child, we expect to find corresponding changes in neural
structures that control language. In fact, such changes are what neuroscientists do find.
At birth, children do not speak, and even extensive speech training would not enable
them to do so. The neural structures that control speech are not yet mature
enough.As language emerges,we can conclude that the speech-related structures in the
brain are undergoing the necessary maturation.
The same reasoning can be applied to frontal-lobe development. As frontal-lobe
structures mature through adolescence and into early adulthood, we look for related
changes in behavior, but we can also do the reverse: because we observe new abilities
emerging in the teenage years and even later, we infer that they must be controlled by
late-maturing neural structures and connections.
INFLUENCES ON BRAIN AND BEHAVIOR
The third way to study interrelations between brain and behavioral development is to
identify and study factors that influence both. From this perspective, the mere emergence
of a certain fully developed brain structure is not enough; we must also know
the events that shape how that structure functions and produces certain kinds of behaviors.
Some of the events that influence brain function are sensory experience, injuries,
and the actions of hormones and genes.
Logically, if behavior is influenced by one of these factors, then structures in the
brain that are changed by that factor are responsible for the behavioral outcomes. For
example, we might study how the abnormal secretion of a hormone affects both a certain
brain structure and a certain behavior. We can then infer that, because the observed
behavioral abnormality results from the abnormal functioning of the brain
structure, that structure must normally play some role in controlling the behavior.
NEUROBIOLOGY OF DEVELOPMENT
Some 2000 years ago, the Roman philosopher Seneca proposed that a human embryo is
an adult in miniature, and thus the task of development is simply to grow bigger. This
idea, known as preformation, was so appealing that it was widely believed for centuries
In Review .
Brain development is variable and is influenced by an interaction of the genetic blueprint
and the pre- and postnatal experiences that the developing brain encounters. Development
can be approached from three different perspectives: structural brain development
correlated with the emergence of behavior, behavioral development analyzed to predict
what underlying neural circuitry must be emerging, and external and internal influences
factored into brain and behavioral development. In this last approach, the idea is that
events that alter behavioral development, such as an injury to the brain or fluctuating hormone
levels, should similarly alter structural development.
190 ! CHAPTER 6
Neural plate. Thickened region of the
ectodermal layer that gives rise to the
neural tube.
Neural tube. Structure in the early stage
of brain development from which the
brain and spinal cord develop.