Describe how you will apply that learning in your daily life, including your work life.

PART 1

It can be argued that short-term exposure to stress is adaptive and can increase positive performance. Long-term exposure to stress is considered maladaptive, yet common, in our society. Describe how stress can be adaptive and its effects on the brain  versus how stress can be maladaptive and its effect

chapter 13 Learning and Memory

Outline

· ■  The Nature of Learning

Section Summary

· ■  Synaptic Plasticity: Long-Term Potentiation and Long-Term Depression

Induction of Long-Term Potentiation

Role of NMDA Receptors

Mechanisms of Synaptic Plasticity

Long-Term Depression

Other Forms of Long-Term Potentiation

· Section Summary

· ■  Perceptual Learning

Learning to Recognize Stimuli

Perceptual Short-Term Memory

· Section Summary

· ■  Classical Conditioning

Section Summary

· ■  Instrumental Conditioning

Basal Ganglia

Reinforcement

· Section Summary

· ■  Relational Learning

Human Anterograde Amnesia

Spared Learning Abilities

Declarative and Nondeclarative Memories

Anatomy of Anterograde Amnesia

Role of the Hippocampal Formation in Consolidation of Declarative Memories

Episodic and Semantic Memories

Spatial Memory

Relational Learning in Laboratory Animals

Section Summary

Patient H. M. had a relatively pure amnesia. His intellectual ability and his immediate verbal memory was apparently normal. He could repeat seven numbers forward and five numbers backward, and he could carry on conversations, rephrase sentences, and perform mental arithmetic. He was unable to remember events that occurred during several years preceding his brain surgery, but he could recall older memories very well. He showed no personality change after the operation, and he was generally polite and good-natured.

However, after his surgery, H. M. was unable to learn anything new. He could not identify by name people he had met since the operation (performed in 1953, when he was twenty-seven years old). His family moved to a new house after his operation, and he never learned how to get around in the new neighborhood. (After his parent’s death, he lived in a nursing home, where he could be cared for.) He was aware of his disorder and often said something like this:

·  Every day is alone in itself, whatever enjoyment I’ve had, and whatever sorrow I’ve had… . Right now, I’m wondering. Have I done or said anything amiss? You see, at this moment everything looks clear to me, but what happened just before? That’s what worries me. It’s like waking from a dream; I just don’t remember. (Milner,  1970 , p. 37)

H. M. was capable of remembering a small amount of verbal information as long as he was not distracted; constant rehearsal could keep information in his immediate memory for a long time. However, rehearsal did not appear to have any long-term effects; if he was distracted for a moment, he would completely forget whatever he had been rehearsing. He worked very well at repetitive tasks. Indeed, because he so quickly forgot what previously happened, he did not easily become bored. He could endlessly reread the same magazine or laugh at the same jokes, finding them fresh and new each time. His time was typically spent solving crossword puzzles and watching television.

On December 2, 2008, H. M., whom we now know as Henry Molaison, died at the age of 82.

Experiences change us; encounters with our environment alter our behavior by modifying our nervous system. As many investigators have said, an understanding of the physiology of memory is the ultimate challenge to neuroscience research. The brain is complex, and so are learning and remembering. However, despite the difficulties, the long years of work finally seem to be paying off. New approaches and new methods have evolved from old ones, and real progress has been made in understanding the anatomy and physiology of learning and remembering.

The Nature of Learning

Learning refers to the process by which experiences change our nervous system and hence our behavior. We refer to these changes as memories. Although it is convenient to describe memories as if they were notes placed in filing cabinets, this is certainly not the way experiences are reflected within the brain. Experiences are not “stored”; rather, they change the way we perceive, perform, think, and plan. They do so by physically changing the structure of the nervous system, altering neural circuits that participate in perceiving, performing, thinking, and planning.

Learning can take at least four basic forms: perceptual learning, stimulus-response learning, motor learning, and relational learning.  Perceptual learning  is the ability to learn to recognize stimuli that have been perceived before. The primary function of this type of learning is the ability to identify and categorize objects (including other members of our own species) and situations. Unless we have learned to recognize something, we cannot learn how we should behave with respect to it—We will not profit from our experiences with it, and profiting from experience is what learning is all about.

 perceptual learning Learning to recognize a particular stimulus.

Each of our sensory systems is capable of perceptual learning. We can learn to recognize objects by their visual appearance, the sounds they make, how they feel, or how they smell. We can recognize people by the shape of their faces, the movements they make when they walk, or the sound of their voices. When we hear people talk, we can recognize the words they are saying and, perhaps, their emotional state. As we shall see, perceptual learning appears to be accomplished primarily by changes in the sensory association cortex. That is, learning to recognize complex visual stimuli involves changes in the visual association cortex, learning to recognize complex auditory stimuli involves changes in the auditory association cortex, and so on.

Stimulus-response learning  is the ability to learn to perform a particular behavior when a particular stimulus is present. Thus, it involves the establishment of connections between circuits involved in perception and those involved in movement. The behavior could be an automatic response such as a defensive reflex, or it could be a complicated sequence of movements. Stimulus-response learning includes two major categories of learning that psychologists have studied extensively: classical conditioning and instrumental conditioning.

 stimulus-response learning Learning to automatically make a particular response in the presence of a particular stimulus; includes classical and instrumental conditioning.

Classical conditioning  is a form of learning in which an unimportant stimulus acquires the properties of an important one. It involves an association between two stimuli. A stimulus that previously had little effect on behavior becomes able to evoke a reflexive, species-typical behavior. For example, a defensive eyeblink response can be conditioned to a tone. If we direct a brief puff of air toward a rabbit’s eye, the eye will automatically blink. The response is called an unconditional response (UR) because it occurs unconditionally, without any special training. The stimulus that produces it (the puff of air) is called an unconditional stimulus (US). Now we begin the training. We present a series of brief 1000-Hz tones, each followed 500 ms later by a puff of air. After several trials the rabbit’s eye begins to close even before the puff of air occurs. Classical conditioning has occurred; the conditional stimulus (CS—the 1000-Hz tone) now elicits the conditional response (CR—the eyeblink). (See  Figure 13.1 . )

 classical conditioning A learning procedure; when a stimulus that initially produces no particular response is followed several times by an unconditional stimulus (US) that produces a defensive or appetitive response (the unconditional response—UR), the first stimulus (now called a conditional stimulus—CS) itself evokes the response (now called a conditional response—CR).

When classical conditioning takes place, what kinds of changes occur in the brain?  Figure 13.1  shows a simplified neural circuit that could account for this type of learning. For the sake of simplicity we will assume that the US (the puff of air) is detected by a single neuron in the somatosensory system and that the CS (the 1000-Hz tone) is detected by a single neuron in the auditory system. We will also assume that the response—the eyeblink—is controlled by a single neuron in the motor system. Of course, learning actually involves many thousands of neurons—sensory neurons, interneurons, and motor neurons—but the basic principle of synaptic change can be represented by this simple figure. (Look again at  Figure 13.1 . )

Let’s see how this circuit works. If we present a 1000-Hz tone, we find that the animal makes no reaction because the synapse connecting the tone-sensitive neuron with the neuron in the motor system is weak. That is, when an action potential reaches the terminal button of synapse T (tone), the excitatory postsynaptic potential (EPSP) that it produces in the dendrite of the motor neuron is too small to make that neuron fire. However, if we present a puff of air to the eye, the eye blinks. This reaction occurs because nature has provided the animal with a strong synapse between the somatosensory neuron and the motor neuron that causes a blink (synapse P, for “puff”). To establish classical conditioning, we first present the 1000-Hz tone and then quickly follow it with a puff of air. After we repeat these pairs of stimuli several times, we find that we can dispense with the air puff; the 1000-Hz tone produces the blink all by itself.

FIGURE 13.1 A Simple Neural Model of Classical Conditioning

When the 1000-Hz tone is presented just before the puff of air to the eye, synapse T is strengthened.

Over sixty years ago, Donald Hebb proposed a rule that might explain how neurons are changed by experience in a way that would cause changes in behavior (Hebb,  1949 ). The  Hebb rule  says that if a synapse repeatedly becomes active at about the same time that the postsynaptic neuron fires, changes will take place in the structure or chemistry of the synapse that will strengthen it. How would the Hebb rule apply to our circuit? If the 1000-Hz tone is presented first, then weak synapse T (for “tone”) becomes active. If the puff is presented immediately afterward, then strong synapse P becomes active and makes the motor neuron fire. The act of firing then strengthens any synapse with the motor neuron that has just been active. Of course, this means synapse T. After several pairings of the two stimuli and after several increments of strengthening, synapse T becomes strong enough to cause the motor neuron to fire by itself. Learning has occurred. (Look once more at  Figure 13.1 . )

 Hebb rule The hypothesis proposed by Donald Hebb that the cellular basis of learning involves strengthening of a synapse that is repeatedly active when the postsynaptic neuron fires.

FIGURE 13.2 A Simple Neural Model of Instrumental Conditioning

When Hebb formulated his rule, he was unable to determine whether it was true or false. Now, finally, enough progress has been made in laboratory techniques that the strength of individual synapses can be determined, and investigators are studying the physiological bases of learning. We will see the results of some of these approaches later in this chapter.

The second major class of stimulus-response learning is  instrumental conditioning  (also called operant conditioning). Whereas classical conditioning involves automatic, species-typical responses, instrumental conditioning involves behaviors that have been learned. And whereas classical conditioning involves an association between two stimuli, instrumental conditioning involves an association between a response and a stimulus. Instrumental conditioning is a more flexible form of learning. It permits an organism to adjust its behavior according to the consequences of that behavior. That is, when a behavior is followed by favorable consequences, the behavior tends to occur more frequently; when it is followed by unfavorable consequences, it tends to occur less frequently. Collectively, “favorable consequences” are referred to as  reinforcing stimuli , and “unfavorable consequences” are referred to as  punishing stimuli . For example, a response that enables a hungry organism to find food will be reinforced, and a response that causes pain will be punished. (Psychologists often refer to these terms as reinforcers and punishers.)

 instrumental conditioning A learning procedure whereby the effects of a particular behavior in a particular situation increase (reinforce) or decrease (punish) the probability of the behavior; also called operant conditioning.

 reinforcing stimulus An appetitive stimulus that follows a particular behavior and thus makes the behavior become more frequent.

 punishing stimulus An aversive stimulus that follows a particular behavior and thus makes the behavior become less frequent.

Let’s consider the process of reinforcement. Briefly stated, reinforcement causes changes in an animal’s nervous system that increase the likelihood that a particular stimulus will elicit a particular response. For example, when a hungry rat is first put in an operant chamber (a “Skinner box”), it is not very likely to press the lever mounted on a wall. However, if it does press the lever and if it receives a piece of food immediately afterward, the likelihood of its pressing the lever increases. Put another way, reinforcement causes the sight of the lever to serve as the stimulus that elicits the lever-pressing response. It is not accurate to say simply that a particular behavior becomes more frequent. If no lever is present, a rat that has learned to press one will not wave its paw around in the air. The sight of a lever is needed to produce the response. Thus, the process of reinforcement strengthens a connection between neural circuits involved in perception (the sight of the lever) and those involved in movement (the act of lever pressing). As we will see later in this chapter, the brain contains reinforcement mechanisms that control this process. (See  Figure 13.2 .)

The third major category of learning,  motor learning , is actually a component of stimulus-response learning. For simplicity’s sake we can think of perceptual learning as the establishment of changes within the sensory systems of the brain, stimulus-response learning as the establishment of connections between sensory systems and motor systems, and motor learning as the establishment of changes within motor systems. But, in fact, motor learning cannot occur without sensory guidance from the environment. For example, most skilled movements involve interactions with objects: bicycles, video game controllers, tennis racquets, knitting needles, and so on. Even skilled movements that we make by ourselves, such as solitary dance steps, involve feedback from the joints, muscles, vestibular apparatus, eyes, and contact between the feet and the floor. Motor learning differs from other forms of learning primarily in the degree to which new forms of behavior are learned; the more novel the behavior, the more the neural circuits in the motor systems of the brain must be modified. (See  Figure 13.3 . )

 motor learning Learning to make a new response.

FIGURE 13.3 An Overview of Perceptual, Stimulus–Response (S-R), and Motor Learning

A particular learning situation can involve varying amounts of all three types of learning that I have described so far: perceptual, stimulus-response, and motor. For example, if we teach an animal to make a new response whenever we present a stimulus it has never seen before, the animal must learn to recognize the stimulus (perceptual learning) and make the response (motor learning), and a connection must be established between these two new memories (stimulus-response learning). If we teach the animal to make a response that it has already learned whenever we present a new stimulus, only perceptual learning and stimulus-response learning will take place.

The three forms of learning I have described so far consist primarily of changes in one sensory system, between one sensory system and the motor system, or in the motor system. But obviously, learning is usually more complex than that. The fourth form of learning involves learning the relationships among individual stimuli. For example, a somewhat more complex form of perceptual learning involves connections between different areas of the association cortex. When we hear the sound of a cat meowing in the dark, we can imagine what a cat looks like and what it would feel like if we stroked its fur. Thus, the neural circuits in the auditory association cortex that recognize the meow are somehow connected to the appropriate circuits in the visual association cortex and the somatosensory association cortex. These interconnections, too, are accomplished as a result of learning.

Perception of spatial location—spatial learning—also involves learning about the relationships among many stimuli. For example, consider what we must learn to become familiar with the contents of a room. First, we must learn to recognize each of the objects. In addition, we must learn the relative locations of the objects with respect to each other. As a result, when we find ourselves in a particular place in the room, our perceptions of these objects and their locations relative to us tell us exactly where we are.

Other types of relational learning are even more complex. Episodic learning—remembering sequences of events (episodes) that we witness—requires us to keep track of and remember not only individual events but also the order in which they occur. As we will see in the last section of this chapter, a special system that involves the hippocampus and associated structures appears to perform coordinating functions required for many types of learning that go beyond simple perceptual, stimulus-response, or motor learning.

SECTION SUMMARY: The Nature of Learning

Learning produces changes in the way we perceive, act, think, and feel. It does so by producing changes in the nervous system in the circuits responsible for perception, in those responsible for the control of movement, and in connections between the two.

Perceptual learning consists primarily of changes in perceptual systems that make it possible for us to recognize stimuli so that we can respond to them appropriately. Stimulus-response learning consists of connections between perceptual and motor systems. The most important forms are classical and instrumental conditioning. Classical conditioning occurs when a neutral stimulus is followed by an unconditional stimulus (US) that naturally elicits an unconditional response (UR). After this pairing, the neutral stimulus becomes a conditional stimulus (CS); it now elicits the response by itself, which we refer to as the conditional response (CR).

Instrumental conditioning occurs when a response is followed by a reinforcing stimulus, such as a drink of water for a thirsty animal. The reinforcing stimulus increases the likelihood that the other stimuli that were present when the response was made will evoke the response. Both forms of stimulus-response learning may occur as a result of strengthened synaptic connections, as described by the Hebb rule.

Motor learning, although it may primarily involve changes within neural circuits that control movement, is guided by sensory stimuli; thus, it is actually a form of stimulus-response learning. Relational learning, the most complex form of learning, includes the ability to recognize objects through more than one sensory modality, to recognize the relative location of objects in the environment, and to remember the sequence in which events occurred during particular episodes.

■ THOUGHT QUESTION

Can you think of specific examples of each of the categories of learning described in this section? Can you think of some examples that include more than one category?

Synaptic Plasticity: Long-Term Potentiation and Long-Term Depression

On theoretical considerations alone, it would appear that learning must involve synaptic plasticity: changes in the structure or biochemistry of synapses that alter their effects on postsynaptic neurons. Recent years have seen an explosion of research on this topic, largely stimulated by the development of methods that permit researchers to observe structural and biochemical changes in microscopically small structures: the presynaptic and postsynaptic components of synapses.

Induction of Long-Term Potentiation

Electrical stimulation of circuits within the hippocampal formation can lead to long-term synaptic changes that seem to be among those responsible for learning. Lømo ( 1966 ) discovered that intense electrical stimulation of axons leading from the entorhinal cortex to the dentate gyrus caused a long-term increase in the magnitude of excitatory postsynaptic potentials in the postsynaptic neurons; this increase has come to be called  long-term potentiation (LTP) . (The word potentiate means “to strengthen, to make more potent.”)

 long-term potentiation (LTP) A long-term increase in the excitability of a neuron to a particular synaptic input caused by repeated high-frequency activity of that input.

First, let’s review some anatomy. The  hippocampal formation  is a specialized region of the limbic cortex located in the temporal lobe. (Its location in a human brain is shown in  Figure 13.6 .) Because the hippocampal formation is folded in one dimension and then curved in another, it has a complex, three-dimensional shape. Therefore, it is difficult to show what it looks like with a diagram on a two-dimensional sheet of paper. Fortunately, the structure of the hippocampal formation is orderly; a slice taken anywhere perpendicular to its curving long axis contains the same set of circuits.

 hippocampal formation A forebrain structure of the temporal lobe, constituting an important part of the limbic system; includes the hippocampus proper (Ammon’s horn), dentate gyrus, and subiculum.

Figure 13.4  shows a slice of the hippocampal formation, illustrating a typical procedure for producing long-term potentiation. The primary input to the hippocampal formation comes from the entorhinal cortex. The axons of neurons in the entorhinal cortex pass through the perforant path and form synapses with the granule cells of the dentate gyrus. A stimulating electrode is placed in the perforant path, and a recording electrode is placed in the dentate gyrus, near the granule cells. (See  Figure 13.4b . ) First, a single pulse of electrical stimulation is delivered to the perforant path, and then the resulting population EPSP is recorded in the dentate gyrus. The  population EPSP  is an extracellular measurement of the excitatory postsynaptic potentials (EPSP) produced by the synapses of the perforant path axons with the dentate granule cells. The size of the first population EPSP indicates the strength of the synaptic connections before long-term potentiation has taken place. Long-term potentiation can be induced by stimulating the axons in the perforant path with a burst of approximately one hundred pulses of electrical stimulation, delivered within a few seconds. Evidence that long-term potentiation has occurred is obtained by periodically delivering single pulses to the perforant path and recording the response in the dentate gyrus. If the response is greater than it was before the burst of pulses was delivered, long-term potentiation has occurred. (See  Figure 13.5 . )

 population EPSP An evoked potential that represents the EPSPs of a population of neurons.

FIGURE 13.4 The Hippocampal Formation and Long-Term Potentiation

This schematic diagram shows the connections of the components of the hippocampal formation and the procedure for producing long-term potentiation.

(Photograph from Swanson, L. W., Köhler, C., and Björklund, A., in Handbook of Chemical Neuroanatomy. Vol. 5: Integrated Systems of the CNS, Part I. Amsterdam: Elsevier Science Publishers, 1987. Reprinted with permission.)

FIGURE 13.5 Long-Term Potentiation

Population EPSPs were recorded from the dentate gyrus before and after electrical stimulation that led to long-term potentiation.

(From Berger, T. W. Science, 1984, 224, 627–630. Copyright 1984 by the American Association for the Advancement of Science. Reprinted with permission.)

Long-term potentiation can be produced in other regions of the hippocampal formation and in many other places in the brain. It can last for several months (Bliss and Lømo,  1973 ). It can be produced in isolated slices of the hippocampal formation as well as in the brains of living animals, which allows researchers to stimulate and record from individual neurons and to analyze biochemical changes. The brain is removed from the skull, the hippocampal complex is dissected, and slices are placed in a temperature-controlled chamber filled with liquid that resembles interstitial fluid. Under optimal conditions a slice remains alive for up to forty hours.

Many experiments have demonstrated that long-term potentiation in hippocampal slices can follow the Hebb rule. That is, when weak and strong synapses to a single neuron are stimulated at approximately the same time, the weak synapse becomes strengthened. This phenomenon is called  associative long-term potentiation  because it is produced by the association (in time) between the activity of the two sets of synapses. (See  Figure 13.6 . )

 associative long-term potentiation A long-term potentiation in which concurrent stimulation of weak and strong synapses to a given neuron strengthens the weak ones.

FIGURE 13.6 Associative Long-Term Potentiation

If the weak stimulus and strong stimulus are applied at the same time, the synapses activated by the weak stimulus will be strengthened.

Role of NMDA Receptors

Nonassociative long-term potentiation requires some sort of additive effect. That is, a series of pulses delivered at a high rate all in one burst will produce LTP, but the same number of pulses given at a slow rate will not. (In fact, as we shall see, low-frequency stimulation can lead to the opposite phenomenon: long-term depression.) The reason for this phenomenon is now clear. A rapid rate of stimulation causes the excitatory postsynaptic potentials to summate, because each successive EPSP occurs before the previous one has dissipated. This means that rapid stimulation depolarizes the postsynaptic membrane much more than slow stimulation does. (See  Figure 13.7 . )

FIGURE 13.7 The Role of Summation in Long-Term Potentiation

If axons are stimulated rapidly, the EPSPs produced by the terminal buttons will summate, and the postsynaptic membrane will depolarize enough for long-term potentiation to occur. If axons are stimulated slowly, the EPSPs will not summate, and long-term potentiation will not occur.

Several experiments have shown that synaptic strengthening occurs when molecules of the neurotransmitter bind with postsynaptic receptors located in a dendritic spine that is already depolarized. Kelso, Ganong, and Brown ( 1986 ) found that if they used a microelectrode to artificially depolarize a neuron in field CA1 and then stimulated the axons that formed synapses with this neuron, the synapses became stronger. However, if the stimulation of the synapses and the depolarization of the neuron occurred at different times, no effect was seen; therefore, the two events had to occur together. (See  Figure 13.8 . )

FIGURE 13.8 Long-Term Potentiation

Synaptic strengthening occurs when synapses are active while the membrane of the postsynaptic cell is depolarized.

Experiments such as the ones I just described indicate that LTP requires two events: activation of synapses and depolarization of the postsynaptic neuron. The explanation for this phenomenon, at least in many parts of the brain, lies in the characteristics of a very special type of glutamate receptor. The  NMDA receptor  has some unusual properties. It is found in the hippocampal formation, especially in field CA1. It gets its name from a drug that specifically activates it: N-methyl-D-aspartate. The NMDA receptor controls a calcium ion channel. This channel is normally blocked by a magnesium ion (Mg2+), which prevents calcium ions from entering the cell even when the receptor is stimulated by glutamate. But if the postsynaptic membrane is depolarized, the Mg2+ is ejected from the ion channel, and the channel is free to admit Ca2+ ions. Thus, calcium ions enter the cells through the channels controlled by NMDA receptors only when glutamate is present and when the postsynaptic membrane is depolarized. This means that the ion channel controlled by the NMDA receptor is a neurotransmitter- and voltage-dependent ion channel. (See  Figure 13.9  and   Simulate the NMDA receptor on MyPsychLab.)

 NMDA receptor A specialized ionotropic glutamate receptor that controls a calcium channel that is normally blocked by Mg2+ ions; involved in long-term potentiation.

FIGURE 13.9 The NMDA Receptor

The NMDA receptor is a neurotransmitter- and voltage-dependent ion channel. (a) When the postsynaptic membrane is at the resting potential, Mg2+ blocks the ion channel, preventing Ca2+ from entering. (b) When the membrane is depolarized, the magnesium ion is evicted. Thus, the attachment of glutamate to the binding site causes the ion channel to open, allowing calcium ions to enter the dendritic spine.

Cell biologists have discovered that the calcium ion is used by many cells as a second messenger that activates various enzymes and triggers biochemical processes. The entry of calcium ions through the ion channels controlled by NMDA receptors is an essential step in long-term potentiation (Lynch et al.,  1984 ).  AP5  (2-amino-5-phosphonopentanoate), a drug that blocks NMDA receptors, prevents calcium ions from entering the dendritic spines and thus blocks the establishment of LTP (Brown et al.,  1989 ). These results indicate that the activation of NMDA receptors is necessary for the first step in the process events that establishes LTP: the entry of calcium ions into dendritic spines.

 AP5 2-Amino-5-phosphonopentanoate, a drug that blocks NMDA receptors.

In  Chapter 2  you learned that only axons are capable of producing action potentials. Actually, they can also occur in dendrites of some types of pyramidal cells, including those in field CA1 of the hippocampal formation. The threshold of excitation for  dendritic spikes  (as these action potentials are called) is rather high. As far as we know, they occur only when an action potential is triggered in the axon of the pyramidal cell. The backwash of depolarization across the cell body triggers a dendritic spike, which is propagated up the trunk of the dendrite. This means that whenever the axon of a pyramidal cell fires, all of its dendritic spines become depolarized for a brief time.

 dendritic spike An action potential that occurs in the dendrite of some types of pyramidal cells.

A study by Magee and Johnston ( 1997 ) proved that the simultaneous occurrence of synaptic activation and a dendritic spike strengthens the active synapse. The investigators injected individual CA1 pyramidal cells in hippocampal slices with calcium-green-1, a fluorescent dye that permitted them to observe the influx of calcium. They found that when individual synapses became active at the same time that a dendritic spike had been triggered, calcium “hot spots” occurred near the activated synapses. Moreover, the size of the excitatory postsynaptic potential produced by these activated synapses became larger. In other words, these synapses became strengthened. To confirm that the dendritic spikes were necessary for the synaptic potentiation to take place, the investigators infused a small amount of tetrodotoxin (TTX) onto the base of the dendrite just before triggering an action potential. The TTX prevented the formation of dendritic spikes by blocking voltage-dependent sodium channels. Under these conditions, long-term potentiation did not occur.

FIGURE 13.10 Associative Long-Term Potentiation

If the activity of strong synapses is sufficient to trigger an action potential in the neuron, the dendritic spike will depolarize the membrane of dendritic spines, priming NMDA receptors so that any weak synapses active at that time will become strengthened.

I think that considering what you already know about associative LTP, you can anticipate the role that NMDA receptors play in this phenomenon. If weak synapses are active by themselves, nothing happens because the membrane of the dendritic spine does not depolarize sufficiently for the calcium channels controlled by the NMDA receptors to open. (Remember that, for these channels to open, the postsynaptic membrane must first depolarize and displace the magnesium ions that normally block them.) However, if the activity of strong synapses located elsewhere on the postsynaptic cell has caused the cell to fire, then a dendritic spike will depolarize the postsynaptic membrane enough to eject the magnesium ions from the calcium channels of the NMDA receptors in the dendritic spines. If some weak synapses become active right then, calcium will enter the dendritic spines and cause the synapses to become strengthened. Thus, the special properties of NMDA receptors account not only for the existence of long-term potentiation but also for its associative nature. (See  Figure 13.10  and   Simulate associative LTP on MyPsychLab.)

Mechanisms of Synaptic Plasticity

What is responsible for the increases in synaptic strength that occur during long-term potentiation? Dendritic spines on CA1 pyramidal cells contain two types of glutamate receptors: NMDA receptors and  AMPA receptors . Research indicates that strengthening of an individual synapse is accomplished by insertion of additional AMPA receptors into the postsynaptic membrane of the dendritic spine (Shi et al.,  1999 ). AMPA receptors control sodium channels; thus, when they are activated by glutamate, they produce EPSPs in the membrane of the dendritic spine. Therefore, with more AMPA receptors present, the release of glutamate by the terminal button causes a larger excitatory postsynaptic potential. In other words, the synapse becomes stronger.

 AMPA receptor An ionotropic glutamate receptor that controls a sodium channel; when open, it produces EPSPs.

FIGURE 13.11 Synaptic Strengthening

(a) When the conditions for long-term potentiation are met, Ca2+ ions enter the dendritic spine through NMDA receptors. The calcium ions activate enzymes in the spine. (b) The activated enzymes cause AMPA receptors to move into the spine. (c) An increased number of AMPA receptors in the postsynaptic membrane strengthens the synapse. (Details of this process are shown in  Figure 13.14 .)

Where do these new AMPA receptors come from? Makino and Malinow ( 2009 ) used a two-photon laser scanning microscope to watch the movement of AMPA receptors in dendrites of CA1 pyramidal neurons in hippocampal slices. They found that the establishment of LTP first caused movement of AMPA receptors into the postsynaptic membranes of dendritic spines from adjacent nonsynaptic regions of the dendrites. Several minutes later, AMPA receptors were carried from the interior of the cell to the dendritic shaft, where they replaced the AMPA receptors that had been inserted in the postsynaptic membrane of the spines. (See  Figure 13.11 . )

How does the entry of calcium ions into the dendritic spine cause AMPA receptors to move into the postsynaptic membrane? This process appears to begin with the activation of several enzymes, including  CaM-KII  (type II calcium-calmodulin kinase), an enzyme found in dendritic spines. CaM-KII is a calcium-dependent enzyme, which is inactive until a calcium ion binds with it and activates it. Many studies have shown that CaM-KII plays a critical role in long-term potentiation. For example, Silva et al. ( 1992a ) found that LTP could not be established in field CA1 of hippocampal slices taken from mice with a targeted mutation against the gene responsible for the production of CaM-KII. A two-photon laser scanning microscope study by Shen and Meyer ( 1999 ) found that after LTP was established in cultured hippocampal neurons, CaM-KII molecules accumulated in the postsynaptic densities of dendritic spines. Lledo et al. ( 1995 ) found that injection of activated CaM-KII directly into CA1 pyramidal cells strengthened synaptic transmission in those cells.

 CaM-KII Type II calcium-calmodulin kinase, an enzyme that must be activated by calcium; may play a role in the establishment of long-term potentiation.

Two other changes that accompany LTP are alteration of synaptic structure and production of new synapses. Many studies have found that the establishment of LTP also includes changes in the size and shape of dendritic spines. For example, Bourne and Harris ( 2007 ) suggest that LTP causes the enlargement of thin spines into fatter, mushroom-shaped spines.  Figure 13.12  shows the variety of shapes that dendritic spines and their associated postsynaptic density can take. (See  Figure 13.12 . ) Nägerl et al. ( 2007 ) found that the establishment of LTP even causes the growth of new dendritic spines. After about fifteen to nineteen hours, the new spines formed synaptic connections with terminals of nearby axons. (See  Figure 13.13 . )

FIGURE 13.12 Dendritic Spines in Field CA1

According to Bourne and Harris ( 2007 ), long-term potentiation may convert thin spines into mushroom-shaped spines. (a) Colorized photomicrograph. Dendrite shafts are yellow, spine necks are blue, spine heads are green, and presynaptic terminals are orange. (b) Three-dimensional reconstruction of a portion of a dendrite (yellow) showing the variation in size and shape of postsynaptic densities (red).

(From Bourne, J., and Harris, K. M. Current Opinion in Neurobiology, 2007, 17, 381–386. Reprinted with permission.)

s on the brain. Please support your answers using scholarly research addressing stress with regard to physiological functioning.

PART 2

Provide one example of a learning disorder or a memory disorder that you would find in the Diagnostic Statistical Manual 5 (DSM5) ? Describe the specific disorder you have selected including presentation and symptoms. What are some methods or instruments that could be used to help a therapist determine this diagnosis?

PART 3

Review this week’s course materials and learning activities, and reflect on your learning so far this week. Respond to one or more of the following prompts in one to two paragraphs:

1. Provide citation and reference to the material(s) you discuss. Describe what you found interesting regarding this topic, and why.
2. Describe how you will apply that learning in your daily life, including your work life.
3. Describe what may be unclear to you, and what you would like to learn.