Among our most cherished abilities are learning and remembering. Neuroplasticity is a requirement for learning and memory and a characteristic of the mammalian brain. In fact, it is a trait of the nervous systems of all animals, even the simplest worms. Larger brains with more connections are more plastic, however, and thus likely to show more adaptability in neural organization.

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Greater adaptability happens because experience can alter the synapse. Not only are synapses versatile in structure and function, they are plastic: they can change. The synapse, therefore, is the site for the neural basis of learning, a relatively permanent change in behavior that results from experience.

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 The Organization of Behavior was novel 65 years 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). Simply put, cells that fire together wire together. A synapse that physically adapts in this way is called a Hebb synapse today.

Eric Kandel was awarded a Nobel Prize in 2000 for his descriptions of the synaptic basis of learning in a way that Hebb envisaged: learning in which the conjoint activity of nerve cells serves to link them. Kandel’s subject, the marine slug Aplysia californica, is an ideal subject for learning experiments. Slightly larger than a softball and lacking a shell, Aplysia has roughly 20,000 neurons. Some are quite accessible to researchers, who can isolate and study circuits having 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 stroking or shocking the slug’s appendages, Kandel and his coworkers (Bailey et al., 2015) produced enduring changes in its defensive behaviors. They used these behavioral responses to study underlying changes in Aplysia’s nervous system.

We illustrate the role of synapses in two kinds of learning that Kandel has studied: habituation and sensitization. For humans, both are called unconscious because they do not depend on a person’s knowing precisely when and how they occur.

In habituation, the response to a stimulus weakens with repeated stimulus presentations. If you are accustomed to living in the country, 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 soon it is as if the shoe were not 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 simply has habituated to the customary background sensation of a shoe on your foot.

Aplysia habituates to waves in the shallow tidal zone where it lives. These slugs are constantly buffeted by the flow of waves against their body, 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 slug 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.

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 gill movement is recorded. If the water jet 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. The decrement in the strength of the withdrawal is habituation, which can last as long as 30 minutes.

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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; in actuality, about 300 neurons may take part in this response. The water jet 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? 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 as habituation develops, the excitatory postsynaptic potentials (EPSPs) 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.

Reduced Sensitivity of Calcium Channels Underlies Habituation

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 from Figure 5-5 that neurotransmitter release in response to an action potential requires an influx of calcium ions across the presynaptic membrane. As habituation takes place, that Ca²⁺ influx decreases in response to the voltage changes associated with an action potential. Presumably, with repeated use, voltage-sensitive calcium channels become less responsive to voltage changes and more resistant to the passage of calcium ions.

The neural basis of habituation lies in the change in presynaptic calcium channels. Its mechanism, which is summarized close up in the Results section of Experiment 5-2, is a reduced sensitivity of calcium channels and a consequent decrease in neurotransmitter release. Thus, habituation can be linked to a specific molecular change, as summarized in the experiment’s Conclusion.

A sprinter crouched in her starting blocks is often hyperresponsive to the starter’s gun: its firing triggers in her a rapid reaction. The stressful, competitive context of the race helps to sensitize the sprinter 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-typical responses to all kinds of stimulation. If a loud noise startles you suddenly, you become much more responsive to other stimuli in your surroundings, including some to which you previously were habituated. In posttraumatic stress disorder (PTSD), physiological arousal related to recurring memories and dreams surrounding a traumatic event persist for months or years after the event. One characteristic of PTSD is a heightened response to stimuli, suggesting that the disorder is in part related to sensitization.

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The same thing happens to Aplysia. Sudden, novel stimuli can heighten a slug’s responsiveness to familiar stimulation. When attacked by a predator, for example, the slug displays heightened responses to many other stimuli in its environment. 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 slug’s tail enhances its gill withdrawal response for a period that lasts for minutes to hours.

Neural Basis of Sensitization

The neural circuits participating in sensitization differ from those that take part in a habituation response. The Results section of Experiment 5-3 shows the sensory and motor neurons that produce the gill withdrawal response and adds an interneuron that is responsible for sensitization.

An interneuron that receives input from a sensory neuron in Aplysia’s tail (and so carries information about the shock) makes an axoaxonic synapse with a sensory neuron in the siphon. 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 5-HT onto the axon of the siphon sensory neuron. Information from the siphon still comes through the sensory neuron to activate the motor neuron leading to the gill muscle, but the interneuron’s action in releasing 5-HT onto the sensory neuron’s presynaptic membrane amplifies the gill withdrawal response.

At the molecular level, shown close up in Experiment 5-3 Results, the serotonin released from the interneuron binds to a metabotropic serotonin receptor on the siphon’s sensory neuron axon. 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 second messenger cyclic adenosine monophosphate (cAMP) in the presynaptic membrane of the siphon’s sensory neuron.

Through several chemical reactions, cAMP attaches a phosphate molecule (PO₄) to potassium channels, rendering them less responsive. The close-up in Experiment 5-3 sums it up. In response to an action potential traveling down the axon of the siphon’s sensory neuron (such as one generated by a touch to the siphon), the potassium channels on that neuron are slower to open. Consequently, K⁺ ions cannot repolarize the membrane as quickly as normal, so the action potential lasts longer than it usually would.

Less-Responsive Potassium Channels Underlie Sensitization

The longer-lasting action potential that occurs because potassium channels are slower to open prolongs Ca²⁺ inflow. Ca²⁺ influx is necessary for neurotransmitter release. Thus, greater Ca²⁺ influx results in more neurotransmitter being released from the sensory synapse onto the motor neuron.

This increased neurotransmitter release produces greater activation of the motor neuron and thus a larger-than-normal gill withdrawal response. If the second messenger cAMP mobilizes more synaptic vesicles, making more neurotransmitter ready for release into the sensory–motor synapse, gill withdrawal may also be enhanced.

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Sensitization, then, is the opposite of habituation at the molecular level as well as at the behavioral level. In sensitization, more Ca²⁺ influx results in more transmitter being released, whereas in habituation, less Ca²⁺ 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.

Neural changes associated with learning must last long 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 long-term changes associated with learning and memory?

Repeated stimulation produces habituation and sensitization that can persist for months. Brief training produces short-term learning; longer training periods produce more enduring learning. If you cram for an exam the night before you take it, you might forget the material quickly, but if you study a little each day for a week, your learning may tend to endure. What underlies this more persistent form of learning?

Researchers working with Eric Kandel (Bailey et al., 2015) 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 5-19. 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.

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, including the formation of new synapses and new dendritic spines. Research Focus 5-5, Dendritic Spines: Small but Mighty, summarizes experimental evidence about structural changes in dendritic spines.

The second messenger cAMP plays an important role in carrying instructions regarding these structural changes to nuclear DNA. The evidence for cAMP’s involvement comes from studies of the fruit fly Drosophila. Two genetic mutations in the fruit fly can produce similar learning deficiencies. Both render the second messenger cAMP inoperative, but in opposite ways. One mutation, called dunce, lacks the enzymes necessary to degrade cAMP, so the fruit fly has abnormally high cAMP levels. The other mutation, called rutabaga, reduces levels of cAMP below the normal range for Drosophila neurons.

Significantly, fruit flies with either mutation 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 carry instructions to form them. Figure 5-20 summarizes these research findings.

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More lasting habituation and sensitization are mediated by relatively permanent changes in neuronal structure—by fewer or more synaptic connections—and the effects can be difficult to alter. As a result of sensitization, for example, symptoms of PTSD can persist indefinitely.

Adaptive Role of Synapses in Learning and Memory

Before you continue, check your understanding.

Question 1

Question 2

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Question 3

Question 4

Question 5

Question 6

Answers appear in the Self Test section of the book.