Chapter 19 and Memory

et me begin by telling a little story. because we practice–repeat something over When I was a graduate student we had and over. A further definition says, Lto take an exam that Cornell does in “[Learning is] either a case of differential an interesting way. They put you in a swivel- strengthening of one from a number of chair surrounded by your committee responses evoked by a situation of need, or composed of 4-5 faculty members. You are the formation of receptor-effector spun around, and a question comes from the connections de novo; the first occurs direction you face when you stop. One of the typically in simple selective learning and the questions I was asked was, “What will be second in conditioned reflex learning" (Hull, the most important accomplishment in the 1943). It is the strengthening of existing field of neuroscience in the next 10 years?” responses and the formation of new Knowing that knowledge usually advances responses to existing stimuli that make this in small steps, I said that we would definition unique. So what is learning? It gradually know more about most aspects of isn’t clear that we have an inclusive the field, but I didn’t expect any major definition. It appears that learning is the breakthroughs. To a man, the committee strengthening of existing responses or agreed that in 10 years we would have a formation of new responses to existing complete solution to the problem of learning stimuli that occurs because of practice or and memory. The word complete was their repetition. How much practice? Sometimes a term, presumably meaning that we would single practice session is sufficient as in know everything there was to know about avoidance of painful or noxious stimuli. learning and memory. Well, at the 10-year Sometimes a lot of practice is necessary as mark, I sent them all a letter saying, “I told in learning to drive a car. you so!” Their predicted event didn’t What then is memory? Again happen. However, we have made some according to Kandel (2000), ". . . memory is progress; that progress is what this chapter is the process by which that knowledge of the about. world is encoded, stored, and later retrieved." By this definition, memory is not Definitions a thing; it’s a process. Interesting! In another What is learning? According to Eric definition, "Memory is a phase of learning . . Kandel (2000) “Learning is the process by . learning has three stages: 1. acquiring, which we acquire knowledge about the wherein one masters a new activity . . . or world.” While this definition is erudite, it memorizes verbal material . . . 2. retaining doesn’t help us much in knowing what to the new acquisition for a period of time; and study. Another definition (Kimble, 1961), 3. remembering, which enables one to "Learning refers to a more or less permanent reproduce the learned act or memorized change in behavior which occurs as a result material. In a narrower sense learning of practice," is a little better. It tells us that merely means acquiring skill . . ." (Sargent learning is more or less permanent; it won’t & Stafford, 1965). From these definitions, always be there, but often will. It also tells we see that memory has to do with keeping us that this is something that happens “knowledge” someplace and then retrieving it when it is needed. What we don’t see here when given only the first few letters of the is that the “knowledge” doesn’t have to word. At the same time, they deny ever come into consciousness. I have two having learned the word previously. Implicit cars–one with an automatic transmission, memory is often further parceled as one with a stick shift. I don’t have to bring associative and non-associative. There are into consciousness the process for shifting two well-known types of non-associative gears when I get into the car that requires me learning: and . to do that–I just do it! Habituation is a decrease in response to a benign stimulus when the stimulus is Types of Memory presented repeatedly. A dog will be aroused There are actually two basic kinds of when a strange tone is played. If the tone is learning and memory. One is declarative or played over and over, the dog will explicit; the other is non-declarative or eventually no longer be aroused by the tone. implicit. Knowledge of facts–what we know We say that it has habituated. This kind of about places, things and people–and the learning makes sense; it is not efficient for meaning of these facts is explicit memory. an organism to go on responding to a These things must be recalled into stimulus that has no meaning. The other consciousness to be used. Patients who have form of non-associative learning, bilateral medial temporal lobe lesions have sensitization, is an enhanced response to an inability to learn and remember items of many different stimuli after experiencing an factual knowledge. They can’t remember intense or noxious one. For example, an people that they met the day before. They animal responds more vigorously to a tone can’t remember what they did the day of lesser intensity once a painfully loud tone before. Some people will further parcel has been played. Here we say that the animal explicit memories as episodic (we remember is sensitized. events) or semantic (we remember facts). As These two forms of learning also Kandel (2000) points out, in either case the interact. Once a response has been content of all explicit memories can be habituated, it can be restored by expressed by declarative statements such as sensitization. In this case, we say that the “I was here yesterday” (episodic) and “The animal is dishabituated. As an example: a hippocampus has something to do with habituated startle response to a noise can be memory” (semantic). restored by strongly pinching the skin. Implicit memory involves In non-associative learning, it is not information about how to perform necessary that the animal learns to associate something; it’s recalled unconsciously. We the stimuli involved (thus the name). For use implicit memory in trained, reflexive example, the dishabituated animal does not motor or perceptual skills. I know how to learn to associate the noise with the pinch. drive my car; I know how to get to work. As we shall see shortly, this is the hallmark The same people with bilateral medial of associative learning. Not all forms of non- temporal lobe lesions can learn simple associative learning are as simple as reflexive skills–they habituate and are habituation and sensitization. For example, sensitized, they can be classically and we learn language by imitation of people operantly conditioned (see later). They can who already speak. This involves no learn certain perceptual tasks. For example, association of stimuli and is clearly more they can recall a word learned previously complicated than habituation. In associative learning, we “learn” conditioned stimulus (CS). The response to that two stimuli are associated with each it (again salivation) is called the conditioned other or that a response is associated with a response (CR). The UR and the CR are given event or has a given consequence. usually similar but often not identical in type Perhaps important in clinical considerations, or strength. a person can also learn that an outcome is Initially investigators thought that not associated with a response. So a person involved simply may learn that what happens to him is not learning that two stimuli were related to what he does. Two sorts of contiguous–that they occurred close together associative learning have been well studied: in time, one after the other. Now we think classical conditioning and operant that what the animals learn is conditioning. Classical conditioning is well contingencies–that existence of something demonstrated by Pavlov’s famous depends upon existence of something else. experiment in which he presented meat With this in mind, it is possible to see that powder to a dog, causing it to salivate. He simply learning that two stimuli were repeated the presentation, and each time the contiguous could often lead to behaviors that dog salivated. If he repeatedly rang a bell were maladaptive, with animals associating just before presenting the meat powder (they environmental events that had no real were paired), the animal came to associate relationship. On the other hand, the the bell with the presentation of the meat existence of superstitious behaviors, even in powder, and it would begin to salivate when humans, suggests that this does occur. the bell was rung. In fact, for a while it It is tempting to think of extinction would salivate if the bell was rung but no as an example of forgetting, but alas it is not. meat powder was presented (they were The difference is that something new is unpaired). After a while, the bell stopped learned during the process of extinction–the predicting the presentation of meat powder animal learns that the CS is no longer a for the dog, and it ceased salivating when it signal that the US is about to occur, rather it was rung. (This process is called extinction.) is a signal that the US will not occur. It should be noted that for classical In (sometimes conditioning to occur the ringing of the bell called trial-and-error learning), a person or must precede the presentation of the meat animal learns that it gets a reward if it does powder, often by a certain critical interval of something. So, a pigeon learns that it gets time (of the order of 0.5 sec). One way to food if it pecks at a certain key, but not if it look at classical conditioning is to think of pecks at another. A rat learns that it can the bell as becoming a signal that the meat avoid getting an electric shock if it presses a powder is about to be presented. bar at a certain time. Presumably what the In Pavlov’s paradigm, the meat animal learns is that one of its many powder normally elicits salivation without behaviors (pecking or bar pressing) is experimenter intervention (it is innate or followed by food. It is constitutional in perhaps previously strongly learned), and it animals to repeat behaviors that lead to is called the unconditioned stimulus (US). positive reinforcement (something pleasant The response is called the unconditioned or the absence of something unpleasant) and response (UR). The bell comes to elicit avoid behaviors that lead to punishment or salivation only after it is repeatedly paired negative reinforcement. with meat powder; so it’s called the Neuroscience of Learning and Memory

A great deal has been written about is shown in Fig. 19-2. the kinds and properties of learning. What has been said here is probably enough for the purposes of this chapter. If you want to know more, you can consult any good textbook on learning or the psychology of learning. We want to know about what is going on in the brain when a person or animal learns something, stores what has been learned and later retrieves it for use in Figure 19-2 - Block diagram of the supposed flow of information behavior. between areas associated with learning and memory.

Explicit Memory Different forms of learning are In overview, experiments on learning affected differentially by lesions in different can be interpreted to say that explicit locations. Damage to parahippocampal, memory is first acquired through one or perirhinal and entorhinal cortices produces more of the three polymodal association greater deficits in memory storage for object areas of the cerebral cortex, namely recognition than does hippocampal damage. prefrontal, limbic and parieto-occipital- Right hippocampal damage produces greater temporal. Then, the information is deficits in memory for spatial representation, transferred to parahippocampal and whereas left hippocampal damage produces perirhinal cortices, entorhinal cortex dentate greater deficits in memory for words, objects gyrus, hippocampus, subiculum and back to or people. In either case, the deficits are in entorhinal, parahippocampal and perirhinal formation of new, long-term memory; old cortex. The locations of these areas relative memories are spared. to one another are shown in Fig. 19-1, Current thought is that the whereas a block diagram of the connections hippocampal system does the initial steps in long-term memory storage–different parts being more important for different kinds of memory. The results of hippocampal machinations–presumably memories–are transferred to the association cortex for storage. There is no general semantic (factual) memory store; rather memories of a single event can be stored in multiple locations. This make sense when it is recalled that a single memory has multiple Figure 19-1. The relative positions of parts of the facets–each event contains sounds, smells, limbic system involved in learning and memory. tastes, somatosensory experiences, visual images and so forth. Long-term storage of storage. episodic (event) memories seems to occur in prefrontal association cortex. Processes of Learning So, each new explicit memory is formed by four sequential processes: Given the definitions for learning Encoding-information for each and memory, what sort of mechanisms memory is assembled from the would we expect to find in the nervous different sensory systems and system? One early thought was that neurons translated into whatever form in “memory” pathways were arranged in necessary to be remembered. This is reverberating circuits. In such a circuit, one presumably the domain of the neuron excites another and the other excites association cortices and perhaps the one such that, once the circuit is other areas. activated, action potentials run around Consolidation-converting the continuously. An example of this kind of encoded information into a form that arrangement is shown in Fig. 19-3. Here are can be permanently stored. The shown only 2 neurons in the circuit but any hippocampal and surrounding areas number may be included. If this kind of apparently accomplish this. arrangement accounts for memory, then any Storage-the actual deposition of the event that temporarily stopped activity in the memories into the final resting circuit should disrupt memory. places–this is though to be in Unfortunately for association cortex. supporters of the Retrieval-memories are of little use if idea, they cannot be read out for later use. electroconvulsive Less is known about this process. shock, which temporarily stops Implicit Memory or resets all Implicit memories are stored electrical activity differently depending upon how they are in the nervous acquired. “Fear conditioning” (training that Figure 19-3 - A reverber- system produces involves use of fearful stimuli) involves the ating circuit: Neuron A only a significant, amygdala. Operant conditioning involves the excites B and vice versa. transitory loss of striatum and cerebellum. For example, eye recent memory, but blink conditioning is disrupted by lesions of no loss of older memories. the dentate and interpositus nuclei of the Some years ago, the psychologist cerebellum. Classical conditioning, Donald Hebb (Hebb, DO (1949) The sensitization and habituation involve the Organization of Behavior: A sensory and motor systems involved in Neuropsychologi-cal Theory. New York: producing the motor responses being John Wiley) mulled this problem and came conditioned. Perhaps surprisingly, certain up with a principle that has become known simple reflexes mediated by the spinal cord as Hebb’s rule. Briefly, the principle is can be classically conditioned even after the “When an axon of cell A . . . excites cell B cord has been surgically isolated from the and repeatedly or persistently takes part in brain. So, it appears that all regions of the firing it, some growth process or metabolic nervous system may be capable of memory change takes place in one or both cells so activation, the stimulus leads to a decrease in the number of dopamine-containing vesicles that release their contents onto the motoneuron. There appears to be no change in the sensitivity of postsynaptic NMDA or non-NMDA receptors. As yet, we don’t know why the dopamine release decreases. It is presumed that habituation in vertebrates, including man, occurs by a similar process.

Sensitization In sensitization, a stimulus to one pathway enhances reflex strength in another. An example, again taken from experiments in Aplysia, is shown in Fig. 19-5. Again, stimulation of the siphon leads the animal to withdraw the gill by activating sensory neuron 1, which in turn activates a Figure 19-4 - Simplified neural circuits involved in the habituation process in Aplysia. There are about 24 sensory neurons in the siphon; these are glutaminer- gic. They synapse on 6 motor neurons that innervate the gill and various interneurons as shown. The control condition is shown on the left, the habituated condition on the right. that A’s efficiency as one of the cells firing B is increased.” As we shall see, current thought is an extension of Hebb’s rule.

Habituation What happens in the nervous system Figure 19-5 - Sensitization is produced by applying a to produce habituation? Experiments noxious stimulus to the tail of the Aplysia’s tail, performed in Aplysia californica, the sea activated sensory neuron 2. This, in turn activates a facilitating interneuron that enhances transmission in slug, were designed to address this problem. the pathway from the siphon to the motor neuron. Their results are shown schematically in Fig.19-4. If the siphon of the animal is stimulated mechanically the animal motoneuron. If the tail of the animal is withdraws the gill, presumably for stimulated just before the siphon is, then the protection. That action is known to occur withdrawal of the gill is quicker and more because the stimulus activates receptors in forceful. The mechanism of this appears to the siphon, which activates, directly or involve serotoninergic, axo-axonic synapses. indirectly through an interneuron, the As shown in the figure, activation of the motoneuron that withdraws the gill. This is a sensory receptors in the tail activates, simple reflex circuit. All of this is shown on through sensory neuron 2, a facilitating the left side of the figure. With repeated interneuron that excites sensory neuron 1 in the pathway leading the gill withdrawal. It opens Ca channels. The end result is that does this either at the cell body or at the activation of this 5HT pathway by tail terminals of the sensory neuron on the stimulation causes more transmitter motoneuron or the interneuron. The substance to be released by siphon consequence of the sensitization process is stimulation, the resulting larger EPSP leads to increase the size of the EPSP in the to a larger response by the gill. motoneuron without increasing the response of sensory neuron 1. This will cause a With only short-term tail stimulation, greater response in the motoneuron and the sensitization will fairly quickly disappear therefore a greater withdrawal of the gill. when tail stimulation ceases. However, the How all this occurs is illustrated in sensitization can be made relatively Fig. 19-6, which shows an axo-axonic permanent by repeated tail stimulation. This synapse as might occur between the long-term sensitization (and also long-term facilitating interneuron and sensory neuron habituation) occurs because there are 1. Serotonin (5-hydroxytryptamine or 5HT) structural changes that occur in the is released by the presynaptic axon onto the presynaptic terminals (sensory neuron 1, for postsynaptic axon where it binds to example). With sensitization, there is an up to 2-fold increase in the number of synaptic terminals in both sensory and motoneurons. Alternatively, with habituation, there is a one-third reduction in the number of

Figure 19-6 - The synaptic and chemical events underlying presynaptic facilitation involved in producing sensitization. See text for details. receptors and activates a G protein that, in turn, activates adenylyl cyclase to produce cAMP. This cAMP activates a cAMP- dependent protein kinase, PKA. Along with another kinase, PKC, PKA phosphorylates Figure 19-7 - Long-term storage of implicit memory and closes K channels (hypopolarizing the for sensitization involves changes shown in Fig. 19-6 cell), mobilizes vesicles for exocytosis and plus changes in protein synthesis that result in formation of new synaptic connections. synaptic terminals. Both of these changes been termed cooperativity, and it results require altered protein synthesis by from the requirement of NMDA receptors mechanisms shown in Fig. 19-7. that glutamate bind to them and the cell be hypopolarized, the binding opens the Long-term Potentiation channel and the hypopolarization displaces As previously detailed, the Mg++ that blocks the channel lumen. Also hippocampus is important in storage of required is that the pre- and postsynaptic declarative memory. In 1973, a phenomenon cells both be active at the same time. This was described in the hippocampus that may latter property has been termed associativity. account for declarative memory. Since then The astute student will see that this is the same phenomenon has been observed in precisely the condition that Hebb’s law says various other places known to be involved in should exist. memory storage. This phenomenon is called long-term potentiation (LTP). A high-frequency train of stimuli applied to fibers afferent to the hippocampus increase the amplitude of EPSPs in the target neurons. The increase lasts for days or weeks and requires activation of several afferent axons together. This property has

Figure 19-9 - During normal low-frequency trans- mission, glutamate interacts with NMDA and non- MNDA (AMPA) and metabotropic receptors.

The experimental setup for demonstrating LTP is shown in Fig. 19-8A. Recordings are made intracellularly from CA1 neurons of the hippocampus while stimulation is applied to the Schaffer collaterals of CA3 neurons. The amplitudes of the EPSPs in the CA1 neurons are shown in B. For a single stimulus, the amplitude of the EPSPs is plotted at 100%. When a train of stimuli is applied instead, the amplitude of the EPSPs augment to about 150%, whereas with 4 such trains the amplitude increases to 250%. Many people think that long-term potentiation is an example of Hebb’s rule at work and that it is the Figure 19-8 - A. Experimental setup for demon- physiological basis of memory. strating LTP in the hippocampus. The Schaffer During normal synaptic transmission collateral pathway is stimulated to cause a response (Fig. 19-9), glutamate binds to non-NMDA in pyramidal cells of CA1. B. Comparison of EPSP size in early and late LTP with the early phase receptors allowing cations to flow through evoked by a single train and the late phase by 4 trains the channels and the cell membrane to of pulses. translates to the nucleus of the cell and starts processes that lead to protein synthesis and to structural changes, i.e., the formation of new synapses. Many scientists believe that this is the substrate for long-term memory–the formation of new synapses. There are still unanswered questions about the relationship of LTP to memory. First, memories last decades whereas LTP Figure 19-10 - With high-frequency stimulation other has been observed only for days or weeks. events occur as described in the text. How long LTP can be maintained is difficult to determine. Admittedly, LTP is the hypopolarize. Glutamate also binds to longest lasting process known in metabotropic receptors, activating PLC, and neuroscience. Still memories may last much to NMDA receptors. As you may already longer. LTP occurs in most or all of the know, NMDA receptor channels can bind places where memories are known to be glutamate but no current will flow through stored. What is not known is whether the channels unless the Mg++ that binds to disruption of LTP also interferes with the channel lumen is displaced. The latter memory. event can be effected by hypopolarizing the cell. By contrast, during the early phase of LTP, the high-frequency stimulation opens non-NMDA glutamate channels leading to hypopolarization. This dislodges Mg++ from the NMDA glutamate channels, and Ca++ enters the cells. The calcium triggers the activity of Ca-dependent kinases, PKC and Ca-calmodulin, and tyrosine kinase. Ca- calmodulin kinase phosphorylates non- NMDA channels, increasing their sensitivity to glutamate and a messenger is sent retrogradely to the presynaptic terminal to increase the release of transmitter substance. All of this is illustrated in Fig.19-10. These events increase the transmitter released by presynaptic terminals. With LTP, there is a decrease in transmission failure, i.e., synapses are more reliable in exciting postsynaptic cells. This is also shown in the figure. Figure 19-11 - For LTP to last (Late LTP) the events of Fig. 19-10 must also lead to changes in protein In the late phase of LTP (Fig. 19-11), synthesis and to formation of new synaptic calcium enters the cell and triggers Ca- connections. calmodulin, which in turn activates adenylyl cyclase and cAMP kinase. The latter Summary Behavior: A Neuropsychological Theory. Non-declarative (implicit) memory New York: John Wiley involves different brain regions: fear conditioning involves amygdala; operant Hull, CL (1943) Principles of Behavior. conditioning involves striatum and New York: Appleton-Century-Crofts. cerebellum; and classical conditioning, sensitization and habituation involve sensory Kandel, ER, JH Schwartz and TM Jessell and motor systems used in the responses. (2000) Principles of Neural Science. New This kind of memory involves a number of York: McGraw-Hill. processes: habituation involves decrease in synaptic strength from decreased transmitter Kandel, ER and JH Schwartz (1982) release; sensitization involves increase in Molecular biology of learning: Modulation synaptic strength due to presynaptic of transmitter release. Science 218:433-443 facilitation; and classical conditioning involves increase in synaptic strength due to Kimble, GA (1961) Hilgard and Marquis’ presynaptic facilitation that is dependent on Conditioning and Learning. 2nd Edition. New activity in both pre- and postsynaptic cells. York: Appleton-Century-Crofts. Declarative (explicit) memory also involves a number of brain regions: there is Nicoll, RA, JA Kauer and RC Malenka no general store for explicit memories; (1988) The current excitement in long-term because the subject of memories is potentiation. Neuron 1:97-103. multimodal, storage of different aspects occurs in different locations; the Sargent, SS and KR Stafford (1965) Basic hippocampal formation is important in Teachings of the Great Psychologists. processing information for storage as Garden City, NY: Dolphin Books. memory; and memories are actually stored in association cortex. This kind of memory probably makes use of long-term potentiation. The early phase of LTP involves glutamatergic transmission; postsynaptic processes that produce enhanced sensitivity or receptors to glutamate as well as enhanced release of transmitter substance. In the late phase of LTP, protein synthesis leads to changes in cell structure and formation of new synapses.

References

Dudai, Y (1989) The Neurobiology of Memory: Concepts, Findings, Trends. Oxford: Oxford University Press.

Hebb, DO (1949) The Organization of