Trapped in the Eternal Now 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. --Henry Molaison (B. Milner, 1970, p. 37) Known as "Patient H.M." in a classic series of research articles, Henry Molaison was probably the most famous research participant in the history of neuroscience. Following a bicycle accident when Henry was an adolescent, he started to suffer seizures, and by his late twenties his epilepsy was out of control. Like the epilepsy patients we described at the end of Chapter 2, Henry decided to take the extreme measure of having a surgeon remove the brain sites where the seizures began. Because Henry's seizures began in both temporal lobes, a neurosurgeon removed most of his anterior temporal lobes in 1953. Henry's surgery relieved his epilepsy, but at a terrible, unforeseen price: He couldn't seem to form new memories (Scoville and Milner, 1957). For more than 50 years after
the surgery, until his death in 2008, Henry could retain any new fact only briefly; as soon as he was distracted, the newly acquired information vanished. He didn't know his age or the current date. For a while, he carried a note reminding himself that his father had died and his mother was in a retirement home. Henry knew that something was wrong with him, because he had no memories from the years since his surgery, or even memories from earlier the same day, as the quote above indicates. Henry's inability to form new memories meant that he couldn't have a lasting relationship with anybody new. No matter what experiences he might share with someone he met, Henry would have to start the acquaintance anew the following day, because he would have no recollection of ever having met the person. In some ways, this dreadful loss of memory ended Henry's journey as a human being--he could no longer grow in his experience of historical events, his friendships, or even a sense of his own life story. What happened to Henry, and what does his experience teach us about learning and memory?
A ll the distinctively human aspects of our behavior are learned: the languages we speak, how we dress, the foods we eat and how we eat them, our skills, and the ways we reach our goals. So much of our own individuality depends on learning and memory. We begin this chapter with a discussion of memory because research in the twentieth century revealed that there are fundamentally different types of memory. Then we delve into what we know about how learning alters the structure of the brain, which differs for different types of memory.
13.1There Are Several Kinds of Learning and Memory
View Animation 13.2: Brain Explorer learning The process of acquiring new and relatively enduring information, behavior patterns, or abilities, characterized by modifications of behavior as a result of practice, study, or experience. memory 1. The ability to learn and neurally encode information, consolidate the information for longer-term storage, and retrieve or reactivate the consolidated information at a later time. 2. The specific information that is stored in the brain. amnesia Severe impairment of memory. retrograde amnesia Difficulty in retrieving memories formed before the onset of amnesia. Patient H.M. The late Henry Molaison, a man who was unable to encode new declarative memories because of surgical removal of medial temporal lobe structures. anterograde amnesia Difficulty in forming new memories beginning with the onset of a disorder. hippocampus A medial temporal lobe structure that is important for learning and memory. Brenda Milner Earning her Ph.D. in 1952 a few years before working with Henry Molaison, Dr. Milner is still an active scholar, even after her 102nd birthday.
We begin our discussion about learning and memory by examining how they fail. Studying this material should allow you to: 13.1.1 Understand the two kinds of amnesia, one for memories before an event, and one for memories after an event. 13.1.2 Describe the two fundamentally different categories of memory. 13.1.3 Review the evidence that a particular circuit of three brain regions is crucial for forming certain types of memory. 13.1.4 Understand the two subtypes of declarative memories, the memories we can describe to other people. The terms learning, the process of acquiring new information, and memory, the ability to store and retrieve that information, are so often paired that it sometimes seems as if one necessarily implies the other. We cannot be sure that learning has occurred unless a memory can be elicited later. Many kinds of brain damage, caused by disease or accident, impair both learning and memory. We'll start by looking at some brain damage cases that revealed different classes of learning and memory. For Patient H.M., the present vanished into oblivion Amnesia (Greek for "forgetfulness") is a severe impairment of memory, usually as a result of accident or disease. Loss of memories that formed prior to an event (such as surgery or trauma)--called retrograde amnesia (from the Latin retro, "backward," and gradi, "to go")--is not uncommon. After an accident that damages the brain, people often have retrograde amnesia regarding events that happened a few hours or days before the accident, or even a year before. Despite dramatic depictions you may see on TV, it is unlikely that longer-term (or "complete") retrograde memory loss has ever occurred. Patient H.M.--Henry Molaison, whom we met at the start of the chapter--suffered from a far more unusual symptom. In Henry's case, most old memories remained intact, but he had difficulty recollecting any events that took place after his surgery. What's more, he was unable to retain any new material for more than a brief period. The inability to form new memories after an event is called anterograde amnesia (the Latin antero means "forward"). Over the very short term, Henry's memory was normal. If given a series of six or seven digits, he could immediately repeat the list without error. But when he was given a list of words to study and then tested on them after being distracted by another task, he could not repeat the list or even recall that there was a list. So Henry's case provided clear evidence that short-term memory differs from long-term memory--a distinction, long recognized by psychologists on behavioral grounds (W. James, 1890), that we will discuss in more depth later in this chapter. Henry's surgery removed the amygdala, most of the hippocampus, and surrounding cortex from both temporal lobes (FIGURE 13.1). The memory deficit seemed to be caused by loss of the medial temporal lobe, including the hippocampus, because people who had only the lateral temporal cortex removed had no memory impairment. Despite his obvious memory problems, Henry showed noticeable improvement over days of practice on a mirror-tracing task (FIGURE 13.2A) (B. Milner, 1965). Each day, when asked if he remembered the test, Henry said no, yet his performance was better than at the start of the first day (FIGURE 13.2B). So, was Henry's memory loss limited to tasks that relied on verbal processing? Not quite.
FIGURE 13.1 Brain Regions Crucial for Forming New Memories (A)
Hippocampus is Latin for "sea horse," and you can see how the brain structure resembles that animal. Hippocampus
As a young man, Henry Molaison (Patient H.M.) had the hippocampus (H) from both hemispheres surgically removed, with disastrous results. The surgeons did not remove the cerebellum (Cer), but the loss of hippocampal inputs caused it to shrink as he aged.
Brain scans from S. Corkin et al., 1997. J. Neurosci., 17: 3964. Courtesy of Suzanne Corkin
Entorhinal cortex Perirhinal cortex Watson/Breedlove The Mind's Machine Foundations of Brain and Behavior 4e MM4e_13.01 09/01/20
Optic tract Tail of the caudate nucleus Hippocampus Lateral ventricle
Henry's surgery removed not only the hippocampus, but also nearby associated cortical regions shown here.
FIGURE 13.2 Henry's Performance on
a Mirror-Tracing Task (After B. Milner, 1965 in P. M. Milner and S. E. Glickman
recognized the task, his performance progressively
[Eds.], Cognitive processes and the brain;
declarative memory A memory that can be stated or described. nondeclarative memory Also called procedural memory. A memory that is shown by performance rather than by conscious recollection. delayed non-matching-to-sample task A test in which the individual must respond to the unfamiliar stimulus in a pair of stimuli. Watson/Breedlove The Mind's Machine Foundations of Brain and Behavior 4e MM4e_13.02 03/06/20
For example, people with amnesia like Henry's can learn the skill of reading mirrorreversed text (FIGURE 13.3), which is a verbal task. The important distinction in Henry's deficit is not between motor and verbal performances, but rather between two general categories of memory: 1. Declarative memory is what we usually think of as memory: facts and information acquired through learning. It is memory we are aware of accessing, which we can declare to others. This is the type of memory that was so profoundly impaired by Henry's surgery. Tests of declarative memory take the form of requests for specific information that was learned previously. It is the type of memory we use to answer"what"questions--and thus is difficult to test in animals. 2. Nondeclarative memory, or procedural memory--that is, memory about perceptual or motor procedures--is shown by performance rather than by conscious recollection. Examples of procedural memory include learning the mirror-tracing task, at which Henry excelled, and the skill of mirror reading, or riding a bike (FIGURE 13.4). It is the type of memory we use for"how"problems and is often (but not always) nonverbal. A clever way to measure declarative memory in monkeys and other animals is the delayed non-matching-to-sample task (FIGURE 13.5), a test of object recognition that requires monkeys to declare what they remember by identifying which of two objects was not seen previously (Winters et al., 2010). Monkeys with damage to the medial temporal lobe, similar to H.M., are severely impaired on this task, as we'll see next. Long-term memory
Patients like Henry can learn to read mirror-reversed text quite well, even though they don't remember practicing it. This ability shows that their problem is not in learning verbal material, but in forming new declarative memories.
FIGURE 13.3 Reading MirrorReversed Text
Declarative: Things you know that you can tell others
Nondeclarative (procedural): Things you know that you can show by doing
Declarative memory can be tested readily in humans because they can talk. Henry Molaison was unable to form new declarative memories, indicating that the hippocampus is needed to retain these memories.
Nondeclarative memory can be tested readily in other animals, as well as in humans. Henry could form this type of memory, as when he learned the skill of mirror tracing.
FIGURE 13.4 Two Main Kinds of Memory: Declarative and Nondeclarative.
Memory and Learning 411 Food found under the nonmatching object
The monkey is initially presented with a sample object. When he displaces it, he nds a pellet of food beneath.
After a variable delay (seconds to minutes) the monkey is presented with the original object and another object.
FIGURE 13.5 The Delayed Non-Matching-to-Sample Task
Over a series of trials with different pairs of objects, the monkey learns that food is present under the object that differs from the sample.
The monkey declares his memory of the key by not choosing it.
The MindW's Mhaicchhine brain structures Foundations of Brain and Behavior 4e are important for
To determine which parts of the temporal lobe are crucial for declarative memory,
Hypothesis Particular portions of the medial temporal lobe are required for the formation of new declarative memories. Test Selectively remove different portions of the temporal lobe from both sides of the brain, and test for declarative memories using the
researchers selectively removed specific parts of the medial temporal lobes of monkeys to confirm that the amygdala-- one of the structures removed in Henry's
delayed non-matching-to-sample task (see Figure 13.5).
Result (A) Ventral view of monkey brain showing areas
(B) Scores of groups with different lesions
Lesions of the amygdala had no effect on declarative memories (data not shown).
alone impaired declarative memory only modestly. Lesions of
nounced when the hippocampal damage was paired with lesions of nearby cortical regions that communicate with the hippocampus: entorhinal, parahippocampal, and perirhinal cortices (Zola-Morgan et
al., 1994). Humans similarly show larger impairments when both the hippocampus and medial temporal cortex are
So Henry's symptoms were probably caused by loss of the medial temporal
Lesion extended to include entorhinal cortex and parahippocampal cortices
lobe on both sides of the brain. The experiments with monkeys,
Lesion extended forward to also include the anterior entorhinal and perirhinal cortices
together with Henry's case, indicate that we need at least one intact medial temporal lobe (including the hippocampus) in order to make new declarative memories.
Conclusion The severe disruption of new declarative memories in Henry Molaison and patients like him is due to damage to both the hippocampus itself and to nearby cortex. But these regions aren't the only brain structures needed for new declarative memories, as we'll see next.
FIGURE 13.6 Memory Performance after Medial Temporal Lobe Lesions
(Part A after L. R. Squire and S. Zola-Morgan, 1991. Science 253: 1380;
B after S. Zola-Morgan et al., 1994. Hippocampus 4: 482.)
412CHAPTER13 Patient N.A. A still-living man who is unable to encode new declarative memories, because of damage to the dorsomedial thalamus and the mammillary bodies. dorsomedial thalamus A limbic system structure that is connected to the hippocampus. mammillary body One of a pair of limbic system structures that are connected to the hippocampus. Korsakoff's syndrome A memory disorder, caused by thiamine deficiency, that is generally associated with chronic alcoholism. confabulate To fill in a gap in memory with a falsification. Confabulation is often seen in Korsakoff's syndrome.
Damage to the medial diencephalon can also cause amnesia In 1960, a young man known as Patient N.A. had a bizarre accident in which a miniature sword entered his nostril and injured his brain. Like Henry, N.A. has shown profound anterograde amnesia ever since his accident (Squire and Moore, 1979), and he can give little information about events since his accident, although his memory for earlier events is near normal (Kaushall et al., 1981). MRI study of N.A. (FIGURE 13.7) shows damage to several limbic system structures in the medial diencephalon that have connections to the hippocampus: the dorsomedial thalamus and the mammillary bodies (so called because they are shaped like a pair of breasts--see Figure 13.1A). Like Henry Molaison, N.A. shows normal short-term memory and can gain new nondeclarative/procedural memories, but he is impaired in forming declarative long-term memories. The similarity in symptoms suggests that the medial temporal lobe damaged in Henry's brain and these midline regions damaged in N.A. are parts of a larger memory system. That idea is reinforced by studies of people with Korsakoff's syndrome, a degenerative disease in which damage is found in the mammillary bodies (FIGURE 13.8) and dorsomedial thalamus (Mair et al., 1979), but not in temporal lobe structures like the hippocampus. The mammillary bodies may serve as a processing system connecting the medial temporal lobes (which were removed from Henry Molaison) to the thalamus and, from there, to other cortical sites (Vann and Aggleton, 2004). People with Korsakoff's syndrome often fail to recognize or sense any familiarity with some items, even those presented repeatedly, yet frequently they deny that anything is wrong with them. They often confabulate--that is, fill a gap in memory with a falsification that they seem to accept as true. Damage to the frontal cortex, also found in people suffering from Korsakoff's syndrome, probably causes the denial and confabulation that differentiates them from other people who have amnesia, such as Henry. The main cause of Korsakoff's syndrome is lack of the vitamin thiamine (Arts et al., 2017). Alcoholics who obtain most of their calories from alcohol and neglect their diet often suffer this deficiency. Treating them with thiamine can prevent further deterioration of memory functions but will not reverse the damage already done.
FIGURE 13.7 The Brain Damage in Patient N.A.
MRI scans show a prominent lesion of the dorsomedial thalamus on the left side of the brain (yellow arrows), as well as a lesion on the oor of the third ventricle where the mammillary bodies should be (red arrows).
Scans from L. R. Squire et al., 1989. Exp. Neurol. 105: 23
These studies make it clear that a brain circuit that includes the hippocampus, the mammillary bodies, and the dorsomedial thalamus is needed to form new declarative memories. But these case studies also clearly show that established declarative memories, formed before brain damage, are not stored in these structures for the long term. If they were, they would have been lost when the structures were damaged. So where are memories stored? We'll see next that a leading candidate is the cerebral cortex.
Image courtesy of D. P. Agamanolis, http: //neuropathology-web.org/
Brain damage can destroy autobiographical memories while sparing general memories
One striking case study suggests that at least some declarative
memories are stored in the cortex, and it also illustrates an im-
portant distinction between two subtypes of declarative mem-
ory. Kent Cochrane, known to the world as Patient K.C., suf-
fered brain damage in a motorcycle accident at age 30. He could no longer retrieve any personal memory of his past, although his
These oval-shaped mammillary bodies are darkened as a result
general knowledge remained good. He conversed easily and
played a good game of chess but could not remember where
he learned to play chess or who taught him the game. Detailed FIGURE 13.8 Brain Damage in People with Korsakoff's Syndrome
autobiographical declarative memory of this sort is known as
episodic memory; you show episodic memory when you recall
a specific episode in your life or relate an event to a particWulaatrsotnim/Bereaenddlopvleace. In contrast, semantic memory is generalized declarative memory, suThcehMasinkdn'soMwaicnhgintehe meaning of Foundations of Brain and Behavior 4e a word without knowing where or when you learned that word (Tulving, 1972). If care was taken to space out the trials, Kent could acquire newMsMe4me_a1n3t.0ic8 kn0o3w/0l6e/d2g0e (Tulving et al., 1991). But even with this method, Kent could not acquire new episodic knowledge--he wouldn't remember where he had learned that new material. Scans of Kent's brain revealed extensive damage to the left frontoparietal and the right parieto-occipital cerebral cortex, as well as severe shrinkage of both right and left hippocampus and nearby cortex (Rosenbaum et al., 2005). As with Henry, the bilateral
Patient K.C. The late Kent Cochrane, who sustained damage to the cortex that rendered him unable to form and retrieve episodic memories. episodic memory Also called autobiographical memory. Memory of a particular incident or a particular time and place. semantic memory Generalized declarative memory, such as knowing the meaning of a word.
hippocampal damage probably accounts for Kent's anterograde declarative amnesia.
But that damage cannot account for Kent's selective loss of nearly all his autobiograph-
ical memory, because other people with damage restricted to the medial temporal
lobe, like H.M., retain their autobiographical memories. Kent's inability to recall any
autobiographical details of his life from many years before his accident may instead be
a consequence of injuries to frontal and parietal cortex (Tulving, 1989). (Unlike dra-
matic portrayals of retrograde amnesia in fiction, Kent knew his name and recognized
his family, although he couldn't remember any particular past events with those peo-
ple.) FIGURE 13.9 reviews our current view of the sequence of brain regions important
From E. Tulving, 2002. Annu. Rev. Psychol. 53: 1
Parahippocampal, entorhinal, perirhinal cortex
Medial diencephalon, including mammillary bodies
Damage to either the medial temporal lobe or the medial diencephalon/mammillary bodies will prevent the formation of any new declarative memories without loss of previously formed memories.
FIGURE 13.9 Current Model of Declarative Memory Formation
Patient K.C. Brain damage from a severe motorcycle accident left Kent Cochrane (1951-2014) unable to retrieve episodic memories.
1. What are the two main types of amnesia, and which deficit was more severe for Henry Molaison? 2. What are the two main types of memory, and which type was affected in Henry? 3. How did research with animals help pin down the brain regions required for forming new memories that we can declare to others? 4. Name the two brain regions, in addition to the medial temporal lobe, that are required to form new declarative memories. 5. What are the two main subtypes of declarative memory?
13.2Different Forms of Nondeclarative Memory Involve Different Brain Regions
skill learning The process of learning to perform a challenging task simply by repeating it over and over. basal ganglia A group of forebrain nuclei, including the caudate nucleus, globus pallidus, and putamen, found deep within the cerebral hemispheres. They are crucial for skill learning. priming Also called repetition priming. The phenomenon by which exposure to a stimulus facilitates subsequent responses to the same or a similar stimulus.
Now let's consider the different types of nondeclarative memory and the brain regions associated with each. Studying this material should allow you to: 13.2.1 List the different categories of nondeclarative memory. 13.2.2 Name the stages of memory formation and the vulnerability for losing information at each stage. 13.2.3 Describe a model of how we encode, consolidate, and retrieve memories. 13.2.4 Explain how retrieving a memory makes it vulnerable to distortion. 13.2.5 Describe the effects of emotional arousal for memory, and the prospects of a drug treatment to soften traumatic memories. So far, we've seen that there are two different kinds of declarative memory: semantic and episodic. Likewise, there are several different types of nondeclarative memory, and we'll see that different brain regions are involved in these different forms. Different types of nondeclarative memory serve varying functions Skill learning is the process of learning how to perform a challenging task simply by doing it over and over. Improving at the mirror-tracing task performed by Henry Molaison (see Figure 13.2) or learning to read mirror-reversed text (see Figure 13.3) are examples of skill learning. So too is the acquisition of everyday skills like learning to ride a bike or to juggle (well, okay, maybe juggling isn't an "everyday" skill, but you get the idea). Henry demonstrated that the medial temporal lobe is not required to gain skills and retain them. Imaging studies have investigated learning and memory for different kinds of skills, including sensorimotor skills (e.g., mirror tracing), perceptual skills (e.g., r eading mirror-reversed text), and cognitive skills (tasks involving planning and problem solving, common in puzzles like the Tower of Hanoi problem. All three kinds of skill learning are impaired in people with damage to the basal ganglia (see Figure 1.14A). Damage to other brain regions, especially the motor cortex and cerebellum, also affects aspects of some skills. Neuroimaging studies confirm that the basal ganglia, cerebellum, and motor cortex are important for sensorimotor skill learning (Makino et al., 2016; Spampinato and Celnik, 2018). Priming (or repetition priming) is a change in the way you process a stimulus, usually a word or a picture, because you've seen it, or something similar, previously. For example, if a person is shown the word stamp in a list and later is asked to complete the word stem STA-, then she is more likely to reply "stamp" than, say, "start." Priming does not require declarative memory of the stimulus--Henry Molaison and other
FIGURE 13.10 Pavlovian (Classical) Conditioning
Before conditioning, the dog re exively salivates in response to food--an unlearned response.
Before conditioning, ringing of the bell produces no salivation.
During conditioning, the bell is rung repeatedly, and shortly Bell after each ringing, food is presented to the dog. Response +
Eventually the dog begins salivating in response to the bell, before the food is presented, and will salivate in response to the bell alone. Bell Response
The dog has been classically conditioned to salivate in response to the bell.
people with amnesia have shown priming for words they don't remember having seen. In contrast with skill learning, priming is not impaired by damage to the basal ganglia. In functional-imaging studies, perceptual priming (priming based on the visual form of words) is related to reduced activity in bilateral occipitotemporal cortex (WScahtsaocnt/eBrreeetdalol.v,e2007), while conceptual priming (priming based on word meaning) is aTshseoMciantde'sdMwaicthhinreeduced activation of the left frontal cortex (Buckner and Koutstaal, 1F9ou9n8d).atSioonsporfiBmraiinnganadpBpeehaavrsiorto4ebe at least partly a function of the cortex. MMO4et_h1e3r.1t0yp0e3s/o06f/n2o0ndeclarative memories include learning that involves relations between events--for example, between two or more stimuli, between a stimulus and a response, or between a response and its consequence--and is called associative learning. In the best-studied form, classical conditioning, an initially neutral stimulus comes to predict an event. In famous experiments, Ivan Pavlov (1849-1936) found that a dog would learn to salivate when presented with an auditory or visual stimulus if the stimulus came to predict the presentation of food. So, repeatedly ringing a bell before putting meat powder in a dog's mouth will eventually cause the dog to start salivating when it hears the bell alone. In this case the meat powder in the mouth is called the unconditioned stimulus (US), which already evokes an unconditioned response (UR; salivation in this example). The sound of the bell is called the conditioned stimulus (CS), and the learned response to the CS alone (salivation in response to the bell) is called the conditioned response (CR) (FIGURE 13.10). By the way, several sources on the web smugly declare that Pavlov never actually used a bell for a CS, but there's plenty of evidence that he did (R. K. Thomas, 1994; Tully, 2003). Some web "myths" are themselves myths! Experimental evidence in lab animals shows that circuits in the cerebellum are crucial for simple eye-blink conditioning, in which a tone or other stimulus is associated with eye blinking in response to a puff of air. A PET study in humans confirmed this idea by showing a progressive increase in activity in the cerebellum during eye-blink conditioning (Logan and Grafton, 1995). People with hippocampal lesions can acquire the conditioned eye-blink response, but people with damage to the cerebellum on one side can acquire a conditioned eye-blink response only on the side where the cerebellum is intact (Papka et al., 1994). In instrumental conditioning (also called operant conditioning), an association is formed between the animal's behavior and the consequence(s) of that behavior. An example of an apparatus designed to study instrumental conditioning is called the Skinner box, named for its originator, B. F. Skinner (FIGURE 13.11). In a common setup, the animal FIGURE 13.11
associative learning A type of learning in which an association is formed between two stimuli or between a stimulus and a response. It includes both classical and instrumental conditioning. classical conditioning Also called Pavlovian conditioning. A type of associative learning in which an originally neutral stimulus acquires the power to elicit a conditioned response when presented alone. cerebellum A structure located at the back of the brain, dorsal to the pons, that is involved in the central regulation of movement and in some forms of learning. instrumental conditioning Also called operant conditioning. A form of associative learning in which the likelihood that an act (instrumental response) will be performed depends on the consequences (reinforcing stimuli) that follow it. Inside this Skinner box, a rat presses a bar for food. A Skinner Box
From E. I. Moser & M-B. Moser. 2013. Neuron 80: 765 From E. Pastalkova et al., 2008. Science 321: 1322. Image courtesy of Eva Pastalkova
(A) Place cells In this simple maze, each dot represents the rat's position when a hippocampal place neuron red. Different neurons are encoded by different colors.
The neuron denoted by yellow dots red when the animal was in this part of the maze.
FIGURE 13.12 Hippocampal Spatial Neurons
The neuron denoted by green dots red when the rat was in this part of the maze.
The gray trace shows the path of a rat exploring an enclosure. Each black dot represents the point at which one particular grid cell in the entorhinal cortex red.
learns that performing a certain action (e.g., pressing a bar) is followed by a reward (such as a food pellet). Research in animals has not pinpointed the brain regions that are crucial for instrumental conditioning, perhaps because this type of learning taps so many different aspects of behavior.
Animal research confirms the various brain regions involved
The caricature of the white-coated scientist watching rats run in mazes, a staple of carMM4e_13.12 06/09/20 toonists to this day, has its origins in the intensive memory research of the early twen-
tieth century. The early work indicated that rats and other animals don't just learn a
series of turns but instead form a cognitive map (an understanding of the relative spa-
tial organization of objects and information) in order to solve a maze (Tolman, 1949).
Animals apparently learn at least some of these details of their spatial environment
simply by moving through it (Tolman and Honzik, 1930).
We now know that, in parallel with its role in other types of declarative memory,
the hippocampus is crucial for spatial learning. The rat hippocampus contains many
neurons that selectively encode spatial location (O'Keefe and Burgess, 2005; Moser
et al., 2017). These place cells become active when the animal is in--or moving to-
ward--a particular location (FIGURE 13.12A). If the animal is moved to a new envi-
ronment, place cell activity indicates that the hippocampus remaps to the new loca-
tions (Moita et al., 2004). Some rat hippocampal neurons act like "grid cells," likened
to a latitude and longitude in a maze (FIGURE 13.12B), which have been recorded in
people too (J. Jacobs et al., 2013). The Nobel Prize in Physiology or Medicine for 2014
was awarded to John O'Keefe, May-Britt Moser, and Edvard Moser for their work on
Bird species that hide food in many locations have a larger hippocampus than
other birds have (Croston et al., 2015), indicating that natural selection favors enlarge-
cognitive map A mental representation of the relative spatial organization of
ment of the hippocampus to enhance spatial learning, as we discuss in A STEP FURTHER 13.1, on the website.
objects and information. place cell A neuron in the hippocampus that selectively fires when the animal
Brain regions involved in learning and memory: A summary FIGURE 13.13 updates and summarizes the classification of long-term memory
that we've been discussing. Several major conclusions should be apparent by now,
FIGURE 13.13 Subtypes of Declarative and Nondeclarative Memory (After T. Bartsch and C. Butler. 2013. Nat. Rev. Neurol. 9: 86.)
Prefrontal cortex, different regions for different attributes
especially (1) that many regions of the brain are involved in learning and memory; (2) that different forms of memory rely on at least partly different brain mechanisms, which may include several different regions of the brain; and (3) that the same brain structure can be a part of the circuitry for several different forms of learning. Next we'll discuss the stages by which memories, of any sort, can be preserved for a lifetime. Watson/Breedlove The Mind's Machine Fou1n.daNtiaonmseoftBhrraeine adnidffeBerehanvtiotryp4ees of nondeclarative memory, giving an example of each. What different parts of the brain have been implicated in each type? MM4e_13.13 03/06/20 2. What is a cognitive map? 3. What are hippocampal place cells, and why do they suggest a role for the hippocampus in spatial learning? Successive processes capture, store, and retrieve information in the brain The span of time over which a piece of information is retained in the brain varies. There are at least three different stages of memory. The briefest memories are called sensory buffers (for visual stimuli, they are sometimes called iconic memories); an example is the fleeting impression of a glimpsed scene that vanishes from memory seconds later. These brief memories are thought to be residual activity in sensory neurons. Somewhat longer than sensory buffers are short-term memories (STMs). If someone tells you a website name and you keep it in mind (perhaps through rehearsal) just until you type it into your browser, you are using STM. In the absence of rehearsal, STMs last only about 30 seconds (J. Brown, 1958; L. R. Peterson and Peterson, 1959). With rehearsal, you may be able to retain an STM until you turn to a new task a few minutes later, but when the STM is gone, it's gone for good. Eventually, some memories become really long-lasting--the address of your childhood
sensory buffer A very brief type of memory that stores the sensory impression of a scene. In vision, it is sometimes called iconic memory. short-term memory (STM) A form of memory that usually lasts only seconds, or as long as rehearsal continues. Working memory can be considered a portion of STM where information can be manipulated.
1 A subset of the sensory information that enters sensory buffers is encoded and placed into short-term memory (STM).
2 If the information is rehearsed or used, it may be consolidated into long-term memory (LTM), lasting for minutes up to a lifetime.
FIGURE 13.14 The Stages of Memory
3 When we probe a participant's memory, they must retrieve information from LTM and place it into STM to perform a task, such as reporting the items in a list.
4 At any stage of the process, information may be forgotten.
home, how to ride a bike, your first crush--and are called long-term memories
(LTMs). A related concept is working memory, which refers to the ability to actively
manipulate information in your STM, perhaps retrieving information from LTM, to
solve a problem or otherwise make use of the information (Aben et al., 2012). We
will consider working memory to be a subset of STM where information can be ana-
lyzed and manipulated by some "executive" part of our mind.
As shown in FIGURE 13.14, the memory system consists of at least three process-
long-term memory (LTM) An enduring form of memory that lasts days, weeks, months, or years. LTM has a very large capacity.
es: (1) encoding of raw information from sensory channels into STM, (2) consolidation of the volatile STM into more-durable LTM, and (3) eventual retrieval of the stored information from LTM for use in working memory. A problem at any stage can cause us to lose information. Although not depicted in the figure, this model
encoding The first process in the memory system, in which the information
suggests that the flow of information into and out of working memory is supervised by another part of the mind, an executive function, which we will discuss in more
Not all memories are created equal. We all know from firsthand experience that
emotion can powerfully affect our memory for past events. For example, an emo-
tionally arousing story is remembered significantly better than a closely matched
in short-term memory is transferred to long-term memory. Watson/Breedlove
but emotionally neutral story (Reisberg and Heuer, 1995). But if people are treated
with propranolol (a beta-adrenergic antagonist, or beta-blocker, that blocks the ef-
retrieval The thirdFporuoncdeatsisonosfofthBeramineamnd- Behaviofre4cets of epinephrine), this emotional enhancement of memory vanishes. It's not that
used by an organismM. M4e_13.14 09/01/20 treated volunteers perceive the story as being any less emotional; in fact, they rate
the emotional content of the stories just the same as untreated people do. Instead,
the drug seems to directly interfere with the ability of adrenal stress hormones to
act on the brain to enhance memory (Bolsoni and Zuardi, 2019), a topic we take up
SIGNS & SYMPTOMS Emotions and Memory Almost everyone knows from personal experience that strong emotions can affect memory formation and retrieval. Examples of memories enhanced in this way might include a strong association between special music and a first kiss, or uncomfortably vivid recollection of the morning of September 11, 2001. A large-scale research effort in many labs has identified a suite of biochemical agents that participate in the emotional enhancement of memory. Epinephrine (adrenaline), released from the adrenal glands during times of stress and strong emotion, appears to affect memory formation by influencing the amygdala, a brain region that is critical for fear conditioning (see Chapter 11). Electrical stimulation or lesions of the amygdala potently alter the memory-enhancing effects of epinephrine injections (Cahill and McGaugh, 1991), and tiny doses of epinephrine injected directly into the amygdala enhance memory formation in the same way that systemic injections do. This treatment appears to cause the release of norepinephrine within the amygdala, as do emotional experiences. Injecting propranolol, a blocker of beta-adrenergic receptors, into the amygdala blocks the memory-enhancing effects. In humans, the same drug can ease fears that have been conditioned in the lab (Kindt et al., 2009). Can we develop pharmacological treatments to weaken or erase unwanted memories outside the lab? Some disorders would benefit greatly from such treatments. For example, people
who have had life-threatening or other catastrophic experiences often develop post-traumatic stress disorder (PTSD) (see Chapter 12), characterized as "reliving experiences such as intrusive thoughts, nightmares, dissociative flashbacks to elements of the original traumatic event, and ... preoccupation with that event" (Keane, 1998, p. 398). In PTSD, each recurrence of the strong emotions and memories of the traumatic event may reactivate memories that, when reconsolidated in the presence of stress signals like epinephrine, become even stronger. Therefore, one strategy to prevent PTSD formation could be to block the effects of epinephrine in the amygdala by treating victims with antiadrenergic drugs either shortly before a traumatic experience (e.g., in rescue workers) or as quickly as possible after it (in the case of victims of violence, for example) (Giustino et al., 2016). This treatment would not delete memories of the event but might diminish the traumatic aspects, and it might also be useful for weakening existing traumatic memories. Perhaps one day it will be possible to selectively interfere with other neurotransmitters at work in the amygdala to provide more-specific and more-complete relief from traumatic memories. Whatever that treatment might be, it will probably have to be administered soon after the accident to effectively dull the painful memories.
Long-term memory has vast capacity but is subject to distortion Henry Molaison's case and the research it inspired have already told us several ways in which STM and LTM differ from one another. While the medial temporal lobe is not needed to encode sensory information into STM, or to retrieve that information from STM (Henry could repeat back to you a list of words or numbers), it is crucial for moving information from STM into LTM. In terms of the model (see Figure 13.14), an intact hippocampus is required to consolidate declarative STMs into LTMs, indicating that the information is somehow transformed into a different format, one that may make it available for a lifetime. How much information can be stored in LTM? There must be a limit, but no one has been able to come up with a way to measure it. In one classic experiment, people viewed long sequences of color photos of various scenes; several days later, they were shown pairs of images--in each case a new image plus one from the previous session--and asked to identify the images seen previously. Astonishingly, participants performed with a high degree of accuracy for series of up to 10,000 different stimuli (Standing, 1973)! For all practical purposes, there seems to be no upper bound to LTM capacity (Brady et al., 2014). Pigeons have a similarly impressive visual memory (Vaughan and Greene, 1984). We take this capacity for granted and barely notice, for example, that knowledge of a language involves remembering at least 100,000 pieces of information. Most of us also store a huge assortment of information about faces, tunes, odors, skills, stories, and so on. The late Kim Peek (1951-2009) was a savant (from the French for "knowing"), a person with an unusually well-developed ability or skill. Born with several brain structural abnormalities, including an absence of the corpus callosum (Treffert and Christensen, 2005), Kim eventually memorized about 9,000 books, each taking
Flashbulb Memories Many people have vivid, detailed memories of where they were when they learned of the September 11, 2001, terrorist attack on the World Trade Center towers in New York City.
memory trace Also called an engram. A persistent change in the brain that reflects the storage of memory. reconsolidation The return of a memory trace to stable long-term storage after it has been temporarily made changeable during the process of recall. 9,000 books
about an hour. For example, he read the 656-page novel The Hunt for Red October in 75 minutes, and when asked, 4 months later, to name a minor character, not only did Kim know the name, but he cited the page number where the character appeared and quoted several passages on the page verbatim! Case studies of such individuals with exceptional memory indicate that without the usual process of pruning out unimportant memories, continual perfect recall can become uncontrollable, distracting, and exhausting (Luria, 1987; Parker et al., 2006). Despite the vast capacity of LTM, forgetting is a normal aspect of memory, helping to filter out unimportant information and freeing up needed cognitive resources (Kuhl et al., 2007). Interestingly, research indicates that the memory trace (the record laid down in memory by a learning experience, also known as an engram) doesn't simply deteriorate from disuse and the passage of time; instead, memories tend to suffer interference from events before or after their formation. For example, the process of retrieving information from LTM causes the memories to become temporarily unstable and susceptible to disruption or alteration before undergoing reconsolidation and returning to stable status (Nader and Hardt, 2009). Thus we can create false memories when we use leading questions to have people retrieve memories. Asking "Did you see the broken headlight?" rather than "Was the headlight broken?" can incorporate the false detail as the memory is reconsolidated (Loftus, 2003). This possibility of planting false memories clouds the issue of "recovered memories" of childhood sexual or physical abuse, because controversial therapeutic methods such as hypnosis or guided imagery (in which the person is encouraged to imagine hypothetical abuse scenarios) can inadvertently plant false memories. On the other hand, you can use the power of reconsolidation when studying--as long as you're careful to check your facts. One of the best ways to improve learning is simply repeated retrieval (and thus, repeated reconsolidation) of the stored information with feedback to let you know what you got right or wrong (Karpicke and Roediger, 2008). In other words, test yourself repeatedly, as with the How's It Going? questions in this book. For your next exam, try making up some additional practice tests for yourself, or have a friend quiz you, instead of simply "cramming." We still haven't talked about the nitty-gritty of memory in the brain--what exactly changes in the brain when we learn? That's our next topic.
1. What are the stages of memory, and what do we call the processes by which information moves from one stage to the next? 2. What is the memory trace, and what are two explanations of why we sometimes cannot retrieve it? 3. Explain how reconsolidation makes us vulnerable to distorted memories.
13.3Memory Storage Requires Physical Changes in the Brain
Empire State Building A Prodigious Memory Kim Peek (1951-2009) was a savant who memorized about 9,000 books.
In this part of the chapter, we will look at some of the ways in which new learning involves changes in synapses. Reading this material should enable you to: 13.3.1 List the possible ways in which changes in neural function and structure could encode memories. 13.3.2 Review evidence that exposure to an enriched environment can affect brain structure and affect future behavior. 13.3.3 Describe how a circuit involving the cerebellum mediates certain types of conditioning.
In introducing the term synapse, Charles Sherrington (1897) speculated that synaptic alterations might be the basis of learning. Sherrington's notion anticipated what remains one of the most intensive efforts in all of neuroscience, since most theories of learning focus on neuroplasticity (or neural plasticity), changes in the structure and function of synapses. Plastic changes at synapses can be physiological or structural Synaptic changes that may store information can be measured physiologically. The changes can be presynaptic, postsynaptic, or both. They can include changes in the amount of neurotransmitter released and/or changes in the number or sensitivity of the postsynaptic receptors, resulting in larger (or smaller) postsynaptic potentials. Inhibiting inactivation of the transmitter (by altering reuptake or enzymatic degradation) can produce a similar effect (FIGURE 13.15A). Synaptic activity can also be influenced by inputs from other neurons, causing extra depolarization or hyperpolarization of the axon terminals and therefore changes in the amount of neurotransmitter released (FIGURE 13.15B).
neuroplasticity Also called neural plasticity. The ability of the nervous system to change in response to experience or the environment.
Several different changes can result in a more effective synapse.
Before training (A) Axon terminal Dendritic spine
A neural circuit that is (C) used more often increases the number of synaptic contacts.
More transmitter is released from the axon terminal.
Postsynaptic membrane becomes larger and/or more sensitive to transmitter.
Synapse enlarges both pre- and postsynaptically.
A more frequently (D) used neural pathway takes over synaptic sites formerly occupied by a less active competitor.
FIGURE 13.15 Synaptic Changes That May Store Memories
422CHAPTER13 impoverished condition (IC) Also called isolated condition. An environment for laboratory rodents in which each animal is housed singly in a small cage without complex stimuli. standard condition (SC) The usual environment for laboratory rodents, with a few animals in a cage and adequate food and water, but no complex stimulation.
Long-term memories may require changes in the nervous system so substantial that they can be directly observed (with the aid of a microscope, of course). After all, structural changes resulting from use are apparent in other parts of the body, as when exercise tones and shapes muscle. In a similar way, new synapses can form (or old synapses may die back) as a result of use (FIGURE 13.15C). Training can also lead to the reorganization of synaptic connections. For example, it can cause a more active pathway to take over sites formerly occupied by a less active competitor (FIGURE 13.15D). Varied experiences and learning cause the brain to change and grow The remarkable plasticity of the brain is not all that difficult to demonstrate. Simply living in a complex environment, with its many opportunities for new learning, produces pronounced biochemical and anatomical changes in the brains of rats (Renner and Rosenzweig, 1987). In standard studies of environmental enrichment, rats are randomly assigned to one of three housing conditions: 1. Impoverished condition (IC) Animals are housed individually in standard lab cages (FIGURE 13.16A). 2. Standard condition (SC) Animals are housed in small groups in standard lab cages (FIGURE 13.16B). This is the typical environment for laboratory animals.
(C) Enriched condition (EC) Interaction with an enriched environment has measurable effects on the brain, on stress reactions, and on learning.
FIGURE 13.16 Experimental Environments to Test the Effects of Enrichment on Learning and Brain Measures (After M. R. Rosenzweig et al., 1972. Sci. Am. 226: 22.)
3. Enriched condition (EC) Animals are housed in large social groups in special cages containing various toys and other interesting features (FIGURE 13.16C). This condition provides enhanced opportunities for learning perceptual and motor skills, social learning, and so on. In dozens of studies over several decades, a variety of changes in the brain were linked to environmental enrichment. For example, compared with IC animals: · EC animals have a heavier, thicker cortex, especially in somatosensory and visual cortical areas (M. C. Diamond, 1967). · EC animals show enhanced cholinergic activity throughout the cortex (Rosenzweig et al., 1961). · EC animals have more dendritic branches on cortical neurons, and many more dendritic spines on those branches (FIGURE 13.17) (Greenough, 1976). · EC animals have larger cortical synapses (M. C. Diamond et al., 1975), consistent with the storage of long-term memory in cortical areas through changes in synapses and circuits. · EC animals have more neurons in the hippocampus because newly generated neurons (see Chapter 4) live longer (Kempermann et al., 1997). · EC animals show enhanced recovery from brain damage (Will et al., 2004). These cerebral effects of experience, which were surprising when first reported for rats in the early 1960s, are now seen to occur widely in the animal kingdom--from flies to philosophers (Mohammed, 2001; Chan et al., 2018). But how can we study the physiology of learning when the mammalian cortex has many billions of neurons, organized in vast networks, and upwards of a billion synapses per cubic centimeter (Merchán-Pérez et al., 2009)? Researchers made progress by studying simple learning circuits, in various species, uncovering basic cellular principles of memory formation that may generalize to neurons throughout the brain.
enriched condition (EC) Also called complex environment. An environment for laboratory rodents in which animals are group-housed with a wide variety of stimulus objects.
An enlarged image of a neuron is used to quantify branching either by counts of the number of branches of different orders...
...or by counts of the number of intersections with concentric rings.
Analyzing basal dendrites revealed that rats kept for a month in enriched environments had more branches than did rats in other conditions.
FIGURE 13.17 Measurement of Dendritic Branching (From W. T. Greenough, 1976 in M. R. Rosenzweig and E. L. Bennett [Eds.], Neural mechanisms of learning and memory (pp. 255-278) MIT Press. Cambridge, MA)
In Aplysia's usual posture, the siphon is extended and
Invertebrate nervous systems show synaptic plasticity As we've discussed, neuroplasticity and the ability to learn are ancient adap-
the gill is spread out on the back, with only the tip of the siphon visible.
tations found throughout the animal kingdom. At the neuronal level, even species that are only remotely related likely share the same basic cellular processes for information storage. Indeed, one fruitful research strategy has been to focus on memory mechanisms in the very simple nervous systems
of certain invertebrates. Invertebrate nervous systems have relatively few
neurons (on the order of hundreds to tens of thousands). Because these neu-
rons are arranged identically in different individuals, it is possible to con-
struct detailed neural circuit diagrams for particular behaviors and study the
same few identified neurons in multiple individuals.
Even in these "simple" organisms, the search for memory mechanisms
began with the simplest types of learning. Earlier we discussed one of the
most basic forms of learning--associative learning about two stimuli, such
as the case of a dog learning to associate the sound of a bell with food. Even
FIGURE 13.18 The Sea Slug Aplysia (After E. R. Kandel, 1976. Cellular basis of behavior. Freeman. San Francisco.)
simpler than associative learning are the types of learning that involve only one stimulus, called nonassociative learning. Perhaps the simplest form of nonassociative learning is habituation--a decrease in response to a stimulus
as it is repeated. To be true habituation, the decreased response cannot be
due to failure of the sensory system to detect the stimulus or due to an in-
ability of the motor system to respond. Sitting in a café, you may stop noticing the door
chime when someone enters. Your ears still detect the chime, and your body is per-
fectly capable of looking up to see what happened, but you've habituated to the sound.
Scientists uncovered how the sea slug Aplysia learns to habituate to a stimulus
(Kandel, 2009). If you squirt water at the slug's siphon--a tube through which it draws
water--the animal protectively retracts its delicate gill (FIGURE 13.18). But with re-
peated stimulation the animal retracts the gill less and less, as it learns that the stim-
ulation represents no danger to the gill. Eric Kandel and associates demonstrated that
this short-term habituation is caused by changes in the synapse between the sensory
cell that detects the squirt of water and the motor neuron that retracts the gill. As less
and less transmitter is released at this synapse, the gill withdrawal in response to the
stimulation slowly fades (FIGURE 13.19A) (M. Klein et al., 1980).
The number and size of synapses can also vary with training in Aplysia. For exam-
ple, if a slug is tested in the habituation paradigm over a series of days, each successive
day the animal habituates faster than it did the day before. This phenomenon rep-
resents long-term habituation (as opposed to the short-term habituation that we just
described), and in this case there is a reduction in the number of synapses between
the sensory cell and the motor neuron (FIGURE 13.19B) (C. H. Bailey and Chen, 1983).
Thus, a very simple organism taught us that learning can be accomplished either
through a reduction in the strength of existing synapses or through a reduction in
the number of synapses. A similar research program aimed at understanding simple
learning in much more complicated species--mammals--revealed that learning could
also increase the strength of synaptic connections, as we'll see next.
habituation A form of nonassociative learning in which an organism becomes less responsive following repeated presentations of a stimulus.
Classical conditioning relies on circuits in the mammalian cerebellum Success at studying the more complicated mammalian brain came when researchers probed simple associative learning: classical conditioning of the eye-blink reflex (R. F. Thompson and Steinmetz, 2009). When a puff of air is aimed at the cornea of a rabbit, the animal reflexively blinks. The eye-blink reflex can be classically conditioned. Over several trials, if an acoustic tone (CS) precedes the air puff (US) repeatedly, a simple conditioned response develops: the rabbit comes to blink (CR) when the tone is sounded (to review these terms and the basics of conditioning, see Figure 13.10). The neural circuit of the eye-blink reflex is also simple, involving cranial nerves and some interneurons that connect their
When the siphon is rst stimulated by a squirt of water, Aplysia retracts its gill to protect it. This re ex is mediated by the sensory neurons synapsing directly upon the motor neurons that withdraw the gill.
If the siphon is squirted repeatedly, the animal soon habituates to the stimulus. It no longer retracts its gill. This short-term habituation results because the sensory neurons release less transmitter.
If the siphon is squirted repeatedly over days, the animal habituates faster and faster each day and eventually shows almost no response. This long-term habituation is due to a retraction of some synaptic terminals.
FIGURE 13.19 Synaptic Plasticity Underlying Habituation in Aplysia
Watson/Breedlove TnhuecMlein(dF'IsGMUaRchEin1e3.20A). Sensory fibers from the eye's cornea run along cranial nerve V F(tohuendtartiigonesmofiBnraalinnaenrdvBee)htaoviiotrs4ne ucleus in the brainstem. From there, some interneurons' MaxMon4ea_l1e3n.1d9ing03s/e1x1c/i2te0 other cranial nerve motor nuclei (VI and VII), which in turn activate the muscles of the eyelids, causing the blink. Early studies showed that destruction of the hippocampus and the rest of the medial temporal lobe has little effect on the conditioned eye-blink response in rabbits (Lockhart and Moore, 1975). Instead, researchers found that a cerebellar circuit is necessary for eye-blink conditioning (Poulos and Thompson, 2015). The trigeminal (cranial nerve V) pathway that carries information about the corneal stimulation (the US) to the cranial motor nuclei also sends axons to the brainstem. These brainstem neurons, in turn, send axons called climbing fibers to synapse on cerebellar neurons. The same cerebellar cells also receive information about the auditory CS by a pathway through auditory centers (FIGURE 13.20B). So information about the US and CS converges in the cerebellum. After conditioning, the occurrence of the CS--the tone--has an enhanced effect on the cerebellar neurons, so they now trigger eye blink even in the absence of an air puff (FIGURE 13.20C). Imaging studies confirm that the cerebellum is important for conditioning of the eye-blink reflex and other simple conditioning in humans (Timmann et al., 2010). How does the training change the strength of those synapses, so that now the tone triggers a blink? At least some of these plastic changes in the cerebellar neurons rely on a special synaptic mechanism that has been best studied in the hippocampus (Mao and Evinger, 2001), so we'll turn our attention there to conclude the chapter.
Re ex pathway Corneal air puff (US) (B) Training Bell (CS)
FIGURE 13.20 The Neural Circuit for Conditioning the Eye-Blink Reflex (After R. F. Thompson and D. J. Krupa, 1994. Annu. Rev. Neurosci. 17: 519.)
1 Before training, a puff of air on the surface of the eye triggers a re exive eye blink. 2 Information about the puff of air is also sent (via a polysynaptic pathway) to the interpositus nucleus of the cerebellum. Although the cerebellum can send information to the cranial motor nuclei that trigger the eye blink, at this stage those synapses are inactive. 3 During conditioning, information about the sound of the bell also reaches the cerebellum. There, impulses from this auditory signal and the air puff converge on particular neurons. With repeated pairings of bell (CS) and air puff (US), particular synapses within the cerebellum are strengthened. 4 After training is complete, the sound of the bell now triggers activity in the cerebellum that drives the cranial motor nuclei to trigger an eye blink even if the air puff never happens. This is a conditioned response. 5 Repeated presentation of the bell without the air puff begins to weaken the cerebellar connections so that eventually the bell stops eliciting an eye blink.
Watson/Breedlove The Mind's Machine Foundations of Brain and Behavior 4e MM4e_13.20 07/02/20
1. What are some of the ways that learning could alter synaptic structure or function? 2. Describe the effects of different environments on the brains of rats. 3. How does the circuitry in Aplysia change in the course of short-term and long-term habituation? 4. Which brain region is crucial for classical conditioning in mammals, and how does it play its role? 13.4Synaptic Plasticity Can Be Measured in Simple Hippocampal Circuits In the final part of the chapter, we will look at the biochemical signals that alter the strength of synapses that underlie memory. Reading this material should enable you to: 13.4.1 Explain the properties of a particular type of glutamate receptor that support long-term changes in synaptic strength. 13.4.2 Critically evaluate the possibility that such long-term changes in synaptic strength play a role in memory formation. Modern ideas about synaptic plasticity have their origins in the theories of Donald Hebb, who proposed that when a presynaptic and a postsynaptic neuron were repeatedly
activated together, the synaptic connection between them would become stronger and more stable (the phrase "Cells that fire together wire together" captures the basic idea). These Hebbian synapses could then act together to store memory traces (Hebb, 1949). This idea was eventually confirmed in the 1970s when researchers discovered an impressive form of neuroplasticity in the hippocampus, which appeared to confirm Hebb's theories about synaptic changes (Bliss and Lømo, 1973; Schwartzkroin and Wester, 1975). In the classic experiments, electrodes are placed within the hippocampus, positioned so that the researchers can stimulate a group of presynaptic axons and record the electrical response of a group of postsynaptic neurons. Normal, low-level activation of the presynaptic cells produces stable and predictable excitatory postsynaptic potentials (EPSPs) (see Chapter 2), as expected. But when a brief high-frequency burst of electrical stimuli, called a tetanus, is applied to the presynaptic neurons, causing them to produce a high rate of action potentials that drive the postsynaptic cells to fire repeatedly, the response of the postsynaptic neurons changes. Now the postsynaptic cells produce much larger EPSPs; in other words, the synapses appear to have become stronger, more effective. This stable and long-lasting enhancement of synaptic transmission, termed long-term potentiation (LTP; potentiation means "strengthening"), is illustrated in FIGURE 13.21.
Hebbian synapse A synapse that is strengthened when it successfully drives the postsynaptic cell. tetanus An intense volley of action potentials. long-term potentiation (LTP) A stable and enduring increase in the effectiveness of synapses following repeated strong stimulation.
If axons in the circuit are stimulated only once every second, the size of the response in the postsynaptic neurons is quite stable. Tetanus
After a brief tetanus, however, the excitatory postsynaptic potential (EPSP) response increases markedly and remains high. This greater responsiveness is called long-term potentiation (LTP).
FIGURE 13.21 Long-Term Potentiation Occurs in the Hippocampus
Hippocampal formation Commissural bers to opposite hippocampus
Three pathways in the hippocampal formation that display LTP: Perforant pathway (entorhinal cortex to dentate gyrus) Mossy ber pathway (dentate gyrus to CA3 pyramidal cells) Schaffer collaterals (CA3 pyramidal cells to CA1 pyramidal cells)
dentate gyrus A strip of gray matter in the hippocampal formation. glutamate An amino acid transmitter; the most common excitatory transmitter. NMDA receptor A glutamate receptor that also binds the glutamate agonist NMDA (N-methyl-d-aspartate) and that is both ligand-gated and voltage-sensitive. AMPA receptor A fast-acting ionotropic glutamate receptor that also binds the glutamate agonist AMPA.
We now know that LTP can be generated in conscious and freely behaving animals, in anesthetized animals, and even in isolated slices of brain. LTP is also evident in a variety of invertebrate and vertebrate species. Once induced by a tetanus, LTP can last for weeks or more. So, at least superficially, LTP appears to have the hallmarks of a cellular mechanism of memory: a long-lasting change in synaptic strength. This hint at a cellular origin prompted research into the molecular and physiological mechanisms underlying LTP. NMDA receptors and AMPA receptors collaborate in LTP The region called the hippocampal formation consists of two interlocking C-shaped structures: the hippocampus itself and the dentate gyrus. At least three different pathways in the hippocampal formation display LTP, and it is seen in other brain regions too (Malenka and Bear, 2004). The most studied form of LTP occurs at synapses that use the excitatory neurotransmitter glutamate, and it is critically dependent on a glutamate receptor subtype called the NMDA receptor (after its selective ligand, N-methyl-d-aspartate). Treatment with drugs that selectively block NMDA receptors completely prevents new LTP in this region, but it does not affect synaptic changes that have already been established. As you might expect, these postsynaptic NMDA receptors--working in conjunction with other glutamate receptors called AMPA receptors--have some unique characteristics, which are responsible for LTP. During normal, low-level activity, the release of glutamate at the synapse activates only the AMPA receptors. So the EPSP is mediated entirely by these AMPA receptors. The NMDA receptors cannot respond to the glutamate, because magnesium ions (Mg2+) block the NMDA receptor's calcium ion (Ca2+) channel (FIGURE 13.22A); thus, few Ca2+ ions can enter the neuron. The situation changes, however, if larger quantities of glutamate are released--say, in response to a barrage of action potentials caused by a tetanus. That stronger stimulation of the AMPA receptors depolarizes the
1 Normally, the NMDA channel is blocked by a Mg2+ molecule and only the AMPA channel functions in exciting the neuron.
2 With repeated activation of AMPA receptors, depolarization of the neuron drives Mg2+ out of the NMDA channel, allowing Ca2+ ions in.
(B) Induction of LTP Enhances subsequent transmitter release Ca2+ Glu Na+ Mg2+
3 The rapid entry of Ca2+ ions triggers second-messenger systems that lead to LTP, increasing the effectiveness of existing AMPA receptors and moving more into the membrane.
4 Retrograde transmitters, perhaps nitric oxide, reach the presynaptic terminal to enhance neurotransmitter release.
postsynaptic membrane so much that the Mg2+ plug is repulsed from the NMDA receptor's channel (FIGURE 13.22B). Now the NMDA receptors are also able to respond to glutamate, admitting large amounts of Ca2+ into the postsynaptic neuron. Thus, NMDA receptors are fully active only when "gated" by a combination of strong depolarization (via AMPA receptors) and the ligand (glutamate). The large influx of Ca2+ at NMDA receptors activates a variety of intracellular enzymes that affect AMPA receptors in several important ways (FIGURE 13.22C) (Lisman et al., 2002; Kessels and Malinow, 2009). First, the enzymes cause existing nearby AMPA receptors to move to the active synapse (T. Takahashi et al., 2003), and they modify the AMPA receptors to increase their conductance of Na+ and K+ ions (Sanderson et al., 2008). In addition, more AMPA receptors are produced and inserted into the postsynaptic membrane. Thus, after the tetanus there are more AMPA receptors, and those receptors are more effective, so the synaptic response to glutamate is strengthened (see Figure 13.22B). There are presynaptic changes in LTP too. When the postsynaptic cell is strongly stimulated and its NMDA receptors become active and admit Ca2+, an intracellular process causes the postsynaptic cell to release a retrograde transmitter--often a diffusible gas--that travels back across the synapse and alters the functioning of the presynaptic neuron (see Figure 13.22B). The retrograde transmitter induces the presynaptic terminal to release more glutamate than previously, thereby strengthening the synapse some more. So, LTP involves active changes on both sides of the synapse. So far, we've talked about how activity can make existing Hebbian synapses stronger. However, evidence suggests that the same mechanisms can affect whether new synapses are formed and old synapses retracted. In these systems it appears that when several presynaptic neurons fire at the same time, they "gang up" on the postsynaptic cell, depolarizing it enough that the NMDA receptors are activated to strengthen those connections. Conversely, any presynaptic neurons that tend to fire out of synchrony
retrograde transmitter A neurotransmitter that is released by the postsynaptic neuron, diffuses back across the synapse, and alters the functioning of the presynaptic neuron. View Animation 13.3: AMPA and NMDA Receptors
(C) Enhanced synapse, after induction of LTP
5 These changes make the synapse more responsive. Glu Mg2+ NMDA receptor
6 The postsynaptic cell now has a stronger response, as more transmitter is released and more AMPA receptors are present.
FIGURE 13.22 Roles of the NMDA and AMPA Receptors in the Induction of LTP in the CA1 Region CaMKII, calcium/calmodulin-dependent protein kinase II; CREB, cAMP responsive element-binding protein; Glu, glutamate; PKC, protein kinase C; TK, tyrosine kinase.
These cells tend to re synchronously. Because they re together, they tend to drive the postsynaptic neuron to re. These cells tend to re at random, out of synchrony with one another. They rarely cause the postsynaptic neuron to re.
FIGURE 13.23 At Hebbian Synapses, Neurons That Fire Together Wire Together
Strengthening of synapses that successfully drive postsynaptic cell Loss of ineffective inputs Postsynaptic cell
Watson/Breedlove The Mind's Machine Foundations of Brain and Behavior 4e MM4e_13.23 03/09/20 See Video 13.4: Morris Water Maze
with the other inputs are not likely to depolarize the postsynaptic neurons enough to activate NMDA receptors. Eventually, the strengthened inputs seem to sprout new, additional connections, while the weakened synapses fade away (FIGURE 13.23). Many scientists are excited about LTP because this momentary burst of neural activity, the tetanus, can change synaptic strength for a long time. It's easy to imagine how another momentary burst of neural activity, in this case triggered by a learning experience, could change synaptic strength, and that change in synaptic strength might be a memory trace. But is this just a case of an overactive imagination, or is LTP truly involved in learning? Is LTP a mechanism of memory formation? Even the simplest learning involves circuits of multiple neurons and many synapses, and more-complex declarative and procedural memory traces must involve vast networks of neurons, so we are unlikely to conclude that LTP is the only mechanism of learning. However, evidence from several research perspectives implicates LTP in at least some forms of memory: 1. Correlational observations The time course of LTP bears strong similarity to the time course of memory formation. 2. Somatic intervention experiments In general, pharmacological treatments that interfere with LTP also tend to impair learning. So, for example, NMDA receptor blockade interferes with performance in the Morris water maze (a test of spatial memory) and other types of memory tests (R. G. Morris et al., 1989). Knockout mice that lack functional NMDA receptors only in the CA1 region of the hippocampus appear normal in many respects, but their hippocampi are incapable of LTP and their declarative memory is impaired (Rampon et al., 2000). Conversely, mice engineered to overexpress NMDA receptors in the hippocampus have enhanced LTP and better-than-normal long-term memory (Y. P. Tang et al., 2001). (For the full story of these mice, see A STEP FURTHER 13.2, on the website.)
3. Behavioral intervention experiments In principle, the most convincing evidence for a link between LTP and learning would be"behavioral LTP": a demonstration that training an animal in a memory task induces LTP somewhere in the brain. Such research is difficult because of uncertainty about exactly where to put the recording electrodes in order to detect any induced LTP. Nevertheless, several examples of successful behavioral LTP have been reported (Whitlock et al., 2006). Taken together, these findings support the idea that LTP is a kind of synaptic plasticity that underlies (or is very similar to) certain forms of learning and memory. Thus it seems that the cause of Henry Molaison's tragic amnesia may have been the loss of medial temporal lobe structures like the hippocampus, which normally use LTP to consolidate short-term memories into long-term memories somewhere in the brain, probably the cortex. It's strange to think that microscopic changes in synapses in a particular brain region could be so crucial for living a full human life. Eventually Henry seemed to stop being shocked when he saw his reflection, and he learned he was no longer in his twenties. But it's not clear whether he understood, for long, that his parents had passed away. As a final act of generosity to a field of science that he helped launch, Henry arranged to donate his brain for further study after he died. Through webcasting technology, the dissection of Henry's brain was viewed live by thousands of people (see https://www.thebrainobservatory.org/project-hm), and a series of more than 2,000 brain sections are available. To the end, although Henry could remember so little of his entire adult life, he was courteous and concerned about other people. Henry remembered the surgeon he had met several times before his operation: "He did medical research on people.... What he learned about me helped others too, and I'm glad about that" (Corkin, 2002, p. 158). Henry never knew how famous he was or how much his dreadful condition taught us about learning and memory; despite being deprived of one of the most important characteristics of a human being, he held fast to his humanity. 1. Describe how LTP is measured in the hippocampus. 2. What happens to AMPA receptors and NMDA receptors during LTP? 3. What evidence suggests that LTP may underlie some forms of learning and memory? Recommended Reading Baddeley, A. D., Eysenck, M., and Anderson, M. C. (2020). Memory (3rd ed.). London, UK: Routledge Press. Clark, R. E., and Martin, S. J. (2018). Behavioral Neuroscience of Learning and Memory. Cham, Switzerland: Springer. Gluck, M. A., Mercado, E., and Myers, C. E. (2020). Learning and Memory: From Brain to Behavior (4th ed.). New York, NY: Worth. Rudy, J. W. (2021). The Neurobiology of Learning and Memory (3rd ed.). Sunderland, MA: Oxford University Press/Sinauer. Slotnick, S. D. (2017). Cognitive Neuroscience of Memory. Cambridge, UK: Cambridge University Press.
You should be able to relate each summary to the adjacent illustration, including structures and processes. The online version of this Visual Summary includes links to figures, animations, and activities that will help you consolidate the material.
1 The hippocampus, mammillary bodies, and dorsomedial thalamus are part of a network that must be intact to form new declarative memories--memories that we can declare to others. Damage to these regions can cause amnesia, the impairment of memory. Review Figure 13.1, Animation 13.2 3 Declarative memory consists of semantic memory of facts as well as episodic memory of particular incidents in the past. Brain damage can remove one type of declarative memory without affecting the other, indicating that the two kinds of memories are processed separately. Review Figures 13.4 and 13.13
Declarative: Things you know that you can tell others
Nondeclarative (procedural): Things you know that you can show by doing
2 Removal of the medial temporal lobe, including the hippocampus and nearby cortex, left Patient H.M. unable to form declarative memories that lasted more than a few minutes. He could, however, learn new skills, such as mirror tracing, showing that his nondeclarative memory (or procedural memory) for perceptual and motor behaviors was intact. Review Figures 13.2-13.4 4 Nondeclarative memory, which includes skill learning, priming, and conditioning, is demonstrated through performance. In nonhuman animals, most tests of memory measure nondeclarative memory, an exception being the delayed non-matching-tosample task. Review Figures 13.3-13.6
5 Nonassociative learning includes habituation, while associative learning includes classical conditioning (or Pavlovian conditioning) and instrumental conditioning (or operant conditioning). In the slug Aplysia, habituation is due to a weakening of the synapse between the sensory neuron and the motor neuron. In mammals, classical conditioning happens through increases in synaptic strength in the cerebellum. Review Figures 13.10, 13.19-13.20
Stimulus Siphon Sensory neuron (cell body)
7 Memories are classified by how long they last. The sensory buffer is a very brief recollection of sensations Shortterm memory (STM) lasts for seconds to a few minutes. Then the memory is either lost or transferred to long-term memory (LTM), which may last a lifetime. Review Figure 13.14
6 Different kinds of learning depend on different brain regions. Spatial learning requires an intact hippocampus, while skill learning relies on the basal ganglia, and recognition relies on the cortex. Review Figures 13.12 and 13.13, Activity 13.1 8 The successive processes transferring information from one store to the other are encoding, consolidation, and retrieval. Memories are subject to distortion during recall and reconsolidation. Strong emotion can affect the strength of memories, as in post-traumatic stress disorder (PTSD). Review Figure 13.14, Box 13.1
9 Long-term potentiation (LTP) is a lasting increase in amplitude of the re-
sponse of neurons caused by tetanus, a brief high-frequency stimulation
of their afferents. In the hippocampus, LTP depends on the activation
of NMDA receptors, which induces an increase in the number of postsynaptic AMPA receptors and greater neurotransmitter release. These
are examples of changes in Hebbian synapses, which become stronger
if they successfully drive the postsynaptic cell, and weaker if they are
unsuccessful. Review Figures 13.21-13.23, Animation 13.3, Video 13.4 Watson/Breedlove The Mind's Machine Foundations of Brain aTndheBeMhaivniodr'4seMachine digital resources include additional videos, flashcards, and other study tools.