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Chapter 18
Learning and Memory
L
et me begin by telling a little story.
When I was a graduate student we had
to take an exam that Cornell does in
an interesting way. They put you in a swivelchair surrounded by your committee
composed of 4-5 faculty members. You are
spun around, and a question comes from the
direction you face when you stop. One of the
questions I was asked was, “What will be
the most important accomplishment in the
field of neuroscience in the next 10 years?”
Knowing that knowledge usually advances
in small steps, I said that we would
gradually know more about most aspects of
the field, but I didn’t expect any major
breakthroughs. To a man, the committee
agreed that in 10 years we would have a
complete solution to the problem of learning
and memory. The word complete was their
term, presumably meaning that we would
know everything there was to know about
learning and memory. Well, at the 10-year
mark, I sent them all a letter saying, “I told
you so!” Their predicted event didn’t
happen. However, we have made some
progress; that progress is what this chapter is
about.
Definitions
What is learning? According to Eric
Kandel (2000) “Learning is the process by
which we acquire knowledge about the
world.” While this definition is erudite, it
doesn’t help us much in knowing what to
study. Another definition (Kimble, 1961),
"Learning refers to a more or less permanent
change in behavior which occurs as a result
of practice," is a little better. It tells us that
learning is more or less permanent; it won’t
always be there, but often will. It also tells
us that this is something that happens
because we practice–repeat something over
and over. A further definition says,
“[Learning is] either a case of differential
strengthening of one from a number of
responses evoked by a situation of need, or
the formation of receptor-effector
connections de novo; the first occurs
typically in simple selective learning and the
second in conditioned reflex learning" (Hull,
1943). It is the strengthening of existing
responses and the formation of new
responses to existing stimuli that make this
definition unique. So what is learning? It
isn’t clear that we have an inclusive
definition. It appears that learning is the
strengthening of existing responses or
formation of new responses to existing
stimuli that occurs because of practice or
repetition. How much practice? Sometimes a
single practice session is sufficient as in
avoidance of painful or noxious stimuli.
Sometimes a lot of practice is necessary as
in learning to drive a car.
What then is memory? Again
according to Kandel (2000), ". . . memory is
the process by which that knowledge of the
world is encoded, stored, and later
retrieved." By this definition, memory is not
a thing; it’s a process. Interesting! In another
definition, "Memory is a phase of learning . .
. learning has three stages: 1. acquiring,
wherein one masters a new activity . . . or
memorizes verbal material . . . 2. retaining
the new acquisition for a period of time; and
3. remembering, which enables one to
reproduce the learned act or memorized
material. In a narrower sense learning
merely means acquiring skill . . ." (Sargent
& Stafford, 1965). From these definitions,
we see that memory has to do with keeping
“knowledge” someplace and then retrieving
it when it is needed. What we don’t see here
is that the “knowledge” doesn’t have to
come into consciousness. I have two
cars–one with an automatic transmission,
one with a stick shift. I don’t have to bring
into consciousness the process for shifting
gears when I get into the car that requires me
to do that–I just do it!
Types of Memory
There are actually two basic kinds of
learning and memory. One is declarative or
explicit; the other is non-declarative or
implicit. Knowledge of facts–what we know
about places, things and people–and the
meaning of these facts is explicit memory.
These things must be recalled into
consciousness to be used. Patients who have
bilateral medial temporal lobe lesions have
an inability to learn and remember items of
factual knowledge. They can’t remember
people that they met the day before. They
can’t remember what they did the day
before. Some people will further parcel
explicit memories as episodic (we remember
events) or semantic (we remember facts). As
Kandel (2000) points out, in either case the
content of all explicit memories can be
expressed by declarative statements such as
“I was here yesterday” (episodic) and “The
hippocampus has something to do with
memory” (semantic).
Implicit memory involves
information about how to perform
something; it’s recalled unconsciously. We
use implicit memory in trained, reflexive
motor or perceptual skills. I know how to
drive my car; I know how to get to work.
The same people with bilateral medial
temporal lobe lesions can learn simple
reflexive skills–they habituate and are
sensitized, they can be classically and
operantly conditioned (see later). They can
learn certain perceptual tasks. For example,
they can recall a word learned previously
when given only the first few letters of the
word. At the same time, they deny ever
having learned the word previously. Implicit
memory is often further parceled as
associative and non-associative. There are
two well-known types of non-associative
learning: habituation and sensitization.
Habituation is a decrease in response to a
benign stimulus when the stimulus is
presented repeatedly. A dog will be aroused
when a strange tone is played. If the tone is
played over and over, the dog will
eventually no longer be aroused by the tone.
We say that it has habituated. This kind of
learning makes sense; it is not efficient for
an organism to go on responding to a
stimulus that has no meaning. The other
form of non-associative learning,
sensitization, is an enhanced response to
many different stimuli after experiencing an
intense or noxious one. For example, an
animal responds more vigorously to a tone
of lesser intensity once a painfully loud tone
has been played. Here we say that the animal
is sensitized.
These two forms of learning also
interact. Once a response has been
habituated, it can be restored by
sensitization. In this case, we say that the
animal is dishabituated. As an example: a
habituated startle response to a noise can be
restored by strongly pinching the skin.
In non-associative learning, it is not
necessary that the animal learns to associate
the stimuli involved (thus the name). For
example, the dishabituated animal does not
learn to associate the noise with the pinch.
As we shall see shortly, this is the hallmark
of associative learning. Not all forms of nonassociative learning are as simple as
habituation and sensitization. For example,
we learn language by imitation of people
who already speak. This involves no
association of stimuli and is clearly more
complicated than habituation.
In associative learning, we “learn”
that two stimuli are associated with each
other or that a response is associated with a
given event or has a given consequence.
Perhaps important in clinical considerations,
a person can also learn that an outcome is
not associated with a response. So a person
may learn that what happens to him is not
related to what he does. Two sorts of
associative learning have been well studied:
classical conditioning and operant
conditioning. Classical conditioning is well
demonstrated by Pavlov’s famous
experiment in which he presented meat
powder to a dog, causing it to salivate. He
repeated the presentation, and each time the
dog salivated. If he repeatedly rang a bell
just before presenting the meat powder (they
were paired), the animal came to associate
the bell with the presentation of the meat
powder, and it would begin to salivate when
the bell was rung. In fact, for a while it
would salivate if the bell was rung but no
meat powder was presented (they were
unpaired). After a while, the bell stopped
predicting the presentation of meat powder
for the dog, and it ceased salivating when it
was rung. (This process is called extinction.)
It should be noted that for classical
conditioning to occur the ringing of the bell
must precede the presentation of the meat
powder, often by a certain critical interval of
time (of the order of 0.5 sec). One way to
look at classical conditioning is to think of
the bell as becoming a signal that the meat
powder is about to be presented.
In Pavlov’s paradigm, the meat
powder normally elicits salivation without
experimenter intervention (it is innate or
perhaps previously strongly learned), and it
is called the unconditioned stimulus (US).
The response is called the unconditioned
response (UR). The bell comes to elicit
salivation only after it is repeatedly paired
with meat powder; so it’s called the
conditioned stimulus (CS). The response to
it (again salivation) is called the conditioned
response (CR). The UR and the CR are
usually similar but often not identical in type
or strength.
Initially investigators thought that
classical conditioning involved simply
learning that two stimuli were
contiguous–that they occurred close together
in time, one after the other. Now we think
that what the animals learn is
contingencies–that existence of something
depends upon existence of something else.
With this in mind, it is possible to see that
simply learning that two stimuli were
contiguous could often lead to behaviors that
were maladaptive, with animals associating
environmental events that had no real
relationship. On the other hand, the
existence of superstitious behaviors, even in
humans, suggests that this does occur.
It is tempting to think of extinction
as an example of forgetting, but alas it is not.
The difference is that something new is
learned during the process of extinction–the
animal learns that the CS is no longer a
signal that the US is about to occur, rather it
is a signal that the US will not occur.
In operant conditioning (sometimes
called trial-and-error learning), a person or
animal learns that it gets a reward if it does
something. So, a pigeon learns that it gets
food if it pecks at a certain key, but not if it
pecks at another. A rat learns that it can
avoid getting an electric shock if it presses a
bar at a certain time. Presumably what the
animal learns is that one of its many
behaviors (pecking or bar pressing) is
followed by food. It is constitutional in
animals to repeat behaviors that lead to
positive reinforcement (something pleasant
or the absence of something unpleasant) and
avoid behaviors that lead to punishment or
negative reinforcement.
Neuroscience of Learning and
Memory
A great deal has been written about
is shown in Fig. 18-2.
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 18-2 - Block diagram of the supposed flow of information
between areas associated with learning and m emo ry.
behavior.
Explicit Memory
In overview, experiments on learning
can be interpreted to say that explicit
memory is first acquired through one or
more of the three polymodal association
areas of the cerebral cortex, namely
prefrontal, limbic and parieto-occipitaltemporal. Then, the information is
transferred to parahippocampal and
perirhinal cortices, entorhinal cortex dentate
gyrus, hippocampus, subiculum and back to
entorhinal, parahippocampal and perirhinal
cortex. The locations of these areas relative
to one another are shown in Fig. 18-1,
whereas a block diagram of the connections
Figure 18-1. The relative positions of parts of the
limbic system involved in learning and mem ory.
Different forms of learning are
affected differentially by lesions in different
locations. Damage to parahippocampal,
perirhinal and entorhinal cortices produces
greater deficits in memory storage for object
recognition than does hippocampal damage.
Right hippocampal damage produces greater
deficits in memory for spatial representation,
whereas left hippocampal damage produces
greater deficits in memory for words, objects
or people. In either case, the deficits are in
formation of new, long-term memory; old
memories are spared.
Current thought is that the
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
facets–each event contains sounds, smells,
tastes, somatosensory experiences, visual
images and so forth. Long-term storage of
episodic (event) memories seems to occur in
prefrontal association cortex.
So, each new explicit memory is
formed by four sequential processes:
Encoding-information for each
memory is assembled from the
different sensory systems and
translated into whatever form
necessary to be remembered. This is
presumably the domain of the
association cortices and perhaps
other areas.
Consolidation-converting the
encoded information into a form that
can be permanently stored. The
hippocampal and surrounding areas
apparently accomplish this.
Storage-the actual deposition of the
memories into the final resting
places–this is though to be in
association cortex.
Retrieval-memories are of little use if
they cannot be read out for later use.
Less is known about this process.
Implicit Memory
Implicit memories are stored
differently depending upon how they are
acquired. “Fear conditioning” (training that
involves use of fearful stimuli) involves the
amygdala. Operant conditioning involves the
striatum and cerebellum. For example, eye
blink conditioning is disrupted by lesions of
the dentate and interpositus nuclei of the
cerebellum. Classical conditioning,
sensitization and habituation involve the
sensory and motor systems involved in
producing the motor responses being
conditioned. Perhaps surprisingly, certain
simple reflexes mediated by the spinal cord
can be classically conditioned even after the
cord has been surgically isolated from the
brain. So, it appears that all regions of the
nervous system may be capable of memory
storage.
Processes of Learning
Given the definitions for learning
and memory, what sort of mechanisms
would we expect to find in the nervous
system? One early thought was that neurons
in “memory” pathways were arranged in
reverberating circuits. In such a circuit, one
neuron excites another and the other excites
the one such that, once the circuit is
activated, action potentials run around
continuously. An example of this kind of
arrangement is shown in Fig. 18-3. Here are
shown only 2 neurons in the circuit but any
number may be included. If this kind of
arrangement accounts for memory, then any
event that temporarily stopped activity in the
circuit should disrupt memory.
Unfortunately for
supporters of the
idea,
electroconvulsive
shock, which
temporarily stops
or resets all
electrical activity
in the nervous
system produces
Figure 18-3 - A reverberating circuit: Neuron A
only a significant,
excites B and vice versa.
transitory loss of
recent memory, but
no loss of older memories.
Some years ago, the psychologist
Donald Hebb (Hebb, DO (1949) The
Organization of Behavior: A
Neuropsychologi-cal Theory. New York:
John Wiley) mulled this problem and came
up with a principle that has become known
as Hebb’s rule. Briefly, the principle is
“When an axon of cell A . . . excites cell B
and repeatedly or persistently takes part in
firing it, some growth process or metabolic
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.
Figure 18-4 - Simplified neural circuits involved in
the habituation process in Aplysia. There are about 24
sensory neurons in the siphon; these are glutaminergic. T hey synapse o n 6 motor neuro ns that inne rvate
the gill and various interneurons as shown. The
control condition is shown on the left, the habituated
condition o n the right.
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. 18-5. Again,
stimulation of the siphon leads the animal to
withdraw the gill by activating sensory
neuron 1, which in turn activates a
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
to produce habituation? Experiments
performed in Aplysia californica, the sea
slug, were designed to address this problem.
Their results are shown schematically in
Fig.18-4. If the siphon of the animal is
stimulated mechanically the animal
withdraws the gill, presumably for
protection. That action is known to occur
because the stimulus activates receptors in
the siphon, which activates, directly or
indirectly through an interneuron, the
motoneuron that withdraws the gill. This is a
simple reflex circuit. All of this is shown on
the left side of the figure. With repeated
Figure 18-5 - Sensitization is produced by applying a
noxious stimulus to the tail of the Aplysia’s tail,
activated sensory neuron 2. This, in turn activates a
facilitating interneuron that enhances transmission in
the pathway from the siphon to the motor neuron.
motoneuron. If the tail of the animal is
stimulated just before the siphon is, then the
withdrawal of the gill is quicker and more
forceful. The mechanism of this appears to
involve serotoninergic, axo-axonic synapses.
As shown in the figure, activation of the
sensory receptors in the tail activates,
through sensory neuron 2, a facilitating
interneuron that excites sensory neuron 1 in
the pathway leading the gill withdrawal. It
does this either at the cell body or at the
terminals of the sensory neuron on the
motoneuron or the interneuron. The
consequence of the sensitization process is
to increase the size of the EPSP in the
motoneuron without increasing the response
of sensory neuron 1. This will cause a
greater response in the motoneuron and
therefore a greater withdrawal of the gill.
How all this occurs is illustrated in
Fig. 18-6, which shows an axo-axonic
synapse as might occur between the
facilitating interneuron and sensory neuron
1. Serotonin (5-hydroxytryptamine or 5HT)
is released by the presynaptic axon onto the
postsynaptic axon where it binds to
opens Ca channels. The end result is that
activation of this 5HT pathway by tail
stimulation causes more transmitter
substance to be released by siphon
stimulation, the resulting larger EPSP leads
to a larger response by the gill.
With only short-term tail stimulation,
the sensitization will fairly quickly disappear
when tail stimulation ceases. However, the
sensitization can be made relatively
permanent by repeated tail stimulation. This
long-term sensitization (and also long-term
habituation) occurs because there are
structural changes that occur in the
presynaptic terminals (sensory neuron 1, for
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 18-6 - The synaptic and chem ical events
unde rlying pre synaptic facilitation involve d in
prod ucing sensitization. See text for details.
receptors and activates a G protein that, in
turn, activates adenylyl cyclase to produce
cAMP. This cAMP activates a cAMPdependent protein kinase, PKA. Along with
another kinase, PKC, PKA phosphorylates
and closes K channels (hypopolarizing the
cell), mobilizes vesicles for exocytosis and
Figure 18-7 - Long-term storage of implicit memory
for sensitization involves changes sho wn in Fig. 18-6
plus changes in pro tein synthesis that result in
formation of new synaptic connections.
synaptic terminals. Both of these changes
require altered protein synthesis by
mechanisms shown in Fig. 18-7.
Long-term Potentiation
As previously detailed, the
hippocampus is important in storage of
declarative memory. In 1973, a phenomenon
was described in the hippocampus that may
account for declarative memory. Since then
the same phenomenon has been observed in
various other places known to be involved in
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
been termed cooperativity, and it results
from the requirement of NMDA receptors
that glutamate bind to them and the cell be
hypopolarized, the binding opens the
channel and the hypopolarization displaces
Mg++ that blocks the channel lumen. Also
required is that the pre- and postsynaptic
cells both be active at the same time. This
latter property has been termed associativity.
The astute student will see that this is
precisely the condition that Hebb’s law says
should exist.
Figure 18 -9 - During normal low-frequency transmission, glutamate interacts with NM DA and nonMND A (AM PA) and metabotrop ic receptors.
Figure 18-8 - A. Experimental setup for demonstrating LTP in the hippocampus. The Schaffer
collateral pathway is stimulated to cause a respo nse
in pyramidal cells of CA1. B. Comparison of EPSP
size in early and late LTP with the early phase
evoked by a single train and the late phase by 4 trains
of pulses.
The experimental setup for
demonstrating LTP is shown in Fig. 18-8A.
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
physiological basis of memory.
During normal synaptic transmission
(Fig. 18-9), glutamate binds to non-NMDA
receptors allowing cations to flow through
the channels and the cell membrane to
Figure 18-10 - With high-frequency stimulation other
events occu r as described in the text.
hypopolarize. Glutamate also binds to
metabotropic receptors, activating PLC, and
to NMDA receptors. As you may already
know, NMDA receptor channels can bind
glutamate but no current will flow through
the channels unless the Mg++ that binds to
the channel lumen is displaced. The latter
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. Cacalmodulin kinase phosphorylates nonNMDA 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.18-10. 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.
In the late phase of LTP (Fig. 18-11),
calcium enters the cell and triggers Cacalmodulin, which in turn activates adenylyl
cyclase and cAMP kinase. The latter
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
has been observed only for days or weeks.
How long LTP can be maintained is difficult
to determine. Admittedly, LTP is the
longest lasting process known in
neuroscience. Still memories may last much
longer. LTP occurs in most or all of the
places where memories are known to be
stored. What is not known is whether
disruption of LTP also interferes with
memory.
Figure 18-1 1 - For LT P to last (Late LT P) the events
of Fig. 18-10 must also lead to chang es in protein
synthesis and to forma tion of new synaptic
connec tions.
Summary
Non-declarative (implicit) memory
involves different brain regions: fear
conditioning involves amygdala; operant
conditioning involves striatum and
cerebellum; and classical conditioning,
sensitization and habituation involve sensory
and motor systems used in the responses.
This kind of memory involves a number of
processes: habituation involves decrease in
synaptic strength from decreased transmitter
release; sensitization involves increase in
synaptic strength due to presynaptic
facilitation; and classical conditioning
involves increase in synaptic strength due to
presynaptic facilitation that is dependent on
activity in both pre- and postsynaptic cells.
Declarative (explicit) memory also
involves a number of brain regions: there is
no general store for explicit memories;
because the subject of memories is
multimodal, storage of different aspects
occurs in different locations; the
hippocampal formation is important in
processing information for storage as
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
Behavior: A Neuropsychological Theory.
New York: John Wiley
Hull, CL (1943) Principles of Behavior.
New York: Appleton-Century-Crofts.
Kandel, ER, JH Schwartz and TM Jessell
(2000) Principles of Neural Science. New
York: McGraw-Hill.
Kandel, ER and JH Schwartz (1982)
Molecular biology of learning: Modulation
of transmitter release. Science 218:433-443
Kimble, GA (1961) Hilgard and Marquis’
Conditioning and Learning. 2nd Edition. New
York: Appleton-Century-Crofts.
Nicoll, RA, JA Kauer and RC Malenka
(1988) The current excitement in long-term
potentiation. Neuron 1:97-103.
Sargent, SS and KR Stafford (1965) Basic
Teachings of the Great Psychologists.
Garden City, NY: Dolphin Books.