Memory and the Brain

Lee T. Robertson, Ph.D.

Abstract: This review summarizes some of the recent advances in the neurobiology of memory. Current research helps us to
understand how memories are created and, conversely, how our memories can be influenced by stress, drugs, and aging. An
understanding of how memories are encoded by the brain may also lead to new ideas about how to maximize the long-term
retention of important information. There are multiple memory systems with different functions and, in this review, we focus on
the conscious recollection of ones experience of events and facts and on memories tied to emotional responses. Memories are
also classified according to time: from short-term memory, lasting only seconds or minutes, to long-term memory, lasting months
or years. The advent of new functional neuroimaging methods provides an opportunity to gain insight into how the human brain
supports memory formation. Each memory system has a distinct anatomical organization, where different parts of the brain are
recruited during phases of memory storage. Within the brain, memory is a dynamic property of populations of neurons and their
interconnections. Memories are laid down in our brains via chemical changes at the neuron level. An understanding of the
neurobiology of memory may stimulate health educators to consider how various teaching methods conform to the process of
memory formation.
Dr. Robertson is Professor and Chair, Department of Biological Structure and Function, School of Dentistry, Oregon Health
Sciences University. Direct correspondence and reprint requests to him at the Department of Biological Structure & Function,
Oregon Health Sciences University, 611 SW Campus Drive, Portland, OR 97201-3097; 503-494-8966 phone; 503-494-8554 fax;
robertso@ohsu.edu.
Key words: memory, hippocampus, amygdala, prefrontal cortex, long-term potentiation
Submitted for publication 6/7/01; accepted 9/9/01
Editors Note: This article by Robertson and the one following by Hendricson and Kleffner are presented as companion
papers.

ost people do not think much about

memory until they forget a name, a critical piece of information, or the place the
car is parked. During such common lapses in
memory, the possibility of Alzheimers disease may
jokingly come to mind. In reality, the patient with
Alzheimers disease illustrates how essential memory
is for performing simple everyday activities, for synthesizing and analyzing new information, and for
applying that information to new situations. Memory
is a fundamental process of being human, since what
we remember determines largely who we are. Without memory, we are capable of only simple reflexes
and stereotyped behaviors.
Websters New World College Dictionary1 defines memory as what is learned and retained through
nonconscious associative mechanisms. However,
neuroscientists and experimental psychologists distinguish several types of memory (Figure 1), each of
which is served by different combinations of brain
regions.2,3 Two general kinds of memory are described: 1) explicit memoryconscious recollection
of ones own previous experiences, and 2) implicit
memorypast experiences that influence current
behavior but are not consciously recalled. The explicit memory, referred to as simply memory in

30

ordinary language, can be further subdivided into

events that are personally experienced (for example,
what you had for breakfast) and memories containing factual information (for example, information
learned in a basic science course). The implicit
memories involve the how to aspects of our behavior that include motor skills and emotional associations with particular stimuli or events, which form
our likes and dislikes. Implicit memories also include
priming, which is the ability to identify an item as a
result of previous exposure to it, even if you are unaware of the previous exposurea phenomenon well
known to advertisers.
There is evidence, however, that the brain does
not really store whole memories, but rather stores
pieces of information that later can be used to create
memories. We often recall facts incorrectly, suggesting that memory is not simply replayed as from a
tape recorder. Memory can be considered a place
where we store and process information, where we
update existing knowledge as new information is
acquired, and where we compare one experience to
another. Different regions of the brain participate in
the encoding, storage, and retrieval of particular experiences, events, facts, and skills. During retrieval
of a memory, various brain areas are simultaneously

Journal of Dental Education Volume 66, No. 1

Techniques Used to Study

Memory

Figure 1. Memory can be classified into two major

types and several subtypes. Explicit memories are
those events and facts that can be consciously
recalled. Implicit memories are skills, habits, and
information that are acquired and retrieved unconsciously.

activated, a process that occurs within milliseconds,

which results in a unified memory in our consciousness.
In this review, we will focus on the neurobiology of explicit memories, particularly those involved
in the storage of facts, and emotionally related memories, such as those that might be associated with a
bad dental experience. After summarizing some of
the techniques used to study memory, we will explain that explicit memories can be dissociated into
short and long-lasting memories and that different
brain regions participate in the creation of explicit
memories. We will then describe the storage of
memories related to emotional events. Since the same
cellular processes are likely to be involved in the storage of both explicit and emotionally related memories, we will present some of the evidence supporting the main hypotheses of the cellular and molecular
mechanisms of memory. Finally, although beyond
the scope of this review of the neurobiology of
memory, we will briefly suggest a few procedures to
enhance memory in our students. This topic is more
fully explored in the following companion paper by
Hendricson and Kleffner.

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Some of the first insights into where and how

the brain processes memory came from the study of
brain-injured amnesic patients.4 Clinical observations
gave rise to the practice of creating controlled lesions in experimental animals, from which other
methods have evolved.5 The lesioning technique
became increasingly accurate and specific, although
experimental lesions may block circuits involved in
the acquisition or retrieval of information and not
actually affect the storage of information. After an
experimentally induced lesion, the undamaged neural tissue may also undergo various types of reorganization, which can affect the interpretation of subsequent behavioral studies. Consequently, researchers
have developed a number of other strategies to study
the various processes involving memory.
By recording the activity of a single neuron or
groups of neurons in animals during separate phases
of learning and memory, researchers have identified
characteristic patterns of brain activity that change
moment by moment as the brain reacts to stimuli and
executes learned responses. The synchronized actions
of networks of neurons provide insight into possible
interactions among different brain regions for various aspects of memory storage. Recently, researchers have used isolated cells in cultures and genetic
engineering to provide insights into the ability of the
brain to change its structure and chemistry in response to environmental experiences and to reveal
that several biochemical steps are necessary to convert short-term memories into permanent memories.
However, there are significant limitations to studying memory in animal models or in single cell preparations. For example, it is difficult to know whether
animals encode personal events.
In the past decade, new techniques in brain
imaging of normal people while they perform learning and memory tasks have provided an explosion
of knowledge about the basic mechanisms of
memory. These techniques, such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) scans, allow researchers to
see the brains metabolic activity and regional cerebral blood flow in specific brain regions as people
carry out various kinds of memory tasks. The fMRI
and PET-based studies reveal that specific cortical
regions are active during specific tasks (such as ver-

31

bal), whereas other areas are engaged during other

types of processing (such as visuospatial).

Explicit Memories Can Be

Dissociated into Short and LongLasting Memories
Explicit memories are also classified according to time (Figure 2). Input from our senses is processed in fractions of a second and, if deemed important enough, either consciously or unconsciously,
the input is stored in short-term memory. Short-term
memory is typically defined as the ability to remember five to nine items, such as a telephone number.
Like telephone numbers, short-term memories are
easy to lose without rehearsing. If we rehearse and
use information, it can be kept in working memory, a
type of short-term memory, for minutes to hours.
Depending on the extent of rehearsal or use, the
memory is either discarded or planted in the

long-term memory. Long-term memories are for recalling specific events and facts, recognition of
people and locations, and particular skills, which can
be retained for a long period, especially if revisited
periodically. A unique subset of long-term memory
is remote memory that includes deeply embedded
knowledge about language and music, which are often the last memories to be lost in conditions such as
Alzheimers disease.
An important question has been whether shortterm memory, working memory, and long-term
memory are simply different phases of long-term
memory or are separate or sequential phenomena.
An accompanying issue has been whether single or
multiple brain structures or cellular mechanisms account for all memory or, rather, the structures and
cellular mechanisms change overtime. The idea that
different forms of explicit memory use distinct anatomical circuits is supported by the existence of patients with an impairment that prevents the formation of only some types of memory and by

Figure 2. A time-dependent process underlies the creation of different stages of memory. Short-term memory
involves retaining information or events only for seconds. Working memory involves the online processing of
information to accomplish a particular task. Long-term memory includes a relatively permanent type of memory
storage that lasts from hour to months, although some memories last a lifetime. (Modified from McGaugh JL.
Memory: a century of consolidation. Science 2000;287:248-51.)

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Journal of Dental Education Volume 66, No. 1

experimental studies that indicate memories are actively transferred from one phase to the next.
The Story of HM. In 1957, Scoville and Miller4
published a landmark case study of a twenty-sevenyear-old man (HM) with a history of epilepsy, who
underwent a neurosurgical procedure to bilaterally
remove the medial temporal lobes including the hippocampus and the amygdala that lie deep within the
lobe. The surgery successfully eliminated the seizures, but immediately after the surgery, HM was
severely amnesic of events leading up to his operation and he had a profound inability to learn and retain any new memories of facts and events. Extensive psychological testing revealed that HMs
personality, perception, and intelligence did not
change, nor did he have problems with short-term
memory or with learning new motor skills. However,
HM was completely unable to form any explicit
memories after the surgery. To this day, more than
forty years since his surgery, HM is unable to recall
the current date, where he lives, what he had for
breakfast, or whom he may have met a few minutes
earlier. As HM has aged, he has even become unable
to recognize a current picture of himself! Since the
report about HM, new models of learning and
memory have evolved. Models have been proposed
for the dissociation of the neuronal substrate for

short-term and long-term memory and for explicit

versus implicit memories.
Consolidation Hypothesis. A series of experiments has been conducted to examine whether shortterm and long-term memories occur sequentially or
act independently, but in parallel (Figure 3). One
popular idea is that a memory is somehow consolidated from a temporary, fragile state to one that is
relatively permanent.6 Many treatments can affect
short-term memory while leaving long-term memory
intact. As the example of HM demonstrated, the surgical bilateral destruction of the temporal lobes in
this individual did not affect most of his presurgical
long-term memories. However, those brain structures
that transfer short-term memories into long-term
memory were compromised. A concussion, such as
might occur in a car accident, also typically results
in memory loss of the events just prior to losing consciousness. One explanation for this brief amnesia is
that the loss of consciousness prevents the consolidation of short-term memories into long-term memories. Evidence that time-dependent stages of memory
are being processed independently also comes from
various drugs that can disrupt either short-term or
long-term memory.
Not all short-term memories are consolidated
into long-term storage. We clearly do not want all

Figure 3. A model of how the brain stores explicit information. The brain receives information about events and fact
(for example, a diagram or a verbal explanation) by means of its sensory systems. After the information has been
processed by the sensory association cortex, it is held in short-term or working memory. If the person is told to
specifically attend to the information, then the information may be consolidated directly from short-term memory
into long-term memory. If the person rehearses or uses the information, then the working memory can be consolidated into long-term memory.

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33

the details of everyday experience in permanent storage, since the details would interfere with focusing
on what matters. Would you want to remember what
you had for dinner last night for the rest of your life?
When consolidation is too effective, the results are
devastating. People with superhuman memories,
classified as savants,7 can recall long streams of numbers and endless facts and words, but they have extreme difficulty with abstract thought. A savant might
recite long sections of a novel verbatim, for example,
but have little understanding of the story.
Studies of brain activity suggest that we may
consolidate our memories of the days events while
sleeping. During sleep, the brain activity of a rat has
a similar pattern to the activity triggered when the
animal explored new environments shortly before
sleeping.8 Similar results have been found for human subjects. PET scans of human subjects during
the learning of a task and then during rapid eye movement (REM) sleep (REMs are characteristic of
dreaming) revealed common brain areas that were
more active in people who had learned the task than

in people who had not learned it.9 The increased activity during sleep suggests that the brain is spending energy to reinforce prior learning, which researchers speculate might be a means by which
memories are put into permanent storage. Although
the molecular events underlying sleep are not fully
known, the increases in cholinergic activity and the
decreases in the levels of serotonin that occur in various neuronal structures during REM are good candidates for the modulation of cellular pathways.10

Different Brain Regions Participate

in the Creation of Explicit Memory
Many differences exist among the various types
of memory at the systems level. Figure 4 shows some
of the brain regions that are recognizably active during short-term working memory (the prefrontal cortex and areas of the medial temporal gyrus) or in the
storage of information from short-term into longterm (hippocampus and adjacent cortical areas of the

Figure 4. The lateral and medial views of the cerebral cortex show the locations of the prefrontal cortex that participates in working memory, the hippocampus that is important in the consolidation of short-term memories into longterm memories, and the amygdala that takes part in the storage of memories related to emotional events. The
coronal section through the rostral part of the temporal lobe shows the relationship of the hippocampus to the
entorhinal and parahippocampal cortex that are part of the medial temporal lobe.

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Journal of Dental Education Volume 66, No. 1

temporal lobe).11 For long-term memory, considerable evidence now supports a learning and memory
system that is different for events versus facts.2 A
separate neural structure completely supporting the
storage of each kind of memory probably does not
exist. It is likely that the memory critically depends
on the joint functioning of these neural structures.
The important question, then, is how do the various
brain areas interact?
Short-Term and Working Memory. Evidence
for a correlation between conscious experiences and
sustained neural activity stems from tasks involving
verbal and visuospatial working memory, that is, the
ability to rehearse or keep in mind such things as a
spatial location.12 While short-term memory may be
used to briefly hold some information, working
memory is responsible for the short-term storage and
online manipulation of information necessary for
higher cognitive functions, such as language, planning, and problem-solving. Working memory is usually divided into two types of processes: active maintenance, which is keeping information available, and
executive control, which governs the encoding and
retrieval of information in working memory.13
Distinct regions within the prefrontal lobe appear to handle the two types of working memory,
with the executive control processes being handled
in anterior and ventral parts of the lobe, and the content-specific information (such as verbal versus
visuospatial) subserved by the cortex in the more
dorsal and posterior regions. With regard to active
maintenance, human neuroimaging studies show that
the prefrontal cortex is most consistently activated
by verbal, spatial, and object information.12
Several regions of the left prefrontal cortex
show higher activity as the amount and complexity
of fact processing rise. Such findings have been taken
as evidence that the left prefrontal cortex underpins
the beneficial effects of semantic processing of subsequent memory.14 Support of this hypothesis was
recently provided by Wagner et al. 15 Using
neuroimagining studies, Wagner showed an increase
in activity in the left prefrontal cortex when words
were categorized on the basis of semantic rather than
physical attributes. The prefrontal neuronal activity
increases when the tasks include analysis of the meaning of the item.
Working memory may also involve the ventromedial region of the temporal lobe, which consists
of the parahippocampal gyrus and the entorhinal
cortex (Figure 4). This region is known through lesion studies to be required for the formation of du-

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rable memories. The ventromedial region of the temporal lobe also receives information already processed by other cortical regions, such as the visual
or somatosensory regions. Functional neuroimaging
(such as an fMRI) studies consistently reveal an increase in activity during memory of particular concepts or facts. For example, Wagner et al.15 presented
subjects with words that were later classified by the
subject as remembered well, only weakly, or forgotten. The items remembered well were correlated with increased activity in the prefrontal cortex
and the left parahippocampal-entorhinal regions.
Comparable results were reported in subjects scanned
as they studied pictures of everyday scenes and later
tried to remember them, although the recalled pictures were associated with increased activity in both
the left and right parahippocampal region. Conversely, neuroimaging studies in elderly people with
non-Alzheimer dementia (that is, characterized by
impoverished memory of facts) demonstrate a
neurodegenerative process within the ventromedial
parts of the temporal lobe.16
Storage of Information from Short Term into
Long Term. Deep within the temporal lobe are the
hippocampus (from the Latin word for seahorse
because of its arching shape) and the surrounding
tissue, which is collectively called the hippocampal
formation. This region somehow transfers explicit
information (perhaps during sleep) to permanent storage sites throughout the cerebral cortex. 17
Neuropsychologists have studied patients with damage limited to the hippocampal formation and have
concluded that it is sufficient to impair only the formation of new long-term memories, whereas extensive damage of the hippocampal formation, the connecting fiber bundles, and adjacent cortical tissue
can produce a complete loss of all new explicit memories.18 However, animal studies and recent human
neuroimagining studies question whether the hippocampal formation is equally important for the memory
of both events and facts. Neuroimaging results suggest that human hippocampal formation subserves
the storage of events more than the storage of specific facts19 and that the structure is particularly important during the learning of spatial or novel informationcharacterized as the binding of all
components of new pictorial scenes in memory.
The hippocampal formation is described as a
memory staging area that connects the multitude of
stimuli associated with various events. Anatomically,
the hippocampus consists of numerous axons forming two-way connections among the temporal, fron-

35

tal, and parietal lobes (Figure 5). The massive parallel connections involved in laying down a memory
may enable us to synthesize information that involves
several sensory modalities, which allows for flexibility in our ability to think. The hippocampus is
able to synthesize information from multiple sensory
modalities and, in turn, sends connections widely to
many parts of the cerebral cortex.20 Thus, the hippocampal formation is thought to play a critical role
in memory by relating different sensory stimuli of a
particular event (such as place, sounds, smells, and
people), binding the stimuli together, and temporarily
holding the information while making interconnections with other parts of the brain.
Schacter21 describes how the hippocampus may
operate with the example of meeting a friend for
lunch. Such an event involves the integration of various stimulithe look (the friends appearance and
manner), the spatial map used to travel to the restaurant, the feel or smell of the restaurant, and the words
on the menuinto a compendium of images and
words. No one knows exactly how the hippocampal
formation lays down memories, but the general hypothesis is that it brings together disparate, previously unassociated elements into a cohesive

memory.22 Because new memories build on prior

memories, the hippocampal formation may play a
role in the development of patterns of connections
that are activated by similar pairing of sensory stimuli.
After further repetitions of the same or similar events
and facts, the connections are reinforced and our
memory becomes deeply embedded in our brain.
An important question raised by recent
neuroimaging studies concerns the nature of the relation between the hippocampus and the cortical areas of prefrontal lobe, parahippocampal cortex, and
the entorhinal cortex during the encoding of information:23 Do these regions operate serially to support memory encoding, or do they act independently,
perhaps by providing separate inputs to a common
structure such as the hippocampus? Recently,
Fernandes and associates24 tracked the serial encoding of memories within the hippocampus and the
surrounding cortical areas (that is, the parahippocampal gyrus and entorhinal cortex; see Figure 1). These investigators recorded the electrical activity with microelectrodes inserted into the brains
of epileptic patients in whom the hippocampus and
the adjacent cortex were unaffected by their disease.
During the electrophysiological recordings, the pa-

Figure 5. Summary of possible connections between the hippocampus and possible memory storage regions. A
convergence of sensory information flows to the parahippocampal gyrus, which has reciprocal connections with the
entorhinal cortex and then the hippocampus. The hippocampus has widespread connections with multiple cortical
areas within the prefrontal cortex, and the parietal and temporal lobes.

36

Journal of Dental Education Volume 66, No. 1

tients memorized words and, after a brief distraction,

attempted to recall them. The investigators ultimately
found temporally staggered encoding, with the
parahippocampal region activated before the
hippocampus. This is consistent with the hypothesis
that the parahippocampal cortex is an input pathway
to the hippocampus, whereas the outputs of the hippocampus and possible memory storage sites involve
large areas of the cerebral cortex (Figure 5). The hippocampus forms widespread reciprocal connections
with the prefrontal lobe and large areas of the temporal and parietal lobes. It has been suggested that
the hippocampus consolidates memories of facts and
concepts by its connections with the language-related
cortical areas.
Factors That Influence Memory Storage.
Most of the changes in hormones and neurotransmitters that affect memory are mediated through
functional and, in some cases, structural changes in
the prefrontal cortex, hippocampus, and medial temporal lobe. Those factors that negatively affect these
structures would be expected to disrupt various types
of memory. For example, interference with normal
hippocampus function could impede the consolidation of short-term memories into long-term memories. Chronic stress, besides interfering with our sleep,
can knock out molecules that transport glucose to
the hippocampus, suppress ongoing cell growth in
parts of the hippocampus, and eventually produce
neuronal damage within the hippocampus.25 Loss of
sleep and disruption of REM, caused by sleeping
pills, alcohol, or a dysfunctional thyroid gland, can
all disrupt normal hippocampal function. Chronic
stress and high blood pressure can also impair working memory.26
Changes in various hormones, such as estrogen, can affect memory, although the mechanisms
are not fully understood. During normal aging, estrogen helps maintain verbal memory in women and
may forestall the deterioration of storage of new
memories.27 It appears that estrogen exerts a specific
effect on memory, since it enhances verbal memory
without influencing spatial memory. One explanation for this phenomenon is that estrogen may increase the level of neurotransmitters, such as acetylcholine, which affect synaptic action. A second
hypothesis is that estrogen increases the number of
synaptic contacts of hippocampal neurons.28
A number of hormonal and other biochemical
changes that occur during normal aging result in
subtle impairments both in accessing new information and maintaining it in working memory.29 Age-

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related impairments in long-term memory mainly

involve the acquisition and early retrieval of new information, and have less effect on the memory of
language, visuospatial ability, and abstract reasoning.30 Neuroimaging studies also show a decrease in
activity of the prefrontal cortex, hippocampus, and
medial temporal lobe that correlates with aging. In
some cases, vascular disease or Alzheimers disease
can produce marked deficits in specific types of
memory and leave other memories unaffected.

Storage of Memories Related

to Emotional Events
It is now generally accepted that the amygdala,
an almond-shaped structure in the anterior part of
the temporal lobe (Figure 4), plays a critical role in
emotions and emotionally loaded memories.6,31 A
memory may be imprinted forever as the result of a
strong emotion, which explains why so many people
recall what they were doing, in considerable detail,
when President John F. Kennedy was assassinated
or when the space shuttle Challenger crashed.
During high-stress situations, information takes
the primary pathway through the thalamus and then
the amygdala, although other brain areas are also
involved. Information then flows both ways between
the amygdala and the cerebral cortex. The amygdala
of the monkey, for example, processes visual information derived from visual cortical areas where neurons respond to the identity of faces and to facial
expression. In primate social behavior, identifying
and understanding the signals of facial expression
of another monkey are of great importance. The brain
receives the signals that the body sends during emotional experiences, so emotions can then influence
the subsequent behavior. Human neuroimaging studies reveal increases in activity within the amygdala
when a person demonstrates an emotional response
to different facial expressions (for example, facial
signs of fear).32 We behave differently if we see anger in a persons face than when we see a friendly
smile. Seeing anger, we might immediately withdraw
or avoid the person, whereas seeing a friendly smile,
we might approach or embrace the person.
Although the amygdala has not been shown to
process all types of emotions,33 convincing evidence
from animal and human studies suggests that the
amygdala is strongly involved in memories associated with emotional arousal. Destroying, electrically

37

stimulating, or inactivating the amygdala of rats immediately after they receive an electric shock to the
foot impairs the retention of the negative experience.34
In human neuroimaging studies, the amygdala is activated by cues that connote a threat, fear conditioning, and the general negative effects induced by viewing unpleasant pictures.35,36 Although considerable
evidence indicates that the amygdala is crucial for
memory associated with events that are intrinsically
punishing, the amygdala also appears to participate
in memory associated with positive emotional reinforcement.37
Two possible explanations are proposed for the
way emotionally charged events are emblazoned in
our memories. One explanation for intense emotionally linked memories is that they are novel. People
tend to discuss and, in effect, replay events in their
lives that are unique and/or important to them, which
strengthens the memory. The other explanation is that
stress hormones and neurotransmitters are released
during emotional experiences, which give the event
special significance and prominence in the memory

pathways.31 While both explanations may be correct,

numerous animal studies and human neuroimaging
studies support the hypothesis that emotional events
elicit specific hormones that increase the activity of
the amygdala, which leads to the long-term memory
storage of the associated event.
The amygdala interacts with endogenous stress
hormones, which are released as part of an emotional
event, to modulate long-term memory storage in other
parts of the brain. Injections of the adrenal medullary hormone adrenaline enhance memory only when
the injections are given immediately after a learning
experience. The effects of adrenaline on memory
appear to be mediated by activation of -adrenergic
receptors of the vagal nerve, which projects to the
nucleus of the solitary tract located in the brainstem.
Signals from the solitary nucleus are then relayed to
the amygdala.
Emotional experiences are also associated with
a release of hormones from the hypothalamic-pituitary system. The release of both adrenocorticotropin and glucocorticoids can modulate memory stor-

Figure 6. A proposed neural circuit of the storage of an emotionally linked event. The event can be stored in various
brain regions, but, during a period of emotional arousal, the memory of the event can be modulated by activation of
the amygdala and emotionally activated hormones. (Reprinted from Cahill L, McGaugh JL. Mechanisms of emotional
arousal and lasting declarative memory. Trends Neurosci 1998;18:411-8. With permission of Elsevier Science.)

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Journal of Dental Education Volume 66, No. 1

age.38 McGaugh6 and his associates have proposed

that memories of emotionally arousing events can
simultaneously affect the amygdala and several stressrelated hormonal systems, which then can also modulate the activity of the amygdala (Figure 6). Since
the amygdala has widespread connections to other
brain areas, the amygdala can affect memory processes in many parts of the cortex. However, once
the memory is stored, the amygdala is not required
for the normal retrieval of stored information or experiences, since bilateral destruction of the amygdala
has no effect on an emotionally remembered event
once it is stored in long-term memory.

Cellular and Molecular

Mechanisms Controlling
Memory
What happens at the cellular and molecular
level when the brain forms new memories and then
somehow translates short-term transient experiences
into long-lasting memories that can last for days,
weeks, or years? One popular hypothesis is that alternations occur in the synapses, where neurons communicate with other neurons. The strength of the
connection between neurons is somehow improved
by repeated experience. Repetition of an event, idea,
or fact results in the simultaneous and coordinated
activation of a pattern of neuronal connections, which
makes it easier for the same neuronal connections to
reactivate later. The change in the efficacy of the synapse is considered a basic mechanism of how memory
traces are encoded.39
In laboratory experiments where the ionic currents are recorded through channels of individual cells
(the patch-clamp method), the strengthening of synaptic connections has been shown to occur when
neural pathways are electrically stimulated in coordination with other activity of neurons. This enhancement in synaptic strength, which can last for hours
or even days, is known as long-term potentiation
(LTP), and the molecular changes that underlie LTP
are the key ingredients of memory storage.39
Since the hippocampus is somehow involved
in consolidating short-term memories into long-term
memories, many studies have examined the synaptic
plasticity in a hippocampal slice preparation (where
a piece of hippocampal tissue is maintained in a culture dish so that the ionic currents of individual hip-

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pocampal neurons can be studied). These studies reveal that LTP has input-specificity because enhanced
synaptic strength occurs in only the synapses involving the active pathway, whereas other synapse sites
on the same cell that do not receive input are unaffected. However, LTP is also associative because the
activation of one set of synapses on a cell can bolster
neighboring synapses with a different input if both
inputs are activated simultaneously. Producing an
effect in neighboring synapses may explain the phenomenon of associative learning, in which pairing
two stimuli can individually produce an identical response. Pavlovs dogs learned to salivate when a bell
sounded whether or not food was presented.
LTP is a kind of molecular switch that initiates
a biochemical mechanism to improve synaptic efficacy. The key to LTP is the NMDA receptor (N-methyl-D-asparate), which sits on the postsynaptic cell
membrane and binds to the neurotransmitter
glutamate. The NMDA receptor is a minuscule pore
in the cells membrane that controls the entry of calcium ions into the neuron. If one neuron sends signals to another neuron via the neurotransmitter
glutamate, the NMDA receptor reacts to glutamate
and unleashes a cascade of chemical reactions within
the postsynaptic neuron. However, the NMDA receptor needs more than just the glutamate signal. It
also must receive an electrical discharge from its own
cell by activating another ion channel at the same
time and in neighboring synapses (that is, the depolarization of the postsynaptic membrane causes the
removal of a Mg2+ from the pore of the NMDA receptor) before the NMDA channel permits calcium
ions to flow into the postsynaptic cell. This makes it
easier for the cell to turn on the next time it receives
the same synaptic input. Thus, two separate signals,
the binding of the glutamate and the membrane depolarization, serve as coincidence detectors to help
the brain associate the two events.40 Although no
single source may be sufficient to activate the neuron, hippocampal neurons receive inputs from many
sources and, when simultaneously and repeatedly
presented (that is, temporal and spatial summation),
it is sufficient to activate the neuron. Synaptic plasticity not only occurs in the hippocampus, but in the
amygdala34,41 and throughout the cerebral cortex,
where NMDA receptors help to establish connections
among various cortical inputs.39
The NMDA hypothesis has been tested by either blocking NMDA receptors with drugs or developing genetic strains of mice without NMDA receptors. In both cases, the animals become

39

memory-disabled. When NMDA receptor blockers

are injected into the hippocampus of rats, for instance,
they fail to learn the pattern of a maze. Likewise, the
genetic engineering of mice that lack a critical part
of the NMDA receptor in the hippocampus produces
mice with poor spatial memory.40 Tsien and his colleagues have also tried to improve memory by stimulating the NMDA receptor and, thereby, making a
strain of mice that learn faster than their normal counterparts.42,43 These researchers altered a gene in such
a way that the NMDA receptor works more efficiently. The mice were tested with a series of standardized memory tasks and, compared to normal
mice, the gene-altered smart mice were superior
every time. Taken together, the various studies of LTP
and NMDA demonstrate that these receptors appear
to play an important role in synaptic efficacy and
memory processes. It may be possible to genetically
engineer an animal to perform either brilliantly or
poorly: it all depends on whether the brain can consolidate a memory and whether the appropriate genes
are activated to produce the proteins that consolidate
the memory. However, the genetic engineering to
make smart human beings is not ethical. Because
NMDA receptors are found throughout the brain,
human genetic alteration could cause unforeseen and
unpredictable complications. Further, some scientists
dispute the connection between LTP and memory,
since LTP typically last only hours or, at best, days,
but memories can last a lifetime.44 Ultimately, the
LTP role in memory is also only part of the story,
since it is not yet known how memories are represented by ensembles of neurons.45

Procedures to Enhance
Memory within Dental
Education
Major marketing opportunities exist for products and strategies to enhance memoryfrom brainboosting supplements to special diets, from memory
training seminars to exercise programs that ensure
an ample supply of blood to the brain, and from TV
talk shows to technique books on memory improvement. But for dental educators, the question is how
we can use the information about the neurobiology
of memory to improve classroom instruction. How
can we maximize the acquisition of information into
working memory, and facilitate short-term to long-

40

term memory consolidation, thereby improving overall long-term memory retention? The first step is
gaining the learners complete attention. Attention
filters incoming information, allowing only relevant
information into working memory.46 Intense attention has a strong positive effect on tests of explicit
memory, whereas attention has minimal value during the learning of implicit memories, such as acquiring fine hand motor skills.47 Psychologists have
found that retention of events and facts is increased
when students are instructed to pay particular attention or when their attention is directed to understanding concepts or abstract meaning rather than concentrating on superficial attributes of presented
information.21
Involving multiple sensory systems (visual,
auditory, and somatosensory) in the acquisition of
new information will improve the retention of the
information. Memory is influenced by the sensory
modality in which the information is presented. For
example, using a dual-mode presentationauditory
information with visual illustrationsresults in improved memory performance compared to single
modality formats.48 It is easier to remember the content of a lecture when interesting visual illustrations
are included, as opposed to simply listening to a verbal presentation. However, if only one modality is
used, an auditory presentation results in better
memory than a visual presentation of same the material. This is an indication that words are processed
in a distinct manner. An excellent example of an optimal learning environment is the gross anatomy laboratory in which learning involves vision, sounds,
smells, and touch; such multimodality experiences
result in the elaborate encoding of three-dimensional
anatomical structures in long-term memory.
We can get facts and events into long-term
memory simply by rehearsing them.49 The brain
strives to make associations. If you already have an
established neuronal circuit for a particular type of
information, then the hippocampus effectively stores
related information alongside the previous information. It is essential, however, to allow the brain time
to transfer the information from working memory
into long-term memory. The traditional, one-hour
didactic lecture potentially fills working memory to
capacity, but allows little opportunity for the consolidation of the information into long-term memory.
Holding information in working memory is effortful,
attention-demanding, and prone to failure when the
information load or other cognitive demands are

Journal of Dental Education Volume 66, No. 1

high.49 During the didactic lecture, there is usually

little opportunity for rehearsals of gained information, a process that is necessary to refresh the decaying working memory. Likewise, working memory is
made less efficient when a lecture contains too many
divergent points or is immediately followed by another lecture on a different subject. Information loss
appears to occur when new information interferes
with information already existing in working
memory.50 Yet, the crowded predoctoral dental curriculum affords little opportunity for the student to
digest material from one lecture before being inundated with new facts, details, and concepts from another lecture.
The transfer of most new information into longterm memory probably occurs when a student reviews
new material shortly after class. During this postclass review, students can focus their attention on
the material, integrate the new data and concepts with
information learned previously, analyze the new information for its potential relation to other
coursework, and rehearse the key points and concepts. Examinations, including the National Board
Examinations, encourage students to review the material, a process that strengthens existing circuits and
further integrates the material with other memory
circuits. Group discussions and conferences provide
a way for students to rehearse material both mentally and verbally and transfer it into their own experience. Since student experiences are different, students will retain different aspects of identical
material. If learning engages strong emotions (that
is, engaging amygdaloid complex), the ability to remember will be improved.
Because our memory systems have evolved
over millions of years, it is not easy to understand
how our brains select, capture, store, and process
information. However, understanding the latest concepts on the various types of memory and the underlying cellular and molecular mechanisms will enable
us to develop specific strategies and techniques to train
our memories in order to maximize mental agility.

Acknowledgments
I would like to thank Phyllis Stewart and
CharEll Melfi for their help with preparation of the
manuscript and the figures. I would also like to thank
Joel Ito for the illustration of the brain.

January 2002

Journal of Dental Education

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Journal of Dental Education Volume 66, No. 1