Most people do not think much about

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 one s 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 Editor s Note: This article by Robertson and the one following by Hendricson and Kleffner are presented as companion papers. Most 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 Alzheimer s disease may jokingly come to mind. In reality, the patient with Alzheimer s 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. Webster s New World College Dictionary 1 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 memory conscious recollection of one s own previous experiences, and 2) implicit memory past experiences that influence current behavior but are not consciously recalled. The explicit memory, referred to as simply memory in 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 exposure a 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 30 Journal of Dental Education Volume 66, No. 1

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. Techniques Used to Study Memory 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 brain s 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- January 2002 Journal of Dental Education 31

bal), whereas other areas are engaged during other types of processing (such as visuospatial). Explicit Memories Can Be Dissociated into Short and Long- Lasting 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 Alzheimer s 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.) 32 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 Miller 4 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 HM s 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. January 2002 Journal of Dental Education 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 day s 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. 34 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 durable 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 facts 19 and that the structure is particularly important during the learning of spatial or novel information characterized 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- January 2002 Journal of Dental Education 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. Schacter 21 describes how the hippocampus may operate with the example of meeting a friend for lunch. Such an event involves the integration of various stimuli the look (the friend s appearance and manner), the spatial map used to travel to the restaurant, the feel or smell of the restaurant, and the words on the menu into 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 associates 24 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 Agerelated 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 Alzheimer s 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 person s 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 January 2002 Journal of Dental Education 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 β-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.) 38 Journal of Dental Education Volume 66, No. 1

age. 38 McGaugh 6 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 hippocampal 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. Pavlov s 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 cell s 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 Mg 2+ 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 amygdala 34,41 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 January 2002 Journal of Dental Education 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 memory from 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 longterm memory consolidation, thereby improving overall long-term memory retention? The first step is gaining the learner s 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 presentation auditory information with visual illustrations results 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 40 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. REFERENCES 1. Webster s New World College Dictionary, 4 th ed. Cleveland, OH: Webster New World, 2001. 2. Beggs JM, Brown TH, Byrne JH, et al. Learning and memory: basic mechanisms. In: Zigmond MJ, Bloom FE, Landis SC, Roberts JL, Squire LR, eds. Fundamental neuroscience. San Diego: Academic Press, 1999:1411-54. 3. Eichenbaum H, Cahill LF, Gluck MA, et al. Learning and memory: systems analysis. In: Zigmond MJ, Bloom FE, Landis SC, Roberts JL, Squire LR, eds. Fundamental neuroscience. San Diego: Academic Press, 1999:1455-86. 4. Scoville WB, Miller B. Loss of recent memory after bilateral hippocampal lesions. J Neurol Neurosurg Psych 1957;20:11-21. 5. Izquierdo I, Medina JH. On brain lesions, the milkman and Sigmunda. Trends Neurosci 1998;21:423-6. 6. McGaugh JL. Memory: a century of consolidation. Science 2000;287:248-51. 7. Treffert DA. The idiot savant: a review of the syndrome. Am J Psychiatry 1988;145:563-72. 8. Sutherland GR, McNaughton B. Memory trace reactivation in hippocampal and neocortical neuronal ensembles. Curr Opin Neurobiol 2000;10:180-6. 9. Maquet P, Laureys S, Peigneux P, et al. Experiencedependent changes in cerebral activation during human REM sleep. Nat Neurosci 2000;3:831-6. 10. Graves L, Pack A, Abel T. Sleep and memory: a molecular perspective. Trends Neurosci 2001;24:237-43. 11. Rolls ET. Memory systems in the brain. Annu Rev Psychol 2000;51:599-630. 12. Smith ED, Jonides J. Storage and executive processes in the frontal lobes. Science 1999;283:1657-61. 13. Fuster JM. Prefrontal neurons in networks of executive memory. Brain Res Bull 2000;52:331-6. 14. Fletcher PC, Frith CD, Rugg MD. The functional neuroanatomy of episodic memory. Trends Neurosci 1997;20:213-8. 15. Wagner AD, Schacter DL, Rotte M, et al. Building memories: remembering and forgetting of verbal experiences as predicted by brain activity. Science 1998;281:1188-91. 16. Garrard P, Hodges JR. Semantic dementia: clinical, radiological and pathological perspectives. J Neurol 2000;247:409-22. 17. Squire LR. Memory and the hippocampus: a synthesis from findings with rats, monkeys, and humans. Psychol Rev 1992;99:195-231. 18. Henke K, Kroll NE, Behniea H, et al. Memory lost and regained following bilateral hippocampal damage. J Cogn Neurosci 1999;11:682-97. 19. Vargha-Khadem F, Gadian DG, Watkins KE, Connelly A, Van Paesschen W, Mishkin M. Differential effects of early hippocampal pathology on episodic and semantic memory. Science 1997;277:376-80. 20. Eichenbaum H. The hippocampus and mechanisms of declarative memory. Behav Brain Res 1999;103:123-33. 21. Schacter D. Searching for memory: the brain, the mind, and the past. New York: Basic Books, 1969. January 2002 Journal of Dental Education 41

22. Cohen NJ, Ryan J, Hunt C, Romine L, Wszalek T, Nash C. Hippocampal system and declarative (relational) memory: summarizing the data from functional neuroimaging studies. Hippocampus 1999;9:83-98. 23. Lavenex P, Amaral DG. Hippocampal-neocortical interaction: a hierarchy of associativity. Hippocampus 2000;10:420-30. 24. Fernandes G, Effern A, Grunwald T, et al. Real-time tracking of memory formation in the human rhinal cortex and hippocampus. Science 1999;285:1582-5. 25. McEwen BS. The neurobiology of stress: from serendipity to clinical relevance. Brain Res 2000;886:172-89. 26. Brand N, Hanson E, Godaert G. Chronic stress affects blood pressure and speed of short-term memory. Percept Mot Skills 2000;91:291-8. 27. Sherwin BB. Estrogen effects on cognition in menopausal women. Neurology 1997;48(Suppl 7):S21-6. 28. Brake W, Alves S, Dunlop J, et al. Novel target sites for estrogen action in the dorsal hippocampus: an examination of synaptic proteins. Endocrinology 2001;142:1284-9. 29. Swanson HL. What develops in working memory? a life span perspective. Dev Psychol 1999;35:986-1000. 30. Small SA, Stern Y, Tang M, Mayeux R. Selective decline in memory function among healthy elderly. Neurology 1999;52:1392-6. 31. Cahill L, McGaugh JL. Mechanisms of emotional arousal and lasting declarative memory. Trends Neurosci 1998;21:294-9. 32. Whalen PJ, Rauch SL, Etcoff NL, McInerney SC, Lee MB, Jenike MA. Masked presentations of emotional facial expression modulate amygdala activity without explicit knowledge. J Neurosci 1998;18:411-8. 33. Blair RJ, Morris JS, Frith CD, Perrett DI, Dolan RJ. Dissociable neural responses to facial expressions of sadness and anger. Brain 1999;122:883-93. 34. LeDoux JE. Emotion circuits in the brain. Annu Rev Neurosci 2000;23:155-84. 35. LaBar KS, Gatenby JC, Gore JC, LeDoux JE, Phelps EA. Human amygdala activation during conditioned fear acquisition and extinction: a mixed-trial fmri study. Neuron 1998;20:937-45. 36. Buchel C, Dolan RJ. Classical fear conditioning in functional neuroimaging. Curr Opin Neurobiol 2000;10:219-23. 37. Holland PC, Gallagher M. Amygdala circuitry in attentional and representational processes. Trends Cogn Sci 1999;3:65-73. 38. Bohus B, Koolhaas JM, Luiten PG, Korte SM, Roozendaal B, Wiersma A. The neurobiology of the central nucleus of the amygdala in relation to neuroendocrine and autonomic outflow. Prog Brain Res 1996;107:447-60. 39. Martin SJ, Grimwood PD, Morris RG. Synaptic plasticity and memory: an evaluation of the hypothesis. Annu Rev Neurosci 2000;23:649-711. 40. Tsien JZ. Linking Hebb s coincidence-detection to memory formation. Curr Opin Neurobiol 2000;10:266-73. 41. Maren S. Long-term potentiation in the amygdala: a mechanism for emotional learning and memory. Trends Neurosci 1999;22:561-7. 42. Tang Y, Shimizu E, Dube G, et al. Genetic enhancement of learning and memory in mice. Nature 1999;401:63-9. 43. Tsien JZ. Building a brainier mouse. Sci Am 2000;282:62-8. 44. Shors TJ, Matzel LD. Long-term potentiation: what s learning got to do with it? Behav Brain Sci 1997;20:597-614; discussion 614-55. 45. Martinez JL, Derrick BE. Long-term potentiation and learning. Ann Rev Psychol 1996;47:173-203. 46. Downing, Paul E. Interactions between visual working memory and selective attention. Psych Sci 2000;11:467-73. 47. Szymanski KF, MacLeod CM. Manipulation of attention at study affects an explicit but not an implicit test of memory. Conscious Cogn 1996;5:165-75. 48. Brand N, Jolles J. Learning and retrieval rate of words presented auditorily and visually. J Gen Psychol 1985;112:201-10. 49. Gathercole SE. Cognitive approaches to the development of short-term memory. Trends Cogn Sci 1999;3:410-9. 50. Dutta A, Nairne JS. The separability of space and time: dimensional interaction in the memory trace. Mem Cognit 1993;21:440-8. 42 Journal of Dental Education Volume 66, No. 1