Chapter 3. Contributions Of The Psychological Sciences 3.4

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Chapter 3. Contributions Of The Psychological Sciences 3.4

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3.4 BIOLOGY OF MEMORY
Kaplan & Sadock’s Comprehensive Textbook of Psychiatry
CHAPTER 3. CONTRIBUTIONS OF THE PSYCHOLOGICAL SCIENCES
3.4 BIOLOGY OF MEMORY
LARRY R. SQUIRE, PH.D., AND KEN A. PALLER, PH.D.
Memory as Synaptic Change Cortical Organization of Memory Insights from Amnesia Memory Systems Implications Assessment of Memory Functions
The topic of memory is fundamental to the discipline of psychiatry. Memory provides the essential substrate for the cognitive activities that define human experience, it allows one to connect the present moment to what came before, and it is the basis of cultural evolution.
An individual's personality reflects habits and dispositions that have developed from experience. Adaptive and maladaptive coping strategies, anxieties, and phobias are largely products of learning. Neurotic or psychotic symptoms can be the consequences of specific experiences or repeated patterns of experience. Psychotherapy is a process by which new behaviors are acquired through the accumulation of new experiences. Thus, memory is at the heart of psychiatry's concern with the effects of early experience, the development of the individual, and the possibility of change.
Disorders of memory and complaints about memory lapses are pervasive in both neurology and psychiatry. Memory problems are also of special concern as side effects of psychopharmacological treatments and electroconvulsive therapy. Accordingly, the effective clinician needs to understand memory, its psychological and neurological foundations, the varieties of memory dysfunction, and how memory can be evaluated. The biological perspective on memory developed here rests on a growing body of neuroscientific evidence that relates mental events to the functioning of the brain.
MEMORY AS SYNAPTIC CHANGE
Memory is a special case of the more general phenomenon of neural plasticity. Neurons can show

history-dependent behavior by responding differently as a function of recent input, and this plasticity of nerve cells and synapses is the basis of memory. In the last decade of the nineteenth century, researchers proposed that the persistence of memory could be accounted for by nerve cell growth. Others have restated this idea, developing the hypothesis that the synapse is the critical site of change. In principle, there are many possible ways for such structural change to be realized, including alterations in the number of synaptic contacts or in the strength of existing contacts.
Plasticity Neurobiological evidence from animal studies supports two basic conclusions about the biology of memory. First, specific synaptic events, including an increase in neurotransmitter release, are responsible for short-lasting plasticity, which may last for seconds or minutes. Second, long-lasting memory depends on new protein synthesis, physical growth of neural processes, and an increase in the number of synaptic connections.
A major source of information has been the extended study of the marine mollusc Aplysia californica. A sufficient number of individual neurons and connections between neurons have been identified to allow the wiring of some simple behaviors to be diagrammed. Aplysia is capable of both associative learning (including classical conditioning and operant conditioning) and nonassociative learning (habituation and sensitization). Figure 3.4-1 shows the circuitry responsible for the gill-withdrawal reflex, a defensive reaction whereby tactile stimulation causes the gill and siphon to retract. When tactile stimulation is preceded by stimulation to the head, gill withdrawal is facilitated. The cellular mechanisms underlying this sensitization are based on an enhanced release of neurotransmitter by the facilitatory neuron (labeled “Int” in Fig. 3.4-1) and accompanied by covalent modifications of preexisting proteins. Under some training conditions, sensitization can persist for weeks, and these longer-lasting changes can also be produced by repeated applications of serotonin, distributed over a period of 1½ hours. Although both short- and long-lasting plasticity are based on enhanced transmitter release, the long-lasting change uniquely requires the expression of genes and the synthesis of proteins. In addition, the long-term change, but not the short-term change, is accompanied by the growth of neural processes of neurons within the reflex circuit.
FIGURE 3.4-1 A schematic diagram of the neuronal circuit underlying behavioral habituation and sensitization of the gillwithdrawal reflect in Aplysia. The relative simplicity of the nervous system of Aplysia makes it a valuable organism for studying cellular and synaptic mechanisms of memory. The synapse between the sensory neuron (SN) and the motor neuron (MN) is an important site of habituation. Sensitization results from activation of the interneuron (Int) pathway. (Reprinted with permission from Kandel ER: Cellular Basis of Behavior. Freeman, San Francisco, 1976.)

In vertebrates, behavioral manipulations can also result in measurable changes in the brain's architecture. For example, rats reared in enriched environments show an increase in the number of synapses ending on individual neurons in neocortex. These changes are accompanied by small increases in cortical thickness, in the diameter of neuronal cell bodies, and in the number and length of dendritic branches. New synapses may be formed directly or synapses may be selectively preserved from a population that is continuously being replaced. Behavioral experience thus exerts powerful effects on the wiring of the brain.
Many of these same structural changes have been found in adult rats exposed to an enriched environment, and some have been found in adult rats given extensive maze training. In this case opaque contact-lens occluders were used to restrict vision to one eye, and the corpus callosum was transected to prevent information received by one cerebral hemisphere from reaching the other hemisphere. In these monocularly trained animals, increases in the size of dendritic fields of pyramidal neurons of occipital cortex were found only in the trained hemisphere. This finding rules out a number of nonspecific influences including motor activity, indirect effects of hormones, and overall level of arousal. Therefore it seems likely that long-term memory in vertebrates is generally based on specific changes within the neurons that lie along specific pathways.
Long-Term Potentiation The phenomenon of long-term potentiation (LTP) is a form of neural plasticity likely to be important for memory in vertebrates. LTP is observed when a postsynaptic neuron is persistently depolarized following a brief burst of high-frequency stimulation. LTP has a number of properties that make it a promising candidate as a physiological substrate of memory. First, it is established quickly and then lasts for a long time. Second, it is associative in that it depends on the cooccurrence of presynaptic activity and postsynaptic depolarization. Third, it occurs only at the potentiated synapses, not at all the synapses terminating on the postsynaptic cell. Finally, LTP occurs prominently in the hippocampus, a structure with important memory functions. The induction of LTP is known to be mediated postsynaptically and to involve activation of the N-methyl-D-aspartate (NMDA) receptor, which permits influx of calcium into the postsynaptic cell. The mechanism whereby LTP is maintained is not clearly established, but evidence has been presented in favor of a presynaptic locus of change (increased transmitter release). Rapidly developing structural changes in the dendritic spines of the postsynaptic neuron have also been described in association with LTP.
A new method for studying molecular mechanisms of memory relies on introducing specific mutations into the genome. For example, by altering a single cloned gene, a mutant strain of mice can be produced with specific receptors or cell-signaling molecules inactivated or altered. This knock-out technique can provide greater specificity than pharmacological blocking methods. Recently, it has been possible to study mice with a selective deletion of one type of NMDA receptor in the CA1 field of the hippocampus. Although many aspects of CA1 physiology remain intact, the CA1 cells do not exhibit LTP. In addition, an impairment is observed on a learning task. If reversible gene knock-outs can be achieved, it will be possible to induce specific molecular changes in a developmentally normal adult.

Associative Learning Additional insights into memory have been gleaned from the study of the neural circuitry underlying classical conditioning of the eyeblink-nictitating membrane response in rabbits. Repeated pairings of a tone (conditioned stimulus) and an airpuff to the eye (unconditioned stimulus) lead to a conditioned eyeblink in response to the tone. Reversible lesions of the deep nuclei of the cerebellum eliminate the conditioned response without affecting the unconditioned response, which indicates that the cerebellum contains part of the essential circuitry for learned association, the conditioned stimulis–unconditioned stimulus link. Reversible lesions of the deep nuclei also prevent learning from occurring, and the rabbits begin learning from the naive state when the lesion is reversed. This finding does not mean that all the changes occurring in the animal during conditioning involve the cerebellum; it means only that essential neural changes responsible for the conditioned stimulus– unconditioned stimulus link depend on this circuitry. The relevant plasticity appears to be distributed between the cerebellar cortex and the deep nuclei (Fig. 3.4-2). An analogous pattern of plasticity is thought to underlie motor learning in the vestibulo-ocular reflex, and perhaps associative learning of motor responses in general. Based on the idea that learned motor responses depend on coordinated control of changes in both timing and strength of response, it has been suggested that synaptic change in the cerebellar cortex is crucial for learned timing, whereas synaptic change in the deep nuclei is crucial for learned changes in the strength of the response.
FIGURE 3.4-2 A schematic diagram of the circuitry of the mammalian cerebellum (top). In the classically conditioned blink response, input from the air-puff unconditioned stimulus and input from the auditory conditioned stimulus comes in through parallel pathways to the cerebellar cortex and to the deep cerebellar nucleus, and plasticity occurs in both pathways (bottom). (Reprinted with permission from Raymond JL, Lisberger SG, Mauk MD: The cerebellum: A neuronal learning machine? Science 272:1126, 1996. © 1996 American Association for the Advancement of Science.)
Understanding the biology of memory requires more than just an understanding of the synaptic events that store memory. It is also essential to understand how and where synaptic events are organized in the brain. Many levels of analysis can be identified between synaptic change and behavioral memory, and many important questions about memory address levels of biological analysis that are intermediate to synapses and behavior.
CORTICAL ORGANIZATION OF MEMORY
The question of where memories are stored in the brain has long been a major research issue. In the 1920s Karl Lashley carried out a series of experiments that were directed at this problem. Lashley

recorded the number of trials that rats needed to relearn a preoperatively learned maze problem after removal of different amounts of cerebral cortex. The deficit was proportional to the amount of cortex removed and, further, it seemed to be qualitatively similar, regardless of what region of cortex was removed. Lashley concluded that memory for the maze habit was not localized in any one part of the brain, but instead was distributed equally over the entire cortex. Subsequent work has led to a revision of this idea. Maze learning in rats depends on many forms of information, including visual, tactual, spatial, and olfactory information. These various forms of information are processed and stored in different areas. Thus, the correlation between retention score and lesion size that Lashley observed reflects the progressive encroachment on specialized cortical areas serving the many components of cognition important to maze learning.
The specialized cortical areas responsible for processing and storing visual information have been studied most extensively in nonhuman primates. Nearly half of the primate neocortex is specialized for visual functions. Cortical pathways for visual information processing (Fig. 3.4-3) begin in primary visual cortex (V1) and proceed from there along parallel pathways or streams. One stream projects ventrally to the inferotemporal cortex (area TE in the monkey) and processes information about the quality of visual percepts. Another stream projects dorsally to the parietal cortex and processes information about spatial location. Electrophysiological studies in the monkey show that neurons in area TE register specific and complex features of visual stimuli, like shape, and may even respond selectively to patterns and objects. These specific visual processing areas, along with connections to corresponding regions in dorsolateral prefrontal cortex, are involved in the immediate experience of perceptual processing, and in what has been called immediate memory or working memory. These areas also serve as the ultimate repositories of the memories that result from their activity. Accordingly, lesions in these areas lead to impairments in visual perception as well as in visual learning and memory, although elementary visual functions such as acuity remain intact. Inferotemporal cortex can thus be thought of both as a higher-order visual processing system and a storehouse of the visual memories that result from that processing. These stored visual memories can be used and manipulated according to current processing demands, and they can also be quite long-lasting.
FIGURE 3.4-3 Summary of cortical visual areas and some of their connections. There are two major pathways from striate cortex (V1). The processing stream for object vision follows a ventral route into the temporal lobe via V4 (dark gray boxes) and the processing stream for spatial vision follows a dorsal route into the parietal lobe via MT (light gray boxes). Solid lines indicate connections arising from both central and peripheral visual field representations; dotted lines indicate connection restricted to peripheral field representations. Shaded region on the lateral view of the brain represents the extent of the cortex included in the diagram. Abbreviations: DP, dorsal prelunate area; FST, fundus of superior temporal area; HIPP, hippocampus; LIP, lateral intraparietal area; MSTc, medial superior

temporal area, central visual field representation; MSTp, medial superior temporal area, peripheral visual field representation; MT, middle temporal area, MTp, middle temporal area, peripheral visual field representation; PO, parieto-occipital area; PP, posterior parietal sulcal zone; STP, superior temporal polysensory area; VIP, ventral intraparietal area; STS, rostral superior temporal sulcus; and VTF, visual responsive portion of area TF. (Reprinted with permission from Ungerleider LG: Functional brain imaging studies of cortical mechanisms for memory. Science 270:769, 1995. © 1995 American Association for the Advancement of Science.)
Many parts of the nervous system participate in storing representations of an event in memory. During an event, visual information is stored in inferotemporal cortex so that the same visual material can later be recognized as familiar. Concurrently, other components of the event—including spatial, temporal, tactile, olfactory, emotional, and other sorts of information—are processed and stored separately. Memory storage in the cerebral cortex thus depends on a fractionation of experience as follows. First, any particular event or learning task is composed of a number of components. Second, each component engages a particular processing site or set of sites. Third, each processing site stores information as an outcome of the processing that is done.
Thus, memory is both distributed and localized in the nervous system. It is distributed in the sense that, as Lashley concluded, there is no unitary cortical center dedicated solely to the storage of memories. Yet, memory is localized in the sense that different aspects or dimensions of events are stored at specific cortical sites—the same regions specialized to analyze and process those particular aspects or dimensions of information.
INSIGHTS FROM AMNESIA
The idea that the functional specialization of cortical regions governs both information processing and information storage is important, but it does not provide a complete account of the organization of memory in the brain. If it did, then particular cortical injuries would disrupt only particular domains of learning and memory (i.e., visual memory or spatial memory) and no global disruption of memory would occur. Brain injury would always produce a difficulty in learning a restricted type of new information along with a loss of previously learned information of that same type. Yet common neurological syndromes of memory impairment conflict with these expectations.
The hallmark of neurological memory impairment is a profound anterograde amnesia, or loss of new learning ability, that extends across all sensory modalities. Typically, this occurs together with retrograde amnesia, a memory loss for information acquired prior to the onset of amnesia. The retrograde deficit often has a temporal gradient, such that recall for recent events is impaired, but recall for remote events is intact. Other cognitive functions are preserved, including attention, immediate memory, personality, and social skills.

The selectivity of the memory deficit in amnesia implies that the brain has isolated intellectual and perceptual functions from the ability to lay down a record of information processing. The cognitive dysfunction experienced by amnesic patients affects memory storage but does not affect a wide range of other intellectual capabilities. The fact that memory storage is affected for all sensory modalities without a parallel disruption of perception implies that the memory function is superimposed on normal cortical processing. The fact that anterograde amnesia often occurs together with intact remote memory implies that viable retrieval mechanisms are intact, and also that the brain structures damaged in amnesia are not the ultimate repositories of memory. Detailed studies of amnesic patients and models of amnesia in nonhuman animals have illuminated these issues considerably.
Specialized Memory Function Amnesia results from damage to either of two brain regions: the medial temporal lobe or the midline diencephalon. Early studies of a severely amnesic patient known as HM markedly stimulated investigation of the role of the medial temporal lobe.
H.M. became amnesic in 1953, when he sustained a bilateral resection of the medial temporal lobe to relieve severe epilepsy. The removal included approximately half of the hippocampus, most of the amygdala, and the neighboring entorhinal and perirhinal cortices. Following the surgery, H. M.'s seizure condition was much improved. Moreover, he retained normal language, normal intellectual functions, and normal immediate memory (e.g., as tested with a digit span test). However, he exhibited profound forgetfulness, and this deficit has persisted for more than 40 years.
Extensive investigations of other amnesic patients have also been used to explore the memory functions of the medial temporal lobe. For example, patient R.B. became amnesic following an episode of global ischemia. He suffered from a moderately severe anterograde amnesia with minimal retrograde amnesia. After his death 5 years later, extensive histological study of his brain revealed a circumscribed bilateral lesion of hippocampal field CA1, whereas the minor additional pathology that was found could not reasonably explain the memory impairment. Similar pathological findings in the hippocampus have also been observed in other amnesic patients (Fig. 3.4-4). Magnetic resonance imaging (MRI) with high-resolution protocols can reveal pathology in the hippocampal region of amnesic patients in vivo. Two conclusions about the anatomical correlates of amnesia follow. First, damage limited to the hippocampus itself can result in clinically significant memory impairment; second, medial temporal regions in addition to hippocampal field CA1 also make a critical contribution to memory.
FIGURE 3.4-4 Coronal sections through the hippocampal region stained with thionin in a normal subject (A) and three amnesic patients with bilateral damage to the hippocampal formation (B-D). The hippocampus proper can be divided into three distinct fields, designated CA1, CA2, and CA3. The CA1 field extends to the subiculum (S). Other structures include the dentate gyrus (DG), presubiculum (PrS), parasubiculum (PaS), and entorhinal cortex (EC). In patient GD (B), damage included CA1; in patient LM (C), damage included CA1, CA2, CA3, DG, and EC; in patient WH (D), damage included CA1,

CA2, CA3, DG, S, and EC. For additional details, see RempelClower N, Zola SM, Squire LR, Amaral DG: Three cases of enduring memory impairment following bilateral damage limited to the hippocampal formation. J Neurosci 16:5233, 1996. (Reprinted with permission from Squire LR, Zola SM: Memory, memory impairment, and the medial temporal lobe. In Cold Spring Harbor Symposia on Quantitative Biology, vol 61. Cold Spring Harbor Laboratory Press, Plainview, New York, 1996.)
The findings from human amnesia inspired the development of models of amnesia in experimental animals. Early animal studies yielded contradictory findings that could not be easily related to memory impairment. In part, the difficulty was that human amnesia itself was poorly understood. Memory is now known to be a collection of different abilities and not a unitary mental faculty. Human amnesia does not affect all kinds of memory. Until researchers understood this, selecting memory tasks for making comparisons across species was problematic. Indeed, obtaining memory performance measures that reflect parallel memory functions in humans and experimental animals requires a high degree of control over the cognitive strategies used.
Nonetheless, a model of human amnesia in the nonhuman primate became available in the early 1980s, and subsequent investigations identified the crucial structures and connections. In the medial temporal lobe, these include the hippocampus proper (CA fields, dentate gyrus, and subiculum) and adjacent regions of entorhinal, perirhinal, and parahippocampal cortex. Monkeys with surgical damage to specific structures were trained to perform tasks analogous to tasks sensitive to memory impairment in humans. Large medial temporal lesions intended to approximate the damage that occurred in patient H.M. caused monkeys to exhibit many features of human amnesia. For example, the impairment occurred in more than one sensory modality, short-term memory was intact, the deficit was enduring, skill learning was preserved, and retrograde amnesia was temporally graded.
Within the medial temporal lobe separate contributions can be identified for memory and emotion. The participation of the medial temporal lobe region in emotional expression was first studied systematically in 1937 by Heinrich Kluver and Paul Bucy, who found that monkeys with bilateral temporal lobectomy became tame, approached animals and objects without reluctance, examined objects by mouth instead of by hand, and exhibited abnormal sexual behavior. Subsequent studies have indicated that emotional behavior is related not to the hippocampus but to the adjacent set of nuclei known collectively as the amygdala. In addition, other work has shown that the amygdala is part of a set of structures essential for fear conditioning.
Amnesia can also result from circumscribed damage to structures of the medial diencephalon, including the mammillary nuclei, the dorsomedial nucleus of the thalamus, the anterior nucleus, the internal medullary lamina, and the mammillothalamic tract. Korsakoff's syndrome is the best studied example of diencephalic amnesia. Patients with alcoholic Korsakoff's syndrome typically have frontal lobe

pathology in addition to diencephalic damage. Frontal lobe pathology produces a pattern of cognitive impairment that is dissociable from amnesia itself. In the case of the patient with Korsakoff's syndrome, frontal lobe pathology is superimposed on severe memory impairment (Table 3.4-1).
Table 3.4-1 Associated and Dissociated Deficits in Amnesia
One limitation of conventional methods for assessing neuropathology is that remote functional damage may be overlooked. For example, standard MRI scans may show structural damage limited to a particular region, but this damage may lead indirectly to disrupted functioning in other regions. Accordingly, functional neuroimaging may be useful for characterizing more fully the neural dysfunction responsible for amnesia. In Korsakoff's syndrome, results from positron emission tomography (PET) have revealed functional damage in widespread cortical regions (Fig. 3.4-5). Accordingly, diencephalic amnesia may often reflect a disruption of thalamocortical connections that are critical for memory storage.
FIGURE 3.4-5 PET and MRI scans in a patient with Korsakoff's syndrome. Neural dysfunction was evident as reduced glucose utilization in multiple cortical regions in the frontal and parietal lobes, and in the cingulate. Functional neuroimaging can reveal brain dysfunction that might otherwise not be evident if limited to structural neuroimaging results. In Korsakoff's syndrome, the memory impairment probably reflects a disruption of thalamocortical circuitry. (Reprinted with permission from Paller KA, Acharya A, Richardson BC, Plaisant O, Shimamura AP, Reed BR, Jagust WJ: Functional neuroimaging of cortical dysfunction in alcoholic Korsakoff's syndrome. J Cogn Neurosci 9:277, 1997.)
Although amnesia can result from damage to either the medial temporal lobe or to the diencephalon, the distinctive functions of these two regions have been difficult to elucidate. It may be reasonable to expect the medial temporal lobe and diencephalic brain regions to make different contributions to normal

memory, but there is currently no compelling evidence for a corresponding qualitative difference in memory impairment. This could be because the two regions function together as one system that facilitates the formation of links between neocortical storage sites, or because the two regions function separately but each makes an essential contribution to linking neocortical storage sites. In any event, memory clearly relies on an elaborate complex of neural circuits extending across multiple brain areas; Figure 3.4-6 shows the chief components of this circuitry. Ongoing research continues to improve our understanding of the neuroanatomy of amnesia and the normal functions of this neural circuitry.
FIGURE 3.4-6 A schematic view of some of the chief brain regions critical for declarative memory. The entorhinal cortex is the major source of projections to the hippocampus, and nearly two thirds of the cortical input to the entorhinal cortex originates in the perirhinal and parahippocampal cortex. Entorhinal cortex also receives direct connections from cingulate, insula, orbitofrontal, and superior temporal cortex.
Retrograde Amnesia Memory loss in amnesia typically affects recent memories more than remote memories (Fig. 3.4-7). Temporally graded amnesia has been demonstrated retrospectively in studies of amnesic patients and prospectively in studies of monkeys, rats, mice, and rabbits. These findings have important implications for understanding the nature of the memory storage process. Memories are dynamic, not static. Apparently, memory storage can become more robust over time. As time passes after learning, some memories are forgotten while others become stronger because of a process of consolidation that depends on cortical, limbic, and diencephalic structures. The limbic-diencephalic contribution diminishes over time such that the neocortical component of the memory eventually becomes self-sufficient. In other words, the limbic-diencephalic structures are needed at the time of learning and during this gradual process. After sufficient time has elapsed, long-term memories can be retrieved whether or not limbic-diencephalic structures are intact. Thus, the permanent repositories of memory are the distributed neocortical regions, not diencephalic or hippocampal regions.
FIGURE 3.4-7 Remote memory performance of amnesic patients with Korsakoff's syndrome (KOR), alcoholic control subjects (ALC), amnesic patients with confirmed or suspected damage to the hippocampal formation (AMN), healthy control subjects (CON), and patients with transient global amnesia (TGA). The left column shows recall scores for past public events that had occurred in one of the four decades from 1950 to
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