CASE 49. What type of memory is available for conscious retrieval? Which part of the brain stores semantic (factual) memories?

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1 CASE 49 A 43-year-old woman is brought to her primary care physician by her family because of concerns about her forgetfulness. The patient has a history of Down syndrome but no other medical problems. She had been living in an assisted living environment for many years. Over the last year, she has become more forgetful. Once-easy-tasks are becoming increasingly difficult such as placing a telephone call, following directions, and housekeeping. She has become lost walking around the grounds and has difficulty naming objects and telling time. She often does not recognize old friends and forgets previous conversations. Physical examination confirms many of the memory and cognitive deficits. After a thorough workup, no specific etiology can be found, and the patient is diagnosed with Alzheimer disease. What type of memory is available for conscious retrieval? Which part of the brain stores semantic (factual) memories?

2 394 CASE FILES: PHYSIOLOGY ANSWERS TO CASE 49: LEARNING AND MEMORY Summary: A 43-year-old woman has Down syndrome and symptoms consistent with Alzheimer disease. Conscious memory: Explicit (declarative) memory. Part of brain that stores semantic memory: Neocortex. CLINICAL CORRELATION Alzheimer disease is a common cause of dementia and memory impairment. Early in the disease the memory losses are gradual, but they eventually increase to the point where daily activities such as driving, following instructions, and shopping are impaired. As the disease progresses, patients require daily supervision and have difficulty remembering names and conversations. Simple tasks such as telling time and changing clothes become extremely difficult. Age and a family history of Alzheimer disease are important risk factors. The pathogenesis is not understood completely, but senile plaques are present and cytoplasmic neurofibrillary tangles occur in increased numbers and frequency in Alzheimer patients. Magnetic resonance imaging (MRI) in the later stages of the disease will show diffuse cortical atrophy, with dramatic loss of neurons in the entorhinal cortex and hippocampus. There has been an association of Down syndrome and Alzheimer disease. The amyloid precursor protein (APP) gene on chromosome 21 is an important membrane-spanning protein that is processed into smaller units, including Abeta amyloid, and is deposited in neuritic plaques in patients with Alzheimer disease. The extra chromosome 21 may lead to excessive production of Abeta amyloid. APPROACH TO LEARNING AND MEMORY Objectives 1. Know the types of memory and their general anatomic locations. 2. Know about basic mechanisms of learning and memory. Definitions Long-term synaptic potentiation (LTP): A long-lasting (for hours, days, or longer) increase in the effectiveness of a synapse produced by transient, high-frequency activation of the synapse, resulting in an alteration within the brain circuit that can contribute to learning and memory. Long-term synaptic depression (LTD): A long-lasting decrease in the effectiveness of a synapse produced by low-frequency activation of the synapse, resulting in alterations opposite to those produced by LTP, which can also contribute to learning and memory.

3 CLINICAL CASES 395 DISCUSSION Learning is defined as a process by which information, skills, or habits are acquired, whereas memory is defined as a phenomenon by which information, skills, or habits are stored. Memory typically is divided into general categories. Explicit (declarative) memory is the storage and retrieval of information about the world and one s personal experiences, and it generally is recalled by conscious effort. Explicit memory is subdivided into episodic memory (about personal experiences) and semantic memory (about facts that have been learned from others). All other forms of memory are lumped into the intrinsic (nondeclarative) memory category. Implicit memory includes priming (unconscious facilitation of recognition of previously presented objects) and memories acquired by various forms of learning, including procedural learning (skills and habits), associative learning (classical and operant conditioning), and nonassociative learning (habituation and sensitization). Orthogonal to these classifications are divisions of memory into long-term and short-term forms (including working memory, which briefly keeps information available for immediate processing before being discarded or stored). Learning and memory depend on mechanisms of neural plasticity, especially synaptic plasticity. Such plasticity occurs in nearly all parts of the central nervous system (CNS), including the spinal cord, and plasticity in many parts of the CNS is involved in learning and memory. By definition, explicit memory is the form of memory that people are most conscious of, and the gradual loss of explicit memory caused by conditions such as Alzheimer disease can be devastating to patients and their families. The effects of pathologic lesions in human patients and experimental lesions in animals have shown that the formation of explicit memory depends critically on the hippocampus and the rest of the medial temporal lobe of the cerebral cortex (ie, the parahippocampal cortex, entorhinal cortex, perirhinal cortex, dentate gyrus, and subiculum). The earliest pathologic changes detected in Alzheimer disease are a marked loss of neurons in the entorhinal cortex, an observation consistent with the earliest symptoms being impairment of explicit memory formation. Lesions in the hippocampus and medial temporal lobe caused by Alzheimer disease or other insults have little effect on previously established memories, only on the formation of new memories. This and other observations indicate that the hippocampal system controls the initial phases of memory storage, but that long-term storage ultimately takes place in the association areas of neocortex, outside the medial temporal lobe. The hippocampus is particularly important for processing memories involving spatial representation, whereas the other parts of the medial temporal lobe can be more important for processing memories involving other forms of information, such as object recognition. Long-term storage of semantic information is distributed throughout the neocortex, whereas long-term storage of episodic memory is stored in the association areas of the frontal lobes.

4 396 CASE FILES: PHYSIOLOGY There are many forms of implicit memory, and different forms are stored in different parts of the CNS. For example, memories with a strong emotional component often involve alterations in the amygdala. Memories associated with operant conditioning (ie, learning that a particular motor action has a consequence) may involve alterations in the striatum and cerebellar cortex. Some forms of classical conditioning (ie, learning that one stimulus predicts another) involve alterations in both the cerebellar cortex and the deep cerebellar nuclei, and others involve alterations in sensory or motor cortex. The simplest forms of learning habituation and sensitization of reflex responses may involve alterations in sensory and motor systems in the spinal cord and brain. Many different cellular mechanisms contribute to learning and memory. The mechanism that has been studied most intensively and appears to be associated with many forms of learning and memory (both explicit and implicit) is long-term synaptic potentiation (LTP) induced by the opening of a class of glutamate receptors called NMDA receptors, named for the selective agonist N-methyl-D-aspartate. Under normal conditions, NMDA receptor channels are blocked by the binding of Mg 2+ to a site in the pore even when the channel is opened by glutamate. During strong depolarization caused by intense synaptic input (as occurs in relevant neurons during learning events), electrostatic repulsion expels the Mg 2+ and permits Na +,K +, and, most important, Ca 2+ to pass through the pore when it is opened by glutamate. Influx of Ca 2+ leads to the activation of various enzymes, including Ca 2+ /calmodulindependent protein kinase and protein kinase C, as well as protein kinase A, which trigger various plastic changes. The early phase of LTP (lasting 1-2 hours) is thought to involve increases in glutamate release from the presynaptic terminal and/or insertion of additional AMPA glutamate receptors (named for the selective agonist α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid), which are not blocked by Mg 2+ and thus open fully when bound by glutamate at normal resting potentials. Both of these effects increase the amplitude of subsequently evoked excitatory synaptic potentials (EPSPs) and thus increase the functional strength of the altered synapse. A late phase of LTP also can be induced and may last for weeks or longer. It involves the growth of new synapses, which depends on changes in protein synthesis and gene transcription. These long-term effects appear to be induced, at least in part, by the ability of protein kinase A and Ca 2+ /calmodulin-dependent protein kinase to activate transcription factors in the nucleus such as the Ca 2+ -cyclic AMP response element binding (CREB) protein. An effect opposite to that of LTP, called long-term synaptic depression (LTD), is produced by low-frequency activation of many of the same synapses that exhibit LTP after highfrequency activation. Information storage in a neural network depends upon patterns of expression of LTP and LTD distributed across enormous numbers of synapses throughout the network.

5 CLINICAL CASES 397 COMPREHENSION QUESTIONS [49.1] On mental status examination, a 72-year-old woman is noted to have some difficulty with explicit (declarative) memory. This type of memory includes which of the following? A. Conscious memory of personal experiences B. Habituation C. Memories acquired during operant conditioning D. Neural alterations underlying new skills E. Unconscious memory of food-induced illness [49.2] An 82-year-old man has been noted by his family to be forgetful and often to get lost. He is diagnosed with very mild Alzheimer disease. Which of the following areas of the brain is likely to be affected by neuronal loss? A. Basal ganglia B. Deep cerebellar nuclei C. Entorhinal cortex D. Hypothalamus E. Prefrontal cortex [49.3] NMDA-receptor-dependent LTP is induced if which of the following occurs? A. Ca 2+ influx during low-frequency synaptic input activates protein phosphatases. B. γ-aminobutyric acid (GABA) is released near an NMDA receptor. C. Glutamate release is inhibited. D. Strong depolarization expels Mg 2+ from the pore of the NMDA receptor channel. E. The equilibrium potential for Ca 2+ becomes less positive. Answers [49.1] A. By definition, explicit or declarative memory is composed of episodic memory about personal experiences and semantic memory of facts learned from others. These memories can be recalled by conscious effort, unlike the other forms of memory listed in this question. [49.2] C. The earliest signs of neuronal loss during Alzheimer disease have been found in the entorhinal cortex, which is a gateway to the hippocampus. Degeneration is thought to spread to the hippocampus and later appear in other areas of the brain. Intense efforts are under way to develop methods for the early diagnosis of Alzheimer disease (when memory impairment first becomes apparent) by utilizing advanced imaging techniques to compare the relative volumes of the entorhinal cortex and hippocampus with those in other parts of the brain.

6 398 CASE FILES: PHYSIOLOGY [49.3] D. NMDA-receptor-dependent LTP is induced when sufficient depolarization is received postsynaptically, during the release of glutamate from the presynaptic terminal, so that Mg 2+ is expelled from the pore of the NMDA receptor channel and substantial amounts of Ca 2+ can then enter through the pore. The surge of Ca 2+ activates various enzymes, including protein kinases, triggering cascades that result in a strengthening of that synapse. High-frequency stimulation of multiple presynaptic fibers usually is needed to cause enough depolarization and allow enough Ca 2+ to enter to activate the protein kinases. Low-frequency stimulation allows a much smaller amount of Ca 2+ to enter, which can selectively activate protein phosphatases to produce the opposite effect, reducing the strength of the synapse (termed long-term depression [LTD]). PHYSIOLOGY PEARLS Explicit (declarative) memory includes factual information about the world (semantic memory) and recollections of personal experiences (episodic memory) that can be retrieved consciously. Implicit (nondeclarative) memory refers to all forms of unconscious memory, including memories acquired or expressed during priming, procedural learning of skills and habits, classical conditioning, operant conditioning, habituation, and sensitization. The initial formation of explicit memories depends critically on processing in the medial temporal lobe and especially the hippocampus and entorhinal cortex. Long-term storage of semantic information (facts) is distributed in the neocortex, whereas long-term storage of episodic memory (personal experiences) occurs in the association areas of the frontal cortex. Formation and storage of various forms of implicit memory occur in many different parts of the CNS, including the amygdala, striatum, cerebellum, and spinal cord. A widespread mechanism that is likely to contribute to many forms of learning and memory is NMDA-receptor-dependent LTP, in which strong depolarization of NMDA receptors relieves a block of the pore by Mg 2+ and allows Ca 2+ to enter the cell and trigger enzymatic responses that lead to a marked enhancement of subsequent synaptic transmission. Long-term memory and persistent synaptic plasticity depend on changes in gene transcription and protein synthesis, often involving activation of the CREB protein transcription factor in the neuronal nucleus.

7 CLINICAL CASES 399 REFERENCES Byrne JH. Learning and memory. In: Johnson LR, ed. Essential Medical Physiology. San Diego, CA: Elsevier Academic Press; 2003: Kandel ER. Kupfermann I. and Iversen S. Learning and memory. In: Kandel ER, Schwartz JH, Jessell TM. Principles of Neuroscience. New York, NY: McGraw- Hill 2000: Kandel ER. Cellular mechanisms of learning and the biological basis of individuality. In: Kandel ER, Schwartz JH, Jessell TM. Principles of Neuroscience. New York, NY: McGraw-Hill; 2000:

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