Brain Regions in Memory
Clinical studies of amnesia (loss of memory) suggest that several different brain regions are involved in memory storage and retrieval. Amnesia has been found to result from damage to the temporal lobe of the cerebral cortex, the hippocampus, the head of the caudate nucleus (in Huntington's disease), or the dorso-medial thalamus (in alcoholics suffering from Korsakoff's syndrome with thiamine deficiency). A number of researchers now believe that there are several different systems of information storage in the brain. One system relates to the simple learning of stimulus-response that even invertebrates can do to some degree. This, together with skill learning and different kinds of conditioning and habits, are retained in people with amnesia.
People with amnesia have an impaired ability to remember facts and events, which some scientists have called "declarative memory." This system of memory can be divided into two major categories: short-term memory and long-term memory. People with head trauma, for example, and patients who undergo electroconvulsive shock (ECS) therapy may lose their memory of recent events but retain their older memories. Recent evidence suggests that the consolidation of long-term memory requires the activation of genes, leading to altered protein synthesis and synaptic connections. The consolidation of short-term memory into long-term memory is the function of the medial temporal lobe, an area that includes the hippocampus, amygdaloid nucleus, and adjacent areas of the cerebral cortex (fig. 8.14). Once the memory is put into long-term storage, however, it is independent of the medial temporal lobe.
Using functional magnetic resonance imaging (fMRI) of subjects asked to remember words, scientists detected more brain activity in the left medial temporal lobe and left frontal lobe for words that were remembered compared to words that were subsequently forgotten. When pictures of scenes rather than words were used, the scenes that were remembered evoked more fMRI activity in left and right medial temporal lobes and right frontal lobe compared to that evoked by scenes that were subsequently forgotten. The increased fMRI activity in these brain regions seems to indicate the encoding of the memories. Indeed, lesions of the left medial temporal lobe impairs verbal memory, while lesions of the right medial temporal lobe impairs nonverbal memories, such as the ability to remember faces.
Surgical removal of the right and left medial temporal lobes was performed in one patient, designated "H.M.," in an effort to treat his epilepsy. After the surgery he was unable to consolidate any short-term memory. He could repeat a phone number and carry out a normal conversation; he could not remember the phone number if momentarily distracted, however, and if the person to whom he was talking left the room and came back a few minutes later, H.M. would have no recollection of seeing that person or of having had a conversation with that person before. Although his memory of events that occurred before the operation was intact, all subsequent events in his life seemed as if they were happening for the first time.
The effects of bilateral removal of H.M.'s medial temporal lobes were due to the fact that the hippocampus and amygdaloid nucleus (fig. 8.14) were also removed in the process. Surgical removal of the left medial temporal lobe impairs the consolidation of short-term verbal memories into long-term memory, and removal of the right medial temporal lobe impairs the consolidation of nonverbal memories.
On the basis of additional clinical experience, it appears that the hippocampus is a critical component of the memory system. Magnetic resonance imaging (MRI) reveals that the hippocampus is often shrunken in living amnesic patients. However, the degree of memory impairment is increased when other structures, as well as the hippocampus, are damaged. The
hippocampus and associated structures of the medial temporal lobe are thus needed for the acquisition of new information about facts and events, and for the consolidation of short-term into long-term memory, which is stored in the cerebral cortex. Emotional arousal, acting via the structures of the limbic system, can enhance or inhibit long-term memory storage. The amygdala appears to be particularly important in the memory of fear responses. Studies demonstrate increased neural activity of the human amygdala during visual processing of fearful faces, and patients with bilateral damage to the amygdala were unable to read danger when shown threatening pictures.
The cerebral cortex is thought to store factual information, with verbal memories lateralized to the left hemisphere and visuospatial information to the right hemisphere. The neurosurgeon Wilder Penfield was the first to electrically stimulate various brain regions of awake patients, often evoking visual or auditory memories that were extremely vivid. Electrical stimulation of specific points in the temporal lobe evoked specific memories so detailed that the patients felt as if they were reliving the experience. The medial regions of the temporal lobes, however, cannot be the site where long-term memory is stored, since destruction of these areas in patients being treated for epilepsy did not destroy the memory of events prior to the surgery. The inferior temporal lobes, on the other hand, do appear to be sites for the storage of long-term visual memories.
The left inferior frontal lobe has recently been shown to participate in performing exact mathematical calculations. Scientists have speculated that this brain region may be involved because it stores verbally coded facts about numbers. Using fMRI, researchers have recently demonstrated that complex, problem-solving and planning activities involve the most anterior portion of the frontal lobes, an area called the prefrontal cortex. There is evidence that signals are sent from the pre-frontal cortex to the inferior temporal lobes, where visual long-term memories are stored. Lesions of the prefrontal cortex interfere with memory in a less dramatic way than lesions of the medial temporal lobe.
The amount of memory destroyed by ablation (removal) of brain tissue seems to depend more on the amount of brain tissue removed than on the location of the surgery. On the basis of these observations, it was formerly believed that the memory was diffusely located in the brain; stimulation of the correct location of the cortex then retrieved the memory. According to current thinking, however, particular aspects of the memory— visual, auditory, olfactory, spatial, and so on—are stored in particular areas, and the cooperation of all of these areas is required to elicit the complete memory.
Since long-term memory is not destroyed by electroconvulsive shock, it seems reasonable to conclude that the consolidation of memory depends on relatively permanent changes in the chemi cal structure of neurons and their synapses. Experiments suggest that protein synthesis is required for the consolidation of the "memory trace." The nature of the synaptic changes involved in memory storage has been studied using the phenomenon of long-term potentiation (LTP) in the hippocampus, as described in chapter 7.
Long-term potentiation is a type of synaptic learning, in that synapses that are first stimulated at high frequency will subsequently exhibit increased excitability. Long-term potentiation has been studied extensively in the hippocampus, where most of the axons use glutamate as a neurotrans-mitter. Here, the induction of LTP requires activation of the NMDA receptors for glutamate (described in chapter 7). Activation of NMDA receptors—where the receptor channels for Ca2+ and Na+ open—requires not only binding by glutamate, but also binding by another ligand (glycine or D-serine) and a simultaneous partial depolarization of the postsynaptic membrane by different membrane channels. This can involve the binding of glutamate to different receptors, known as AMPA receptors. It is interesting in this regard that AMPA receptors move into the postsynaptic membrane during LTP. Once glutamate is able to activate its NMDA receptors, their channels for Ca2+ are opened in the dendritic plasma membrane. Long-term potentiation is thus characterized by the diffusion of Ca2+ into the dendrites of the postsynaptic neuron (fig 8.15).
Morphological (structural) changes also occur in the post-synaptic neuron as a result of LTP. Dendritic spines, which are tiny spikelike extensions from the dendrites, grow as a consequence of LTP. Recent evidence suggests that, as a result of LTP, the growth of new dendritic spines results in increased area of contact between the presynaptic axon terminal and the postsynaptic membrane.
The induction of LTP may also involve presynaptic changes, so that there is increased release of neurotransmitter. This may involve a "retrograde messenger," sent from the postsynaptic neuron to the presynaptic axon. Some scientists have proposed that nitric oxide plays this role. In this proposed sequence of events:
1. The binding of glutamate to its NMDA receptors and simultaneous depolarization of the postsynaptic membrane causes the NMDA receptor channels to open.
2. This opening of the NMDA receptor channels allows Ca2+ to enter.
3. The entry of Ca2+ into the postsynaptic neuron causes long-term potentiation in that neuron.
4. The entry of Ca2+ into the postsynaptic neuron also activates nitric oxide synthase, causing nitric oxide production.
5. The nitric oxide then acts as a retrograde messenger, diffusing into the presynaptic neuron and somehow causing it to release more neurotransmitter.
In these ways, synaptic transmission is strengthened through frequent use. Although the mechanisms by which LTP
The Central Nervous System
Postsynaptic membrane of dendrite
Postsynaptic membrane of dendrite
■ Figure 8.15 Role of glutamate receptors in long-term potentiation (LTP). The neurotransmitter glutamate (Glu) can bind to two different receptors, designated AMPA and NMDA. The activation of the NMDA receptors promotes an increased concentration of Ca2+ in the cytoplasm, which is needed in order for LTPto be induced. LTP is believed to be a mechanism of learning at the level of the single synapse.
is produced are still incompletely understood, and the causal association between LTP and learning still unproven, the evidence suggests that LTP is involved in the changes that occur when memories are made.
As mentioned previously, mammalian brains have recently been demonstrated to contain neural stem cells—cells that both renew themselves through mitosis and produce differentiated (specialized) neurons and neuroglia. It is particularly exciting that one of the brain regions shown to contain stem cells, the hippocampus, is required for the consolidation of long-term memory and for spatial learning.
Given this observation, it is natural to wonder if the production of new neurons, called neurogenesis, is involved in learning and memory. There is now evidence, at least in rats, that this is the case for the learning and retention of a particular type of task. There is also indirect evidence linking neurogene-sis in the hippocampus with learning and memory. For example, conditions of stress inhibit neurogenesis in the hippocampus (and retard hippocampus-dependent forms of learning), while increased environmental complexity has the opposite effects on both neurogenesis and learning. Mitotically active neural stem cells have recently been surgically isolated from the human hippocampus of adult patients, in the hope that cells obtained in this way may someday be useful in treating people with a damaged or degenerated hippocampus.
Test Yourself Before You Continue
1. Describe the locations of the sensory and motor areas of the cerebral cortex and explain how these areas are organized.
2. Describe the locations and functions of the basal nuclei. Of what structures are the basal nuclei composed?
3. Identify the structures of the limbic system and explain the functional significance of this system.
4. Explain the difference in function of the right and left cerebral hemispheres.
5. List the areas of the brain believed to be involved in the production of speech and describe the different types of aphasias produced by damage to these areas.
6. Describe the different forms of memory, list the brain structures shown to be involved in memory, and discuss some of the experimental evidence on which this information is based.
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