Review of Medical Physiology - William F. Ganong 2002

Functions of the Nervous System
Higher functions of the nervous system: conditioned reflexes, learning, and related phenomena
Learning and Memory

A characteristic feature of living organisms, humans above all, is The ability to modify behavior based on acquired experience. This happens thanks to learning, which is The process of acquiring information, and memory, that is, the storage and accumulation of information. These two closely related phenomena must be considered inseparably from one another.

Forms of Memory

From a physiological perspective, memory is divided into conscious and subconscious (Table 16-1). Conscious memory, also referred to as declarative or cognitive memory, is associated with a state of consciousness or, at least, wakefulness. It is mediated by the hippocampus and other Regions of the medial temporal lobes of the Brain. This form of memory is subdivided into memory for events (episodic memory) and memory for words, rules, language, etc. (semantic memory). Subconscious memory does not involve a state of wakefulness; it is also called nondeclarative or procedural memory, and its storage in most cases is independent of the hippocampus. Subconscious memory includes skills, habits, conditioned Reflexes, etc. (see Table 16-1). However, conscious memory required, say, for riding a bicycle becomes subconscious as soon as a person learns to do it well.

Conscious memory and many forms of subconscious memory are associated, first, with short-term memory, which lasts from several seconds to several hours, during which processes in the hippocampus and other regions establish long-term Changes in the strength of synaptic connections; and second, with long-term memory, which preserves memories for years or sometimes a lifetime. Memories stored in short-term memory are susceptible to disruption by trauma or various drugs, whereas long-term memories are more stable. Working memory is a form of short-term memory that keeps information readily available, typically for very brief periods, while an individual plans an action based upon it.

Subconscious Memory

As shown in Table 16-1, subconscious memory encompasses skills and habits that immediately upon acquisition become unconscious and automatic, as well as priming, which is the facilitation of the recognition of words or objects through their prior presentation. An example is a situation where a person finds it easier to recall a word if given a cue of the first few letters.

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Fig. 16-1. PET scan image of the left cerebral hemisphere showing areas of highest neural activity when a subject performs various tasks. A - looking at words; active primary visual cortex and part of the visual association cortex. B - listening to words; active area at the junction of the temporal and parietal cortices. C - speaking words; active Broca's area and adjacent frontal lobe. D - thinking about words; large active areas, including a significant part of the frontal lobe (based on PET scans from Kandel ER, Schwartz JH, Jessell TM: Essentials of Neural Science and Behavior. McGraw-Hill, 1995).

Other forms of subconscious memory can be divided into nonassociative and associative. In nonassociative learning, the Organism learns about a single stimulus, whereas in associative learning, the relationships between different stimuli are learned.

Habituation and Sensitization

Habituation is a simple form of learning in which a neutral stimulus is frequently repeated. Initially, this stimulus is fully effective and elicits a response (an orientational reflex, or the "what is it?" response); with an increasing number of repetitions, it elicits an progressively weaker bioelectrical response. Eventually, the subject becomes accustomed to the stimulus and ignores it. Sensitization is in a sense the opposite. A repeated stimulus elicits a stronger response if it is paired once or several times with a noxious or rewarding stimulus. It is well known that an arousal-increasing stimulus heightens responses in humans. For example, a mother whose Sleep is undisturbed by various Background noises wakes instantly to the cry of her infant.

The process of habituation is a classic example of nonassociative learning. A classic example of associative learning is the conditioned reflex.

Table 16-1. Types of Memory

Conditioned Reflexes

A conditioned (acquired) reflex is a reflex response to a stimulus that previously elicited little or no response, acquired by repeated pairing of this stimulus with another that does elicit such a response. In Pavlov's classic conditioning experiment, salivation induced by placing a piece of meat in a dog's Mouth was studied. Immediately prior to this, a bell was rung, repeating the Procedure until the dog began to salivate at the sound of the bell even when no meat was given. In this experiment, the meat placed in the dog's mouth served as the unconditioned stimulus (US), that is, a stimulus that normally elicits a specific innate response. The conditioned stimulus (CS) was the sound of the bell. After pairing the unconditioned and conditioned stimuli the required number of times, the CS elicited the response originally produced only by the US. For this to occur, the CS must precede the US. Another example is shown in Fig. 16-2. This is so-called classical conditioning. Today, many somatic, visceral, and other neural changes can be established as conditioned reflex responses. The establishment of these responses is often referred to as biofeedback. Changes that may occur in this case include alterations in Heart rate and Blood pressure. It is believed that Hypertension can be treated via conditioned decreases in blood pressure. However, depressor responses induced in this manner are modest.

If the CS is applied for a prolonged period without the US, the conditioned reflex eventually disappears. This process is called extinction, or internal inhibition. If, however, the animal is subjected to an external stimulus immediately after the CS, the conditioned response may fail to occur (external inhibition). Nonetheless, if the conditioned reflex is reinforced from time to time by pairing the CS and US, it will not vanish.

As noted in Chapter 15, conditioned reflexes are difficult to establish unless the US is paired with rewarding or punishing events. A strong US is The stimulation of either the brain's reward system (rewarding, or positive reinforcement) or the avoidance system, or cutaneous pain Shock (punishing, or negative reinforcement). Operant (instrumental) conditioning is a form of conditioning in which an animal is trained to perform certain tasks in order to receive a reward or avoid punishment. The US in this case is a rewarding or punishing event, and the CS is a light or other signal prompting the animal to perform the task. Conditioned motor responses that enable an animal to avoid an aversive event are called avoidance reflexes. For example, an animal is trained that by pressing a lever it can avoid an electric shock to its limbs. Another example is conditioned taste aversion. Animals develop a strong aversion to a particular category of food if an injection of a drug that induces nausea or illness is administered during the consumption of that food. Similar aversion reactions occur in humans. These conditioned responses are very robust, sometimes being acquired after a single pairing of the CS and US, and unlike other conditioned reflexes, they will develop even when the CS and US are separated in time (by an hour or more). The Development of conditioned taste aversions has vital survival significance because these reflexes help avoid poisons. Therefore, it is not surprising that the brain may be genetically programmed to facilitate the development of food aversion responses.

Fig. 16-2. Conditioned reflex in the rabbit. The first arrow indicates the presented sound (CS), and the second indicates a gentle air puff (US) directed at the rabbit's eye. Initially, the nictitating membrane extends in response only to the air puff (top). After repeated pairings of the two stimuli, the nictitating membrane begins to contract in response to the sound that precedes the air puff (bottom) (modified from Alkon DL: Memory storage and neural systems. Sci Am [July] 1989;261:42).

Interhemispheric Transfer of Memory

If a cat or monkey exhibits conditioned reflexes to a visual stimulus with one eye patched and is subsequently tested with the eyepatch moved to the other eye, the animal still demonstrates retention of the conditioned response. This occurs even when the optic chiasm is sectioned, so that the visual signal from each eye goes exclusively to the ipsilateral cortical area. If, however, In addition to the sectioned optic chiasm, the anterior and posterior commissures as well as the corpus callosum are transected ("split-brain animal"), memory transfer does not occur. Experiments with partial transection of the corpus callosum indicate that memory transfer takes place through the anterior region of the corpus callosum. Similar results have been observed in humans born without a corpus callosum or in those who had it surgically removed to prevent epileptic seizures. This proves that the neural encoding required to "remember with one eye what was seen by the other" was transferred to the contralateral cortical area via the commissures. There is evidence that similar information transfer occurs via other sensory pathways.

Molecular Basis of Memory

A key element in memory is the alteration of the strength of relevant synaptic connections. In almost all but the simplest cases, such changes entail Protein Synthesis AND Gene activation. This occurs during the transition from short-term working memory to long-term memory. In animals, the acquisition of long-term learned responses can be prevented if they are subjected to anesthesia, electroconvulsive shock, hypothermia, or Treatment with drugs, Antibodies, or oligonucleotides that block protein synthesis within five minutes after each training session. If such interventions are applied four hours after training sessions, they have no effect on response acquisition.

A human counterpart is the loss of memory for events occurring immediately preceding a concussion or electroconvulsive therapy (retrograde amnesia). Such amnesia is observed over longer periods than in experimental animals (sometimes for many days), but it does not affect more remote memories.

The biochemical processes underlying skill acquisition and sensitization in Aplysia and other invertebrates have been studied in detail. Along with the mechanisms responsible for several

forms of long-term potentiation (LTP) and long-term depression (LTD), these are discussed in Chapter 4.

Skill acquisition results from a decrease in Ca²⁺ levels within the sensory terminals that mediate responses to a specific stimulus. Conversely, sensitization is caused by the prolongation of the Action Potential in these terminals, leading to an increase in intracellular Ca²⁺, which facilitates neurotransmitter release via exocytosis.

Classical conditioning has also been demonstrated in Aplysia and in the isolated Spinal Cord of mammals. In Aplysia, the US acts presynaptically on the terminals of Neurons activated by the CS. As a result, free Ca²⁺ appears within The Cell, inducing a long-term Modification of the adenylyl cyclase molecule.

Consequently, the activation of this enzyme by the conditioned stimulus leads to increased cAMP production. This, in turn, closes K⁺ channels and prolongs action potential duration through the mechanism described in Chapter 4. A crucial factor here is the interaction with the US, which occurs shortly after the CS.

In Aplysia, morphological correlates of learning and memory are clearly observable. For example, 40% of the relevant sensory terminals contain active zones under normal conditions, whereas active zones are present in only 10% of sensory terminals in animals with acquired skills, and in 65% of sensitized animals. Long-term memory triggers the activation of genes that drive an increase in the number of synaptic contacts.

Encoding of Implicit Memory in Mammals

Undoubtedly, molecular processes similar to those occurring in Aplysia underlie certain aspects of implicit memory in mammals. However, these involve processes engaging various regions of the Central Nervous system. Some researchers suggest that the striatum also plays a role in this process.

It is well established that learning is disrupted following damage to the basal nuclei. In addition, there is evidence of cerebellar involvement. For instance, the vestibulo-ocular reflex (nystagmus), which maintains visual fixation during HEAD movements (see Chapter 9), can be adapted to a new eye position. However, this ability is lost in lesions of the cerebellar flocculus. Classical conditioning of the eyeblink reflex, elicited by directing a puff of air to the eye as a US (see Fig. 16-2), is impossible following damage to the interpositus Nucleus. In this case, impulses driven by the US act via the inferior olive and climbing fibers projecting up to the Cerebral Cortex to modify the response of Purkinje Cells to the tonus arising through the pontine nuclei and mossy fibers. The modification of mossy-fiber-carried depolarization of the Purkinje cell is mediated by climbing fibers and is also responsible for changes in the VOR and learned motor movements.

Encoding of Explicit Memory

The encoding of conscious memories involves working memory in the frontal lobes and specific Processing within the hippocampus.

Working Memory

As noted previously, working memory maintains incoming information in an accessible state for a short period while an individual decides what to do with it. This is the form of memory that enables us, for example, to look up a phone number in a directory and keep it in mind just long enough to pick up the receiver and dial. It consists of a so-called central executive system located in the prefrontal cortex, alongside two "rehearsal systems"—a verbal system for storing verbal memories and a parallel visuospatial system for retaining the visual and spatial properties of objects. The executive system directs information into these rehearsal systems.

The Hippocampus and the Medial Temporal Lobe

Working memory areas are connected to the hippocampus and the adjacent hippocampal gyri of the medial temporal cortex (see Figs. 15-1 and 16-3). In humans, bilateral destruction of the ventral hippocampus, Alzheimer's disease, and similar conditions that destroy CA1 neurons result in severe short-term memory deficits. Bilateral lesions produce identical consequences in monkeys. At the same time, such damage in humans does not affect working memory or remote memory. Furthermore, implicit memory processes typically remain intact. Regarding explicit memory, these individuals function adequately as long as they maintain focus on their current task. However, the moment they are distracted—even briefly—all memory of what they were just doing is lost. Thus, while such people are capable of acquiring new knowledge and retaining memories of events that occurred prior to the injury, they cannot form new long-term memories. The hippocampus is closely linked to the hippocampal gyrus in the medial frontal cortex (see Fig. 12-3). Today, memory processes are investigated not only using fMRI, but also by measuring evoked potentials (i.e., event-related potentials [ERPs]) in epileptic patients with implanted electrodes. When these individuals recall words, enhanced activity is observed in the left frontal lobe and the left hippocampal gyrus; conversely, when they recall images or scenes, activity is recorded in the right frontal lobe and bilateral hippocampal gyri.

Fig. 16-3. Brain regions involved in the encoding of explicit memories (modified from Russ MD: Memories are made of this. Science 1998; 281:1151).

Connections between the hippocampus and the Diencephalon are also implicated in memory processes. In certain alcoholics with brain damage, memory for recent events is impaired. This memory loss is attributed to pathological changes in the mammillary bodies, which feature extensive efferent connections running via the fornix to the hippocampus, as well as projection nerve fibers passing through the mammillothalamic tract to the anterior thalamus. Notably, thalamic lesions in monkeys also cause recent memory loss. From the thalamus, memory-related fibers project to the prefrontal cortex, and subsequently to the basal Forebrain, from which diffuse cholinergic projection fibers extend to the entire neocortex, amygdala, and hippocampus originating from The Nucleus basalis of Meynert. In Alzheimer's disease, profound losses of these fibers are evident (see below).

The amygdala is closely connected to the hippocampus and is involved in encoding emotional memories. As noted in Chapter 15, damage to the amygdala renders animals less fearful. Healthy humans remember emotionally charged events significantly better than emotionally neutral ones. In contrast, patients with bilateral amygdala damage show no such difference.

Confabulation is a fascinating yet poorly understood condition that occasionally occurs in individuals with damage to the ventromedial regions of the frontal lobes. Such individuals perform poorly on memory tests while casually describing events that never actually happened. This phenomenon is sometimes referred to as "honest lying."

Long-Term Memory

Unlike short-term memory encoding, which takes place in the hippocampus, long-term memories are stored across various regions of the neocortex. Evidently, distinct components of a memory—visual, olfactory, auditory, and so forth—reside in the corresponding cortical areas dedicated to those Functions. These elements are bound together through long-term modifications in transmission strength at respective synaptic junctions, ensuring that all components of an image are brought to consciousness when an individual retrieves the memory.

Once long-term memories are consolidated, they can be recalled via a vast array of diverse associations. For instance, the memory of a vivid scene can be retrieved not only by encountering a similar scene, but also through sounds or smells associated with it, or simply by words like "scene," "bright," and others. Consequently, there must be numerous pathways leading to each accumulated memory. Furthermore, many memories carry an emotional component; simply put, memories can be pleasant or unpleasant.

The Known and the Unknown

Interestingly, stimulation of certain temporal lobe regions in humans alters their perception of the environment. For example, such stimulation can make a subject feel unusual in a familiar place or generate the sensation that current events have already been experienced in the past. The Emergence of such feelings in appropriate contexts may help a normal individual adapt to their surroundings. In unfamiliar settings, a person experiences anxiety and heightened alertness, whereas in familiar ones, vigilance is relaxed. An inappropriate feeling of familiarity during novel events or in new environments is clinically known as the déjà vu phenomenon (French for "already seen"). This phenomenon occurs occasionally in healthy individuals, but it may also manifest as an aura (a distinct sensory sensation immediately preceding a seizure) in Epilepsy patients with temporal lobe lesions.

Conclusion

Thus, the encoding of conscious memory still requires detailed investigation. According to various views, sensory information is temporarily stored in various regions of the prefrontal cortex as working memory. Information in working memory is transferred to the medial temporal lobe, particularly the parahippocampal gyrus, and from there to the hippocampus, where it is processed in a manner that remains unclear. During this period, as described above, the neural activity is vulnerable. Signals from the hippocampus pass through the subiculum toward the entorhinal cortex, somehow coordinating and reinforcing reverberating circuits across multiple neocortical areas. Over time, this forms stable memories that can be retrieved through A wide variety of associations.

Alzheimer's Disease and Senile Dementia

Alzheimer's disease is characterized by progressive short-term memory loss, followed by a general loss of cognitive function and death in middle-aged individuals. A similar degenerative process in older adults is referred to as senile dementia of the Alzheimer type, though it is frequently also called Alzheimer's disease. While the vast majority of cases are sporadic, familial forms also occur. These conditions account for 50–60% of all cases of senile dementia. Patients with Alzheimer's disease require round-the-clock care. Given that 10–15% of the population over 65 and nearly 50% of those over 85 exhibit some degree of dementia, this condition represents a major socio-economic challenge, particularly as the proportion of older adults in developed nations continues to grow.

Early changes in Alzheimer's disease include Atrophy of the hippocampus and the entorhinal cortex. These changes can be detected via MRI up to two years before a definitive clinical Diagnosis can be made. This pathology involves the loss of cholinergic and other cortical neurons, as well as a severe depletion of cholinergic neurons in the basal nucleus of Meynert and similar cell-group nuclei that project to the hippocampus, amygdala, and neocortex (see Chapter 15). Minor, temporary improvements in Alzheimer's patients can sometimes be achieved using acetylcholinesterase inhibitors, which mitigate the loss of acetylcholine. However, such treatments do not halt the underlying degenerative disease processes.

The exact cause of neuronal degeneration in Alzheimer's disease remains unknown. The cytopathological hallmarks of the condition are intracellular neurofibrillary tangles, composed partly of hyperphosphorylated forms of the microtubule-associated protein tau (see Chapter 1), and extracellular senile plaques consisting of a core of ß-amyloid (Aß) surrounded by dystrophic neurites and reactive glial cells. The beta-amyloids are the Aß₄₀ and Aß₄₂ Peptides derived from the amyloid precursor protein (APP). In particular, Aß₄₂ forms insoluble aggregates as a result of APP proteolysis. A key enzyme in this pathway is y-secretase. In approximately 50% of early-onset Alzheimer's cases, Mutations occur in genes encoding two Membrane Proteins localized in cellular Organelles: presenilin 1, encoded by a gene on chromosome 14, and the nearly identical presenilin 2, encoded by a gene on chromosome 1. Both presenilins are associated with y-secretase activity. Mutations in the APP gene on chromosome 21 also lead to early-onset forms of the disease. Interestingly, patients with Down syndrome possess an extra chromosome 21 (trisomy 21) and invariably develop Alzheimer-type dementia at an early age. When extracellularly accumulated, Aß₄₂ can exhibit neurotoxicity, and it is widely hypothesized that this process drives the Pathogenesis of Alzheimer's disease.

It is now established that estrogen slows the progression of Alzheimer's disease. Furthermore, There is a clear correlation between apolipoprotein E (apoE; see Chapter 17) isoforms and the age of disease onset. The gene encoding this protein is located on chromosome 19 and exists in three major allelic variants that differ by only one or Two Amino Acids. Individuals homozygous for the apoE-4 isoform develop Alzheimer's disease earlier than those homozygous for apoE-2 or apoE-3, or those heterozygous for any combination. Nonetheless, considerable further research is required to fully elucidate the specific roles of Aß, estrogen, and apoE isoforms in the pathogenesis of this disease.

Interestingly, selective degeneration during Aging can affect three distinct classes of central nervous system cells, leading to three progressive, debilitating, and ultimately fatal disorders. As noted above, the degeneration of basal forebrain cholinergic neurons is associated with Alzheimer's disease, the degeneration of dopaminergic neurons in the substantia nigra is linked to Parkinson's disease (see Chapter 12), and the degeneration of cholinergic motor neurons in the Brainstem and spinal cord underlies a form of AMYOTROPHIC LATERAL SCLEROSIS (ALS). ALS is often referred to as Lou Gehrig's disease, named after the famous American baseball player who succumbed to it. All three disorders are predominantly sporadic, though familial variants do exist. Approximately 5% of ALS cases are familial, and 40% of these hereditary cases involve mutations in the gene encoding Cu/Zn superoxide dismutase (SOD-1) on chromosome 21. A defective SOD-1 gene may allow the accumulation of neurotoxic free radicals. Neurodegenerative diseases caused by expanded trinucleotide repeats are discussed in Chapter 12.