Animal research on memory

TYPE OF PSYCHOLOGY: Biological bases of behavior; memory

Research with nonhuman animals has significantly contributed to an understanding of the basic processes of memory, including its anatomy and physiology. Important brain regions, neurotransmitters, and genes have been identified, and this information is now being used to further understand and treat human memory disorders.

Introduction

Nonhuman animals have been used as subjects in memory research since the earliest days of psychology, and much of what is known about the fundamental processes of memory is largely based on work with animals. Rats, mice, pigeons, rabbits, monkeys, sea slugs, flatworms, and fruit flies are among the most commonly used species. The widespread use of animals in psychological research can be attributed to the ability to systematically manipulate and control their environments under strict laboratory conditions and to use procedures and invasive techniques, such as surgery and drugs, that cannot ethically be used with humans. A typical memory research protocol involves training animals on any of a variety of learning paradigms and concurrently measuring or manipulating some aspect of the to examine its relationship to memory.

Although learning is closely related, a distinction should be drawn between learning and memory. Learning is defined as a relatively permanent change in behavior as a result of experience. Memory is the underlying process by which information is encoded, stored, and retrieved by the nervous system. Contemporary learning and memory paradigms are based on the principles of classical and first established by the early behaviorists: Ivan Petrovich Pavlov, Edward L. Thorndike, John B. Watson, and B. F. Skinner. These learning paradigms can be used to examine different types of memory and to explore the underlying brain mechanisms that may mediate them. For classical conditioning, widely used paradigms include eyeblink conditioning, taste-aversion learning, and fear conditioning. For operant conditioning, memory for objects, spatial memory, context discrimination, and maze learning are among the most frequently used procedures. Two other very simple forms of learning, habituation, the gradual decrease in response to a stimulus as a result of repeated exposure to it, and sensitization, the gradual increase in response to a stimulus after repeated exposure to it, are both simple forms of nonassociative learning also extensively used in animal memory research.

Researchers have at their disposal a number of techniques that allow them to manipulate the nervous system and assess its functions. Historically, experimental brain damage has been one of the most widely utilized procedures. This technique involves surgically destroying (known as lesioning) various parts of the brain and assessing the effects of the lesion on memory processes. Pharmacological manipulations are also frequently used and involve administering a drug known to affect a specific or hormonal system thought to play a role in memory. Functional studies involve measuring brain activity while an animal is actually engaged in learning. Recordings can be made from individual brain cells (), groups of neurons, or entire anatomical regions. Beginning in the late 1990s, genetic engineering began to be applied to the study of animal memory. These procedures involve the direct manipulation of genes that produce proteins suspected to be important for memory.

By combining a wide variety of memory paradigms with an increasing number of ways to manipulate or measure the nervous system, animal research has been extremely useful in addressing several fundamental questions about memory, including the important brain structures involved in memory, the manner in which information is stored in the nervous system, and the causes and potential treatments for human memory disorders.

The Anatomy of Memory

One of the first questions about memory to be addressed using animals was its relationship to the underlying structure of the nervous system. American psychologist Karl Lashley was an early pioneer in this field in the mid-twentieth century; his main interest was in finding what was then referred to as the engram, the physical location in the brain where memories are stored. Lashley trained rats on a variety of tasks, such as the ability to learn mazes or perform simple discriminations, and then lesioned various parts of the (the convoluted outer covering of the brain) in an attempt to erase the memory trace. Despite years of effort, he found that he could not completely abolish a memory no matter what part of the cortex he lesioned. Lashley summed up his puzzlement and frustration at these findings in this now well-known quote: “I sometimes feel, in reviewing the evidence on the localization of the engram, that the necessary conclusion is that learning just is not possible.”

While the specific location of the brain lesion did not appear important, Lashley found that the total amount of brain tissue removed was critical. When large lesions were produced, as compared to smaller ones, he found that memories could be abolished, regardless of the location in the cortex where they were made. This led Lashley to propose the concepts of mass action and , which state that the cortex works as a whole and that all parts contribute equally to complex behaviors.

Further research has generally supported Lashley’s original conclusions about the localization of the engram. However, better memory tests and more sophisticated techniques for inducing brain damage have revealed that certain brain regions are more involved in memory than others, and that different brain regions are actually responsible for different types of memory. For example, classical conditioning, which is the modification of a reflex through learning, appears primarily to involve the and cerebellum, which are two evolutionarily old brain structures. Specific circuitry within these structures that underlies a number of forms of classical conditioning has been identified.

In the rabbit, a puff of air blown into the eye produces a reflexive blinking response. When researchers repeatedly pair the air puff with a tone, the tone itself will eventually come to elicit the response. The memory for this response involves a very specific circuit of neurons, primarily in the cerebellum. Once the response is well learned, it can be abolished by lesions in this circuit. Importantly, these lesions do not affect other forms of memory. Similarly, taste-aversion learning, a process by which animals learn not to consume a food or liquid that has previously made them ill, has been shown to be mediated by a very specific circuit in the brain stem, specifically the and medulla. Animals with lesions to the nucleus of the solitary tract, a portion of this circuit in the medulla where taste, olfactory, and illness-related information converge, will not readily learn taste aversions.

More complex forms of learning and memory have been shown to involve more recently evolved brain structures. Many of these are located in either the cortex or the , an area of the brain located between the newer cortex and the older brain stem. One component of the limbic system believed to be heavily involved in memory is the hippocampus. One of its primary functions appears to be spatial memory. Rats and monkeys with damage limited to the hippocampus are impaired in maze learning and locating objects in space but have normal memory for nonspatial tasks. Additionally, animals that require spatial navigation for their survival, such as homing pigeons and food-storing rodents (which must remember the location of the food that they have stored), have disproportionately large hippocampi. Moreover, damage to the hippocampus in these species leads to a disruption in their ability to navigate and to find stored food, respectively.

One area of the cortex that has been shown to be involved in memory is the prefrontal cortex. This area has been implicated in short-term memory, which is the ability to temporarily hold a mental representation of an object or event. Monkeys and rats that received lesions to the prefrontal cortex were impaired in learning tasks that required them to remember briefly the location of an object or to learn tasks that required them to switch back and forth between strategies for solving the task. Studies involving the measurement of brain function have also demonstrated that this area of the brain is active during periods when animals are thought to be holding information in short-term memory.

While experimental brain damage has been one of the predominant techniques used to study structure/function relationships in the nervous system, difficulty in interpretation, an increased concern for animal welfare, and the advent of more sophisticated physiological and molecular techniques have led to an overall decline in their use.

The Molecules of Memory

While lesion studies have been useful in determining the brain structures involved in memory, pharmacological techniques have been used to address its underlying chemistry. Pharmacological manipulations have a long history in memory research with animals, dating back to the early 1900s and the discovery of neurotransmitters. Neurotransmitters are chemical messengers secreted by neurons and are essential to communication within the nervous system. Each neurotransmitter, of which there are more than one hundred, has its own specific to which it can attach and alter cellular functioning. By administering drugs that either increase or decrease the activity of specific neurotransmitters, researchers have been able to investigate their role in memory formation.

One neurotransmitter that has been strongly implicated in memory is glutamate. This transmitter is found throughout the brain but is most highly concentrated in the cerebral cortex and the hippocampus. Drugs that increase the activity of glutamate facilitate learning and improve memory, while drugs that reduce glutamate activity have the opposite effect. The neurotransmitter dopamine has also been implicated in memory formation. In small doses, drugs such as cocaine and amphetamine, which increase dopamine activity, have been found to improve memory in both lower animals and humans. Moderate doses of caffeine can also facilitate memory storage, albeit by a less-well-understood mechanism. Other neurotransmitters believed to be involved in memory include , serotonin, norepinephrine, and the .

Research with simpler organisms has been directed at understanding the chemical events at the molecular level that may be involved in memory. One animal in particular, the marine invertebrate Aplysia californica, a species of sea slug, has played a pivotal role in this research. Aplysia have very simple nervous systems with large, easily identifiable neurons and are capable of many forms of learning, including habituation, sensitization, and classical conditioning. Canadian psychologist Donald O. Hebb , a former student of Lashley, proposed that memories are stored in the nervous system as a result of the strengthening of connections between neurons as a result of their repeated activation during learning. With the Aplysia, it is possible indirectly to observe and manipulate the connections between neurons while learning is taking place. Eric R. Kandel of Columbia University has used the Aplysia as a model system to study the molecular biology of memory for more than thirty years. He demonstrated that when a short-term memory is formed in the Aplysia, the connections between the neurons involved in the learning process are strengthened by gradually coming to release more neurotransmitters, particularly serotonin. When long-term memories are formed, new connections between nerve cells actually grow. With repeated disuse, these processes appear to reverse themselves. Kandel’s work has suggested that memory (what Lashley referred to as the engram) is represented in the nervous system in the form of a chemical or structural change, depending on the nature and duration of the memory itself. For these discoveries, Kandel was awarded the Nobel Prize in 2000.

Modern genetic engineering techniques have made it possible to address the molecular biology of memory in higher mammals (predominantly mice) as well as invertebrates. Two related techniques, genetic knockouts and transgenics, have been applied to the problem. Genetic knockouts involve removing, or “knocking out,” a gene that produces a specific protein thought to be involved in memory. Frequently targeted genes include those for neurotransmitters or their receptors. Transgenics involves the insertion of a new gene into the genome of an organism with the goal of either overproducing a specific protein or inserting a completely foreign protein into the animal. Neurotransmitters and their receptors are again the most frequently targeted sites. A remarkable number of knockout mice have been produced with a variety of short- and deficits. In many ways, this technique is analogous to those used in earlier brain lesion studies but is applied at the molecular level. Dopamine, serotonin, glutamate, and acetylcholine systems have all been implicated in memory formation as a result of genetic knockout studies. Significantly, researchers have also been able to improve memory in mice through genetic engineering. Transgenic mice that overproduce glutamate receptors actually learn mazes faster and have better retention than normal mice. It is hoped that in the future gene therapy for human memory disorders may be developed based on this technique.

Animal Models of Human Memory Disorders

Animal research has many practical applications to the study and treatment of human memory dysfunction. Many types of neurological disorder and brain damage can produce memory impairments in humans, and it has been possible to model some of these in animals. The first successful attempt at this was production of an animal model of brain-damage-induced amnesia. It had been known since the 1950s that damage to the , as a result of disease, traumatic injury, , or infection, could produce a disorder known as , which is the inability to form new long-term memories. This is in contrast to the better-known , which is an inability to remember previously stored information. Beginning in the late 1970s, work with monkeys, and later rats, began to identify the critical temporal lobe structures that, when damaged, produce anterograde amnesia. These structures include the hippocampus and, perhaps more important, the adjacent, overlying cortex, which is known as the rhinal cortex. As a result of this work, this brain region is now believed to be critical in the formation of new long-term memories.

Memory disorders also frequently develop after an interruption of oxygen flow to the brain (known as hypoxia), which can be caused by events such as stroke, cardiac arrest, or carbon monoxide poisoning. There are a variety of animal models of stroke and resultant memory disorders. Significantly, oxygen deprivation produces brain damage that is most severe in the temporal lobe, particularly the hippocampus and the rhinal cortex. Using animal models, the mechanisms underlying hypoxic injury have been investigated, and potential therapeutic drugs designed to minimize the brain damage and lessen the memory impairments have been tested. One potentially damaging event that has been identified is a massive influx of calcium into neurons during a hypoxic episode. This has led to the development of calcium blockers and their widespread utilization in the clinical treatment of complications arising from stroke.

Alzheimer’s disease is probably the best-known human memory disorder. It is characterized by gradual memory loss over a period of five to fifteen years. It typically begins as a mild forgetfulness and progresses to anterograde amnesia, retrograde amnesia, and eventually complete cognitive dysfunction and physical incapacitation. One pathological event that has been implicated in the development of Alzheimer’s disease is the overproduction of a protein known as the beta amyloid protein. The normal biological function of this protein is not known, but at high levels it appears to be toxic to neurons. Beta amyloid deposits are most pronounced and develop first in the temporal and , a fact that corresponds well with the memory functions ascribed to these areas and the types of deficits seen in people with Alzheimer’s disease. The development of an animal model has marked a major milestone in understanding the disorder and developing a potential treatment. Mice have been genetically engineered to overproduce the beta amyloid protein. As a result, they develop patterns of brain damage and memory deficits similar to humans with Alzheimer’s disease. The development of the Alzheimer’s mouse has allowed for a comprehensive investigation of the genetics of the disorder as well as providing a model on which to test potential therapeutic treatments. As of 2024, research was also beginning to show that rats, though costlier and more difficult to obtain, could prove to be even more viable models for Alzheimer's study due to evidence supporting the idea that rats, like humans, have episodic memories. Limited success for potential treatments has been obtained with an experimental vaccine in animals. This vaccine has been shown to reduce both brain damage and memory deficits. As with most experimental drugs, application to the treatment of human Alzheimer’s disease is many years away. Further, studies with rats have illuminated potential early biomarkers for the disease. Research continues to be promising.

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