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-damaged-induced
amnesia. It had been known since the 1950’s that damage to the temporal
lobes, as a result of disease, traumatic injury, epilepsy, or infection, could produce a disorder known as anterograde amnesia, the inability to form
new long-term memories. This is in contrast to the better-known retrograde
amnesia, which is an inability to remember previously stored information.
Beginning in the late 1970’s, 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 use 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 amyloid-beta protein. The normal biological function
of this protein is not known, but at high levels it appears to be toxic to
neurons. Amyloid-beta deposits are most pronounced and develop first in
the temporal and frontal lobes, 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 amyloid-
beta protein. As a result, they develop patterns of brain damage and
memory deficits similar to those in 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. 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.
Application to the treatment of human Alzheimer’s disease is many years
away.

Sources for Further Study
Anagnostopoulos, Anna V., Larry E. Mobraaten, John J. Sharp, and Muriel
T. Davisson. “Transgenic and Knockout Databases: Behavioral Profiles of
Mouse Mutants.” Physiology and Behavior 73 (2001): 675-689. A summary
of an ongoing project to construct a database of genetically engineered
mice designed to facilitate the dissemination of findings among researchers.
The article contains an exhaustive reference section on mutant mice
and their behavioral and physiological profiles.
Cohen, Neil J., and Howard Eichenbaum. Memory, Amnesia, and the Hippocampal
System. Cambridge, Mass.: MIT Press, 1993. A discussion of memory
impairments resulting from damage the hippocampus and adjacent
brain regions.
Duva, Christopher A., Thomas J. Kornecook, and John P. J. Pinel. “Animal
Models of Medial Temporal Lobe Amnesia: The Myth of the Hippocampus.”
In Animal Models of Human Emotion and Cognition, edited by Mark
Haug and Richard E Whalen.Washington, D.C.: American Psychological
Association, 1999. A critical evaluation of the role of the hippocampus in
memory for objects. The article includes a historical description of human
amnesia and attempts to model it in monkeys and rats.
Kiefer, Steven W. “Neural Mediation of Conditioned Food Aversions.” Annals
of the New York Academy of Sciences 443 (1985): 100-109. A comprehensive
review of the brain areas and neural systems involved in food aversion
learning.
Martinez, Joe L., and Raymond P. Kesner. Neurobiology of Learning and Memory.
New York: Academic Press, 1998. An overview of information on
the neurobiology of learning and memory from developmental, pharmacological,
and psychobiological perspectives. A good introductory
source.
Morgan, Dave, et al. “A Peptide Vaccination Prevents Memory Loss in an Animal
Model of Alzheimer’s Disease.” Nature 408 (2000): 982-985. This
original research report describes a successful attempt to vaccinate Alzheimer’s
mice against the disorder and prevent memory loss.
Squire, Larry R., and Eric Kandel. Memory: From Mind to Molecules. New York:
Scientific American Library, 1999. An approachable volume summarizing
the major developments in understanding the anatomy and physiology
of vertebrate and invertebrate learning. This text contains an extensive
discussion of Kandel’s work with the molecular biology of memory in
Aplysia and Squires’s work on the neuroanatomy of memory with monkeys.
An excellent source for people with a limited background in biology
and chemistry.
Tang, Ya-Ping, et al. “Genetic Enhancement of Learning and Memory in
Mice.” Nature 401 (1999): 63-69. An original research report that describes
how memory was improved in a strain of mice by genetically engineering
them to contain an overabundance of glutamate receptors in the
hippocampus.
Thompson, Richard F. “The Neurobiology of Learning and Memory.” Science
233, no. 13 (1986): 941-947. The author summarizes his work on the
brain mechanisms involved in classical conditioning of the eyeblink reflex
in rabbits.
Tulving, Endel, and Fergus I. M. Craik. The Oxford Handbook of Memory. New
York: Oxford University Press, 2000. A comprehensive volume dealing
with a wide variety of topics related to both animal and human memory.
An excellent general reference source.
Christopher A. Duva
See also: Animal Experimentation; Brain Structure; Habituation and Sensitization;
Memory.