Animal Models of Human Cognition

Animal Models of Human Cognition
Oxford Handbooks Online

Jonathon D. Crystal
The Oxford Handbook of Comparative Evolutionary Psychology
Edited by Todd K. Shackelford and Jennifer Vonk
Print Publication Date: Feb 2012 Subject: Psychology, Personality and Social Psychology
Online Publication Date: Sep DOI: 10.1093/oxfordhb/9780199738182.013.0014
2012
Abstract and Keywords
An objective for studying cognition in animals is that it may provide insight into impairments in cognition observed
in people. Cognitive impairments are debilitating, and developing insight into the origins of such impairments may
aid in the development of effective treatments. This chapter focuses on development of animal models of memory
that may aid in the search for effective treatments of memory disorders such as Alzheimer's disease. The case of
modeling episodic memory in animals is considered. Evidence is presented that, at the time of memory assessment,
rats remember a unique earlier event including what occurred, where it happened, and when it took place (what-
where-when memory). The merits and limitations of the model are discussed. Future directions for further
development of the model are highlighted.
Keywords: Episodic memory, episodic-like memory, what-where-when (WWW) memory, Alzheimer's disease, memory disorders, animal models, rats,
mice
Introduction
An objective for studying cognition in animals is that it may provide insight into impairments in cognition observed
in people. Cognitive impairments are debilitating, and developing insight into the origins of such impairments may
aid in the development of effective treatments. Significant obstacles impede the development of such models.
Although there is a long history of studying learning and memory in animals, the types of cognitive processes
involved in many cases of learning and memory may not match the types of impairments observed clinically. Thus,
it is possible that treatments such as drug-development programs may be effective at the preclinical level but may
not be effective in people.
This chapter focuses on development of animal models of memory that may aid in the search for effective
treatments of memory disorders such as Alzheimer's disease. Salient features of Alzheimer's disease and its
memory impairments are described. Next, the case of modeling episodic memory in animals is considered. An
overview of the development of this model is presented followed by a potential model for further development. The
merits and limitations of the model are discussed. Future directions for further development of the model are
highlighted.
Modeling Memory Impairments in Alzheimer's Disease
A brief overview of memory impairments in Alzheimer's disease is presented. First, the significance of the problem
is described. Second, Alzheimer's pathology is described. Third, the potential of preclinical models is discussed.
Significance
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Alzheimer's disease (AD) is a nonreversible brain disorder that develops over a period of years. Memory loss is the
best known symptom of AD, although AD also causes loss of judgment, orientation, ability (p. 262) to understand
and communicate effectively, and changes in personality and behavior. Ultimately, AD leads to a profound loss of
mental function, including the inability to recognize family and friends. Individuals with AD exhibit profound
impairments in episodic memory (i.e., the memory system that stores unique personal past experiences; Tulving,
1983, 2002). Ultimately, AD is fatal, with death typically occurring within 46 years after diagnosis. Currently, there
are no treatments that can slow the progression of AD. Five FDA-approved medications treat symptoms of AD.
However, these drugs do not stop or reverse AD, and they appear to provide benefits for only about 612 months
for approximately half of the people who take them (Alzheimer's Association, 2009).
The limited treatment options for AD exert a significant socioeconomic toll. AD is the sixth leading cause of death in
the United States (and the fifth leading cause of death for those aged 65 and older). Approximately 5.3 million
Americans have AD, with #148 billion in annual costs to Medicare, Medicaid, and business due to decreased
productivity when AD caregivers reduce work for caregiving (Alzheimer's Association, 2009). The financial and
societal consequences of AD are expected to increase as the U.S. population of elderly increases. By 2030 an
estimated 7.7 million Americans will have AD, and the estimate is expected to increase to 1116 million by 2050,
with nearly a million new cases per year by 2050. To put these numbers in another context, today, every 70
seconds, someone in the United States is diagnosed with AD; by 2050 someone will be diagnosed with AD every 33
seconds. Because the greatest risk factor for AD is advancing age (with most cases developing in those aged 65
and older), the costs of AD are expected to increase rapidly after 2011, when the baby boomers begin to reach
age 65. A better understanding of memory impairments in AD may ultimately reduce both escalating health care
costs and unnecessary suffering in AD patients and their families.
Alzheimer's Pathology
Proteins implicated in the pathology of AD include the amyloid precursor protein (APP), fragments produced by
proteolytic processing of APP and tau. The amyloid hypothesis of Alzheimer's disease posits the central role of
these pathways in development of neuropathology (Hardy & Selkoe, 2002). Processing of APP is fundamental to an
understanding of molecular mechanism(s) of neurotoxicity in AD. Proteolytic cleavage of APP to release
accumulation of amyloid- (A) to the extracellular milieu requires sequential cleavage of APP by -secretase and
-secretase (Thinakaran & Koo, 2008). Cleavage by -secretase requires the presenilins, first identified by studies
of the genetic basis of familial Alzheimer's disease (Kennedy, Farrer, Andreasen, Mayeux, & St George-Hyslop,
2003; Selkoe & Kopan, 2003). More recent refinements include the concepts that APP and tau work together in
development of pathology (Hardy, 2006; Roberson et al., 2007). Soluble oligomeric species of A are also capable
of inducing cell damage, decreasing long-term potentiation, and modulating neuronal response to administration of
N-Methyl-D-aspartate (NMDA) (Cleary et al., 2005; Podlisny et al., 1995; Shankar et al., 2007; Walsh et al., 2002).
These oligomeric A species contribute to damage of glutamatergic neurons in vivo (Calabrese et al., 2007). A
major focus of current research is understanding how oligomeric species of A affect cells both in vitro and in vivo.
Although the amyloid hypothesis articulates the central roles of APP and tau in disease progression, the precise
molecular mechanism(s) of loss of synapses and neurotoxicity remain controversial.
Potential of Preclinical Models
Alzheimer's disease is a type of dementia associated with profound memory loss. In AD, severe impairments are
observed in episodic memory (e.g., Fodero-Tavoletti et al., 2009; Leube et al., 2008; Salmon & Bondi, 2009;
Schwindt & Black, 2009; Storandt, 2008), which is the memory system that stores specific events or episodes from
one's own past (Tulving, 1983, 2002). We have focused on discrimination of what, where, and when (WWW)
because the WWW content of episodic memory is impaired in Alzheimer's disease (Bckman et al., 1999; Egerhazi,
Berecz, Bartok, & Degrell, 2007; Kessels, Hobbel, & Postma, 2007; Le Moal et al., 1997; Liscic, Storandt, Cairns, &
Morris, 2007; Nyberg et al., 1996).
Transgenic models mimic neurochemical and neuroanatomical phenotypes associated with AD pathology (Eriksen
& Janus, 2007; Oddo, Caccamo, Kitazawa, Tseng, & LaFerla, 2003; Oddo, Caccamo, Shepherd et al., 2003;
Yoshiyama et al., 2007). According to the amyloid hypothesis of AD (Bates et al., 2009; Hardy & Selkoe, 2002),
accumulation of amyloid- (A), synthesized from the amyloid precursor protein (APP), is central to the pathology
Page 2 of 12
of AD. General measures of learning and memory are also impaired in AD mouse models (Hrard et al., 2009;
O'Leary & Brown, 2008; Palop et al., 2003; Pennanen, Wolfer, Nitsch, & Gtz, 2006; Pike et al., 2007; Roberson et
al., 2007; (p. 263) Stepanichev, Zdobnova, Zarubenko, Lazareva, & Gulyaeva, 2006; Stepanichev et al., 2004;
Timmer et al., 2008; Yates et al., 2008). However, a major translational barrier to progress in AD research is the
lack of an animal model that captures critical features of episodic-memory impairment exhibited by AD patients.
The failure to specifically model episodic memory impairments in models of AD represents a major gap in the
knowledge base.
A major challenge for validating an animal model of episodic memory is ruling out nonepisodic alternative
hypotheses (Roberts et al., 2008). Critically, episodic memory involves memory of a unique episode and is distinct
from judgments of familiarity. Indeed, familiarity is based on distinct neural substrates (Carlesimo et al., 2007;
Eldridge, Knowlton, Furmanski, Bookheimer, & Engel, 2000; Henson et al., 1999; Hofer et al., 2007; Schmitter-
Edgecombe & Anderson, 2007; Shah et al., 2001).
A Case Study: Episodic Memory
Definitions
A critical aspect of human memory is that we remember unique events from our own personal, past experiences.
Tulving (1972) proposed a distinction between semantic and episodic memory. Unlike semantic memory, which
consists of factual knowledge about the world, episodic memory consists of memories of where and when specific
events occurred. Tulving's (1972) classic definition states, Episodic memory receives and stores information
about temporally dated episodes or events, and temporal-spatial relations among these events. (p. 385).
According to this definition, episodic recall involves retrieval of information about three aspects of an event or
episode: what occurred, where it took place, and when it transpired (WWW memory).
Episodic memory may be defined in terms of its content and the subjective experiences that accompany it. The
content of episodic memory is information about what, where, and when a specific event occurred. The subjective
experiences that accompany episodic retrieval are described as a conscious recollection or experience of the
event occurring (Tulving, 1983, 1985, 2001, 2005). Thus, studies of human memory rely on behavioral and
subjective sources of information. Subjective sources of information come from self-reports about the experiences
that accompany memory. Although subjective experience is a rich source of information in human cognition, this
information is not available for work with nonverbal animals.
Development of an Animal Model
Definitions of episodic memory that focus on subjective experiences that accompany recollection (e.g., Tulving,
1983, 2002; Tulving & Markowitsch, 1998) represent a barrier to testing with animals (Griffiths, Dickinson, &
Clayton, 1999) because phenomenology cannot be evaluated in nonverbal animals. Consequently, Clayton and
colleagues (Clayton, Bussey, & Dickinson, 2003; Clayton, Bussey, Emery, & Dickinson, 2003; Clayton, Salwiczek,
& Dickinson, 2007) developed behavioral criteria that focus on Tulving's (1972) classic definition of episodic
memory: what occurred, where it took place, and when it transpired. Clayton and colleagues (Clayton, Bussey, &
Dickinson, 2003) refer to memory that meets the following criteria as episodic-like memory: (1) Content:
recollecting what happened, where and when on the basis of a specific past experience. (2) Structure: forming
an integrated what-where-when representation. (3) Flexibility: episodic memory is set within a declarative
framework and so involves the flexible deployment of information. (p. 686). The behavioral elements of episodic
memory are referred to as episodic-like memory to acknowledge that behavioral criteria do not assess subjective
experiences (Clayton, Bussey, & Dickinson, 2003). Note that episodic-like memory is not equivalent to episodic
memory because subjective experiences are a component of episodic memory but are not a component of
episodic-like memory.
A critical aspect of episodic memory is that they are memories for unique events or episodes. Consequently, a
primary goal of research that seeks to evaluate evidence for episodic-like memory in animals is documentation that
the memory is about a specific earlier event. Critically, it is necessary to rule out alternative explanations that may
exploit rules or strategies that do not require memory for a unique event (Roberts et al., 2008; Zentall, 2005, 2006).
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A Potential Model
We used Clayton's behavioral criteria and approach (Clayton & Dickinson, 1998) to test rats' ability to discriminate
WWW in a radial maze (Babb & Crystal, 2005, 2006a, 2006b; Zhou & Crystal, 2009). Our research question was: If
a distinctively flavored food type (what) replenishes at one location (where) at a different time of day (when) than
other-flavored food items at other locations, will rats adapt their behavior to efficiently exploit the availability of
food? Our rats learned to revisit the location at which the distinctively flavored food type replenished when this
location was about to replenish, (p. 264) while avoiding revisits to that location at the times when that location
would not replenish (Babb & Crystal, 2005, 2006a, 2006b; Zhou & Crystal, 2009). Overall, our studies demonstrate
that (1) at the time of memory assessment, rats remember unique episodes, and (2) rats have a detailed
representation of the content of recent events (what) in addition to information about when and where those
events occurred. They flexibly adapted their visits in time and space to exploit the availability of desirable foods,
and they selectively avoid locations where less desirable foods were available based on new information about the
food types.
Next, a series of experiments by Zhou and Crystal (2009) are described to illustrate a potential model for episodic
memory. In the Zhou and Crystal study, rats were tested once per day, either in the morning or afternoon (see
Figure 14.1a). Chocolate replenished at a daily unique location at only one of these times of day (morning for some
rats; afternoon for other rats). The interval between study and test phases was constant (approximately 2
minutes). Because the location of chocolate varied across days, and the morning and afternoon sessions were
presented in random order, WWW memory would be implicated if the rats visited the chocolate location selectively
on occasions when chocolate was about to replenish. When the chocolate location was about to replenish, the rats
revisited that location at a higher rate relative to nonreplenishment trials (Figure 14.2a). These data suggest that
rats used WWW memories to adjust revisit rates to the daily-unique chocolate location. Importantly, WWW in this
study could not be based on the delay between study and test (i.e., it could not be based on judging relative
familiarity of the study items or timing an interval between study and test).
Next Zhou and Crystal (2009) sought to determine the type of timing mechanism used in WWW memory. There are
two proposals. According to the circadian time-of-day hypothesis, the rats used a circadian signal (i.e., morning
vs. afternoon) to adjust revisit rates at the daily-unique chocolate location. Alternatively, according to the interval-
timing hypothesis, the rats timed the interval from light onset in the colony to the morning and afternoon sessions.
Morning and afternoon sessions occurred one hour and seven hours, respectively, after light onset in the colony.
To test these hypotheses, we used a phase shift of 6 hours. The lights in the colony were turned on six hours
early, and the probe session was conducted at the usual time in the morning (see Figure 14.1b). According to the
circadian time-of-day hypothesis, the rats would treat the probe as a morning session because an endogenous
circadian oscillator is not expected to adjust immediately to a phase shift. Alternatively, according to the interval-
timing hypothesis, the rats would treat the probe as an afternoon session because afternoon sessions typically
occur seven hours after light onset in the colony. The rats did not use the interval between light onset and the
session, suggesting that they used circadian time of day (Figure 14.2b).
Next, we sought to determine if it was the time of day at study or at test that was responsible for the different rates
of revisiting the chocolate location. Because a two-minute delay between study and test is too small for rats to
discriminate based on a circadian oscillator (Pizzo & Crystal, 2004), we increased the delay to seven hours (see
Figure 14.1c). Importantly, the time of day at study was familiar from prior training, but the time of day at test was
unfamiliar (approximately seven hours later than usual). Consequently, if the rats used time of day at study, then
they should continue to differentially revisit the chocolate locations. Alternatively, if the rats used time of day at
test, then there is no basis for them to revisit chocolate locations at different rates in the morning and afternoon
because the test times were unfamiliar. When tested with novel test times of day after familiar morning or
afternoon study times of day, we observed complete transfer (i.e., the differential rates of revisiting occurred on
the very first trial in the morning and afternoon; Figure 14.2cd). These data suggest that, at the time of memory
assessment, the rats remembered the time of day at which the study episode occurred.
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Click to view larger

Figure 14.1 Experimental design from Zhou and Crystal (2009). a. Design of experiment 1. The morning or
afternoon was randomly selected for presentation of first helpings (study phase) and second helpings (test
phase). The figure shows an example of the accessible arms and flavors in a study phase and the
corresponding test phase that would occur after a two-minute retention interval. Chocolate or chow
flavored pellets were available at four randomly selected arms in the study phase; access to the other four
arms was prevented by closed doors. After a two-minute delay, chow-flavored pellets were available at
previously inaccessible locations in the test phase. In the replenishment condition, chocolate replenished
at the location that had chocolate in the study phase (shown for the morning session); in the
nonreplenishment condition, chocolate did not replenish at the other time of day (shown in the afternoon
session). Chocolate replenished at second helpings in the test in the morning (7 A.M. ) session but not in the
afternoon (1 P.M. ) session for half of the rats; these contingencies were reversed (not shown) for the
remaining rats. For each rat, one session (i.e., first and second helpings) was conducted per day. The same
arms were used to illustrate morning and afternoon sessions in the figure to facilitate inspection of
presence and absence of chow and chocolate, but these arms were randomly selected in each session for
each rat. b. Phase-shift design of experiment 2. Light onset occurred at 12 A.M. (i.e., six hours earlier than in
experiment 1) and the first and second helpings occurred at the time of a typical morning session (i.e.,
starting at 7 A.M. ). Note that seven hours elapsed between light onset and the study-test sequence (solid
horizontal line), which is comparable to the time between the typical light onset and a typical afternoon
session (dashed horizontal line) in experiment 1. The design of the experiment puts predictions for time-of-
day and how-long-ago cues in conflict. Thus, a rat would be expected to behave as in its morning baseline
(based on time of day) or as in its afternoon baseline (based on how long ago). c. Transfer-test design of
experiment 3. The time of day at which first helpings occurred was the same as in experiment 1 (i.e., 7 A.M.
in early or 1 p.m. in late sessions). The introduction of seven-hour retention intervals in experiment 3
produced test phases that occurred at novel times of day (2 P.M. in early and 8 P.M. in late sessions). Early
and late sessions had study times (but not test times) that corresponded to those in experiment 1. The first
two sessions in experiment 3 consisted of one replenishment and one nonreplenishment condition. On
subsequent days, an early or late session was randomly selected. Differential revisits to the chocolate
location is expected if the rats were adjusting revisit rates based on the time of day at which the study
episode occurred; revisit rates are expected to be equal in early and late sessions if the rats used time of
day at which the test phase occurred. Study and test phases were as in experiment 1, except that they were
separated by seven-hour delays (shown by horizontal brackets). d. Conflict-test design of experiment 4. The
study and test phases occurred at 1 P.M. and 2 P.M. , respectively. These times correspond to the typical time
of day at which a late-session first helpings and early-session second helpings occurred in experiment 3.
The design of the experiment put predictions for time of day at study and time of day at test in conflict.
Thus, a rat would be expected to behave as in its early-session, second-helpings baseline (based on test
time of day) or as in its late-session, second-helpings baseline (based on study time of day).
Source: Adapted with permission from Zhou, W. & Crystal, J.D. (2009) Evidence for remembering when
events occurred in a rodent model of episodic memory. Proceedings of the National Academy of Sciences
USA, 106, 95259529. Copyright (2009) National Academy of Sciences, U.S.A
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Figure 14.2 a. Rats preferentially revisit the chocolate location when it is about to replenish in experiment 1.
The probability of a revisit to the chocolate location in the first four choices of a test phase is shown for
replenishment and nonreplenishment conditions; replenish and nonreplenish sessions were presented in
random order. b. Rats used time of day, rather than an interval, to adjust revisit rates in experiment 2. Rats
treated the study-test sequence as a morning session, suggesting the use of time of day rather than an
interval-timing mechanism. The figure plots the difference between observed and baseline revisit rates. For
the bar labeled interval, the baseline was the probability of revisiting chocolate in the afternoon; thus, the
significant elevation above baseline shown in the figure suggests that the rats did not use an interval
mechanism. For the bar labeled time of day, the baseline was the probability of revisiting chocolate in the
morning; thus, the absence of a significant elevation above baseline is consistent with the use of time of
day. The horizontal line corresponds to the baseline revisit rate to the chocolate location from experiment 1.
Positive difference scores correspond to evidence against the hypothesis indicated on the horizontal axis. c.
and d. Rats preferentially revisited the chocolate location when it was about to replenish when the study,
but not the test, time of day was familiar in experiment 3. The probability of a revisit to the chocolate
location in the first four choices of a test phase is shown for first replenishment and first nonreplenishment
conditions (c; initial) and for subsequent sessions (d; terminal). e. Rats remembered the time of day at
which the study episode (i.e., first helpings) occurred in experiment 4. Rats treated the novel study-test
sequence as a late-session test phase, suggesting memory of the time of day at study rather than
discriminating time of day at test. The figure plots the difference between observed and baseline revisit
rates. For the bar labeled test time, the baseline was the probability of revisiting chocolate in the second
helpings of the early session (test phase) in experiment 3; thus, the significant elevation above baseline
suggests that the rats did not use the time of day at test to adjust revisit rates. For the bar labeled study
time, the baseline was the probability of revisiting chocolate in the second helpings of the late session (test
phase) in experiment 3; thus, the absence of a significant elevation above baseline is consistent with
memory of the time of day at study. The horizontal line corresponds to the baseline revisit rate to the
chocolate location from experiment 3 (terminal). Positive difference scores correspond to evidence against
the hypothesis indicated on the horizontal axis. ae. Error bars indicate SEM. a, c, and d. The probability
expected by chance is 0.41. Repl = replenishment condition. Nonrepl = nonreplenishment condition. a. * P
0.001 difference between conditions. b. * P 0.04 different from baseline. c and d. * P 0.04 and ** P
0.0001 difference between conditions. e. * P 0.001 different from baseline.
Source: Adapted with permission from Zhou, W. & Crystal, J.D. (2009) Evidence for remembering when
events occurred in a rodent model of episodic memory. Proceedings of the National Academy of Sciences
USA, 106, 95259529. Copyright (2009) National Academy of Sciences, U.S.A.
We obtained an additional line of evidence for the same conclusion by conducting a conflict test. Because the
seven-hour delays between study and test phases produced a one-hour overlap between the two types of trials, it
was possible to start a trial with a late study phase and end the trial with an early test phase (see Figure 14.1d).
Again, we sought to determine if the rats were adjusting revisit rates in the test phase based on the time of day at
test (test-time hypothesis) or based on memory of the time of day at which the study phase occurred (study-time
hypothesis). According to the test-time hypothesis, the rats should revisit at the usual baseline rate that typically
occurred on tests at that time of day. Alternatively, according to the study-time hypothesis, the rats should revisit
at the usual time of day that occurred after a later study time (which usually (p. 265) (p. 266) is followed by a
test seven hours later rather than one hour later). The rats adjusted chocolate revisits based on the time of day at
study rather than the time of day at test (Figure 14.2e). These data also suggest that rats remembered the study
episode, and the time of day at which the study episode occurred.
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Merits
The proposed model for episodic memory has several merits. The model may be used to explore neuroanatomical,
neurochemical, and genetic mechanisms of WWW memory in future work. Such work would exploit the extensive
knowledge about the neuroanatomy and neurophysiology of (p. 267) the rodent hippocampus and utilize
neuroscience (e.g., pharmacological, electrophysiological, RNA interference, and targeted gene expression)
techniques (Eriksen & Janus, 2007; Hwang et al., 2004; Jankowsky et al., 2005; Keri & Siegel, 2009; Maxwell, 2009;
Ueberham et al., 2006). Identifying mechanisms that govern the discrimination of WWW holds enormous potential
to significantly benefit society by providing insights into deficits in memory associated with brain injuries, amnesia,
Alzheimer's disease, or other human memory pathologies. It is noteworthy that deficits in episodic memory in
humans are deficits in the content of episodic memory, not merely in reports of subjective experiences (Bckman
et al., 1999; Clare et al., 1993; Egerhazi et al., 2007; Kessels et al., 2007; Le Moal et al., 1997; Liscic et al., 2007;
McDonald et al., 2006; Nestor et al., 2007; Nyberg et al., 1996; Piolino et al., 2002). Therefore, investigating the
discrimination of WWW in animals holds enormous potential for understanding disorders of human memory.
Limitations
There are potential limitations of the model. The existing procedures for studying WWW memory in rats relied upon
extensive training. Thus, an important next step in this research is to identify optimum conditions that are more
rapidly acquired. The work described here used rats, but the potential to explore genetic models of AD is best done
with mice given the well-developed genetic models of AD in mice. Thus, an important next step in this research is
to develop a working model of episodic-like memory in mice.
Conclusions
Advances in our understanding of cognition may be promoted by evaluating behavior in animal studies of
comparative cognition. Primary advantages of investigating cognitive processes in nonhuman animals include: (1)
the ability to focus exclusively on operationally defined criteria that rely on objective behavioral measures, thereby
eliminating the focus on subjective experiences that accompany cognitive processes in humans, and (2) the ability
to use animals in future investigations of the neurobiological mechanisms of cognitive processes. Combining these
two factors holds enormous potential for translational research that may foster the development of therapeutic
approaches to human diseases with profound cognitive impairments. Identifying mechanisms that govern the
degeneration of episodic memory would significantly benefit society by providing insights into deficits in memory
associated with Alzheimer's disease and other common forms of human memory pathology.
Future directions
An interesting area for future exploration is to map out the forgetting function for episodic-like memory in rats.
There are some hints that suggest that retention is maintained over relatively long periods of time. For example,
when the retention interval was increased from approximately two minutes to seven hours, WWW memory was at
least as good, if not better, after the long delay (i.e., the rats selectively revisited the chocolate location when it
was about to replenish) (Zhou & Crystal, 2009). In other studies, we have used retention intervals as long as 25
hours (Babb & Crystal, 2006a; Crystal & Babb, 2008). Although special procedures (i.e., relatively long intertrial
intervals) are required to support spatial memory with such a long retention interval (Crystal & Babb, 2008), WWW
memory was quite robust (i.e., the rats selectively revisited the distinctively baited location when it was about to
replenish after 25 hours). Indeed, WWW memory appears to be more robust at this time point than memory for
other chow-baited locations, which may rely more on familiarity-based processing. The durability limits of WWW
memory remain to be determined. Ultimately, it should be possible to map out a forgetting function for WWW
memory.
The model has not yet been applied to the case of episodic-memory degeneration. One potential approach is to
use inducible targeted gene expression to induce AD pathology after initially establishing functional episodic-like
memory in mouse models of AD; in this model, the timing of APP expression and A deposits may be controlled.
This approach has high translational significance because it closely mimics the life of a person who has intact
Page 7 of 12
episodic memory throughout the lifespan and develops neurodegeneration later in life, after memories are formed
and tasks are acquired.
By contrast, existing behavioral assessments in mouse models of AD have uncertain translational potential
because they do not model specific impairments of episodic memory observed clinically in AD patients. Thus, it is
possible that therapeutic interventions that facilitate recovery of more general measures of learning and memory
may leave profound impairments in episodic memory in AD patients unimproved. A closer integration of cutting-
edge behavioral assessments and transgenic technologies may, therefore, ultimately facilitate identification of (p.
268) previously unrecognized targets for treating episodic-like memory impairment.
Acknowledgment
Supported by National Institute of Mental Health grant R01MH080052.
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Jonathon D. Crystal
Jonathon D. Crystal, Department of Psychological and Brain Sciences, Indiana University.
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Animal Models of Human Cognition

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Animal Models of Human Cognition

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Animal Models of Human Cognition

Abstract and Keywords

Modeling Memory Impairments in Alzheimer's Disease

Potential of Preclinical Models

A Case Study: Episodic Memory

Development of an Animal Model

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Supported by National Institute of Mental Health grant R01MH080052.

and Alzheimer dementias. Archives Of Neurology, 64, 535540.

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