Psychology and the Mushroom Cloud: Nuclear Testing in the 1950s Jessica Hasty, Jennifer Reck, and Lu

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Establishing a Rodent (Fisher 344 rat) Model of
Mild Cognitive Impairment in Aging
C. LaSarge and J. L. Bizon. Department of
Psychology, Texas AM University, College
Station, TX 77840
Modeling Executive Function
Rationale The Morris water maze task is sensitive
to damage to structures within the medial
temporal lobe system (e.g., hippocampus) that
support declarative memory in humans. Fig. 1 is
a schematic representation of this neural system
in humans and rodents.
Rationale Due to the relatively primitive
prefrontal cortex in rodents relative to
primates, executive functions such as
decision-making are notoriously difficult to
assess in rodents. Nevertheless, we have been
working on establishing a rat analogue of the
Wisconsin Card Sorting task used to assess
executive function in humans (adapted from
Birrell and Brown, 2000). Indeed, accumulating
data indicates that rats do have neural systems
critical to higher order processing/executive
functions. Fig. 4 is a schematic representation
of these neural systems in humans and rodents.
Age-related cognitive decline is a
substantial societal problem, particularly based
on the growing population of elderly in the
United States and in other developed nations. The
number of people over 65 living in the US is
expected to increase from 35 million in 2000 to
71.5 million by the year 2030, comprising almost
20 of the US population (Federal Interagency
Forum on Aging-Related Statistics, 2005). It has
further been estimated that 7-8 of elderly
individuals in the US will develop cognitive
impairment resulting from severe dementia
associated with pathological diseases such as
Alzheimers disease (AD Freedman et al., 2002).
Many more, however, will experience cognitive
decline independent of age-related disease, which
can be equally devastating to ones life quality
and the ability to live independently. The term
mild cognitive impairment (MCI) is used to
describe cognitive impairment at advanced ages
prior to, or independent of, dementia associated
with pathological diseases such as AD. It is
estimated that up to 20 of people over age 65
suffer from MCI (Mayo Foundation, 2004). MCI is
characterized by loss of a range of cognitive
abilities including those associated with
declarative/spatial memory (dependent on the
medial temporal lobe system) and
higher-order/executive functions (associated with
prefrontal cortex). Importantly,
age-related cognitive impairment is not
inevitable some people maintain cognitive
functions on par with young adults into very
advanced ages. Currently the factors that
distinguish aged individuals who develop MCI and
other forms of dementia from aged individuals who
maintain cognitive capacities are not
well-understood. Understanding neurobiological
factors that contribute to cognitive decline with
aging is the initial step in combating and
ultimately reversing these deficits. Animal
models of aging complement human studies, and can
be advantageous for investigating the
neurobiological changes that underlie age-related
cognitive decline. Ultimately, the use of animal
models should contribute significantly to the
discovery of efficacious treatments for
age-related cognitive impairments. The focus
of the current project was to establish reliable
rodent models of MCI in aged rats of the Fisher
344 strain, that can be used in future studies to
examine the relationship between age-related
changes in neurobiological factors (specifically
cholinergic mechanisms) and cognitive function.
Although models have been previously established
using different rat strains (particularly with
respect to medial temporal lobe function),
reliable tasks to assess Fisher 344 cognitive
capacities and, particularly, executive function,
are currently lacking. Such tasks are
particularly significant to aging research as
Fisher 344 rats are one of the few strains
available from the National Institutes of Heath,
and, thus, the strain used for many rodent aging
studies. We would like to thank the following
people for help with this project and its ongoing
progress Barry Setlow, Ph.D., William Griffith,
Ph.D., Simona Slaton, Karienn De Souza,
Catherine Tucker, Angel Mieckowski, Nick Simon,
and Ian Mendez
Fig 1. Schematic of the medial temporal lobe
system and associated structures in human and rat
brain. Top left mid-sagittal view of the human
brain with medial temporal lobe shaded in light
blue and the hippocampal formation shaded in dark
blue. Top right circuit diagram showing flow of
information within this system. Light blue boxes
indicate medial temporal lobe structures. Bottom
rat brain with the hippocampus highlighted in
dark blue.
Fig. 4. This schematic illustrates the
prefrontal cortex and striatum in human (left)
and rat brain (right). In both instances, these
regions are shaded in blue and labeled
respectively. Coronal sections through rat brain
(bottom right) show medial prefrontal cortex
(MFC), cingulate cortex (Cing) and dorsolateral
and dorsomedial striatum (DLS and DMS,
respectively) are highlighted in blue. This rat
schematic is based on behavioral and molecular
evidence suggesting that the diagrammed circuitry
is critical for executive function in rodents.
Experimental Procedures The set-shifting task
(adapted from Birrell and Brown, 2000) is
analogous to the Wisconsin Card Sort Test (WCST)
used to evaluate executive function in humans.
In this task, food-restricted rats (85 of
free-feeding weight) must discriminate between
two flower pots, one of which contains a buried
food reward (a piece of Froot Loop). The food
location is indicated by either the odor of the
pot or the digging medium filling the pot. After
rats are shaped to reliably dig in the pots, they
are tested with five discrimination problems,
starting with a simple discrimination (SD) where
the pots differ only in one perceptual dimension
(e.g. vanilla vs. jasmine, or beads vs. wood
shavings). The rat must learn which pot is baited
and achieve six consecutive correct choices to
move on to the next discrimination problem. This
is followed by a compound discrimination (CD) in
which the other dimension is introduced but is
not relevant to the food location. An
intra-dimensional shift (IDS) is then presented,
in which the relevant dimension is the same but
the stimuli within that dimension are changed.
The IDS is then reversed (REV), such that the
previously positive stimulus is switched with the
negative stimulus, but the irrelevant dimension
remains unpredictive of the food location.
Lastly, they are presented with an
extra-dimensional shift (EDS), in which they must
learn to attend to the previously-irrelevant
stimulus dimension and ignore the
previously-relevant dimension. On each
discrimination problem, both trials and errors to
criterion are calculated and analyzed.
Experimental Procedures Young (6 mon n18 )
and aged (24 mon n 25) Fisher 344 rats were
assessed for spatial learning abilities on a
hidden platform version of the Morris water maze.
The maze consists of a circular tank filled with
water made opaque with white paint, in which an
escape platform is submerged 2 cm below the
waters surface. Rats receive three trials/day
over eight consecutive days. On each trial, rats
are placed into the water at a random start
location (N, S, E, or W) and permitted to swim
until they reach the escape platform. Every
sixth trial is a probe trial on which the escape
platform is lowered in the tank for the first 30
s of the trial to observe the rats search
pattern. On these trials, the platform is raised
after 30 s and rats are allowed to escape as
normal. Rats swim paths in the task were
assessed using a computerized tracking system
(HVS Image). The primary measure of interest
was the rats proximity (in meters) to the escape
platform location during their swims, which
provides an index of the accuracy of their search
(and thus their memory for the platform
location). For training trials, proximity
(calculated each sec) was summed across each
swim, whereas for probe trials, proximity was
averaged, weighted, and summed across all four
probe trials to establish and inviddual spatial
learning index (higher indices worse
learning). After hidden platform training, cue
training was performed to rule out deficits in
visual acuity, sensorimotor function or
motivation that could result in poor performance
in the absence of cognitive impairment. During
cue training, each rat received six consecutive
training trials to a visible platform raised 2 cm
above the water. On each trial, the start
location and platform placement are changed such
that the relationship between extramaze cues and
platform location are made irrelevant. Aged rats
(n2) that exhibited cue training latencies
outside the range of young cohorts were
eliminated from further analyses and
neurobiological studies.
Fig. 5 Photograph showing a rat shaping in the
set-shifting task.
Set-shifting Data
Set-Shifting Data
Fig. 2 Photograph showing a rat on the escape
platform in the water maze apparatus.
Young Long-Evan Rat Performance (n11)
Preliminary Young (n3)and Aged (n3) Fisher 344
Rat Performance
Training Trial Data
Individual Learning Indices
Fig. 6 Bar graphs showing trials (LEFT) and
errors (RIGHT) to criterion performance of Long
Evans rats (n 11) in the attentional set
shifting task. Note the increase in trials and
errors to criterion in reversals (REV) and
extradimentional shifts (EDS) compared to simple
discriminations (SD), compound discriminations
and intradimensional shifts (IDS).
Fig. 7 Preliminary set-shifting data from young
(n3) and aged (n3) Fisher 344 rats. Individual
subject performance is shown overlaid on the
group means. These data demonstrate that young
and aged Fisher 344 rats can perform this task.
Experiments are ongoing to increase the number of
animals per group and determine if there are
age-related deficits in Fisher 344 rats on this
task.
Future Directions

• Finish set-shifting young and aged Fisher 344
  rats and compare individual performance on water
  maze and set shifting tasks.
• Quantify the number and integrity of projections
  of basal forebrain and striatal cholinergic
  neurons in young and aged Fisher 344 rats
  (examples of immunohistochemically-labeled
  cholinergic neurons are shown at right).
• Correlate age-related changes in these
  cholinergic systems with cognitive decline on the
  spatial water maze and set shifting tasks.

cc
Fig. 3 Spatial learning performance in young
(n18) and aged (n23) Fisher 344 rats. Left
Panel shows young and aged rat performance over
the course of training. Young and aged rats did
not perform differently on the first training
trial (F(1,40) 0.02, ns) and both groups
improved over the course of training (F(3,39)
69.09, plt0.01). As a group, however, aged rats
were impaired relative to young rats (F(1,39)
20.63, plt0.01). Right Panel shows individual rat
performance using a proximity measure calculated
from interpolated probe trials (spatial learning
index). Lower index scores indicate better
performance. Note the high degree of individual
variability in performance among aged rats such
that some aged rats performed well within the
range of young cohorts whereas others performed
outside this range, demonstrating impairment on
the task. There were no differences between young
and aged rats on a cued (visible) version of this
task (F(1,39) 0.085, ns), demonstrating that
visual acuity, sensorimotor, or motivational
differences are not responsible for mnemonic
impairment observed in a subset of aged Fisher
344 rats.
MS
Birrell, J.M. Brown, V.J. (2000). Medial
frontal cortex mediates perceptual attentional
set shifting in the rat. J Neuroscience, 20,
4320-4324. Federal Interagency Forum on
Aging-Related Statistics (2005). Older Americans
2004 Key Indicators of Well-Being. Retrieved on
September 25, 2005 from http//www.agingstats.gov/
chartbook2004/population.html Freedman, V.A.,
Martin, L.G., Schoeni, R.F. (2002). Recent
trends in disability and functioning among older
adults in the United States a systematic review.
JAMA, 288, 3137-3146. Mayo Foundation for
Medical Education and Research (2004). Mild
cognitive impairment. Retrieved September 24,
2005 from http//www.mayoclinic.com/invoke.cfm?id
DS00553
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