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Mouse modeling for anxiety disorders in older adults
*Corresponding author: Warren Ladiges
Mailing address: Department of Comparative Medicine, School
of Medicine, University of Washington, Seattle, WA 98195, USA.
E-mail: wladiges@uw.edu
Received: 22 February 2021 / Accepted: 14 April 2021
DOI: 10.31491/APT.2021.09.067
Abstract
Anxiety disorders are common in older adults and are strongly associated with increased risk for numerous age-related conditions. Preclinical mechanistic data are needed to identify more specific therapeutic targets for treating and preventing these disorders. Mice serve as excellent preclinical models as they have been used extensively in aging studies, and behavioral tests have been developed. A panel of tests would capture the important clinical aspects of apathy, anxiety, and psychomotor behavior and allow longitudinal testing strategies in a rigorous and minimally stressful manner.
Anxiety disorders in older adults are associated with an
increased physical disability, increased risk for mild cognitive
impairment and dementia [1]. Current estimates of
the prevalence of anxiety disorders in US older adults suggest
a 1-year prevalence of close to 12 percent [2]. Anxiety
and depressive disorders are often present as comorbid
conditions with strongly increased risks for the onset of
cardiovascular diseases, diabetes, stroke, obesity, and
cognitive decline [3, 4]. Indeed, anxiety and depressive
disorders are often part of non-cognitive neuropsychiatric
symptoms found in dementia, and as such are associated
with high levels of distress in both dementia patients and
caregivers [5, 6]. Depression is among the most common
behavioral and psychological signs of dementia and can
be an early or preclinical indicator. Alzheimer’s disease
(AD) is the major cause of dementia and it has been
shown that a clinical diagnosis of depression in both early
and late-life increases the risk for AD. Hence, depressive
and anxiety disorders need to be considered as important
risk factors for a multitude of aging-related conditions.
A majority of the reported studies on
anxiety
disorders
and aging have been correlative in nature. Preclinical
mechanistic data are needed to identify more specific therapeutic targets for treating and preventing these
disorders
associated with aging. There is no ideal animal model
for this purpose, but rodents have traditionally been used.
Laboratory rats are in general more responsive to behavioral
testing than laboratory mice. However, mice have a
much more extensive background in aging studies, and
behavioral tests have been developed and validated for
a number of mouse strains. The problem is that they are
not well standardized so that it is challenging to replicate
studies from lab to lab. A panel of tests is needed to identify
the various phenotypes associated with anxiety, but a
generally accepted panel has not been developed for this
purpose. Several behavior tests have been demonstrated to
capture the important clinical symptoms of apathy, anxiety,
and psychomotor behavior. Here, we focus on testing
procedures that allow longitudinal testing strategies.
Hence, tests that require aversive experiences such as
social isolation, food restriction, surgical interventions, or
exposure to noxious stimuli like forced swimming or foot
shocks are not included. Some of these excluded tests, like
self-stimulation procedures, may have excellent validity
for measuring domains like anhedonia (loss of interest
in pleasurable activities) or motivation, yet they contain
strong learning components and do lend themselves readily
to longitudinal study designs. Other concerns with
well- established procedures for behavioral despair like
the forced-swim test are not recommended because of the
rather frail health condition of geriatric mice.
Based on published studies and our experience, we
suggest
the following conditions be included in a panel for
mouse models of anxiety disorders. The first is apathy.
Apathy has been defined as a reduction in goal-directed behavior [7].
Many
established procedures to
measure
goal-directed behavior in mice mostly involve strong elements
of learning and are therefore difficult to integrate
into longitudinal experimental designs. Nest building,
self-grooming, and burrowing are goal-directed innate
behaviors that correspond to daily abilities which are often
disrupted in anxiety disorders and neurodegenerative
diseases. These procedures have been tested in rodent
models of apathy [8] and can be performed repeatedly in
longitudinal study designs. Nest building is measured using
Deacon’s comprehensive five-point rating scale [9].
Self-grooming can be assessed with the splash test. For
this test, a 10 percent sucrose solution is squirted on the
dorsal coat of the mice in their home cage, followed by
a recording of the grooming frequency during 5 minutes
immediately after sucrose splashing [10]. In the burrowing
test, mice spontaneously empty a tube filled with food
pellets as described by Deacon [11]. Lower scores for the
nest-building rating scale, reduced grooming frequency
in the splash test, and reduced burrowing are indicators of
apathy and impaired activities of daily living.
Secondly, the novelty-suppressed feeding
test can be used
to measure anhedonia, a depression-like behavior [12].
Mice are food-deprived for 24 hours with free access to
water and then placed into the corner of a novel open-field
apparatus that has a food pellet placed in the center. The
latencies to approach and then eat the pellet are recorded.
Increased latencies are taken as indicators for anhedonia.
Third, anxiety can be measured by the open-field and
elevated-zero maze tests [13]. The movement of the mice
in either maze is video-recorded and analyzed with videotracking
software. Time spent in the center of the openfield
arena over a period of 30 minutes and time spent in
the open areas of the elevated-zero maze over a period
of 5 minutes is calculated as measures of anxiety [14].
Fourth, psychomotor disturbances can be assessed by the
open-field test. The overall distance traveled by mice over
a 30-minute testing period is measured and analyzed as
indicators of overall locomotor agitation or retardation.
Lastly, since attention and working memory are impaired
in anxiety and depressive disorders, the Y-maze procedure
is excellent for testing cognitive abilities. As with the
other tests described above, the Y-maze can be used longitudinally
without skewing results with repeated testing.
In conclusion, mouse modeling for age-related anxiety
disorders can be successful if rigorous and minimally
stressful test procedures are used in combination as a
panel format.
Declarations
Acknowledgement
National Institutes of Health grants R01 AG057381 (WL) and R01-AG062514 (MD).
Conflict of Interest
The authors declare no conflicts of interest.
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