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Novati et al. Ageing Neur Dis 2022;2:17 https://dx.doi.org/10.20517/and.2022.19 Page 9 of 29

A crucial factor in the process of translating behavioral readouts from animal models to humans is the
similarity of the deficits measured in each species. Using similar assessments in animal models and patients
is of great advantage, as this could ultimately increase the predictability of therapy effects. Accordingly,
hippocampus-dependent navigation tasks, commonly used in rats, for example, the Morris water maze,
were adapted for humans in the form of real and virtual versions, and revealed impairments in spatial
memory and navigation abilities in AD subjects [133,134] , consistent with results in transgenic rat models
assessed in mazes for spatial learning [55,123,125,132] . Comparative water maze testing in healthy humans and
wild-type rats showed a similar effect of scopolamine and donepezil normally used to model cognitive
dysfunction and to treat cognitive deficits, respectively , indicating similar behavioral responses to
[135]
pharmacological cholinergic modulation across species. The direct comparison of AD patients and genetic
AD rat models would be more informative regarding the analogy between human and rat results in the
context of AD.

Episodic memory, which allows to store and retrieve information about personal experiences along with the
related spatial and temporal contexts, is dysfunctional in AD . Recognition memory and associative
[136]
learning, linked to episodic memory, are impaired as well [137-139] . McGill-R-Thy1-APP and TgF344-AD rats
display deficits in some aspects of recognition memory and associative learning. In both rat models, deficits
in novel object recognition have been reported, although results are overall mixed [123,124,140-143] . There are also
signs of associative learning impairment in passive avoidance setups [142,144,145] . Additionally, fear conditioning
analyses revealed that multiple memory recall components are impaired in homozygous and hemizygous
McGill-R-Thy1-APP rats . Moreover, testing on automated touch screen setups showed impaired
[124]
associative learning in the McGill-R-Thy1-APP rat model and deficits in episodic-like memory in APP NL-G-F
knock-in rats [70,146] . Touchscreen methods like those applied in McGill-R-Thy1-APP rats are meaningful as
analogous to platforms applied to assess cognition in AD patients .
[147]

A large portion of AD patients suffers from subtle neuropsychiatric symptoms, and the most common are
apathy, depression, anxiety, and sleep disturbances . Neuropsychiatric disorders, especially depression,
[148]
have been associated with phenomena such as decreased hippocampal volume, inflammation, and
alterations of the monoaminergic systems [149-152] . Mood alterations in rodent models of AD and other
neurodegenerative disorders are most commonly assessed in terms of anxiety and depression-like behavior.
Both phenotypes have been more extensively characterized in the TgF344-AD rat model relative to the
McGill-R-Thy1-APP model. In TgF344-AD transgenic rats, anxiety-like behavior was detected at different
ages in the elevated plus maze [128,145,153,154] . In McGill-R-Thy1-APP rats by the age of 5 months, there is
evidence for anxiety-like behavior in the light-dark box . Results obtained in the open field in both rat
[125]
models are contradictory [123,125,143-145,154] . Regarding depression-related parameters, anhedonia-like behavior as
well as behavioral despair were shown in TgF344-AD rats aged 10 months or older [131,145,154] . One of these
[131]
studies assessed both males and females but did not report sex differences . Nevertheless, given the
[155]
evidence for sex differences in the prevalence of depression and apathy in AD , it would be worth
examining sex differences more thoroughly in transgenic rat models. Also, the time course of depression-
like phenotypes and cognitive impairment in TgF344-AD rats cannot be easily defined from the behavioral
analyses in the model. Moreover, given that in AD, depression can predate cognitive symptoms , the
[156]
assessment of depression-like behaviors in animal models from very early ages would be advisable. Apathy,
the most frequent behavioral disturbance in AD , has not been assessed in detail in the genetic rat models
[149]
reviewed here. Signs of apathy-related behavior could be inferred from the presence of anhedonia-like
behavior and the reduced motivation to engage in goal-directed behaviors in some experiments in TgF344-
AD; for example, rats display a decreased number of attempts in a maze test . Similarly, in mouse models
[128]
of AD, parameters of object and social exploration, as well as locomotor activity, have been used as