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

in basic and preclinical research. Their short generation times, relatively easy to establish housing
conditions, and genetic similarities to humans have made them the largest group amongst animal models in
research (EU commission, 2019 report). In general, rats are considered an ideal species for behavioral
studies, and have been used far more than mice in behavioral research in the past, although the increasing
use of transgenic mice in behavioral testing in recent years has inverted this trend . Rats are easy to handle
[3]
[4]
by experimenters and less aggressive towards conspecifics (i.e., members of the same species) than mice .
Rat behavior has been well characterized, and several behavioral tasks currently used in rodents may better
[5,6]
[7,8]
fit the rat , as they were originally developed in rats . In cognitive tests which are used to model
cognitive deficits of human disorders, especially for tasks requiring swimming, such as the Morris water
[9]
maze, rats display less floating and thigmotaxis and perform better than mice [10,11] , probably because they
are adapted to the water environment and are natural swimmers. In a decision-making task, rats were
[12]
shown to learn the task faster than mice . Furthermore, compared to mice, rats display a more complex
behavioral repertoire which is likely to result from the species’ evolutionary history . Increasing evidence
[13]
in the last 15 years suggests that, similar to primates, rats present metacognition, that is, the awareness of
one’s own cognitive processes [14-16] . In the context of neurodegenerative disorders (NDs), this is relevant
given that metacognitive impairment is a feature of Alzheimer’s disease (AD) and other dementias .
[17]

Consequently, using rats to model cognitive symptoms could increase the robustness of cognitive
assessments and enhance the accuracy of phenotypes. However, it is important to bear in mind that
different rodent species differ in their behavioral traits [18,19] that could best mimic specific aspects of a human
disorder, emphasizing the importance of using multiple model species, especially given the heterogeneity of
deficits in several neurodegenerative disorders.

The rat’s body size further offers advantages over mice and other small animal models, as surgical
procedures can be performed more reliably and consistently. Repeated blood and cerebrospinal fluid (CSF)
sampling of larger volumes is possible in rats, and neuroimaging and electrophysiological measurements are
preferentially performed in rats. The rat remains the classical animal model in toxicological studies, as the
eradication of toxins is more closely related between human and rat, than between human and mouse .
[20]
However, a close examination of the individual biological processes affected is necessary, as many
[21]
differences exist between species . Both mouse and rat genomes were published in the early 2000s [22,23]
[20]
opening the way for genetic studies investigating rat genes that share similar traits in rats and humans .
With the advancement of genetic tools, mice have been favored over rats due to technical challenges in
creating rat models carrying genetic mutations. By improving methods for harnessing rat embryonic stem
cells and advances in genetic tools, like zinc finger nuclease and CRISPR/Cas systems, rat models have been
created more successfully in the last two decades. However, with a certain time delay in comparison to
respective mouse models .
[24]

For NDs, like AD, Parkinson’s disease (PD), and Huntington’s disease (HD), no natural mutation in the rat
exists that would provide a rat strain to model the human disease. Therefore, rat lines have been created that
mostly carry and overexpress the human disease gene, in order to elicit phenotypes that resemble pathology
and behavioral alterations, reminiscent of what is observed in patients. However, the most prevalent NDs,
AD and PD, are not monogenetic disorders, with a low proportion of familial cases and, therefore,
inherently difficult to model.

AD is the most common neurodegenerative disorder. Patients suffer from progressive cognitive decline,
affecting, for example, memory and orientation and with disease progression limiting activities of daily life.
The decline in cognitive abilities and behavioral alterations are caused by preceding, exaggerated amyloid