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Zhang et al. Ageing Neur Dis 2022;2:16 https://dx.doi.org/10.20517/and.2022.15 Page 3 of 11

[13]
non-human primates), and, compared with rodents, rabbits are phylogenetically closer to humans and are
[14]
more similar to humans in brain development ; therefore, they may have better precision in disease
modeling. With the development of targeted genome editing tools, producing targeted genome-edited
rabbit models for human neuronal disorders has become attainable.

ADVANTAGES OF RABBITS AS ANIMAL MODELS OF NEUROLOGICAL DISEASES
Rabbits are phylogenetically closer to humans than mice
Genetic similarity to humans is linked with the identity of protein structure and function, and high genetic
similarity could increase the precision of disease modeling. Compared with rodents, rabbits are
[13]
phylogenetically closer to primates , suggesting they may have better precision in disease modeling.
Notably, some human genes do not have orthologs in mice: approximately 1% of human genes cannot find
orthologs in mice’s genomes. For instance, caspase 10, a gene that is linked to neurodegeneration via the
extrinsic apoptosis pathway , is absent in mice but has orthologs in rabbits . However, the phylogenetic
[11]
[15]
similarity between rabbits and humans does not guarantee rabbits would be a better model for all human
diseases; the performance of disease modeling is still dependent on the type of mutant gene, and the
mechanism involved in the pathogenesis should also be considered.

The development of the central nervous system of rabbits has greater similarity to humans
compared with rodents
Neurological features are critical for NDD modeling, and the CNS development of rabbits is highly similar
to that of humans compared with that of rodents. Specifically, the phase of brain development and
myelination in rabbits is more similar to humans than that of rodents, since such a process happens during
the perinatal period in humans and rabbits but postnatally in rodents . Moreover, rabbits have a higher
[14]
brain volume and cerebral surface area than mice. The time point of morphological configuration of major
CNS structures of rabbits is closer to humans. The development of structures such as primitive streak,
neural tube closure, and primary brain vesicles in rabbits is chronologically similar to that in humans . In
[14]
[14]
addition, the development of white matter in rabbits is closer to that of humans , and rabbits have a higher
white matter ratio than mice (approximately 20% vs. 10%) [16,17] [Table 1]. Moreover, rabbits have larger brain
volume, cortex surface area, and number of neurons compared with rodents [Table 1], suggesting that
rabbits may exhibit better cognitive, learning, and memory abilities.

Rabbits can be trained to learn basic skills (e.g., recall signals) through positive reinforcement . Rabbits
[25]
also have both short- and long-term memory [26,27] and can exhibit memory losses when mimicking NNDs
[27]
such as AD . Specifically, in an AD rabbit model constructed by drug induction, the results of novel object
recognition (NOR) and object location memory (OLM) tests suggest that the model can track cognitive
impairment . In other studies, the results of conditional and unconditional response tests also suggest that
[28]
the AD rabbit model has reduced learning ability [29,30] .

Additionally, axon degeneration is a common pathological feature of NDDs, and neurons with longer
projections have a higher vulnerability to axon degeneration, which can be easily affected in NDDs . Some
[31]
mice models of motor neuron diseases exhibit molecular pathological features in neurons but only exhibit
mild or even no behavioral symptoms [32,33] ; vulnerability to axon degeneration might be the explanation for
this phenomenon, since the axon length in rodents is shorter than that in larger animals. Collectively, rabbit
models might have better accuracy in mimicking human neuronal diseases compared to rodents.

Rabbits have a relatively large body size for handling and sampling
In addition to the genetic and neurological features, rabbits also have a bigger body size compared with
rodents, which can facilitate better animal handling and symptom observation. The relatively large body size