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Page 4 of 11 Zhang et al. Ageing Neur Dis 2022;2:16 https://dx.doi.org/10.20517/and.2022.15

Table 1. Major differences in size and structures between rabbits and mice
Human Rabbit Mice
Brain volume [18] 1300-1400 g 10-13 g 0.4-0.5 g
[18]
Spinal cord length 43 to 45 cm 18 cm 7.5
[16,17]
Gray-white matter ratio 40:60 80:20 90:10
[19,20]
Duration to reach adult brain volume 20 years 4 months 2 months
[21]
Glia-neuron ratio (GNR) 1.66 0.32-0.49 0.29-0.42
Number of neurons [22-24] 86,000 million 494.2 million 71 million

of the rabbits is also associated with larger organ size and blood volume (45-75 mL per kg body weight
versus 1.5-2.5 mL) [10,34] , which can be beneficial for diagnostic investment, surgical operation, and sampling
for pathological analysis. Cerebrospinal fluid (CSF) and blood biomarker analyses are commonly used in
the diagnosis of NDDs such as AD and FTD [35-37] . Such assays are hard to perform in mice due to the poor
sample size, especially for experiments that need continuous monitoring; in contrast, for larger animals such
as rabbits, an adequate amount of sample can be collected with minimal harm to the animal.

In addition, medical imaging approaches are usually needed for the prognosis and diagnosis of NDDs [38,39] .
However, it is hard to perform high-definition medical imaging on small animals due to the limitation of
the equipment. High-resolution magnetic resonance imaging (MRI) in mice requires a scanner with an
[40]
ultra-high field strength of 7 T or higher , which is inaccessible for most researchers. Compared with
rodents, rabbits have larger CNS [Table 1]; thus, a normal MRI scanner with a 3.0 T field strength is
adequate for CNS imaging in rabbits . The large body size of rabbits can also benefit electromyography
[41]
tests, which are commonly used in the diagnosis of neuromuscular diseases such as ALS. Additionally, the
scale of the central neuron system also affects the maneuverability of tissue sampling and the
intraparenchymal or epidural injection of therapeutic vectors such as AAV in future translational medical
research.

Collectively, the larger body size of rabbits makes it easier to handle and sample compared with small
animals, which largely facilitate phenotype observation and surgical operation.

The lifespan of rabbits is long enough for the observation of disease progression
The onset of neurodegenerative disease and the speed of progression are affected by both genetic and
[42]
environmental factors . For pathological mutations that induce late onset and slow progression, the
lifespan of animal models should also be considered, since the effect of aging can interfere with the
observation of clinical symptoms . Generally, NDDs are progressive diseases that last from years to
[9]
decades. For instance, the median survival time of ALS patients is 20-48 months , while that of AD
[43]
patients can reach up to 30 years . Moreover, late-onset NDDs such as AD and PD develop late in life;
[44]
[45]
both diseases usually begin at age 60 or older in human patients . However, the normal lifespan of mice is
12-36 months , which means that for diseases that begin late or have a slow rate of progression, mice may
[10]
not fully exhibit the whole course of the disease. For mutations that can only induce late-onset symptoms or
slow progressive disease, mice models may not exhibit observable symptoms in their lifetime without extra
[46]
administration, such as drug stimulation . Furthermore, due to the short lifespan of mice, it is hard to
identify whether a symptom (e.g., vision loss) is caused by pathological neuronal death or age-related
[9]
reasons . In the adult phase, 2.6 mice days is equivalent to one human year, while, in the post-senescence
[10]
phase, 2.069 mice days is equivalent to one human year . Such fast senescence processes can largely limit
the progression of disease and interfere with the observation of disease-related clinical symptoms. In
contrast, the maximum lifespan of laboratory rabbits can reach up to 10 years under proper conditions, and