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observations, BACHD rats exhibit more prominent mHTT aggregates in the cerebral cortex compared to
subcortical areas, with aggregates distributed through all cortical layers, primarily in neurites. tgHD rats
display a similar aggregate distribution pattern. Notably, tgHD rats display abundant mHTT aggregates in
the dorsomedial part of the striatum and BACHD rats have been found to show a similar aggregate load in
the lateral striatum. Interestingly, both HD rat models show a prevalent distribution of HTT aggregates in
the limbic structures, with notable aggregate loads in the ventral striatum (nucleus accumbens), striatal
terminal bed nucleus, and central nucleus amygdala [107,112,113] . In the BACHD rats, aggregates were also found
in the hippocampus and hypothalamus. It is difficult to judge to what extent this relates to human disease,
as the distribution of aggregates outside the striatum and cortex has barely been studied in HD patients.

In contrast to the aggregate pathology seen in patients and rat models, most mouse models display nuclear
inclusion bodies rather than neuropil aggregates. Moreover, they display more abundant aggregates in the
striatum compared to the cerebral cortex, regardless of the genetic construct or modification they are based
[114]
on . It is therefore clear that BACHD and tgHD rats provide a meaningful complement to HD mouse
models for modeling and understanding the mHTT neuropathogenic mechanisms. mHTT aggregation is
affected by several intrinsic factors, including polyQ-flanking sequences of mHTT, mHTT interaction
partners, protein fragmentation, and post-translational modifications (see review ). Different subcellular
[115]
localization of aggregates may initiate different cellular quality-control processes, resulting in different
pathogenic processes. Working with a combination of mouse and rat models of HD, could therefore help
tease apart what exactly causes one type of pathology over the other.

Behavioral phenotypes
Behavioral phenotypes in genetic rat models of Alzheimer’s disease: APP NL-G-F knock-in, TgF344-AD, and
McGill-R-Thy1-APP transgenic rats
Memory impairment is an early symptom in AD patients, followed by language and mathematical deficits,
decreased visuospatial orientation, and attention deficits [116,117] . One of the most common symptoms in
subjects affected by AD is an impairment of spatial navigation which is the ability to define and retain
[118]
trajectories between places . Although attributing cognitive functions to specific brain areas does not
embrace the complexity of brain networks regulating cognition, hippocampus and medial entorhinal cortex
[120]
represent essential areas for spatial navigation and are already affected in the early phases of AD .
[119]
Similar brain areas in humans and rodents appear to be involved in the regulation of specific types of
memory, for example, spatial memory [9,121,122] , which is important for modeling cognitive deficits in animal
models.

Most of the behavioral results in AD genetic models come from the characterization of mouse models. On
the other hand, the use of genetic rat models is increasing, and these models may be advantageous from a
behavioral perspective, given that cognitive testing is central to AD research. In McGill-R-Thy1-APP
transgenic rats, spatial learning and memory deficits already manifest by 3 months of age, prior to amyloid
plaque deposition and are present in both homozygous and hemizygous rats which can sometimes differ in
the degree of impairment. Spatial cognition deficits include reference and working memory impairment as
detected in maze tasks for spatial learning, and problems with object location memory [55,123-125] . TgF344-AD
transgenic rats show spatial cognition deficits as early as 4 months of age [126,127] . Similar to the McGill-R-
Thy1-APP rats, they were shown to have a deficient performance in several paradigms for spatial cognition
including tasks for reference and working memory [68,126,128,129] as well as reversal learning [68,130,131] . Moreover,
TgF344-AD rats display a decreased accuracy in spatial trajectories . In line with the results in the
[132]
transgenic models of AD, five months old APP NL-G-F knock-in rats were reported to display impaired spatial
learning abilities . Hence, defective spatial cognition is reproduced among different categories of AD
[70]
genetic rat models.