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months, respectively. In tgHD rats, cognitive deficits concern, among others, cognitive flexibility, attention,
working memory, visuospatial and visual object memory, temporal perception and psychomotor
performance [210,219,221,249-251] . BACHD rats show impaired reversal learning [111,214,252] , deficits consistent with
[253]
fronto-striatal dysfunction in different short-term memory tests , decreased performance in a decision-
making task and impaired associative memory .
[252]
[254]
Several aspects of social behavior and social cognition are abnormal in HD patients who face problems with
emotion recognition and awareness as well as theory of mind and, to a certain extent, empathy, which have
been associated with altered social skills and self-reported social distress [224,255-257] . Transgenic fragment and
full-length HD mouse models display changes in various social behavior parameters [258-262] . Compared to
mice, rats show lower group aggression and are more interested in the interaction with male
[4]
[18]
conspecifics . Therefore, free social interaction experiments in males can be better performed in rats. Both
male and female tgHD rats tend to interact more than wild-type rats with the same sex conspecific starting
from 1 or 2 months of age, which was interpreted as a low anxiety-like phenotype [210,211] . An automated
analysis of the BACHD rat behavior in a social interaction test between 2 and 8 months of age demonstrated
[263]
alterations in multiple social interaction parameters . Other analyses in the model further revealed
changes in other areas of social cognition [229,263] . It is difficult to draw direct parallels between social behavior
parameters measured in humans and rats as social behavior is highly species-specific. Nevertheless, given
that brain correlates of social behavior are under several aspects comparable in humans and rodents , it is
[264]
still reasonable to model main social behavior related functions in rats. Depending on age, in the BACHD
rats, we find a more aggressive play behavior, decreased tendency to search for or interact with a conspecific
and a decreased social preference [229,263] , which in part indicates higher anxiety and may altogether be
representative of a disrupted socio-cognitive function. It would then be important to relate social behavior
alterations to changes in brain areas relevant to social behavior. In the BACHD rat model, in addition to the
evidence for an involvement of the amygdala in the modulation of anxiety in a social context , a decreased
[230]
BDNF gene expression was also reported in the ventral striatum . While the striatum does not have a
[263]
primary social function, it has been suggested to integrate social information into main striatal functions,
[265]
like reward . Future analyses could consider assessing the expression of markers relevant to social
behavior, such as oxytocin and vasopressin [265,266] , and focus on other brain areas affected in HD, like the
[267]
hypothalamus, which shows changes in neuronal populations expressing these markers . In HD patients,
cerebrospinal fluid oxytocin levels were also found to be decreased and to correlate with social cognitive
[268]
scores . As part of social behavior, aggression is often reported in HD patients , but has not been
[255]
assessed in transgenic rat models. While analyses of aggression could take advantage of well-established
tests in rats, they may be sensitive to the model strain, which adds to the complexity of a phenotypic profile.

Altogether the BACHD and tgHD rat models reproduce many features of the HD triad of symptoms. Both
models present motor and cognitive deficits, and some have been reproduced across studies. These rat
models also display emotional alterations. The bidirectional anxiety phenotype in the BACHD rat model
supports further assessments, especially in terms of underlying mechanisms. Furthermore, several
phenotypes in the HD rat models and in the models of other neurodegenerative disorders have been
assessed only once. Thus, their repeatability must still be determined. In addition, it remains largely unclear
to what extent specific phenotypes in animal models and similar symptoms in humans share the same
biological mechanisms, thereby representing the same kind of impairment.

PHENOTYPIC/ASPECT-REPLICATING MODELS TO STUDY AD, PD, AND HD
There is still a vast gap between preclinical studies to effective treatments for patients [269-271] . To date,
translatability from animal models to humans in terms of treatment efficacy, adverse effects, and tolerability