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Novati et al. Ageing Neur Dis 2022;2:17 https://dx.doi.org/10.20517/and.2022.19 Page 13 of 29

and gait abnormalities [107,213,218] . At late time points, tgHD rats are also affected by choreiform neck
[219]
movements which are more frequent in homozygous individuals . Prepulse inhibition of the startle
[220]
response, a measure of sensorimotor gating, is decreased in HD patients . In BACHD rats, there are mild
[213]
sensorimotor gating deficits at the age of 9 months , whereas in tgHD rats, no sensorimotor deficits have
been detected [216,221] .
Emotional and behavioral symptoms in HD patients can precede motor symptoms by decades. A variety of
psychiatric symptoms characterize the disease where apathy, depression, irritability, aggression, and anxiety
[222]
are frequently reported . Likewise, cognitive deficits in HD patients can be found several years before
motor diagnosis and are heterogeneous, embracing problems with executive function, visuomotor
[223]
integration, psychomotor speed, and social cognition [224-227] . While the available tests in rodents can only
partially assess the multidimensional nature of the neuropsychiatric disturbances in HD patients, emotional
changes have been shown with different behavioral paradigms in HD rat genetic models. Both tgHD and
BACHD rats show a low anxiety phenotype in different behavioral setups [107,108,210,211,214,228] . In tgHD rats, the
emotional phenotype is already detectable at the age of 1 month, before motor deficits , whilst motor and
[210]
emotional alterations in BACHD rats follow the opposite temporal pattern . In BACHD rats, evidence for
[107]
increased anxiety-like behavior was also found in specific paradigms , in line with human data. The
[229]
contradictory anxiety phenotype remains mostly unexplained, although it could in part be dependent on
age and on the different components of anxiety targeted by different typologies of behavioral tests which
could in turn rely on distinct brain mechanisms. One study demonstrated that the disinhibition of the
central nucleus of amygdala via GABA receptor antagonist in BACHD rats increased avoidance and escape
A
responses in an avoidance task as well as the social exploration in a social test , implicating an altered
[230]
activity in the central nucleus of the amygdala as one of the mechanisms at the base of anxiety-related
behavioral alterations. Further investigations of emotional phenotypes in tgHD rats revealed enhanced
emotional learning in discriminative Pavlovian fear conditioning and hyperreactivity to aversive emotional
events which were paralleled but not explained by shrinkage of the central nucleus of the amygdala .
[217]

Depression-like behavior reported in multiple studies in HD fragment and full-length mouse models [231-234]
has not been studied in much detail in HD rat genetic models. An impaired hedonic reaction in response to
sucrose in tgHD rats has been associated with anhedonia-like behavior which was though not confirmed
[217]
by later analyses . BACHD rats show decreased sucrose preference at 3 months and this effect is
[228]
maintained at later time points . Along with hedonic deficits, BACHD rats present impaired reward-
[235]
[235]
directed behavior by the age of 3 months , indicating a lack of motivation which could be representative
of apathy, a core symptom of HD . However, the BACHD rat shows notable obesity, and it is currently
[223]
uncertain how that might interact with behavioral tests that are based on food rewards. Still, there do seem
to be some indicators of the animals putting a lower hedonic value on small reward pellets [236,237] .

A key cognitive impairment in HD is executive dysfunction. One of the main executive function deficits is
impaired inhibitory control, which can be detected in specific behavioral tests in HD patients [238,239] . It was
also shown in HD fragment and knock-in mouse models [240,241] and in transgenic rats [242-245] . Rat models, in
general, may be advantageous over mouse models in the applied paradigms and have been largely used in
preclinical research on impulsive control . Impulsive-like behavior in tgHD rats was detected in both
[246]
sexes at 15 months and with different strain backgrounds [243,245] . Deficits consistent with the inability to
withhold inappropriate lever responses have been shown in BACHD rats already by the age of 3-4
months [242,244] . tgHD and BACHD rats further mimic several other facets of cognitive dysfunction in HD
patients [223,247,248] . Deficits in both animal models were reported at different ages depending on the cognitive
aspect considered. In both BACHD and tgHD rats, the first cognitive deficits were found early, at 3 and 4