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Page 12 of 29 Novati et al. Ageing Neur Dis 2022;2:17 https://dx.doi.org/10.20517/and.2022.19

motivation has been indirectly suggested in α-synuclein BAC rats, based on a faster decline in activity and a
decreased exploration of the central zone of an automated cage apparatus over time, along with suppressed
[167]
[170]
feeding . Regarding depression, DJ-1 KO rats show signs of behavioral despair by 6 months , and in
PINK1 KO female rats, there is evidence for anhedonia by the age of 8 months, whilst PINK1 KO males
were not assessed simultaneously . In the α-synuclein BAC rats, both increased and decreased anxiety-like
[169]
behaviors have been reported [84,201] . In the same rats, locomotor activity is enhanced in a novel environment
by 3 months of age, and deficits in prepulse inhibition emerge as well at a more advanced age . Both
[201]
[202]
behavioral features have been associated with psychosis-like behavior in rodent models . It is worth
noting that the psychosis-like phenotype is stronger in α-synuclein BAC male rats relative to females, in
[203]
agreement with evidence for sex differences in the PD symptomatology in patients . This supports the
assessment of sex differences in psychosis in the human population.

A significant percentage of PD patients suffer from a mild cognitive impairment which can convert into
dementia with disease progression [196,199] . Cognitive deficits in early PD stages commonly impact several
facets of executive functioning, visuospatial skills and memory and have been related to dysfunction in
[199]
multiple neurotransmitter systems as well as common PD neuropathological alterations . Analyses of
some cognitive components have been performed in lesion rat models of PD, which present though some
limitations in terms of cognitive phenotypes that can be reproduced [204,205] . On the contrary, cognition has
rarely been investigated in PD genetic rat models. PINK1 KO rats display normal recognition and spatial
[206]
memory when tested at 3 months . DJ-1 KO rats were found to have altered short-term memory by 4.5
months, but unchanged goal-directed behavior [166,167] . Changes in short-term memory were also observed in
DJ-1 KO mice, but at a later age compared to PINK1 KO rats . Although it may not reflect the deficits in
[207]
patients, the early rat phenotype is more consistent with the early appearance of cognitive deficits in human
symptomatology, if the same temporal dynamics also apply to the familiar PD forms. In the α-synuclein
BAC rats, knowledge of cognitive aspects is very limited.

In summary, all three PD rat models reflect, to a certain extent, the motor impairment in the disease. DJ-1
KO and PINK1 KO rats are ideal for reproducing cranial sensorimotor deficits and studying the underlying
mechanisms. The α-synuclein BAC rats mimic the olfactory dysfunction and specific psychiatric features of
the disease, but cognition remains scarcely examined in any of these models. Apathy, a frequent symptom
in PD patients, has not been sufficiently investigated in genetic rat models of PD. Moreover, tremor, a main
motor feature in the disease, does not appear to be reproduced in genetic rat models.

Behavioral phenotypes in genetic rat models of Huntington’s disease: tgHD and BACHD rats
HD patients present motor impairment, cognitive deficits and psychiatric manifestations . The tgHD and
[208]
BACHD genetic rat models mimic many of these HD behavioral features. Compared to mouse fragment
models, especially R6/2 mice, the phenotype in tgHD rats develops later and progresses at a slower
pace [108,209] . Motor impairment starts earlier and has faster progression in BACHD rats compared to tgHD
[107]
rats, with the first BACHD rat motor abnormalities starting at the age of 1 month and the motor deficits
in tgHD rats beginning at about 6 months . In the tgHD rat model, phenotypes appear stronger in
[210]
homozygous compared to hemizygous animals and male rats were reported to be more sensitive to
[210]
motor coordination impairment relative to females , while in the BACHD rat model, homozygous
[211]
females seem to develop a stronger motor, emotional, and cognitive phenotype than males , although
[212]
information on sex differences and homozygous animals in this model is still limited.
In general, the tgHD and BACHD rat models exhibit reduced motor coordination and
balance [107,108,210,211,213,214] , altered locomotor activity and rearing [107,211,213,215,216] , decreased muscle endurance [215,217]