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Novati et al. Ageing Neur Dis 2022;2:17 https://dx.doi.org/10.20517/and.2022.19 Page 11 of 29

with several results in animal models: (i) in mice overexpressing α-synuclein, vocalization deficits are
[187]
paralleled by α-synuclein aggregates in the periaqueductal gray ; and (ii) in PINK1 KO rats, gene
expression analyses identified associations between the expression of specific gene modules in this brain
[188]
region and female vocal behavior .

Both the PINK1 KO and DJ-1 KO rat models exhibit ultrasonic vocalization deficits [46,47] . DJ-1 KO rats
display an altered call profile and produce ultrasonic vocalization with decreased intensity, as reported
between 2 and 8 months of age . Similarly, male and female PINK1 KO rats have a decreased ultrasonic
[46]
vocalization average intensity at the same age [47,169] , although opposite observations have been reported
regarding ultrasonic vocalization intensity in male PINK1 KO rats at a later age . The vocalization
[189]
intensity deficits in PINK1 KO rats are stronger compared to PINK1 KO mice . The decreased ultrasonic
[190]
vocalization intensity in genetic rat models resembles the decreased vocal intensity or loudness in PD
subjects, which occurs in the early disease stages. Given that the vocalizations recorded in male and female
rats are experimentally induced by exposure to a female and male, respectively, it remains unclear whether a
possibly altered interest in the conspecific of different sex may have contributed to this phenotype in PINK1
KO rats. This is important for two reasons: (i) decreased sexual interest and sexual dysfunction are reported
in PD patients , and (ii) brain areas controlling vocalization in rats are also involved in sexual
[191]
behavior [192,193] . Moreover, the connection of the periaqueductal gray, controlling rat vocalization, with
limbic areas may involve emotional and cognitive aspects in control and in the impairment of vocalization,
which would be interesting to assess in rat models of PD.

Characterization of vocalizations in PINK1 KO male rats indicated progressively decreased peak
frequency and altered bandwidth of frequency-modulated calls, in addition to deficits in call intensity.
[47]
[189]
Although translating these changes from rats to patients seems not as straightforward as the vocalization
intensity, the examined variables may be relevant indicators of vocalization dysfunction in rat models.
Besides altered vocalization, similar to PD patients, both PINK1 KO and DJ-1 KO rats present early
oromotor abnormalities [46,47,194] . Already at early ages, DJ-1 KO rats have a decreased ability to regulate
[46]
tongue force and PINK1 KO rats display an altered tongue function and biting deficits .
[47]
[195]
Videofluoroscopy, normally used to detect swallowing deficits in PD patients , showed that PINK1 KO
rats are dysphagic as assessed at the age of 4 months . Hence, PINK1 KO and DJ-1 KO rats seem
[194]
promising models regarding phenotypes of cranial sensorimotor dysfunction. However, the information on
olfactory abilities in these rat models remains scarce. Sixteen-month-old DJ-1 rats were shown to have
increased olfactory abilities, which is opposite to observations in patients . On the contrary, analyses in
[167]
the BAC α-synuclein rats detected smell discrimination impairment at 3 months, before the appearance of
motor deficits , which would temporally mimic the manifestation of symptoms in human PD.
[84]
PD patients show non-motor symptoms, including psychiatric and cognitive symptoms, sleep disorders,
and autonomic dysfunction [196-199] . Most PD patients experience disturbances such as apathy, anxiety,
[197]
depression, and psychosis and several studies on PD have also reported disorders of impulsive control .
Even though some disturbances, for example, psychosis and impulsive control, may in part arise from or be
enhanced by treatments, neuropsychiatric symptoms are already observed in the early phases of the
disease [197,198,200] . Despite the obvious limitations in translating neuropsychiatric assessments between animal
models and humans, genetic rodent models still offer the possibility to relate neuropsychiatric-like
behaviors to relevant brain changes on multiple levels in treatment-free conditions, and to dissect their
temporal dynamics. To date, neuropsychiatric-like phenotypes have not been characterized in depth in the
genetic rat models described here, and the results obtained so far require further corroboration. Research on
these PD genetic rat models hardly focused on apathy and impulsivity-related behaviors, although altered