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Page 10 of 29 Novati et al. Ageing Neur Dis 2022;2:17 https://dx.doi.org/10.20517/and.2022.19

[160]
[159]
measures of apathy [157,158] . Alternative approaches, e.g., progressive ratio tasks , used in AD mice , may
provide more compelling information on apathy-related motivational aspects.
Sleep disturbances are tightly linked to mood and behavioral disturbances. Sleep behavior characterization
in 17-month-old TgF344-AD rats showed changes in sleep architecture, such as increased sleep
fragmentation and alterations in sleep microstructure, consistent with the sleep alterations observed in the
[161]
prodromal phase of AD . Sleep analyses in McGill-R-Thy1-APP rats are lacking, although changes in
circadian activity have been reported in this rat model by the age of 8-10 months . In conclusion, both the
[125]
McGill-R-Thy1-APP and TgF344-AD rat models reproduce the dysfunction in key memory aspects, typical
of AD patients. Similar deficits are found in APP NL-G-F knock-in rats, although only limited information is
available on their phenotype so far, as this is a recent model. Neuropsychiatric changes have been examined
in more detail in the TgF344-AD rats which manifest anxiety- and depression-like behaviors as well as sleep
disruption. Apathy, a key symptom of AD, remains instead largely unexplored in these models.

Behavioral phenotypes in genetic rat models of Parkinson’s disease: PINK1 KO, DJ-1 KO, and a-synuclein
BAC rats
Typical motor symptoms in PD patients are bradykinesia, impaired fine motor skills, tremor, muscle
rigidity, and deficits in gait, posture, and balance [162-164] . Homozygous PINK1 KO and DJ-1 KO rats display
numerous abnormalities reminiscent of the human PD symptomatology. They have deficits in limb motor
coordination and balance as well as rearing, gait and grip strength [46,101,165-168] . DJ-1 KO rats additionally show
[167]
postural instability , whereas PINK1 KO rats display decreased locomotor activity [101,165] . Interestingly,
female PINK1 KO rats do not exhibit limb motor deficits like the ones observed in males of comparable
age , indicating possible sex differences in the sensorimotor phenotype or in the age when the phenotype
[169]
becomes manifest. Similar to the other models, the main features of motor impairments in α-synuclein BAC
rats are decreased activity and rearing, impaired balance, and gait deficits, although most motor
abnormalities in these rats start later compared to PINK1 KO and DJ-1 KO rats [84,170,171] . Tremor, present in
PD patients, was, to the best of our knowledge, not reported in the literature for any of these models. Fine
paw skills for which specific assays are established in rodents [172,173] have been scarcely assessed, despite the
impairments of fine motor skills and hand grasping in PD patients [162,164] .

Olfactory dysfunction, dysphagia (i.e., difficulty swallowing), as well as hypokinetic dysarthria, a speech
motor control disorder involving reduced voice loudness and altered articulation, are important
components of PD symptomatology in a high percentage of patients [174,175] . These changes are not responsive
[176]
to standard dopaminergic treatments , and knowledge of the underlying brain changes is rather limited.

Altered phonation in PD patients has been related to the rigidity of the phonatory posture of the larynx, and
laryngeal muscle impairment has been associated with deficient motor control by the basal ganglia .
[174]
Moreover, an altered perception of speech volume in PD patients has been suggested to result in poor
[177]
[174]
control of speech production . Studies in PD patients also showed deficits in the production and
perception of speech-related emotions. The latter seems to be connected with cognitive impairment in the
disease .
[177]

Vocalization in humans and ultrasonic vocalizations in rats share similar anatomical structures and neural
pathways [178-182] . The periaqueductal gray, especially, plays an important role in the control of vocalization in
mammals . It receives motor and sensory inputs as well as input from multiple limbic areas including
[183]
[183]
cortex, amygdala, and hypothalamus [184-186] that could regulate social and motivational aspects of
vocalization. The periaqueductal gray has also been linked to vocalization deficits in PD. This is consistent