Aging accelerates locomotor decline in PINK1 knockout rats in association with decreased nigral, but not striatal, dopamine and tyrosine hydroxylase expression

PINK1 knockout rats show premotor cognitive deficits measured through a complex maze

“…This increases the likelihood of capturing relevant neurobiological deficits in affected areas, such as the PFC, that are most responsive and most vulnerable to disease progression ( Kehagia et al, 2013 ; Fang et al, 2020 ; Mishra et al, 2022 ). Our results suggest that the PINK1 −/− rat can serve as an appropriate preclinical model for investigating the early neurobiological mechanisms associated with cognitive functioning also observed in human PD ( Ferris et al, 2018 ; Kelm-Nelson et al, 2021 ; Pinizzotto et al, 2022 ; Zhang et al, 2022 ; Soto et al, 2024 ).…”

“…Considering PINK1 −/− rats eventually develop motor dysfunction, spontaneous locomotion was evaluated using the open-field test (OFT) to address the possibility that the longer navigation time in the PINK1 −/− rats was related to decreased locomotor activity ( Dave et al, 2014 ; Grant et al, 2015 ; Salvatore et al, 2022 ; Soto et al, 2024 ). Rather than a decrease, PINK1 −/− rats displayed hyperactivity during both pre- and post-cognitive testing compared to WT rats, with a significant age and genotype effect in distance traveled ( Figure 4A ) [Genotype, F (1, 31) = 20.67, **** p < 0.0001], Age [ F (1, 31) = 20.73, **** p < 0.0001], Genotype × Age [ F (1, 31) = 1.09, ns], and average speed ( Figure 4B ) [Genotype F (1, 31) = 16.18, *** p = 0.0003], Age [ F (1, 31) = 17.21, *** p = 0.0002].…”

“…Therefore, this multiple T-maze has a suitable translation to human PD assessments. The more commonly used NOR is not a goal-directed task, and the outcomes are highly dependent on the properties of the objects used ( Ennaceur, 2010 ; Soto et al, 2024 ). This is further supported by the NOR results in this study.…”

“…Each rat was evaluated based on the duration of time spent with the novel versus the familiar object. A discrimination index formula [(Novel)/(Novel+Familiar)] was used to evaluate each rat’s ability to differentiate between the objects ( Pinizzotto et al, 2022 ; Soto et al, 2024 ).…”

“…The PINK1 −/− rat, a genetic preclinical model of early-stage PD, may provide an opportunity to evaluate cognitive impairments that manifest during the premotor phase. Still in its infancy, studies using the PINK1 −/− model show some controversy about the age of onset of behavioral symptoms and the extent of these deficits across the lifespan of the rat or mouse models ( Dave et al, 2014 ; Grant et al, 2015 ; Kelm-Nelson et al, 2021 ; Salvatore et al, 2022 ; Soto et al, 2024 ). Apart from motor dysfunction, one lab has reported vocalization deficits in PINK1 −/− rats ( Grant et al, 2015 ), and only one study to date has reported object discrimination deficits at 5 months of age using the novel object recognition (NOR) task as a premotor characteristic in this model ( Pinizzotto et al, 2022 ).…”