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

Soto, Isabel; Nejtek, Vicki A.; Siderovski, David P.; Salvatore, Michael F.

doi:10.1101/2024.01.18.576285

Cited by 2 publications

(3 citation statements)

References 33 publications

(63 reference statements)

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“…al, 2022; Kelm-Nelson et al, 2021; Creed et. al, 2019; Villeneuve et al, 2016; Cai et al, 2019; Hoffmeister et al, 2020; Grant et al, 2015; Cullen et al, 2018; Lechner et al, 2022; Soto et al, 2024). Accordingly, this highlights the apparent complexities related to PINK1 function and its influence on nigrostriatal neurodegeneration and DA regulation (Urrutia, 2014).…”

Section: Discussionmentioning

confidence: 98%

“…Yet, two studies investigating cognitive functioning in this model have failed to note any significant deficits (Cai et al, 2019; Ferris et al, 2018). Nonetheless, the similar NOR scores may be attributed, at least in the younger cohorts, to the task’s inability to capture subtle changes in executive functioning, the domain of cognition initially impacted in PD (Ferris et al, 2018; Dirnberger et al, 2013; Aarsland et al, 2017; Nejtek et al, 2021; Soto et al, 2024). F-FDOPA PET scans have suggested that elevated dopaminergic activity in the PFC and constitutes a pathological feature of early-stage PD (Bruck et al, 2005; Kaasinen et al, 2001; Fallon et al, 2012), which is in alignment with our DA results in PFC.…”

Section: Discussionmentioning

confidence: 99%

“…These less-than-ideal characteristics have led to considerable inconsistency in the timing and severity of the onset of a parkinsonian motor phenotype, beginning as early as 4 months months old (Dave et al, 2014), at 8 months old (de Hass et al,2019; Grant et al, 2015), or not at all unless an environmental stressor is present (Grigoruta et al, 2020). Notably, as PD also impairs cognitive function, some studies with this model have identified memory and learning impairments in the Pink1 KO rat (Pinizzotto et al, 2022; Maynard et al, 2020; Cai et al, 2019; Hoffmeister et al, 2022; Soto et al, 2024).…”

Section: Introductionmentioning

confidence: 99%

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

Soto,

McManus,

Navarrete-Barahona

et al. 2024

Preprint

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Parkinsons disease (PD) rodent models provide insight into the relationship between nigrostriatal dopamine (DA) signaling and locomotor function. Although toxin-based rat models produce frank nigrostriatal neuron loss and eventual motor decline characteristic of PD, the rapid nature of neuronal loss may not adequately translate premotor traits, such as cognitive decline. Unfortunately, rodent genetic PD models, like the Pink1 knockout (KO) rat, often fail to replicate the differential severity of striatal DA and tyrosine hydroxylase (TH) loss, and a bradykinetic phenotype, reminiscent of human PD. To elucidate this inconsistency, we evaluated aging as a progression factor in the timing of motor and non-motor cognitive impairments. Male PINK1 KO and age-matched wild type (WT) rats were evaluated in a longitudinal study from 3 to 16 months old in one cohort, and in a cross-sectional study of young adult (6-7 months) and aged (18-19 months) in another cohort. Young adult PINK1 KO rats exhibited hyperkinetic behavior associated with elevated DA and TH in the substantia nigra (SN), which decreased therein, but not striatum, in the aged KO rats. Additionally, norepinephrine levels decreased in aged KO rats in the prefrontal cortex (PFC), paired with a higher DA content in young and aged KO. Although a younger age of onset characterizes familial forms of PD, our results underscore the critical need to consider age-related factors. Moreover, the results indicate that compensatory mechanisms may exist to preserve locomotor function, evidenced by increased DA in the SN early in the lifespan, in response to deficient PINK1 function, which declines with aging and the onset of motor impairment.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Soto,

McManus,

Navarrete-Barahona

et al. 2024

Preprint

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Positron emission tomography neuroimaging of [18F]fluorodeoxyglucose uptake and related behavior in the Pink1−/− rat model of Parkinson disease

Converse,

Krasko,

Rudisch

et al. 2024

Front. Neurosci.

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IntroductionParkinson disease (PD) is a neurodegenerative condition affecting multiple sensorimotor and cognitive systems. The Pink1−/− rat model exhibits vocal, cognitive, and limb use deficits seen in idiopathic PD. We sought to measure glucose metabolism in brain regions in Pink1−/− and wild type (WT) rats, and to associate these to measures of ultrasonic vocalization, cognition, and limb use behavior.MethodsPink1−/− (n = 12) and WT (n = 14) rats were imaged by [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) in a repeated measures design at approximately 10 months of age and 6 weeks later. Relative regional glucose metabolism was indexed by whole brain normalized FDG uptake, which was calculated for 18 regions identified a priori for comparison. Behavioral measures included tests of communication via ultrasonic vocalization, cognition with 5-Choice Serial Reaction Time Test (5-CSRTT), and limb use with Cylinder Test and Challenge Beam.ResultsRelative glucose metabolism was significantly different in Pink1−/− rats in prelimbic area, striatum, nucleus ambiguus, globus pallidus, and posterior parietal association cortex compared to WT controls. For behavioral measures, Pink1−/− rats demonstrated quieter vocalizations with a restricted frequency range, and they showed increased number of foot-faults and hindlimb steps (shuffling) in limb motor tests. Significant behavior vs. brain correlations included associations of ultrasonic vocalization parameters with glucose metabolism indices in locus coeruleus and substantia nigra.ConclusionFDG PET reveals abnormalities in relative regional brain glucose metabolism in Pink1−/− rats in brain regions that are important to cognition, vocalization, and limb motor control that are also impacted by Parkinson disease. This method may be useful for mechanistic studies of behavioral deficits and therapeutic interventions in translational studies in the Pink1−/− PD model.

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

Cited by 2 publications

References 33 publications

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

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

Positron emission tomography neuroimaging of [18F]fluorodeoxyglucose uptake and related behavior in the Pink1−/− rat model of Parkinson disease

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