Establishing Equivalent Aerobic Exercise Parameters Between Early-Stage Parkinson’s Disease and Pink1 Knockout Rats

Abstract

Background: Rodent Parkinson’s disease (PD) models are valuable to interrogate neurobiological mechanisms of exercise that mitigate motor impairment. Translating these mechanisms to human PD must account for physical capabilities of the patient. Objective: To establish cardiovascular parameters as a common metric for cross-species translation of aerobic exercise impact. Method: We evaluated aerobic exercise impact on heart rate (HR) in 21 early-stage PD subjects (Hoehn Yahr ≤1.5) exercising in non-contact boxing training for ≥3 months, ≥3x/week. In 4-month-old Pink1 knockout (KO) rats exercising in a progressively-increased treadmill speed regimen, we determined a specific treadmill speed that increased HR to an extent similar in human subjects. Results: After completing aerobic exercise for ∼30 min, PD subjects had increased HR∼35% above baseline (∼63% maximum HR). Motor and cognitive test results indicated the exercising subjects completed the timed up and go (TUG) and trail-making test (TMT-A) in significantly less time versus exercise-naïve PD subjects. In KO and age-matched wild-type (WT) rats, treadmill speeds of 8–10 m/min increased HR up to 25% above baseline (∼67% maximum HR), with no further increases up to 16 m/min. Exercised KO, but not WT, rats showed increased locomotor activity compared to an age-matched exercise-naïve cohort at 5 months old. Conclusion: These proof-of-concept results indicate HR is a cross-species translation parameter to evaluate aerobic exercise impact on specific motor or cognitive functions in human subjects and rat PD models. Moreover, a moderate intensity exercise regimen is within the physical abilities of early-stage PD patients and is therefore applicable for interrogating neurobiological mechanisms in rat PD models.

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

“…This is the first study, to our knowledge, to explore the PINK1 -/- rat’s capability to complete a food incentivized maze, during the premotor phase. In line with the findings of this study, prior cohorts of PINK1 -/- rats in our laboratory have consistently exhibited hyperkinetic behavior before the age of 6 months [8]. Notably, these outcomes contrast with reports from other studies, where the timing of initial motor deficits and the extent of dopamine (DA) loss in this model range widely, with some indicating no deficits and others observing deficits emerging between 4 to 8 months [7-9, 31].…”

“…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 of PD. Still in its infancy, studies using the PINK1 -/model show some controversy about the age of onset of symptoms and the extent of these deficits across the lifespan of the rat model [7][8][9][10][11]. Apart from motor dysfunction, one lab has reported vocalization deficits in PINK1 -/rats [9], and only one study to-date has found object discrimination deficits at 5-months-old using the novel object recognition (NOR) task as a premotor feature in this model [11].…”

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

“…The GenElute™ Mammalian Genomic DNA Miniprep kit was used with minor changes to the procedure. The full methodological procedure has been previously published by our lab (Salvatore et al, 2022)…”

“…However, only one study has addressed whether aging may be a relevant factor in the inconsistent timing of motor phenotype onset against impaired DA signaling (Zhi et al, 2019). Thus far, only moderate loss, if any, of nigrostriatal neurons, DA, or tyrosine hydroxylase (TH) has ever been reported in this model (Dave et al, 2014;Villeneuve et al, 2016), and any DA loss is nowhere near the severity seen in human PD at diagnosis (Villeneuve et al, 2017;Dave et al, 2014;Creed et al, 2019Creed et al, , 2020Zhi et al, 2019;Salvatore et al, 2022). Moreover, striatal DA or TH loss has not correlated with motor impairments (Dave et al, 2014;de Haas et al, 2019;Marquis et al, 2020).…”

“…The GenElute™ Mammalian Genomic DNA Miniprep kit was used with minor changes to the procedure. The full methodological procedure has been previously published by our lab (Salvatore et al, 2022) Locomotor Activity: Open-field test (OFT) The open-field test (OFT) was used to capture and measure motor activity and was performed during the awake cycle using the Opto-Varimex-5 Auto-Track System (Columbus Instruments).…”