Exercise Effects on Early Vocal Ultrasonic Communication Dysfunction in a PINK1 Knockout Model of Parkinson’s Disease

Abstract

Background Parkinson’s disease (PD) is a complex neurodegenerative disease with vocal communication deficits that manifest early, progress, and are largely resistant to medical interventions; however, they do respond to exercise-based speech and voice therapies. Objective and Methods To study how exercise-based vocal treatment can affect the progression of communication deficits related to PD, we studied ultrasonic vocalizations (USVs) in rats with homozygous knockout (−/−) of PINK1, a gene mutation known to cause PD, under the manipulation of a behavioral vocal exercise paradigm that allows us to precisely control dose and timing of exercise in the prodromal (prior to diagnosis) stages. Results We show that intensive vocal-training rescues frequency range and intensity deficits as well as leads to an increase in call complexity and duration of calls compared to sham-training; however, over time this training regime loses significant effect as the disease progresses. We also show effects of frequent handling and conspecific (male-female) interaction in the sham-training group as they demonstrated significantly higher call rate, intensity, frequency range, and call complexity compared to rats without any form of training and consequently less handling/interaction. Further, we confirm that this model exhibits progressive gross motor deficits that indicate neurodegeneration. Discussion This study suggests that the evolving nature of vocal communication deficits requires an adjustment of therapy targets and more intensive training over the course of this progressive disease and demonstrates the importance of frequent social experiences.

Vocalization development in common marmosets for neurodegenerative translational modeling

“…Changes in vocalizations in animal models of PD have been demonstrated in several model species. Common findings in rodents with parkinsonism induced by neurotoxin or transgenesis are reduced number of calls, reduced intensity of calls, and reduced call-complexity [24, 41, 42], most of which are improved with behavioral therapy (vocal exercise) [25, 43] but not with levodopa [44]. Studies in common marmosets with neurotoxin-induced parkinsonism have only reported a reduced number of vocalizations, without performing any further acoustic analyses [45, 46, 47, 48, 49].…”

“…These voice and speech deficits are mostly refractory to standard of care medical treatment (levodopa) [20] or surgical treatment (deep brain stimulation) [21, 22]. Although voice and speech changes are not commonly reported by patients with PD until the later stages of the disease [23], there is recent evidence of preclinical communication changes, both in humans [3] and in animal models [24, 25]. Study of vocal changes early in neurodegenerative diseases can result in greater understanding of disease pathology, progression, and identification of behavioral biomarkers, that could improve diagnosis and treatment.…”

Gene expression within the periaqueductal gray is linked to vocal behavior and early-onset parkinsonism in Pink1 knockout rats

“…More recent data suggest that these vocal deficits are not rescued by pharmacological dopamine replacement (levodopa) [28], but can be, as in humans, modulated by a vocal-exercise therapy [29]. In general, these deficits recapitulate findings observed in humans with PD, irregular vocal qualities that impact the ability to effectively communicate.…”

Animal Models for Dysphagia Studies: What Have We Learnt So Far

“…The SOD1-G93A transgenic rodents are validated models of oral-stage dysphagia for bulbar deficits of Amyotrophic Lateral Sclerosis [28, 32]. There are multiple models of Parkinson’s disease, including (6-OHDA)-induced DA depletion [8, 37], surgical lesions [42] and PINK KO genetic models [22, 23]. Surgical or pharmacological models of stroke in rodents have been common, but are now being developed and validated for examining dysphagia [19, 44].…”