Individuals with Parkinson disease (PD) experience devastating vocal communication deficits that negatively impact quality of life. These deficits manifest early and are largely resistant to pharmacological and surgical interventions. Recent research has shown that PD pathology is widespread, including not only central dopamine loss in the midbrain, but additional neuropathology including ?-synuclein aggregation and decreases in neuroproteins (including brain derived neurotrophic factor (BDNF)) within brainstem and cortical regions. Despite these recent data, very little is known about how PD-associated pathologies contribute to vocal communication deficits. Furthermore, it is unknown how behavioral treatments, such as exercise-based voice therapies, affect the pathology. To develop effective treatments for these deficits, relationships between pathology and the consequences on vocal communication function must be defined. These unknowns are addressed in the proposed research by studying a novel transgenic rat model of PD: homozygous knock-out (KO) of PINK1, a gene mutation known to cause autosomal familial PD, by comparing these rats to nonaffected controls (wild type; WT) and by manipulating vocal exercise conditions. This unique approach provides knowledge of previously unexplored pathology and insight into the effects of vocal exercise treatments in a model that represents a direct mechanistic link to PD. PINK1 KO rats will be studied at an age that corresponds to early stage PD (8 months) and compared to WT controls. Our central hypotheses are: (1) PINK1 KO rats will show functional vocal deficits accompanied by brainstem and cortical pathologies, (2) PINK1 KO rats that undergo exercise will show prevention or reversal of functional deficits, modulation of pathology and improvement in vocal communication quality. To address these hypotheses, this proposal has 2 specific aims: (1) To quantify pathological changes to brainstem and cortical regions that mediate vocalization in a model of PD; and (2) To determine impact of vocal exercise on acoustics and brain pathology in a model of PD. Specifically, we will test the hypotheses that there will be an increase in ?-synuclein aggregation and a decrease in BDNF in the periaqueductal gray, nucleus ambiguus, substantia nigra, striatum, nucleus accumbens, amygdala and M1 laryngeal motor cortex in PINK1 KO rats. Additionally, we hypothesize that the pathology will correlate with vocal deficits, and that vocal exercise will improve deficits and modulate pathology by decreasing aggregated ?-synuclein and increasing BDNF in these regions. Further, using playback methodology, we hypothesize that conspecifics will show increased interest in vocalizations from rats that have undergone vocal exercise. Thus, we can explore interactions among pathology, exercise, and the ability of exercise to reduce deficits. The proposed translational research combines techniques and theory from behavioral and physiological sciences and will provide in-depth knowledge of brain pathology related to vocalization deficits and how exercise can prevent or reverse changes in an innovative model of PD.

Public Health Relevance

Vocal communication deficits significantly impact quality of life in Parkinson disease (PD). This study will identify pathology associated with voice deficits and how exercise can improve these deficits and modify brain pathology using a transgenic rat model of Parkinson disease. Insights from this research provide the translational foundation to shape better treatment plans for patients with communication deficits and PD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32DC014399-03
Application #
9118957
Study Section
Special Emphasis Panel (ZDC1)
Program Officer
Rivera-Rentas, Alberto L
Project Start
2014-09-01
Project End
2017-08-31
Budget Start
2016-09-01
Budget End
2017-08-31
Support Year
3
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Surgery
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Kelm-Nelson, Cynthia A; Brauer, Alexander F L; Barth, Kelsey J et al. (2018) Characterization of early-onset motor deficits in the Pink1-/- mouse model of Parkinson disease. Brain Res 1680:1-12
Yang, Katie M; Blue, Katherine V; Mulholland, Haleigh M et al. (2018) Characterization of oromotor and limb motor dysfunction in the DJ1 -/- model of Parkinson disease. Behav Brain Res 339:47-56
Cullen, Kaylee P; Grant, Laura M; Kelm-Nelson, Cynthia A et al. (2018) Pink1 -/- Rats Show Early-Onset Swallowing Deficits and Correlative Brainstem Pathology. Dysphagia 33:749-758
Kelm-Nelson, Cynthia A; Trevino, Michael A; Ciucci, Michelle R (2018) Quantitative Analysis of Catecholamines in the Pink1 -/- Rat Model of Early-onset Parkinson's Disease. Neuroscience 379:126-141
Grant, Laura M; Barth, Kelsey J; Muslu, Cagla et al. (2018) Noradrenergic receptor modulation influences the acoustic parameters of pro-social rat ultrasonic vocalizations. Behav Neurosci 132:269-283
Kelm-Nelson, Cynthia A; Brauer, Alexander F L; Ciucci, Michelle R (2016) Vocal training, levodopa, and environment effects on ultrasonic vocalizations in a rat neurotoxin model of Parkinson disease. Behav Brain Res 307:54-64
Pultorak, Joshua D; Kelm-Nelson, Cynthia A; Holt, Lauren R et al. (2016) Decreased approach behavior and nucleus accumbens immediate early gene expression in response to Parkinsonian ultrasonic vocalizations in rats. Soc Neurosci 11:365-79
Kelm-Nelson, Cynthia A; Stevenson, Sharon A; Ciucci, Michelle R (2016) Data in support of qPCR primer design and verification in a Pink1 -/- rat model of Parkinson disease. Data Brief 8:360-3
Kelm-Nelson, Cynthia A; Stevenson, Sharon A; Ciucci, Michelle R (2016) Atp13a2 expression in the periaqueductal gray is decreased in the Pink1 -/- rat model of Parkinson disease. Neurosci Lett 621:75-82
Kelm-Nelson, Cynthia A; Yang, Katie M; Ciucci, Michelle R (2015) Exercise Effects on Early Vocal Ultrasonic Communication Dysfunction in a PINK1 Knockout Model of Parkinson's Disease. J Parkinsons Dis 5:749-63

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