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Intervention changes acoustic peak frequency and mesolimbic neurochemistry in the Pink1-/- rat model of Parkinson disease.

ABSTRACT: The neural mechanisms underlying behavioral therapy for vocal acoustic deficits in patients with Parkinson disease is unknown. A primary hypothesis is that voice therapy may modulate mesolimbic brainstem regions, including the ventral tegmental area (VTA). The VTA is implicated in ultrasonic call peak frequency, involved in rewarding behaviors, and impacted by Parkinsonism. We tested the hypothesis that chronic (daily) behavioral vocal exercise of male Pink1-/- rats would alter ultrasonic vocalization acoustics and mesolimbic neurochemistry (catecholamines, GABA, mu-opioid receptor) compared to three different controls: sham-exercised Pink1-/-, unexercised Pink1-/-, and unexercised wildtype (WT) rats. A sub-hypothesis is that sham-exercise rats may exhibit changes to VTA neurochemistry as a result of a type or rewarding intervention. Results demonstrate that average bandwidth (frequency range) of ultrasonic vocalizations did not differ between WT, Pink1-/- no exercise vs. sham and vocal-exercise rats. However, average peak frequency is significantly reduced in vocal-exercised Pink1-/- rats compared to Pink1-/- no exercise, and WT groups. Unexpectedly, there were no significant acoustic differences between the vocal- and sham-exercised groups. There were no differences in catecholamine protein concentrations or tyrosine hydroxylase mRNA expression in the VTA between any of the groups. However, there was significant upregulation of all GABA-related genes in both vocal- and sham-exercised Pink1-/- rats (Gad1, Gad2, Gls, Glul); this finding was confirmed with follow up quantitative Western blotting for GAD. Additionally, there were differential results for mu-opioid receptor quantification in the VTA: vocal-exercised Pink1-/- rats showed increased mRNA expression for mu-opioid receptors whereas Western blotting indicated decreased protein levels in all Pink1-/- rats compared to WT controls suggesting the possible onset of pathology in this model. These data demonstrate modulatory effects of a rewarding behavioral paradigm on ultrasonic vocalization peak frequency. The results suggest that neuromodulators such as GABA and opioid activity, as well as the rewarding aspects of therapy may play a key role in shaping vocal treatments.

SUBMITTER: Stevenson SA

PROVIDER: S-EPMC6677310 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Intervention changes acoustic peak frequency and mesolimbic neurochemistry in the Pink1-/- rat model of Parkinson disease.

Stevenson Sharon A SA Ciucci Michelle R MR Kelm-Nelson Cynthia A CA

PloS one 20190802 8

The neural mechanisms underlying behavioral therapy for vocal acoustic deficits in patients with Parkinson disease is unknown. A primary hypothesis is that voice therapy may modulate mesolimbic brainstem regions, including the ventral tegmental area (VTA). The VTA is implicated in ultrasonic call peak frequency, involved in rewarding behaviors, and impacted by Parkinsonism. We tested the hypothesis that chronic (daily) behavioral vocal exercise of male Pink1-/- rats would alter ultrasonic vocali ...[more]

PMID: 31374106

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Project description:Parkinson disease (PD) is associated with speech and swallowing difficulties likely due to pathology in widespread brain and nervous system regions. In post-mortem studies of PD, pathology has been reported in pharyngeal and laryngeal nerves and muscles. However, it is unknown whether PD is associated with neuromuscular changes in the tongue. Prior work in a rat model of PD (Pink1-/-) showed oromotor and swallowing deficits in the premanifest stage which suggested sensorimotor impairments of these functions. The present study tested the hypothesis that Pink1-/- rats show altered tongue function coinciding with neuromuscular differences within tongue muscles compared to wildtype (WT). Male Pink1-/- and WT rats underwent behavioral tongue function assays at 4 and 6 months of age (n = 7-8 rats per group), which are time points early in the disease. At 6 months, genioglossus (GG) and styloglossus (SG) muscles were analyzed for myosin heavy chain isoforms (MyHC), ?-synuclein levels, myofiber size, centrally nucleated myofibers, and neuromuscular junction (NMJ) innervation. Pink1-/- showed greater tongue press force variability, and greater tongue press forces and rates as compared to WT. Additionally, Pink1-/- showed relative increases of MyHC 2a in SG, but typical MyHC profiles in GG. Western blots revealed Pink1-/- had more ?-synuclein protein than WT in GG, but not in SG. There were no differences between Pink1-/- and WT in myofiber size, centrally-nucleated myofibers, or NMJ innervation. ?-synuclein protein was observed in nerves, NMJ, and vessels in both genotypes. Findings at these early disease stages suggest small changes or no changes in several peripheral biological measures, and intact motor innervation of tongue muscles. Future work should evaluate these measures at later disease stages to determine when robust pathological peripheral change contributes to functional change, and what CNS deficits cause behavioral changes. Understanding how PD affects central and peripheral mechanisms will help determine therapy targets for speech and swallowing disorders.

Project description:Purpose: The present study assessed the effects of the GABAA receptor (R) agonist muscimol (MUS), and the GABAAR antagonist bicuculline (BIC) on neocortical and subcortical radioligand binding to dopamine D2/3Rs in relation to motor and exploratory behaviors in the rat. Methods: D2/3R binding was measured with small animal SPECT in baseline and after challenge with either 1 mg/kg MUS or 1 mg/kg BIC, using [123I]IBZM as radioligand. Motor/exploratory behaviors were assessed for 30 min in an open field prior to radioligand administration. Anatomical information was gained with a dedicated small animal MRI tomograph. Based on the Paxinos rat brain atlas, regions of interest were defined on SPECT-MRI overlays. Estimations of the binding potentials in baseline and after challenges were obtained by computing ratios of the specifically bound compartments to the cerebellar reference region. Results: After MUS, D2/3R binding was significantly reduced in caudateputamen, nucleus accumbens, thalamus, substania nigra/ventral tegmental area, and posterior hippocampus relative to baseline (0.005 ? p ? 0.012). In all these areas, except for the thalamus, D2/3R binding was negatively correlated with grooming in the first half and positively correlated with various motor/exploratory behaviors in the second half of the testing session. After BIC, D2/3R binding was significantly elevated in caudateputamen (p = 0.022) and thalamus (p = 0.047) relative to baseline. D2/3R binding in caudateputamen and thalamus was correlated negatively with sitting duration and sitting frequency and positively with motor/exploratory behaviors in the first half of the testing time. Conclusions: Findings indicate direct GABAergic control over nigrostriatal and mesolimbic dopamine levels in relation to behavioral action. This may be of relevance for neuropsychiatric conditions such as anxiety disorder and schizophrenia, which are characterized by both dopaminergic and GABAergic dysfunction.

Dataset Information

Intervention changes acoustic peak frequency and mesolimbic neurochemistry in the Pink1-/- rat model of Parkinson disease.

Publications

Intervention changes acoustic peak frequency and mesolimbic neurochemistry in the Pink1-/- rat model of Parkinson disease.

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