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Vocal Deficits in Parkinson’s Disease
This reviews vocalization deficits in models of Parkinson disease.
2. Vocal Deficits in Parkinson’s Disease
2.2. Alpha-Synuclein Overexpression Models
Overexpressing alpha-synuclein using viral vectors models nigrostriatal pathology by injecting within or near the SNpc. In contrast to transgenic models, overexpression via viral vector allows for induction at different timepoints, allows for the targeting of a defined region of the brain, and results in rapid degeneration of nigrostriatal neurons . Furthermore, viral-vector mediated models also show the presence of limb motor deficits . Until recently, vocal deficits were not studied in alpha-synuclein overexpressing models. This is still a largely understudied area, with only two articles discussing vocal deficits in viral-vector-mediated rat models.
Mouse models overexpressing alpha-synuclein  have also shown relationships between nigrostriatal alpha-synuclein overexpression and early and progressive decline in behavior. Although not widely studied in the context of vocalization, one additional study characterized vocal deficits in mice overexpressing human wild-type alpha-synuclein under a broad neuronal promoter (Thy1-aSyn) . Grant (2014) found call profile of Thy1-aSyn mice to be significantly different compared to wildtype (WT; healthy) controls. The percent of two-cycle calls and jump down calls was significantly reduced in the Thy1-aSyn model at 2–3 months and 6–7 months, respectively. Furthermore, at 2–3 months, the average duration of calls was significantly decreased (for harmonic, jump down, half cycle, and cycle calls) and at 6–7 months, intensity was significantly reduced in the Thy1-aSyn group. Immunohistochemical findings also revealed alpha-synuclein aggregates in the periaqueductal gray at 5 months in the Thy1-aSyn mice . These deficits coincided with previously reported early sensorimotor deficits, deficits in olfaction, circadian rhythm, and gastrointestinal functioning, and high extracellular striatal dopamine levels . Similar to alpha-synuclein overexpressing rat models, mice show early and progressive vocal deficits compared to WTs, suggesting similar underlying mechanisms between both species. Results from these studies indicate that vocal deficits can be induced by alpha-synuclein overexpression, in the absence of dopamine depletion.
2.3. Genetic Models
The DJ1 knockout (DJ1-/-) model demonstrates early onset and progressive limb motor, oromotor, and cranial sensorimotor deficits, including decreased limb, tongue/chewing, and vocalization functions. Yang and colleagues (2018) assessed vocalization abilities in the DJ1-/- rat model in prodromal to early timepoints of disease (2–8 months of age) and correlated findings to noradrenergic cell loss within the locus coeruleus. Compared to WT controls, DJ1-/- rats were found to develop early and progressive ultrasonic vocalization deficits. Specifically, DJ1-/- rats produced longer average and maximum calls, and a greater overall percentage of complex calls. At 8 months of age, DJ1-/- rats showed a lower average intensity of calls, a deficit analogous to the decreased vocal loudness (i.e., hypophonia) PD patients typically experience. Findings also revealed that at 8 months of age, DJ1-/- rats demonstrated loss of tyrosine hydroxylase-immunoprotective cells in the locus coeruleus, a brainstem region responsible for the synthesis and regulation of noradrenaline. With widespread connections to the central nervous system, including projections into the prefrontal cortex, striatum, hippocampus, and thalamus, the locus coeruleus has a large impact on PD pathology. Disruptions in the central noradrenergic system are associated with motor and non-motor signs of PD, including vocalization . Tyrosine hydroxylase-positive cells in the locus coeruleus were also found to be negatively correlated with tongue force, suggesting that the greater the loss of neurons within the locus coeruleus, the greater the disruption to oromotor functioning . Whether the loss of these neurons is progressive, however, is still unknown. Overall, noradrenaline has been shown to have widespread implications for PD pathology, including vocalization deficits.
While hallmark motor deficits are relatively well-understood, certain signs of PD, including vocal deficits, remain poorly understood due to their prodromal onset and complex pathology. As such, multiple complementary models are necessary to provide insights into the progression and pathophysiological underpinnings of communication deficits.
Each of the different models of PD have unique advantages and limitations. Neurotoxin models such as 6-OHDA are useful for the study of mid- to late-stage PD associated with nigrostriatal dopamine depletion, and demonstrate widespread deficits; however, this model shows minimal alpha-synuclein aggregation and does not account for the progressive nature of the disease. In contrast, genetic models like DJ1-/- and Pink1-/- allow for the study of disease progression, as well as the study of intervention at early, prodromal, and later timepoints. However, genetic mutations make up only a small subset of PD cases and may not capture the subtle differences associated with the pathogenesis of other forms of PD.
The entry is from 10.3390/brainsci11070925
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