Pathology and treatment of vocal deficits in Parkinson disease

描述（由申请人提供）：帕金森病（PD）患者经历毁灭性的声音沟通缺陷，对生活质量产生负面影响。这些缺陷早期表现出来，并在很大程度上耐药物和手术干预。最近的研究表明，PD病理学广泛存在，不仅包括中脑的中枢多巴胺丢失，还包括其他神经病理学，包括α-突触核蛋白聚集和脑干和皮质区域内神经蛋白（包括脑源性神经营养因子（BDNF））的减少。尽管这些最近的数据，很少有人知道如何PD相关的病理有助于声乐沟通缺陷。此外，目前还不清楚行为治疗，如基于运动的声音治疗，如何影响病理。为了开发针对这些缺陷的有效治疗方法，必须确定病理学和对声音通信功能的后果之间的关系。这些未知因素在拟议的研究中通过研究一种新的PD转基因大鼠模型来解决：PINK 1的纯合敲除（KO），PINK 1是一种已知导致常染色体家族性PD的基因突变，通过将这些大鼠与未受影响的对照组（野生型; WT）进行比较，并通过操纵发声运动条件。这种独特的方法提供了以前未探索的病理学知识，并在代表与PD直接机械联系的模型中深入了解了发声锻炼治疗的效果。PINK 1 KO大鼠将在对应于早期PD（8个月）的年龄进行研究，并与WT对照进行比较。我们的主要假设是：（1）PINK 1 KO大鼠将显示伴随脑干和皮质病理的功能性发声缺陷，（2）经历运动的PINK 1 KO大鼠将显示功能性缺陷的预防或逆转、病理的调节和发声交流质量的改善。为了解决这些假设，本提案有两个具体目标：（1）量化PD模型中介导发声的脑干和皮质区域的病理变化;（2）确定PD模型中发声练习对声学和脑病理学的影响。具体而言，我们将检验以下假设：在PINK 1 KO大鼠中，导水管周围灰质、疑核、黑质、纹状体、延髓核、杏仁核和M1喉运动皮质中α-突触核蛋白聚集增加，BDNF减少。此外，我们假设病理学将与发声缺陷相关，发声锻炼将通过减少聚集的α-突触核蛋白和增加这些区域的BDNF来改善缺陷和调节病理学。此外，使用回放方法，我们假设同种会表现出更大的兴趣，从大鼠发声，经历了声乐锻炼。因此，我们可以探索病理学，运动和运动能力之间的相互作用，以减少赤字。拟议的转化研究结合了行为和生理科学的技术和理论，并将提供与发声缺陷相关的大脑病理学的深入知识，以及运动如何预防或逆转PD创新模型的变化。

DESCRIPTION (provided by applicant): 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 α-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 α-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 α-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.