Pathology and treatment of vocal deficits in Parkinson disease

描述（由申请人提供）：帕金森病患者（PD）经历毁灭性的声音交流缺陷，对生活质量产生负面影响。这些缺陷在早期表现出来，并且对药物和手术干预有很大的抵抗力。最近的研究表明，PD病理是广泛存在的，不仅包括中脑的中枢多巴胺缺失，还包括脑干和皮质区域内α-突触核蛋白聚集和神经蛋白（包括脑源性神经营养因子（BDNF））的减少。尽管有这些最新的数据，但人们对pd相关病理如何导致语音交流缺陷知之甚少。此外，尚不清楚行为疗法，如基于运动的声音疗法，如何影响病理。为了对这些缺陷进行有效的治疗，必须明确病理与声音交流功能后果之间的关系。通过将这些大鼠与未受影响的对照组（野生型；WT）进行比较，并通过操纵声带运动条件，研究一种新的PD转基因大鼠模型：PINK1的纯合敲除（KO），一种已知导致常染色体家族性PD的基因突变，解决了这些未知问题。这种独特的方法提供了以前未探索的病理学知识，并深入了解了发声运动治疗在一个模型中的作用，该模型代表了与PD的直接机制联系。PINK1 KO大鼠将在与早期PD（8个月）相对应的年龄进行研究，并与WT对照组进行比较。我们的中心假设是：(1)PINK1 KO大鼠会出现功能性发声缺陷并伴有脑干和皮层病变；(2)运动后的PINK1 KO大鼠会出现功能性发声缺陷的预防或逆转、病理调节和发声沟通质量的改善。为了解决这些假设，本研究有两个具体目标：(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)确定发声运动对PD模型声学和脑病理学的影响。具体来说，我们将验证在PINK1 KO大鼠的导管周围灰质、歧义核、黑质、纹状体、伏隔核、杏仁核和M1喉部运动皮层中α-突触核蛋白聚集增加和BDNF减少的假设。此外，我们假设病理将与发声缺陷相关，并且发声锻炼将通过减少这些区域聚集的α-突触核蛋白和增加BDNF来改善缺陷和调节病理。此外，使用回放方法，我们假设同种动物会对经过发声训练的大鼠的发声表现出更大的兴趣。因此，我们可以探索病理、运动和运动减少缺陷的能力之间的相互作用。这项转化研究结合了行为和生理科学的技术和理论，将提供与发声缺陷相关的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.