Vocalization deficits in parkinson rats: Does L-DOPA harm or help therapy?

描述（由申请人提供）：本研究的长期目标是探索复杂感觉运动增强（运动）和药物治疗对早期帕金森病（PD）大鼠模型感觉运动功能的治疗作用，作为加速人类PD治疗影响的转化方法。尽管在人类和动物模型中都有行为和神经化学证据，但PD患者很少在诊断后立即进行运动/感觉运动康复。因此，失去了保护剩余的多巴胺神经元和减缓运动症状进展的机会。诊断后，干预的主要形式是引入药物治疗，主要是左旋多巴。然而，在PD的早期阶段，左旋多巴的使用是有争议的。此外，左旋多巴对早期运动的潜在益处的影响尚不清楚。这项应用反映了一项独特的研究，旨在解决早期运动的治疗效果，并在动物模型中检查多巴胺增强药物对语言和声音（发声）功能结果的作用。我们将采用早期PD大鼠模型来测试多巴胺耗竭对超声发声（大鼠模拟语音/言语感觉运动控制）的影响。大鼠将在对照条件下进行测试，在神经毒素暴露（PD模型）后立即进行测试，并在左旋多巴和不左旋多巴的情况下进行声带运动（治疗）。大鼠超声发声声学参数和多巴胺保留的变化将作为运动或药物治疗后疾病严重程度和功能改善的指标。相关性：本研究将加速获得所需的神经生物学和行为学证据，以使临床和基础科学界相信早期重复性感觉运动富集对减缓人类PD疾病进展的合法治疗价值。此外，它还将为在动物模型中进行左旋多巴有运动和不运动的效果的良好控制研究提供基础。这将为解决人类早期使用多巴胺增强药物的利弊建立一个转化模型。研究问题：运动（声音疗法）是否能减缓早期帕金森病的进展并改善整体功能结局？抗帕金森药物对这一过程有帮助还是有干扰？

DESCRIPTION (provided by applicant): The long-term objective of this research is to explore the therapeutic effects of complex sensorimotor enrichment (exercise) and medication on sensorimotor function in a rat model of early Parkinson's disease (PD) as a translational approach to accelerate the impact for treatment in human PD. Despite the behavioral and neurochemical evidence in both human and animal models, people with PD are rarely referred to exercise/sensorimotor rehabilitation immediately upon diagnosis. As a result, the opportunity to protect the remaining viable dopamine neurons and slow the progression of motor symptoms is lost. Upon diagnosis, the primary form of intervention is the introduction of pharmacotherapy, primarily levodopa. However, in the early stages of PD, administration of levodopa is controversial. Further, the effects of levodopa on the potential benefits of early exercise are unknown. This application reflects a unique study to address the therapeutic effects of early exercise and to examine the role of dopamine-augmenting drugs on functional outcomes in speech and voice (vocalization) in an animal model. A rat model of early PD will be employed to test the effects of dopamine depletion on Ultrasonic Vocalization (rat analogue of voice/speech sensorimotor control). Rats will be tested in a control condition, immediately after neurotoxin exposure (PD model), and after vocal exercise (therapy) with and without levodopa. Changes in rat Ultrasonic Vocalization acoustic parameters and dopamine sparing will be measured as an index of disease severity and functional improvement after exercise or pharmacological treatment. Relevance: This research is will accelerate the acquisition of the neurobiological and behavioral evidence needed to convince both clinical and basic science communities of the legitimate therapeutic value of early repetitive sensorimotor enrichment to slow disease progression in human PD. Further, it is to provide a foundation that will lead to a well-controlled study of the effects of levodopa with and without exercise in an animal model. This will create a translational model for addressing benefits/confounds in early administration of dopamine-augmenting medications in humans. Plain-Language Research Questions: Does exercise (voice therapy) slow the progression of early Parkinson Disease and improve overall functional outcomes? Do anti-Parkinson medications help or interfere with this process?