Neural Substrates of Oral Motor Dysfunction in Parkinson's Disease

描述（由申请人提供）：90%的帕金森病（PD）患者出现语言和吞咽障碍，吸入性肺炎是主要死亡原因。虽然目前的药物和手术干预在缓解帕金森病的一般运动症状方面是有效的，这些症状主要由皮质脊髓束控制，但它们未能对皮质球束控制的功能（如言语和吞咽）提供显着的益处。这表明PD患者的口腔运动和上肢缺陷是由不同的潜在神经病理介导的。我们新建立的PD口腔运动障碍动物模型表明纹状体多巴胺耗竭确实对控制舌和前肢功能的神经回路有不同的影响。这导致了一种假设，即PD患者口腔运动功能的改善可能需要不同于治疗上肢功能的治疗。本研究的目的是分离PD患者口腔运动和上肢功能恢复过程中不同的行为和神经变化。具体来说，本研究将1)确定口腔运动和上肢功能对运动康复和多巴胺替代疗法的不同反应；2)确定运动康复和多巴胺替代疗法对运动皮层内口腔运动和上肢运动表征的不同影响。本研究首先对90只雄性朗埃文斯大鼠进行广泛的运动任务训练，以建立上肢和口腔运动功能的基线测量。通过局部注射6-羟多巴胺，60只动物的纹状体多巴胺将被双侧耗尽。每次注射后一个月，将评估运动障碍。然后，动物将接受1)口腔运动治疗；2)口服运动疗法+左旋多巴；3)上肢治疗；4)上肢治疗+左旋多巴；5)左旋多巴治疗；或者八周内不进行康复治疗。这些治疗的影响将在治疗后对相同的运动任务电池进行评估。然后将使用皮质内微刺激来获得前肢，舌头和下颌运动的运动图，并使用免疫组织化学来确定纹状体多巴胺消耗的水平。本研究将综合行为测试电池与皮质内微刺激相结合，以确定PD中介导口腔运动损伤和恢复的特定神经基质。

DESCRIPTION (provided by applicant): Speech and swallowing impairments occur in 90% of Parkinson's Disease (PD) patients and aspiration pneumonia is the leading cause of death. While current pharmacological and surgical interventions are effective in alleviating general motor symptoms of PD, largely controlled by corticospinal tracts, they have failed to provide significant benefit for functions controlled by corticobulbar tracts such as speech and swallowing. This suggests that oral motor and upper extremity deficits in PD are mediated by different underlying neural pathologies. Our newly developed animal model of oral motor impairment in PD suggests that striatal dopamine depletion does indeed differentially affect the neural circuits controlling lingual versus forelimb function. This has lead to the hypothesis that improvements in oral motor function in PD may require treatments different from those used to treat upper extremity function. The goal of the proposed study is to dissociate the different behavioral and neural changes mediating recovery of oral motor versus upper extremity function in PD. Specifically, this study will 1) determine the differential responses of oral motor and upper extremity function to motor rehabilitation and dopamine replacement therapy and 2) determine the differential effects of motor rehabilitation and dopamine replacement therapy on oral motor versus upper extremity movement representations within the motor cortex. This study involves first training 90 male Long Evans rats on an extensive battery of motor tasks to establish a baseline measure of upper extremity and oral motor function. Striatal dopamine will be depleted bilaterally in sixty of the animals via localized 6-Hydroxydopamine injections. One month following each injection, motor impairments will be assessed. Animals will then receive either 1) oral motor therapy; 2) oral motor therapy + levodopa; 3) upper extremity therapy; 4) upper extremity therapy + levodopa; 5) levodopa therapy; or 6) no rehabilitation for eight weeks. The impact of these treatments will be assessed on the same battery of motor tasks post treatment. Intracortical microstimulation will then be used to derive motor maps of forelimb, tongue and jaw movements and the level of striatal dopamine depletion will be determined using immunohistochemistry. This study integrates a comprehensive behavioral test battery with intracortical microstimulation to determine the specific neural substrates mediating oral motor impairment and recovery in PD. PUBLIC HEALTH RELEVANCE: The results will guide the development of neurobiologically informed therapies that specifically target oral motor impairment that can be translated to the human patient population. More effective treatment strategies of oral motor dysfunction in PD will improve patient quality of life, reduce individual health care cost and ultimately reduce PD related mortality.