Dissociating the Neural Substrates of Cranial and Limb Motor Impairment in an Ani

项目摘要 90%的帕金森病（PD）患者会出现语言和吞咽障碍， 吸入性肺炎构成该患者群体的主要死亡原因。虽然目前的 药物和手术干预可有效缓解PD的一般肢体运动症状， 未能为皮质延髓束控制的颅运动功能提供显著的益处， 说话和吞咽。这表明，颅运动和肢体运动缺陷是由不同的介导的， PD中的潜在神经病理学，然而这些差异的性质目前尚不清楚。的 这项建议的中心目标是研究不同的神经机制介导皮质延髓 与PD动物模型中的皮质脊髓损伤相比。使用皮质内微刺激和 全面的行为测试电池包括颅运动和肢体运动任务，建议 研究将（1）确定单侧与双侧纹状体多巴胺耗竭对 颅和肢体运动功能以及皮质延髓和皮质脊髓回路;（2）确定鉴别 帕金森病患者颅和肢体运动功能对靶向运动康复和多巴胺替代治疗的反应 治疗;（3）确定有针对性的运动康复和多巴胺替代的差异效应 皮质延髓和皮质脊髓回路完整性的治疗。这些结果有可能指导 开发神经生物学信息疗法，专门针对颅运动障碍， 转化为人类患者群体。颅运动功能障碍的有效治疗策略 在PD中，将改善患者生活质量，降低个人医疗保健成本，吸入性肺炎，并最终 这一疾病人群的发病率。

PROJECT SUMMARY Speech and swallowing impairments occur in 90% of individuals with Parkinson's Disease (PD) and aspiration pneumonia constitutes the leading cause of death in this patient population. While current pharmacological and surgical interventions are effective in alleviating general limb motor symptoms of PD, they have failed to provide significant benefit for cranial motor functions controlled by corticobulbar tracts such as speech and swallowing. This suggests that cranial motor and limb motor deficits are mediated by different underlying neural pathologies in PD, however the nature of these differences are not currently understood. The central goal of this proposal is to investigate differences in the neural mechanisms mediating corticobulbar versus corticospinal impairments in an animal model of PD. Using intracorticial microstimulation and a comprehensive behavioral testing battery consisting of both cranial motor and limb motor tasks, the proposed studies will (1) determine the differential effects of unilateral versus bilateral striatal dopamine depletion on cranial and limb motor function and corticobulbar and corticospinal circuits; (2) determine the differential responses of cranial and limb motor function in PD to targeted motor rehabilitation and dopamine replacement therapy; and (3) determine the differential effects of targeted motor rehabilitation and dopamine replacement therapy on the integrity of corticobulbar and corticospinal circuits. The results have the potential to guide the development of neurobiologically informed therapies that specifically target cranial motor impairment that can be translated to the human patient population. More effective treatment strategies of cranial motor dysfunction in PD will improve patient quality of life, reduce individual health care cost, aspiration pneumonia and ultimately morbidity in this disease population.