Project II: Circuit Mechanisms of Attentional-Motor Interface Dysfunction in PD Falls

项目II：概要/摘要 大约三分之二的帕金森病（PD）患者经历福尔斯;这是帕金森病的主要原因。 住院和疗养院入院。PD的这些衰弱特征对多巴胺有抵抗力 替代疗法，强调迫切需要基础研究和治疗发展的重点， 非多巴胺能系统在PD中退化。我们先前建立了PD福尔斯的啮齿动物模型， 开发了反映PD福尔斯关键要素的新行为范例。我们的工作确定了 注意力-运动界面（AMI）网络是步态和平衡受损的主要病理生理学基础 在警局新的密歇根复杂运动控制任务（MCMCT）评估受损AMI导致的福尔斯跌倒 在老鼠身上的功能我们还证明了皮质胆碱能和纹状体多巴胺（DL）双重缺失的大鼠 反映PD跌倒者中基于PET的发现的大鼠）在MCMCT上表现出高的福尔斯率。就像在警局里一样， DL大鼠注意力的损伤预测跌倒率。用α4β2* 烟碱乙酰胆碱受体治疗 激动剂，Achase抑制剂和5-HT 6受体拮抗剂（艾达鲁吡啶）联合治疗可减少跌倒 率，表明我们系统的转化价值。我们现在提出严格的机制研究， 关键AMI节点内的严重突触功能障碍。我们将评估基底前脑胆碱能信号的作用， 在福尔斯（目的1），胆碱能驱动的皮质-纹状体信息传递（目的2），纹状体的作用， 胆碱能中间神经元（Aim 3）。这项工作将直接补充项目一和项目三的研究。的 提出的研究得到了广泛的初步证据的支持，这些证据表明：1）光遗传学的影响 操纵基底前脑胆碱能信号对复杂的运动控制; 2）提示指导 复杂的运动通过皮质-纹状体神经元能活动“输入”到纹状体; 3）DREADD- 基于抑制或刺激纹状体胆碱能中间神经元活动分别引起和防止福尔斯; 4)这些中间神经元广泛编码用于执行动作的线索。拟议的研究将确定 的机制，节点和突触AMI功能障碍，确定新的干预目标，延长有价值的 治疗开发的临床前模型，并证实福尔斯作为一个有用的行为终点研究 AMI的关键节点。

PROJECT II: SUMMARY/ABSTRACT Approximately two thirds of patients with Parkinson’s disease (PD) experience falls; a primary cause of hospitalization and nursing home admission. These debilitating features of PD are resistant to dopamine replacement therapy, emphasizing the urgent need for basic research and therapeutic development focused on non-dopaminergic systems degenerating in PD. We previously established a rodent model of PD falls and developed novel behavioral paradigms that reflect critical elements of PD falls. Our work identified disruptions of the Attentional-Motor Interface (AMI) network as a major pathophysiologic substrate of impaired gait and balance in PD. The novel Michigan Complex Motor Control Task (MCMCT) assesses falls resulting from impaired AMI function in rats. We also demonstrated that rats with dual losses of cortical cholinergic and striatal dopamine (DL rats), reflecting PET-based findings in PD fallers, exhibit high rates of falls on the MCMCT. As in PD fallers, impairments in attention of DL rats predict fall rates. Treatment with an α4β2* nicotinic acetylcholine receptor agonist, combination treatments of AChase inhibitors and a 5-HT6 receptor antagonist (idalopirdine) reduce fall rates, indicating translational value of our system. We now propose rigorous mechanistic studies identifying critical synaptic dysfunction within key AMI nodes. We will assess the role of basal forebrain cholinergic signaling in falls (Aim 1), of cholinergically-driven cortico-striatal information transfer (Aim 2), and of the role of striatal cholinergic interneurons (Aim 3). This work will directly complement the research of Projects I and III. The proposed research is supported by extensive preliminary evidence demonstrating: 1) the impact of optogenetic manipulations of basal forebrain cholinergic signaling on complex movement control; 2) that cues guiding complex movements are “imported’ into the striatum via cortico-striatal glutamatergic activity; 3) that DREADD- based inhibition or stimulation of striatal cholinergic interneuronal activity cause and prevent falls, respectively; 4) that these interneurons broadly code cues utilized to execute movements. The proposed research will identify mechanisms of nodal and synaptic AMI dysfunctions, identify novel intervention targets, extend a valuable preclinical model for therapy development, and substantiate falls as a useful behavioral endpoint for studying key nodes of the AMI.