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

项目二：总结/摘要 大约三分之二的帕金森病 (PD) 患者经历过跌倒；的一个主要原因 住院和入住疗养院。 PD 的这些使人衰弱的特征对多巴胺有抵抗力 替代疗法，强调基础研究和治疗开发的迫切需要 PD 中非多巴胺能系统退化。我们之前建立了PD跌倒的啮齿动物模型 开发了反映 PD 跌倒关键要素的新颖行为范式。我们的工作发现了干扰 注意力运动接口（AMI）网络是步态和平衡受损的主要病理生理基础 在PD。新颖的密歇根复杂运动控制任务 (MCMCT) 评估 AMI 受损导致的跌倒 在大鼠中的功能。我们还证明，皮质胆碱能和纹状体多巴胺双重丧失的大鼠（DL 大鼠），反映了基于 PET 的 PD 跌倒者发现，在 MCMCT 上表现出较高的跌倒率。就像 PD 失败者一样， DL 大鼠的注意力受损可预测跌倒率。使用 α4β2* 烟碱乙酰胆碱受体治疗 激动剂、AChase 抑制剂和 5-HT6 受体拮抗剂（伊达洛吡啶）的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来确定 关键 AMI 节点内的严重突触功能障碍。我们将评估基础前脑胆碱能信号传导的作用 跌倒（目标 1）、胆碱能驱动的皮质纹状体信息传递（目标 2）以及纹状体的作用 胆碱能中间神经元（目标 3）。这项工作将直接补充项目 I 和 III 的研究。的 拟议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 基础前脑胆碱能信号对复杂运动控制的操纵； 2）提示引导 复杂的运动通过皮质纹状体谷氨酸能活动“输入”到纹状体；3）可怕- 基于纹状体胆碱能中间神经元活动的抑制或刺激分别导致和预防跌倒； 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 结节和突触 AMI 功能障碍的机制，确定新的干预目标，扩展有价值的 治疗开发的临床前模型，并证实跌倒是研究的有用行为终点 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.