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

项目二：摘要/摘要 大约三分之二的帕金森病(PD)患者经历过跌倒；这是 住院和养老院入院。帕金森病的这些衰弱特征对多巴胺具有抵抗力。 替代疗法，强调迫切需要以基础研究和治疗开发为重点 帕金森病患者非多巴胺能系统变性。我们之前建立了帕金森病跌倒的啮齿动物模型 开发了新的行为范式，反映了帕金森病跌倒的关键因素。我们的工作发现了 注意-运动接口网络是步态和平衡受损的主要病理生理基础 在警局。新型密歇根复杂运动控制任务(MCMCT)评估急性心肌梗死受损导致的跌倒 在大鼠体内的功能。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 (大鼠)，反映了帕金森病患者基于PET的发现，在MCMCT上显示出较高的跌倒发生率。就像PD Flowers一样， DL大鼠的注意力障碍预示着跌倒的几率。α-4-β-2*烟碱型乙酰胆碱受体治疗 激动剂、AChase抑制剂和5-HT6受体拮抗剂(Idalopirdine)的联合治疗可减少跌倒 费率，表明我们系统的转换价值。我们现在建议进行严格的机械论研究，以确定 急性心肌梗死关键结节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(目标1)，胆碱驱动的皮质-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和项目III的研究。 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)光遗传的影响 基底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)DREADD- 抑制或刺激纹状体胆碱能神经元间活动分别引起和预防跌倒； 4)这些中间神经元广泛地编码用于执行动作的线索。拟议的研究将确定 结节性和突触性急性心肌梗死功能障碍的机制，确定新的干预靶点，扩展了有价值的 用于治疗发展的临床前模型，以及作为研究有用的行为终点的实证性下降 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.