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

项目二：PD跌倒时注意运动接口功能障碍的电路机制

基本信息

批准号：
10282006
负责人：
MARTIN F SARTER
金额：
$ 43.54万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-30 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10282006
关键词：
5-HT6 receptor Address Admission activity Animal Model Attention Attenuated Basic Science Behavioral Behavioral Paradigm Biosensor Clinical Code Complement Complex Corpus striatum structure Coupling Cues Data Deafferentation procedure Denervation Detection Disease Resistance Dopamine Elements Environment Equilibrium Excision Exhibits Fall prevention Freezing Frequencies Functional disorder Funding Gait Gait abnormality Gait speed Gap Junctions Generations Glutamates Hospitalization Human Immobilization Impairment Interneurons Intervention Levodopa Limb structure Link Measures Mediating Michigan Modeling Motor Movement National Institute of Neurological Disorders and Stroke Neurons Nicotinic Receptors Nodal Nursing Homes Oxidases Parkinson Disease Pathway interactions Patients Performance Persons Pharmacology Phase Positron-Emission Tomography Pre-Clinical Model Rattus Recommendation Reporting Research Research Project Grants Resistance Resources Risk Factors Rodent Model Role Signal Transduction Symptoms Synapses System Taxes Testing Virus Work acetylcholine receptor agonist attenuation basal forebrain basal forebrain cholinergic neurons base cholinergic designer receptors exclusively activated by designer drugs dopamine replacement therapy effective therapy equilibration disorder experience experimental study falls glutamatergic signaling in vivo inhibitor/antagonist insight kinematics motor control neural circuit neuronal circuitry neurotransmission novel optogenetics research and development synergism therapeutic development therapy development translational model translational study treadmill

项目摘要

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.

项目II：摘要/摘要大约三分之二的帕金森氏病（PD）患者经历下降；的主要原因住院和护士入院。 PD的这些使人衰弱的特征对多巴胺具有抵抗力替代疗法，强调迫切需要基础研究和治疗性开发 PD中的非多巴胺能系统退化。我们以前建立了PD瀑布的啮齿动物模型，开发的新型行为范式反映了PD跌落的关键要素。我们的工作确定了干扰注意运动界面（AMI）网络是受损和平衡的主要病理生理基质在PD中。新颖的密歇根州复杂运动控制任务（MCMCT）评估降低了AMI受损大鼠的功能。我们还证明了皮质胆碱能和纹状体多巴胺双重损失的大鼠（DL 大鼠）反映了PD堕落者基于宠物的发现，暴露于MCMCT上的高跌幅。就像在PD堕落者中一样 DL大鼠注意力的障碍预测跌倒率。用α4β2*烟碱乙酰胆碱接收器处理激动剂，致死酶抑制剂和5-HT6受体拮抗剂（iDalopirdine）的组合处理减少跌落费率，表明我们系统的翻译价值。现在，我们提出严格的机械研究来识别关键AMI节点内的关键突触功能障碍。我们将评估基本前脑胆碱能信号的作用在秋天（AIM 1），胆碱驱动的皮质 - 纹状体信息转移（AIM 2）和纹状体的作用胆碱能中间神经元（AIM 3）。这项工作将直接完成I和III项目的研究。这拟议的研究得到了广泛的初步证据的支持：1）光遗传学的影响对复杂运动控制的基本前脑胆碱能信号的操纵； 2）指导复杂运动是通过皮质 - 纹状体谷氨酸能活动“进口”到纹状体的； 3）基于纹状体胆碱能的抑制或刺激分别导致并防止下降； 4）这些中间神经元广泛地代码提示来执行运动。拟议的研究将确定淋巴结和突触AMI功能障碍的机制，识别新的干预靶标，扩展值用于治疗开发的临床前模型，证实是研究的有用行为终点 AMI的关键节点。