Udall Catalyst Research Project: Retrosplenial Cholinergic and Attentional-Motor Integration Dysfunction

Udall Catalyst 研究项目：压后胆碱能和注意力运动整合功能障碍

• 批准号: 10493278
• 负责人: Omar Jamil Ahmed
• 金额: $ 21.84万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 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/10493278
• 关键词: Acetylcholine; Anterior; Attention; Behavior; Bilateral; Brain region; Cells; Cholinergic Agonists; Cholinergic Receptors; Code; Cognitive; Communication; Communication impairment; Cues; Data; Disorientation; Emotional; Functional disorder; Future; Gait; Head; Hemorrhage; Hippocampus (Brain); Impairment; Individual; Intervention; Lead; Lesion; Link; Modeling; Motor; Motor Cortex; Movement; Muscarinic Acetylcholine Receptor; Muscarinics; Neurons; Output; Parkinson Disease; Patients; Pattern; Persons; Pharmacology; Phase; Play; Positioning Attribute; Refractory; Research Project Grants; Research Project Summaries; Role; Shelter facility; Signal Transduction; Space Perception; Speed; Stroke; Structure; Synapses; System; Testing; Thalamic structure; Translating; Visual Cortex; Work; basal forebrain; blood oxygenation level dependent response; catalyst; cell cortex; cell type; cholinergic; cholinergic synapse; cingulate cortex; cohort; dopamine replacement therapy; fall risk; in vivo; inhaled nitric oxide; motor control; neuroregulation; optogenetics; relating to nervous system; response; superior colliculus Corpora quadrigemina; way finding

CATALYST RESEARCH PROJECT: SUMMARY/ABSTRACT Many patients with Parkinson’s disease (PD) suffer from spatial disorientation – inability to link external landmark cues to internal estimates of self-orientation. These deficits are not improved by dopamine replacement therapy (DRT). The same spatial disorientation features are found in patients with specific lesions, due to a stroke or hemorrhage, of the retrosplenial cortex (RSC), a brain region critical for encoding the combination of allocentric and egocentric navigational information. Attentional and emotional processing impairments in PD patients are accompanied by altered BOLD responses in the retrosplenial cortex. The retrosplenial cortex is densely interconnected with the secondary motor cortex, hippocampus, visual cortex, cingulate cortex and anterior thalamus (containing head orientation cells), and is therefore part of the Attentional-Motor Interface (AMI) and ideally positioned to help transform attentional and spatial information into planned actions. Furthermore, multiple basal forebrain structures send cholinergic projections to the RSC. There are pronounced increases in acetylcholine (ACh) release in the retrosplenial cortex during attentive spatial navigation. Cholinergic deficits, such as those seen in PD, are likely to severely impair the spatial orientation functions of the retrosplenial cortex. Little is known about 1) how cholinergic inputs influence the synapses, cells and circuits of the retrosplenial circuits, and 2) the impact of cholinergic dysfunction on retrosplenial-dependent spatial orientation and navigation. Our central hypothesis is that dysfunctional cholinergic systems projecting to the retrosplenial cortex will manifest in altered navigational encoding by retrosplenial circuits and spatially disoriented behaviors. In Aim 1, we will decipher the mechanisms of cholinergic control of retrosplenial cells and synapses, with preliminary data suggesting both cell-type- and synapse-specific cholinergic controls. In Aim 2, we will investigate how the loss of cholinergic inputs impairs retrosplenial encoding of space and how it impacts orientation-guided movement. The successful completion of these Aims will elucidate the contributions of the retrosplenial orientation coding circuit to the Attentional-Motor Interface, and lay the groundwork for understanding how altered perception of spatial orientation in Parkinson’s disease can directly impact motor control.

催化剂研究项目：概要/摘要 许多帕金森病（PD）患者患有空间定向障碍-无法连接外部标志 自我定位的内部估计线索。多巴胺替代疗法不能改善这些缺陷 （DRT）。同样的空间定向障碍特征也存在于因中风或 出血，压后皮质（RSC），一个关键的大脑区域编码的组合allocentric 和以自我为中心的导航信息PD患者的注意力和情绪处理障碍是 伴随着压后皮质BOLD反应的改变压后皮质致密 与次级运动皮层、海马、视觉皮层、扣带皮层和前皮层相互连接 丘脑（包含头部定向细胞），因此是注意-运动界面（AMI）的一部分， 理想的位置，以帮助转换注意力和空间信息到计划的行动。此外，多个 基底前脑结构向RSC发送胆碱能投射。有显着增加， 注意空间导航过程中压后皮质乙酰胆碱（ACh）的释放。胆碱能缺陷， 如帕金森病中所见，可能严重损害压后皮质的空间定位功能。 关于胆碱能输入如何影响压后神经元的突触、细胞和回路， 回路，以及2）胆碱能功能障碍对脾后依赖性空间定向的影响， 导航我们的中心假设是，功能失调的胆碱能系统投射到压后皮质 将表现在由压后回路改变的导航编码和空间定向障碍行为。在Aim中 1，我们将破译胆碱能控制压后细胞和突触的机制， 数据表明细胞类型和突触特异性胆碱能控制。在目标2中，我们将研究 胆碱能输入的丧失损害了空间的压后编码，以及它如何影响方向引导 运动这些目标的成功完成将阐明压后肌的贡献， 方向编码电路的注意力-运动接口，并奠定了基础，了解如何 帕金森病患者空间定向感知的改变可直接影响运动控制。