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: 10672423
• 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/10672423
• 关键词: Acetylcholine; Anterior; Attention; Behavior; Bilateral; Brain region; Cells; Cholinergic Agonists; Cholinergic Receptors; Code; Cognitive; Communication; Cues; Data; Disorientation; Emotional; Functional disorder; Future; Gait; Genetic; Head; Hemorrhage; Hippocampus; Impairment; Individual; Intervention; Lead; Lesion; Link; Maps; Modeling; Motor; Motor Cortex; Movement; Muscarinic Acetylcholine Receptor; Muscarinics; Neurons; Output; Parkinson Disease; Patients; Pattern; Persons; Phase; Play; Positioning Attribute; Refractory; Research Project Grants; 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; neural; neuroregulation; optogenetics; pharmacologic; response; superior colliculus Corpora quadrigemina; transmission process; 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：摘要/摘要 许多患有帕金森氏病（PD）的患者患有空间迷失方向 - 无法联系外部地标 提示自我取向的内部估计。多巴胺替代疗法无法改善这些缺陷 （DRT）。由于中风或 出血，肾上腺皮质（RSC），这对于编码同义中心的组合至关重要的大脑区域 和以自我为中心的导航信息。 PD患者的注意力和情感处理障碍是 伴随着盆腔后皮质中的大胆反应改变。脾后皮质无非 与二级运动皮层，海马，视觉皮层，扣带回皮层和前部相互连接 丘脑（包含头取向细胞），因此是注意运动界面（AMI）和 理想的位置可以帮助将注意力和空间信息转化为计划的行动。此外，多个 基本的前脑结构将胆碱能项目发送到RSC。有明显的增加 乙酰胆碱（ACH）在细心的空间导航期间在肾后皮质中释放。胆碱能定义 例如在PD中看到的，可能会严重损害嗜突性皮质的空间取向功能。 关于1）胆碱能输入如何影响后全民的突触，细胞和电路，鲜为人知1） 电路和2）胆碱能功能障碍对肾后依赖性空间取向的影响 导航。我们的中心假设是投射到肾上腺皮质的功能失调的胆碱能系统 将表现出通过后置换电路和空间迷失方向的行为改变的导航编码。目标 1，我们将用初步的胆碱能控制和突触的胆碱能控制的机制解释 表明细胞类型和突触特异性胆碱能对照的数据。在AIM 2中，我们将研究如何 胆碱能输入的损失会损害空间的后全民编码及其如何影响方向引导 移动。这些目标的成功完成将阐明腹腔后的贡献 定向编码电路与注意运动接口，并为理解如何 帕金森氏病的空间取向的看法改变会直接影响运动控制。