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

催化剂研究项目：摘要/摘要 许多帕金森病(PD)患者患有空间定向障碍--无法连接外部地标 暗示了自我取向的内部评估。这些缺陷不能通过多巴胺替代疗法得到改善 (DRT)。同样的空间定向障碍特征在特定病变的患者中也被发现，由于中风或 脾后皮质(RSC)出血，这是一个对编码局部着丝粒组合至关重要的大脑区域 和以自我为中心的导航信息。帕金森病患者的注意力和情绪处理障碍 伴随着脾后皮质大胆反应的改变。脾后皮质密集 与次级运动皮质、海马体、视皮层、扣带回皮质和前部相互连接 丘脑(包含头部定位细胞)，因此是注意-运动接口(AMI)的一部分 非常适合帮助将注意力和空间信息转化为有计划的行动。此外，多个 基底前脑结构向RSC发送胆碱能投射。有明显的增加，在 注意空间导航时，在脾后皮质释放乙酰胆碱(ACh)。胆碱能缺陷， 如帕金森病患者，可能会严重损害脾后皮质的空间定向功能。 关于1)胆碱能输入如何影响脾后区的突触、细胞和回路，我们知之甚少。 2)胆碱能功能障碍对脾后依赖的空间定向和定位的影响。 导航。我们的中心假设是功能障碍的胆碱能系统投射到脾后皮质 将通过脾后回路和空间定向障碍行为表现为导航编码的改变。在AIM 1，我们将破译脾后细胞和突触的胆碱能控制机制，并初步 数据表明细胞类型和突触特异的胆碱能控制。在目标2中，我们将调查 胆碱能输入的丢失损害了脾后空间编码及其对定向引导的影响 有动静。这些目标的成功完成将阐明脾后脾的贡献 定向编码电路到注意-运动接口，并为理解如何 帕金森氏症患者对空间方位的感知改变会直接影响运动控制。

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.