Role of the Cholinergic system in spatial orientation

描述(申请人提供)：空间定位取决于多个神经系统的完整性。急性或慢性神经疾病扰乱了这些系统中的任何一个，都会对个人在环境中保持空间定向的能力造成严重的损害。地形性定向障碍(TD)缺乏有效的治疗方法，再加上人口老龄化，越来越多的人面临持续中风或发展为AD的风险，这给社会在管理这些患者方面带来了严重的挑战。开发TD的治疗方法将取决于识别合适的空间定向动物模型，并应用该模型来研究特定神经递质系统对空间定向的贡献。以前研究空间定向的神经基础的工作主要集中在导航策略的使用上，这些策略依赖于环境中的地标；然而，人类也使用独立于环境地标的导航策略。导航策略的选择取决于线索的可得性和对环境的熟悉程度。这项建议中概述的实验继续研究空间定向的神经基础以下目标是为了建立胆碱能系统在空间定向中的作用：1)调查啮齿动物模型分离海马和皮质胆碱能去传入对空间定向的影响的能力，2)检查胆碱能治疗对恢复空间定向的有效性，3)调查完整的脑结构在调节胆碱能治疗后观察到的恢复的空间定向中的作用。确定胆碱能去传入对空间定位至关重要的导航策略的分离反映了一个理解TD的新框架。这些研究将促进我们对空间定向的神经基础的理解，其结果可能对开发TD的治疗方法具有指导意义。

DESCRIPTION (provided by applicant): Spatial orientation depends on the integrity of multiple neural systems. Acute or chronic neurological conditions that disrupt any of these systems can produce profound impairments in an individual's ability to remain spatially oriented within an environment. The lack of an effective treatment for Topographical Disorientation (TD), in combination with an aging population in which a growing number of individuals will be at risk for sustaining a stroke or developing AD, presents serious challenges for society in the management of these patients. Developing a treatment for TD will depend on the identification of an appropriate animal model of spatial orientation and the application of this model to investigate the contribution of specific neurotransmitter systems to spatial orientation. Previous work examining the neural basis of spatial orientation has focused on the use of navigational strategies that depend on landmarks in the environment; however, humans also use navigational strategies that are independent of environmental landmarks. The choice of navigational strategy depends on cue availability and environmental familiarity. The experiments outlined in this proposal continue a research program investigating the neural basis of spatial orientation The following goals were developed to establish the role of the cholinergic system in spatial orientation: 1) investigate the ability of the rodent model to dissociate the effects of cholinergic deafferentation of the hippocampus and cortex on spatial orientation, 2) examine the effectiveness of cholinergic treatments on restoring spatial orientation, 3) investigate the role of intact brain structures in mediating the recovered spatial orientation observed subsequent to cholinergic treatments. Establishing that cholinergic deafferentation fractionates the navigational strategies that are critical for spatial orientation reflects a novel framework for understanding TD. These studies will advance our understanding of the neural basis of spatial orientation, and the results may have implications for developing treatments for TD.