Multi-Site Analysis of Hippocampal Neuronal Ensembles

描述（由申请人提供）：海马体是一种大脑结构，对形成和保持长期情景记忆至关重要。阿尔茨海默病、中风、癫痫或创伤性脑损伤对海马体的损害会导致深度遗忘综合征，患者无法形成对日常生活事件的持久记忆。来自人类和动物模型的越来越多的证据表明，海马体整合了来自两个并行处理流的信息，这两个处理流传递关于空间位置（环境）和关于单个物体或项目的信息，以创建物体在适当位置（或环境中的事件）的连接表示。该提案将研究通过这些平行加工流进入海马的信息流的组织，以及这些流与海马内CA3和CA1区域加工的相互作用。先前对大鼠海马位置细胞的研究表明，当局部线索和全局标志相互对立时，海马CA3和CA1脑区在整体空间表征的一致性方面存在分离。CA3表现出比CA1更连贯的表征，因为位置场倾向于由局部线索连贯地控制，而CA1表征分为局部和全局地标主导的集合。该提案将测试一系列关于信息进入CA3和CA1区域的解剖流的假设，这些假设可能解释这些区域的不同反应。多电极技术将用于记录自由行为大鼠CA3和CA1区域不同部分的神经元活动及其输入结构，包括内嗅皮层和丘下复合体（副耻骨和下耻骨前）。局部和全局线索集将被改变，以测试海马形成的不同部分是否优先绑定到局部或全局参考框架，以及这些区域之间已知的解剖投影是否可以解释CA3和CA1集合对这些操作的不同反应。这些实验将对信息处理的本质以及进入和通过海马体系统的信息流的组织产生深刻的见解，这些信息对于理解海马体在情景记忆中进行的计算是至关重要的。这些基础知识对于设计治疗策略以改善海马体健忘症的破坏性症状以及针对这些疾病的潜在药物或手术治疗的选择性部位可能至关重要。严重的记忆丧失是阿尔茨海默病等退行性脑部疾病的标志，这种疾病起源于一个叫做内嗅皮层的区域，发展到海马体，最终发展到整个大脑皮层区域。本提案中的实验将解决有关信息处理的本质和内嗅皮层和海马体功能的基本问题，从而深入了解这些大脑区域如何正常工作，以及当这些区域因阿尔茨海默氏症、癫痫、中风或创伤性损伤而受损时，它们是如何出错的。

DESCRIPTION (provided by applicant): The hippocampus is a brain structure that is critical for forming and retaining long-term, episodic memories. Damage to the hippocampus from Alzheimer's Disease, stroke, epilepsy, or traumatic brain injury causes a profound amnesic syndrome in which patients are unable to form lasting memories of the everyday events of their lives. Converging evidence from humans and animal models suggests that the hippocampus integrates information from two parallel processing streams, which convey information about spatial location (context) and about individual objects or items, to create conjunctive representations of objects in place (or events in context). This proposal will investigate the organization of the flow of information through these parallel processing streams into the hippocampus, as well as the interaction of these streams with intrahippocampal processing of the CA3 and CA1 regions. Prior work on hippocampal place cells of rats has demonstrated a dissociation between the hippocampal CA3 and CA1 fields in terms of the coherence of ensemble spatial representations when local cues and global landmarks are pitted against each other. CA3 demonstrated a more coherent representation than CA1, in that the place fields tended to be controlled coherently by the local cues, whereas CA1 representations split into local- and global-landmark dominated ensembles. This proposal will test a series of hypotheses regarding the anatomical flow of information into the CA3 and CA1 regions that may account for the different responses of these regions. Multi-electrode techniques will be used to record the activity of neurons in different parts of the CA3 and CA1 regions and their input structures, including the entorhinal cortex and subicular complex (parasubiculum and presubiculum) in freely behaving rats. Local and global cues sets will be altered to test whether different parts of the hippocampal formation are preferentially bound to local or global frames of reference, and whether the known anatomical projections among these areas can account for the differential responses of CA3 and CA1 ensembles to these manipulations. These experiments will generate great insight into the nature of information processing and the organization of information flow into and through the hippocampal system, information that is critical toward understanding the computations performed by the hippocampus in the service of episodic memory. Such fundamental knowledge may be crucial for devising treatment strategies to ameliorate the devastating symptoms of hippocampal amnesia and to target selective sites for potential pharmaceutical or surgical therapies for these disorders. Profound memory loss is a hallmark of such degenerative brain disorders as Alzheimer's Disease, which originates in an area called the entorhinal cortex, progresses into the hippocampus, and eventually progresses throughout the brain's cortical regions. The experiments in this proposal will address fundamental issues regarding the nature of information processing and functions in the entorhinal cortex and hippocampus, generating insight into how these brain regions work normally and how they may go awry when the regions are damaged by Alzheimer's epilepsy, stroke, or traumatic injury.