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，对于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伤导致严重的遗忘综合征，其中患者无法形成对其生活中日常事件的持久记忆。来自人类和动物模型的证据表明，海马体整合了来自两个平行处理流的信息，这两个处理流传达了关于空间位置（上下文）和单个物体或物品的信息，以创建物体（或上下文中的事件）的联合表示。该提案将调查组织的信息流通过这些并行处理流进入海马，以及这些流与海马内处理的CA3和CA1区域的相互作用。先前的工作对大鼠海马位置细胞已经证明了分离的海马CA3和CA1字段的整体空间表示的一致性时，当地的线索和全球的地标相互对立。CA3表现出更连贯的表示比CA1，在地方领域往往是一致的控制本地线索，而CA1表示分裂成本地和全球地标为主的合奏。该提议将测试一系列关于进入CA3和CA1区域的解剖信息流的假设，这些假设可能解释这些区域的不同反应。将使用多电极技术记录自由行为大鼠的CA3和CA1区域不同部分及其输入结构（包括内嗅皮层和下托复合体（旁下托和前下托））中神经元的活动。局部和全局线索集将被改变，以测试海马结构的不同部分是否优先绑定到局部或全局参考系，以及这些区域之间的已知解剖投影是否可以解释CA3和CA1合奏对这些操作的差异反应。这些实验将产生对信息处理的性质和进入和通过海马系统的信息流的组织的深刻见解，这些信息对于理解海马在情景记忆服务中执行的计算至关重要。这些基础知识可能是至关重要的设计治疗策略，以改善海马健忘症的破坏性症状，并针对这些疾病的潜在药物或手术治疗的选择性位点。深刻的记忆丧失是阿尔茨海默病等退行性脑疾病的标志，其起源于称为内嗅皮层的区域，进展到海马体，并最终进展到整个大脑的皮层区域。该提案中的实验将解决有关内嗅皮层和海马体中信息处理和功能的性质的基本问题，深入了解这些大脑区域如何正常工作，以及当这些区域被阿尔茨海默氏症癫痫，中风或创伤性损伤损坏时，它们如何出错。

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.