THE ORIGIN AND FUNCTION OF SENSORY CUE AND PLACE RESPONSES IN THE DENTATE GYRUS

齿状回感觉线索和位置反应的起源和功能

• 批准号: 10626680
• 负责人: Rene Hen
• 金额: $ 32.13万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10626680
• 关键词: Alzheimer' s Disease; Animals; Apical; Axon; Behavior; Brain; Calcium; Cells; Cognition; Cognition Disorders; Cognitive; Computer Models; Cues; Cytoplasmic Granules; Defect; Dementia; Dendrites; Dependence; Desire for food; Diagnosis; Disease; Dorsal; Environment; Episodic memory; Exhibits; Fire - disasters; Functional disorder; Gene Expression; Halorhodopsins; Head; Hilar; Hippocampus (Brain); Human; Image; Impaired cognition; Individual; Label; Lateral; Learning; Learning Disorders; Light Exercise; Location; Maps; Medial; Memory; Memory impairment; Methods; Modernization; Motion; Movement; Mus; Neuronal Dysfunction; Neurons; Opsin; Optics; Pathologic; Patients; Pattern; Perforant Pathway; Periodicity; Pharmacology; Play; Population; Process; Rabies virus; Role; Running; Sensory; Signal Transduction; Spatial Behavior; Stimulus; Suggestion; Synapses; System; Techniques; Technology; Testing; Time; Work; age related; analytical tool; base; calcium indicator; conditioning; dentate gyrus; design; entorhinal cortex; experimental study; granule cell; hippocampal subregions; in vivo; in vivo two-photon imaging; insight; mild cognitive impairment; nervous system disorder; neural circuit; optogenetics; response; sensory input; sensory integration; spatial memory; treadmill; two-photon; way finding

Project Summary Human patients with the neurological disorders of Alzheimer’s disease and age-related dementia commonly show defects in spatial navigation, which correlates strongly with dysfunction in other aspects of cognition such as episodic memory. During spatial exploration animals form an internal cognitive map of an environment by integrating online sensory input with information about the animal’s movement through space, a process which involves the hippocampus. Accordingly, the hippocampus has also been found to exhibit pathological changes in many disorders of learning and memory. Yet it is still unclear how different subregions of the hippocampus contribute to the integration of sensory cue and self-motion information in the formation of a spatial map for navigation, and therefore may underlie the dysfunction in human cognitive disorders. The dentate gyrus (DG) is the initial stage of the classical ‘trisynaptic circuit’ of the hippocampus, and receives its principal inputs from the lateral and medial entorhinal cortex (LEC and MEC), which are proposed to carry information about sensory cues and self-motion, respectively. Thus it has been suggested that the DG integrates cue (“what”) and spatial (“where”) information to form discrete spatial representations such as those found in place cells elsewhere in the hippocampus and which are proposed to underlie an animal’s overall map of an environment. We have documented strong sensory cue responses in dentate granule cells during spatial tasks in head fixed mice, but it is unknown to what degree cue representations are integrated with purely spatial information in the DG. In this proposal we will examine the microcircuitry of cue and spatial representations in the dentate gyrus using modern in vivo population imaging, circuit tracing, and optogenetic technologies combined with precise behaviors designed to isolate independent cue and spatial influences on dentate granule cell activity. We will leverage these powerful techniques along with cutting edge analytical tools to test the hypothesis that cue and spatial representations remain distinct at the level of the dentate gyrus, and thus the DG population consists of separate classes of “cue cells” driven primarily by the LEC and “place cells” driven by the MEC. Furthermore, we will utilize the new light-and-activity dependent gene expression system FLiCRE to selectively label and manipulate functionally distinct cue and place cell populations, in order to determine their inputs and role in spatial behavior. Together, these experiments will help us better understand the progressive transformation of information within the hippocampus in the formation of a cognitive map of an environment, and how these processes may be defective in human cognitive disorders of learning and memory.

项目摘要 患有阿尔茨海默氏病神经疾病和年龄相关痴呆的人类患者 在空间导航中显示缺陷，这与认知其他方面的功能障碍密切相关 作为情节记忆。在空间探索期间，动物形成了环境的内部认知图 将在线感官输入与有关动物在太空中运动的信息集成在一起，这一过程 涉及海马。彼此之间，还发现海马表现出病理变化 在许多学习和记忆的疾病中。然而，目前尚不清楚海马的不同子区域如何 有助于在形成空间地图中的感觉提示和自我运动信息的整合 导航，因此可能是人类认知障碍的功能障碍的基础。齿状回（DG）是 海马的经典“ Trisynronnaptic Cource”的初始阶段，并从 侧向和内侧内部皮层（LEC和MEC），提议携带有关感觉的信息 提示和自我运动。有人建议DG整合提示（“什么”）和空间 （“ where”）信息以形成离散空间表示，例如在其他地方的其他地方发现的信息 海马并提议为动物的整体环境地图提供基础。我们有 在头部固定小鼠的空间任务中，记录了牙齿颗粒细胞中强的感觉提示反应，但 在DG中纯粹将纯粹的空间信息集成了哪种程度提示表示形式尚不清楚。在这个 提案我们将使用现代的齿状回检查提示和空间表示的微电路 体内种群成像，电路跟踪和光遗传技术与精确行为相结合 旨在分离独立的提示和空间对齿状颗粒细胞活性的影响。我们将利用 这些功能强大的技术以及最先进的分析工具，以测试提示和空间的假设 表示在齿状回的水平上保持不同，因此DG人口由单独的 由MEC驱动的LEC和“位置细胞”驱动的“ CUE细胞”类别。此外，我们将使用 新的依赖性基因表达系统的新效率，可有选择地标记和操纵 在功能上不同的提示和放置细胞群体，以确定其输入和在空间行为中的作用。 这些实验将共同帮助我们更好地了解信息的逐步转换 在形成环境的认知图中的海马以及这些过程如何 人类的学习和记忆认知障碍有缺陷。