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.

项目概要 人类患者通常患有阿尔茨海默病和年龄相关性痴呆等神经系统疾病 显示出空间导航的缺陷，这与其他认知方面的功能障碍密切相关，例如 作为情景记忆，动物在空间探索过程中通过以下方式形成环境的内部认知地图。 将在线感官输入与动物在空间中运动的信息相结合，这一过程 涉及海马体，因此，海马体也被发现出现病理变化。 然而，目前还不清楚海马体的不同分区如何影响许多学习和记忆障碍。 有助于将感觉线索和自我运动信息整合到空间地图的形成中 导航，因此可能是人类认知障碍的功能障碍的根源。 海马体经典“三突触回路”的初始阶段，并从 外侧和内侧内嗅皮层（LEC 和 MEC），被认为携带有关感觉的信息 因此，有人建议 DG 将提示（“什么”）和空间结合起来。 （“哪里”）信息以形成离散的空间表示，例如在其他地方的位置单元中发现的空间表示 海马体，被认为是动物整体环境地图的基础。 记录了头部固定小鼠的空间任务期间齿状颗粒细胞的强烈感觉提示反应，但是 尚不清楚 DG 中线索表示与纯粹空间信息的集成程度。 建议我们将使用现代技术来检查齿状回中线索和空间表征的微电路 体内群体成像、电路追踪和光遗传学技术与精确行为相结合 旨在隔离对齿状颗粒细胞活动的独立线索和空间影响。 这些强大的技术以及尖端的分析工具可以检验提示和空间的假设 表征在齿状回水平上仍然不同，因此 DG 群体由单独的 主要由 LEC 驱动的“提示单元”类别和由 MEC 驱动的“位置单元”。 新的光和活性依赖性基因表达系统 FLiCRE 可选择性标记和操作 功能上不同的提示和位置细胞群，以确定它们的输入和在空间行为中的作用。 总之，这些实验将帮助我们更好地理解内部信息的渐进转变。 海马体在环境认知地图的形成中的作用，以及这些过程是如何进行的 人类学习和记忆的认知障碍。