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 患有阿尔茨海默病和年龄相关性痴呆的神经系统疾病的人类患者通常 显示出空间导航的缺陷，这与认知的其他方面的功能障碍密切相关， 情景记忆在空间探索过程中，动物通过以下方式形成对环境的内部认知地图： 将在线感官输入与动物在空间中的运动信息相结合，这一过程 与海马体有关因此，海马体也被发现表现出病理变化 在许多学习和记忆障碍中。然而，海马体的不同亚区域 有助于整合感官线索和自我运动信息，形成空间地图， 导航，因此可能是人类认知障碍的基础。齿状回（DG）是 海马体经典的“三突触回路”的初始阶段，并从海马体接收其主要输入。 外侧和内侧内嗅皮层（LEC和MEC），这被认为是携带有关感觉的信息， 线索和自我运动。因此，有人建议，DG整合线索（"什么"）和空间 （"where"）信息以形成离散空间表示，诸如在空间中的其他地方的位置单元中发现的那些。 海马体，被认为是动物对环境的整体地图的基础。我们有 在头部固定小鼠的空间任务中，记录了齿状颗粒细胞的强烈感觉线索反应， 不知道在DG中将提示表示与纯空间信息集成到什么程度。在这 建议我们将研究微电路的线索和空间表征的齿状回使用现代 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 旨在隔离独立的线索和空间的影响，齿状颗粒细胞的活动。我们将利用 这些强大的技术沿着最先进的分析工具，以测试假设，线索和空间 在齿状回的水平上，代表仍然是不同的，因此DG群体由独立的 主要由LEC驱动的"提示细胞"和由MEC驱动的"位置细胞"的类别。此外，我们将利用 新的光和活性依赖的基因表达系统FLiCRE选择性标记和操纵 功能上不同的线索和位置细胞群体，以确定它们的输入和空间行为中的作用。 总之，这些实验将帮助我们更好地理解信息的渐进转换， 海马体在形成环境认知地图中的作用，以及这些过程如何 人类认知障碍的学习和记忆缺陷。