Dissecting the neural circuit for discrete cue representation in the Dentate Gyrus

剖析齿状回中离散线索表示的神经回路

• 批准号: 10263315
• 负责人: Sebnem Nur Tuncdemir
• 金额: $ 15.01万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-14 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10263315
• 关键词: Acute; Adult; Alzheimer' s Disease; Animals; BRAIN initiative; Behavior; Behavioral; Behavioral Paradigm; Brain region; Cells; Complement; Complex; Computer Analysis; Cues; Data; Development; Discrimination; Disease; Dissection; Educational process of instructing; Environment; Episodic memory; Evolution; Fund Raising; Genetic; Goals; Heterogeneity; Hippocampus (Brain); Image; Imaging Techniques; Impaired cognition; Impairment; Knowledge; Laboratories; Lateral; Learning; Link; Location; Maps; Medial; Mentors; Mentorship; Methods; Mus; Neurons; Optics; Output; Parahippocampal Gyrus; Pattern; Phase; Physiology; Population; Positioning Attribute; Post-Traumatic Stress Disorders; Research; Resolution; Rewards; Role; Running; Sensory; Space Perception; Tactile; Techniques; Testing; Time; Training; Viral; Work; adult neurogenesis; base; career; clinically relevant; cognitive function; dentate gyrus; design; entorhinal cortex; experimental study; granule cell; in vivo calcium imaging; in vivo imaging; in vivo two-photon imaging; insight; irradiation; memory encoding; multisensory; neural circuit; neural network; neurogenesis; neuromechanism; neuropsychiatric disorder; novel; optogenetics; parallel processing; programs; recruit; relating to nervous system; skills; treadmill; way finding

The goal of this project is to provide the building blocks for an independent research program focused on the mechanisms by which neural networks incorporate multisensory cues into episodic memories. Discrimination of different contexts composed of distinct constellations of multisensory cues is a hallmark of both episodic memory and spatial navigation, two functions ascribed to the mammalian hippocampus. The Dentate Gyrus of the hippocampus is central to spatial and contextual discrimination; yet the neural mechanisms by which contextual representations are encoded by principal granule cells has remained a significant knowledge gap. Preliminary data based on in vivo two photon imaging indicates a novel elevation of cue-associated activity in the granule cells that correlates with spatial discrimination, both of which are reduced in mice without adult hippocampal neurogenesis. Thus, this project proposes to test the hypothesis that specialized cue cells in the dentate gyrus are critical for anchoring contextual representations and are modulated both by adult neurogenesis and by entorhinal cortical inputs. These studies represent a number of firsts in linking the physiology and behavioral function of the Dentate Gyrus during learning of spatial discrimination by investigating 1) the evolution of spatial and cue-associated activity of granule cells over time in order to support the encoding of contextual representations; 2) the activity of adult born granule cells and their distinct contributions to cue representations; and 3) the activity of the entorhinal cortex afferents to the Dentate Gyrus, and the mechanisms by which multisensory information arriving from the external world generate internal hippocampal representations. To achieve this detailed circuit dissection, I will use an integrative approach that merges in vivo imaging techniques, genetic-based circuit manipulation strategies and computational analysis of multi-neuronal activity. The technical and scientific skills that I will develop during the training period of this project will become the pillars of an independent research career investigating the function and development of the complex neural dynamics which support cognitive functions implicated in neuropsychiatric disorders. This training will be complemented by intense carrier developmental activities and mentorship that will prepare me for the practical aspects of laboratory management, teaching and fund raising. Overall, these studies will provide novel insights into how the Dentate Gyrus local and long-range circuits contribute to cue representations and facilitate contextual discrimination. Since hippocampal damage has been implicated in the cognitive discrimination impairments associated with Alzheimer’s disease and PTSD, constructing a dynamic picture of the Dentate Gyrus, an often overlooked hippocampal region, at cellular and circuit resolutions during the formation of episodic memories may have an important clinical relevance.

这个项目的目标是为一个独立的研究计划提供基础，重点是 神经网络将多感官线索结合到情节记忆中的机制。 对由不同的多感官线索星座组成的不同语境的辨别是 情节记忆和空间导航都属于哺乳动物的海马体。这个 海马齿状回是空间和语境辨别的中心；然而，神经 主粒单元格对上下文表示进行编码的机制仍然是 巨大的知识鸿沟。基于活体双光子成像的初步数据表明， 颗粒细胞中与空间辨别相关的线索相关活动，这两者都 在没有成年海马神经发生的小鼠中减少。因此，该项目建议测试 假设齿状回中的特殊提示细胞对锚定上下文至关重要 它既受成体神经发生的调节，又受内嗅皮层输入的调节。 这些研究是第一次将齿状回的生理和行为功能联系起来 通过调查1)空间和线索相关活动的演变在空间辨别学习中的作用 颗粒细胞随时间的变化，以支持上下文表征的编码；2)成人的活动 Born颗粒细胞及其对线索表征的不同贡献；3)内嗅觉的活动 大脑皮质传入齿状回，以及从齿状回传入的多感觉信息的机制 外部世界产生内部海马区的表征。为了实现这一详细的电路剖析，我将 使用融合了活体成像技术、基于遗传的电路操作 多神经元活动的策略和计算分析。 我将在这个项目的培训期间发展的技术和科学技能将成为 研究复杂神经的功能和发展的独立研究生涯的支柱 支持与神经精神障碍有关的认知功能的动力学。这次培训将是 辅以紧张的承运人开发活动和指导，这将使我为实际的 实验室管理、教学和资金筹集等方面。 总体而言，这些研究将为齿状回局部和远程回路提供新的见解 有助于提示语的表达，促进语境辨别。因为海马区的损伤已经 与阿尔茨海默病和创伤后应激障碍相关的认知歧视障碍有关， 构建一幅齿状回的动态图像，齿状回是一个经常被忽视的海马区，在细胞和 情节记忆形成过程中的回路分辨率可能具有重要的临床意义。