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: 10761825
• 负责人: Sebnem Nur Tuncdemir
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 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 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10761825
• 关键词: Acute; Adult; Alzheimer' s Disease; Animals; BRAIN initiative; Behavior; Behavioral; Behavioral Paradigm; Brain region; Calibration; 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; 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; With laterality; Work; adult neurogenesis; career; clinically relevant; cognitive function; dentate gyrus; design; entorhinal cortex; experimental study; genetic approach; granule cell; in vivo calcium imaging; in vivo imaging; in vivo two-photon imaging; insight; irradiation; memory encoding; multisensory; neural; neural circuit; neural network; neurogenesis; neuroimaging; neuromechanism; neuropsychiatric disorder; novel; optogenetics; parallel processing; programs; recruit; 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.

该项目的目标是为一个独立的研究计划提供基础， 神经网络将多感官线索纳入情景记忆的机制。 区分由不同的多感官线索星座组成的不同背景是一个标志， 情景记忆和空间导航，这两种功能归因于哺乳动物海马体。的 海马齿状回是空间和背景辨别的中心，然而， 背景表征由主颗粒细胞编码的机制仍然是一个研究热点。 巨大的知识差距。基于体内双光子成像的初步数据表明， 与空间辨别力相关的颗粒细胞中的线索相关活动， 在没有成年海马神经发生的小鼠中减少。因此，本项目建议测试 假设齿状回中的专门提示细胞对于锚定上下文至关重要， 的代表，并调制成人神经发生和内嗅皮质输入。 这些研究在齿状回的生理和行为功能的联系上代表了许多第一次 在空间辨别学习过程中，通过研究1）空间和线索相关活动的演变 为了支持上下文表征的编码，颗粒细胞的活动随着时间的推移; 2）成年人的活动 出生颗粒细胞及其对线索表征的独特贡献;和3）内嗅的活动 皮层传入齿状回，以及多感觉信息来自齿状回的机制 外部世界产生内部海马表征。为了实现这个详细的电路解剖，我将 使用一种整合的方法，将体内成像技术、基于基因的电路操作 多神经元活动的策略和计算分析。 我将在本项目的培训期间开发的技术和科学技能将成为 研究复杂神经系统的功能和发展的独立研究生涯的支柱 动力学支持神经精神障碍中涉及的认知功能。将培训以文件形式进行 辅之以密集的载体开发活动和指导，这将使我为实际的 实验室管理、教学和经费筹措等方面的问题。 总的来说，这些研究将为齿状回的局部和远程回路提供新的见解。 有助于线索表征和促进上下文歧视。由于海马损伤已经 与阿尔茨海默病和创伤后应激障碍相关的认知辨别障碍有关， 构建齿状回的动态图片，一个经常被忽视的海马区，在细胞和 在情景记忆形成期间的电路解析可能具有重要的临床相关性。