Space-time processing in the hippocampus; behavioral paradigms and functional mechanism of integration

海马体的时空处理；

基本信息

批准号：
10198669
负责人：
William D Marks
金额：
$ 6.86万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10198669
关键词：
Alzheimer&apos s Disease Apical Attention deficit hyperactivity disorder Automobile Driving Behavior Behavioral Behavioral Paradigm Brain Calcium Cell Maintenance Cell physiology Cells Cues Data Decision Making Dendrites Dependence Development Discrimination Distal Episodic memory Event Exposure to Fiber Fire - disasters Fright Generations Head Hippocampus (Brain)Image In Vitro Institution Investigation Laboratories Learning Length Maintenance Medical center Memory Microscope Modality Movement Mus Nose Pattern Phase Population Process Pyramidal Cells Research Rewards Role Route Schizophrenia Signal Transduction Specificity Stream Synapses Techniques Testing Time Training Validation arm base cell type data integration data streams dentate gyrus design entorhinal cortex experience experimental study in vivo calcium imaging insight memory recall nervous system disorder novel optogenetics recruit skills time use

项目摘要

Project Summary Episodic memory is the unique recollection of a specific event in time, requiring the processing and integration of multiple information types, including spatial context and temporal information. While numerous studies on the processing of space and time as separate events have been undertaken, the understanding of the mechanisms underlying temporal processing are limited. Additionally, the means by which these information streams are integrated to form a singular memory are poorly understood. Previous research demonstrates that the hippocampus has the capability to integrate multiple spatially bound inputs with relevant contextual and nonspatial information into a singular representation. The mechanism for this integrative event as it relates to space and time is likely found more specifically within the CA1 subfield, as a discrete input carrying temporal information from entorhinal cortex layer III synapses onto the distal segments of the apical dendrites of CA1 pyramidal cells, while contextual information from EC layer II is routed through the Dentate Gyrus and CA3 before synapsing onto the proximal segments of the CA1 pyramidal cell apical dendrites. To better understand the processes underlying temporal processing, and to test whether this circuit has integrative function in episodic memory, we propose first to develop nose-poke based timing tasks for use with in-vivo calcium imaging in freely moving mice. These tasks will allow for a more refined time cell metric, give insight into the temporal encoding process, and provide a means for optogenetic investigation of circuit components with concurrent imaging of time cells. Utilizing this capability, we will optogenetically investigate the role of MECIII inputs to CA1 on time cell function and maintenance. The role of context in time cell functionality will be examined with a held nose-poke test, in which mice are trained to maintain a nose poke for a set period across multiple contexts while passive recordings of CA1 calcium activity are taken across multiple context presentations. In the final phase of this project, we will utilize cell-type specific optogenetic manipulation to inhibit terminals projecting to CA1 from ECIII or CA3 to gain a more mechanistic understanding of the integration mechanism and context dependency in time cell activity. This project will give novel insight into the mechanisms underlying episodic memory formation, temporal encoding, and how time is integrated with other data in the brain. This project will be performed at UT Southwestern Medical Center, a top tier research institution with a large variety of institutional support available. The training plan is designed to increase the applicant’s skills in in-vitro techniques, optogenetics, and behavior while also developing the applicant’s skills in presentation, grantsmanship, and laboratory management.

项目摘要情节记忆是对特定事件及时的独特识别，需要处理和集成多种信息类型，包括空间上下文和临时信息。而许多研究处理空间和时间作为单独事件的处理，对机制的理解潜在的临时处理是有限的。此外，这些信息流的方式整合以形成单数记忆的人是很少的理解。以前的研究表明海马有能力将多个空间绑定的输入与相关的上下文集合在一起非空间信息为单一表示。与此相关的集成事件的机制在CA1子字段中更具体地发现了空间和时间，作为临时的离散输入来自内嗅皮层III的信息突触到CA1的顶端树突的远端段锥体细胞，而来自EC II层的上下文信息通过齿状回和CA3进行了路由在突触到CA1锥体细胞顶端树突的近端片段之前。更好地理解临时处理的基础过程，并测试该电路是否在情节中集成了功能记忆，我们首先建议开发基于鼻子的计时任务，以与体内钙成像一起使用移动老鼠。这些任务将允许更精致的时间单元格，可深入了解临时编码流程，并提供一种与同时成像的电路组件进行光遗传学投资时间单元。利用这种能力，我们将光遗传学研究MECIII输入到CA1的作用功能和维护。上下文在时间细胞功能中的作用将使用固定的鼻孔进行检查测试，在该测试中，培训小鼠以在多个上下文中保持鼻子戳，而被动 CA1钙活性的记录是在多个上下文演示中进行的。在最后阶段项目，我们将利用细胞类型特异性的光遗传操作来抑制ECIII投射至CA1的终端或CA3，以更机械地理解时间的整合机制和上下文依赖性细胞活性。该项目将对情节内存形成的机制进行新颖的见解，临时编码，以及如何与大脑中的其他数据集成在一起。该项目将在UT执行西南医学中心，一家顶级研究机构，拥有各种各样的机构支持。该培训计划旨在提高申请人在体外技术，光遗传学和行为方面的技能同时还发展了申请人在演讲，授予技巧和实验室管理方面的技能。