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

项目摘要 情景记忆是对特定时间事件的独特回忆，需要加工和整合 多种信息类型，包括空间上下文和时间信息。虽然许多研究表明， 空间和时间作为独立事件的处理已经开始，对机制的理解 潜在的时间处理是有限的。此外，这些信息流被 整合形成单一记忆的方法知之甚少。以前的研究表明， 海马体具有将多个空间绑定输入与相关上下文和 将非空间信息转化为单一表示。这一整合事件的机制，因为它涉及到 空间和时间可能更具体地在CA1子场中发现，作为携带时间的离散输入， 来自内嗅皮层第III层突触的信息到CA 1的顶树突的远段 锥体细胞，而来自EC层II的上下文信息通过齿状回和CA3路由 在突触到CA 1锥体细胞顶端树突的近端节段上之前。更好地了解 时间加工的基础过程，并测试该回路是否具有整合功能， 记忆，我们建议首先开发鼻子戳为基础的定时任务，用于在体内钙成像在自由 移动的老鼠这些任务将允许更精确的时间单元度量， 过程，并提供了一种方法，用于光遗传学研究的电路组件与并发成像的 时间细胞利用这一能力，我们将光遗传学研究MECIII输入CA1的作用， 功能和维护。上下文在时间单元功能中的作用将通过一个固定的鼻子来检查 测试，其中小鼠被训练在多个环境中保持鼻子戳一段时间，而被动 CA1钙活性的记录是在多个背景呈现中进行的。在最后阶段， 项目，我们将利用细胞类型特异性的光遗传学操作来抑制ECIII投射到CA1的末端 或CA3，以便及时获得对集成机制和上下文依赖性的更机械的理解 细胞活性这个项目将提供新的见解情节记忆形成的机制， 时间编码，以及时间如何与大脑中的其他数据整合。该项目将在UT进行 西南医学中心，一个顶级的研究机构，提供各种各样的机构支持。 培训计划旨在提高申请人在体外技术、光遗传学和行为学方面的技能 同时也培养申请人在演讲、演讲和实验室管理方面的技能。

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.