Dynamics of Hippocampal Inputs in Alzheimer's Disease

项目摘要 在美国，阿尔茨海默病(AD)是第六大致死原因，影响着11%以上的人口 65美元，每年花费3550亿美元。阿尔茨海默病最早的障碍之一是空间记忆，它涉及 海马区CA1。CA1编码新的信息，由内侧内嗅皮层(MEC)的输入驱动， 在来自海马区CA3的输入的驱动下，检索和巩固旧的信息。海马区 在阿尔茨海默病早期丢失的抑制性神经元可以减少这些输入的影响。然而，我们 不了解AD中抑制性神经元的丢失或功能障碍如何影响CA1的输入，以及这是如何 随后扰乱了空间表达，从而破坏了记忆。这项提案将探讨投入的动态 抑制神经元调控的CA1及其对空间记忆的影响，可作为治疗AD的途径。我的 中心假说是CA1生长抑素表达抑制神经元的缺失开启了MEC对CA1的传入 在提取和巩固过程中，阿尔茨海默病患者的空间地图不稳定，记忆受损。我会检查这个的 假说使用了我开发的一种慢性可修复植入物设计，它能够同时记录 来自CA1、CA3和MEC的数十个神经元。我将记录野生型和AD模型小鼠的神经活动 在空间交替任务和空间语境中对记忆进行编码、巩固和提取。在这三年中 记忆阶段，我将测量：CA3和MEC对CA1的输入驱动及其学习动力(目标1)， CA1、CA3和MEC空间图(目标2)与CA1生长抑素放电模式的关系 表达和表达小白蛋白的抑制神经元(目标3.1)。然后我会刺激每个抑制性神经元 在老年AD模型小鼠的三个记忆阶段中的每一个阶段键入，以挽救AIMS 1中确定的缺陷， 2和3.1(目标3.2)。这项研究将促进我们对海马体如何动态变化的理解 对信息进行编码、检索和整合，以及在AD中如何出错，以及如何处理、推进 应对阿尔茨海默病的国家计划的目标1B。我在空间记忆、活体电生理学和AD方面的专业知识 使我独一无二地有资格在基础研究和翻译研究的交汇点从事这一新颖的研究 神经科学。这些目标将得到由Tony Lisa Giocomo博士组成的杰出指导团队的支持 Wyss-Coray和Scott Linderman，John Huguenard博士、Ivan Soltesz博士和Gareth Howell博士的顾问团队， 和斯坦福大学的训练环境。这项研究将为我提供神经数据方面的重要培训 统计学、神经退变机制、基于证据的包容性指导和实验室管理。这 该项目及其提供的培训将为研究海马区抑制神经元的作用开辟新的途径 在健康、年迈和AD的条件下，并帮助我过渡到独立的教职员工职位。

Project Summary In the US, Alzheimer’s disease (AD) is the sixth leading cause of death, affects 11% of the population over age 65, and costs $355 billion each year. One of the first impairments in AD is spatial memory, which involves the hippocampal area CA1. CA1 encodes new information, driven by inputs from medial entorhinal cortex (MEC), and retrieves and consolidates old information, driven by inputs from hippocampal area CA3. Hippocampal inhibitory neurons, which are lost early in AD, can reduce the influence of, or gate, these inputs. However, we do not understand how loss or dysfunction of inhibitory neurons in AD affects inputs to CA1 and how this subsequently disrupts spatial representations and thus memory. This proposal will explore the dynamics of inputs to CA1, as gated by inhibitory neurons, and its effects on spatial memory, as an avenue for AD treatment. My central hypothesis is that loss of CA1 somatostatin-expressing inhibitory neurons ungates MEC inputs to CA1 during retrieval and consolidation, destabilizing spatial maps and impairing memory in AD. I will examine this hypothesis using a chronic recoverable implant design I have developed which enables simultaneous recording from dozens of neurons in CA1, CA3, and MEC. I will record neural activity while wild type and AD model mice encode, consolidate, and retrieve memories in a spatial alternation task and spatial contexts. During these three memory phases, I will measure: CA3 and MEC input drive to CA1 and its dynamics over learning (Aim 1), the relationship between CA1, CA3, and MEC spatial maps (Aim 2), and the firing patterns of CA1 somatostatin- expressing and parvalbumin-expressing inhibitory neurons (Aim 3.1). I will then stimulate each inhibitory neuron type in aged AD model mice during each of the three memory phases to rescue the deficits identified in Aims 1, 2, and 3.1 (Aim 3.2). This research will advance our understanding of how the hippocampus dynamically encodes, retrieves, and consolidates information, how it goes awry in AD, and how it can be treated, advancing Goal 1B of the National Plan to Address AD. My expertise in spatial memory, in vivo electrophysiology, and AD makes me uniquely qualified to pursue this novel line of research at the intersection of basic and translational neuroscience. These aims will be supported by an exceptional mentoring team of Drs. Lisa Giocomo, Tony Wyss-Coray, and Scott Linderman, advisory team of Drs. John Huguenard, Ivan Soltesz, and Gareth Howell, and training environment of Stanford University. This research will provide me with crucial training in neural data statistics, mechanisms of neurodegeneration, evidenced-based inclusive mentorship, and lab management. This project and the training it provides will open new lines of inquiry about the role of hippocampal inhibitory neurons in healthy, aged, and AD conditions and facilitate my transition to an independent faculty position.