Dynamics of Hippocampal Inputs in Alzheimer's Disease

项目摘要 在美国，阿尔茨海默病（AD）是第六大死亡原因，影响11%的老年人 65，每年花费3550亿美元。AD的第一个障碍是空间记忆，它涉及到 海马CA 1区。CA 1编码新信息，由来自内侧内嗅皮层（MEC）的输入驱动， 并在海马CA 3区的输入驱动下检索和巩固旧信息。海马 在AD早期丢失的抑制性神经元可以减少这些输入的影响或门控这些输入。但我们 我不了解AD中抑制性神经元的丧失或功能障碍如何影响CA 1的输入，以及这是如何影响CA 1的输入的。 随后破坏空间表征，从而破坏记忆。本提案将探讨投入的动态 CA 1，作为抑制性神经元门控，及其对空间记忆的影响，作为AD治疗的途径。我 中心假设是表达CA 1生长抑素的抑制性神经元的丧失解除了MEC对CA 1的输入 在提取和巩固，不稳定的空间地图和损害记忆的AD。我会检查这个 假设使用慢性可恢复的植入物设计，我已经开发，使同步记录 来自CA 1，CA 3和MEC的几十个神经元。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情境中编码、巩固和检索记忆。这三 记忆阶段，我将测量：CA 3和MEC输入驱动CA 1和它的动态学习（目标1）， CA 1、CA 3和MEC空间图之间的关系（目的2），以及CA 1生长抑素的放电模式- 表达和表达小清蛋白的抑制性神经元（Aim 3.1）。然后我会刺激每个抑制神经元 在三个记忆阶段中的每一个期间在老年AD模型小鼠中进行分型以挽救目的1中鉴定的缺陷， 2和3.1（目标3.2）。这项研究将推进我们对海马体如何动态地 编码、检索和整合信息，它如何在AD中出错，以及如何处理， 《国家防治AD计划》的目标1B。我在空间记忆体内电生理学和AD方面的专长 使我有资格在基础和翻译的交叉点上从事这一新颖的研究。 神经科学这些目标将得到丽莎Giocomo博士，托尼 Wyss-Coray和Scott Linderman，John Huguenard、Ivan Soltesz和Gareth豪厄尔博士的顾问团队， 以及斯坦福大学的培训环境。这项研究将为我提供神经数据方面的重要培训 统计学，神经退行性疾病的机制，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抑制性神经元的作用开辟新的途径 在健康，老年和AD条件下，并促进我过渡到一个独立的教师职位。

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.