Neural circuit mechanisms underlying AD-related memory impairments

AD 相关记忆障碍的神经回路机制

基本信息

批准号：
10121076
负责人：
XIANGMIN XU
金额：
$ 192.13万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
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：
2020-09-11 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10121076
关键词：
Adult Age Age-associated memory impairment Alzheimer associated neurodegeneration Alzheimer like pathology Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Amyloid beta-Protein Amyloid deposition Animals Autopsy Axon Back Behavior Behavioral Brain Cells Data Defect Dementia Disease Disease Progression Elderly Environment Etiology Experimental Designs Genetic Head Health Hippocampus (Brain)Human Image Impairment Individual Knock-in Knock-in Mouse Lead Learning Link Literature Location Maps Measures Memory Memory impairment Microscope Modeling Morphologic artifacts Mus Mutation Nerve Degeneration Neurons Neurosciences Output Pathogenicity Pathologic Pathway interactions Pattern Performance Physiological Population Publishing Rabies Research Resolution Route Running Simplexvirus Specific qualifier value Techniques Testing Time Tracer Transgenic Mice United States Wild Type Mouse aged base behavior test behavioral impairment excitatory neuron experimental study improved in vivo information processing memory encoding microscopic imaging mouse model neural circuit neural correlate neuromechanism new therapeutic target optogenetics overexpression prevent relating to nervous system spatial memory treatment strategy

项目摘要

Project Summary / Abstract Dementia and age-related cognitive decline is an escalating major health concern in the United States. Approximately 20% of the US population will be 65 or older by year 2030, and roughly 8 million of these individuals are expected to suffer from Alzheimer’s disease (AD). We propose to examine detailed AD-related neural circuit mechanisms that will be critical for developing new AD treatment strategies by use of two complementary AD mouse models, which share many features of human AD. Our guiding hypothesis is that AD-related neurodegeneration causes maladaptive changes of memory circuit connections and neural ensemble activities in the hippocampus. We discovered recently in the mouse that non-canonical subicular back- projections to hippocampal CA1 underlie object-place learning, a prominent impairment in AD. This circuit has been recently identified in human brain. We will test our hypothesis that significant impairments in bidirectional information processing between hippocampal CA1 and the subiculum (SUB) develop over time during AD progression. In Aim 1, we will determine the effect of AD-like neurodegeneration on local and global circuit connections to hippocampal CA1 and SUB excitatory neurons. We will map and compare circuit input connections and output projections of excitatory CA1 and SUB neurons in adult control, and AD-like mice using retrograde monosynaptic rabies tracing and anterograde monosynaptic herpes simplex virus (HSV) tracing. Further, we will perform experiments in postmortem human hippocampus of aged-matched control and AD patients to map the SUB-CA1 pathway in human brains and understand detailed changes of this brain circuit in AD patients. In Aim 2, we will test the hypothesis that neurodegeneration in AD-like mice degrades object- location memory encoded by hippocampal CA1 and SUB excitatory neurons. To map neuronal activity to behavioral performance, we will use in vivo miniature microscopic imaging to examine and compare spatial representations of CA1 excitatory neurons and SUB excitatory neurons during open-field exploration, track- based route-running and object-location memory tasks. Thus, we can longitudinally track progressive AD-like functional defects. In Aim 3, we will determine whether spatial memory can be rescued by patterned stimulation of the non-canonical SUB-CA1 back-projection in the AD model mice. Human literature and our preliminary data show high relevance of our proposed research for Alzheimer’s disease. Together, the proposed research will advance our understanding of specific neural mechanisms underlying AD etiology and help to identify new therapeutic targets in humans.

项目概要/摘要痴呆症和与年龄相关的认知能力下降是美国日益严重的主要健康问题。到 2030 年，大约 20% 的美国人口将达到 65 岁或以上，其中大约 800 万我们建议对患有阿尔茨海默病 (AD) 的个体进行详细检查。神经回路机制对于通过使用两种方法开发新的 AD 治疗策略至关重要互补的 AD 小鼠模型，具有人类 AD 的许多特征，我们的指导假设是： AD 相关的神经变性导致记忆回路连接和神经系统的适应不良变化我们最近在小鼠身上发现了非典型的下皮回活动。对海马 CA1 的投射是物体位置学习的基础，这是 AD 中的一个突出障碍。最近在人类大脑中发现了这种现象，我们将检验我们的假设，即双向性存在显着损伤。 AD 期间海马 CA1 和下托 (SUB) 之间的信息处理随着时间的推移而发展在目标 1 中，我们将确定 AD 样神经变性对局部和整体回路的影响。与海马 CA1 和 SUB 兴奋性神经元的连接我们将绘制并比较电路输入。成年对照和 AD 样小鼠中兴奋性 CA1 和 SUB 神经元的连接和输出预测逆行单突触狂犬病追踪和顺行单突触单纯疱疹病毒 (HSV) 追踪。此外，我们将在年龄匹配的对照和 AD 死后人类海马体中进行实验患者绘制人脑中的 SUB-CA1 通路图并了解该脑回路的详细变化在目标 2 中，我们将检验 AD 样小鼠的神经变性会导致物体退化的假设。由海马 CA1 和 SUB 兴奋性神经元编码的位置记忆将神经元活动映射到。行为表现，我们将使用体内微型显微成像来检查和比较空间 CA1 兴奋性神经元和 SUB 兴奋性神经元在旷场探索、跟踪过程中的表征因此，我们可以纵向跟踪渐进的类似 AD 的任务。在目标 3 中，我们将确定空间记忆是否可以通过模式刺激来挽救。 AD 模型小鼠中的非规范 SUB-CA1 反投影的人类文献和我们的初步数据。表明我们提出的研究与阿尔茨海默氏病具有高度相关性，该研究将共同发挥作用。我们对特定神经机制的理解推进了AD病因学的发展，并有助于识别新的神经机制人类的治疗目标。