Neural circuit mechanisms underlying AD-related memory impairments

项目总结/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800万人 预期个体患有阿尔茨海默病（AD）。我们建议仔细研究与广告有关的 神经回路机制，这将是至关重要的开发新的AD治疗策略，通过使用两个 互补的AD小鼠模型，其共享人类AD的许多特征。我们的指导假设是， AD相关性神经退行性变导致记忆回路连接和神经系综的适应性改变 海马体的活动。我们最近在老鼠身上发现了非典型的下托背- 海马CA 1区的投射是物体位置学习的基础，这是AD的一个突出障碍。该电路具有 最近在人类大脑中被发现。我们将测试我们的假设，即双向 AD患者海马CA 1区和海马下托之间的信息处理随着时间的推移而发展 进展在目标1中，我们将确定AD样神经变性对局部和全局回路的影响 连接到海马CA 1和海马兴奋性神经元。我们将映射和比较电路输入 成年对照组和AD样小鼠兴奋性CA 1和CA 2神经元的连接和输出投射， 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组和AD的死后人海马中进行实验 患者绘制人脑中的SUB-CA 1通路，并了解大脑回路的详细变化， AD患者。在目标2中，我们将检验AD样小鼠的神经变性降解目标的假设， 位置记忆由海马CA 1区和海马神经元编码。将神经元活动映射到 行为表现，我们将使用在体内微型显微镜成像，检查和比较空间 CA 1兴奋性神经元和CA 2兴奋性神经元在旷场探索、跟踪、 基于路由运行和对象定位内存任务。因此，我们可以纵向跟踪进行性AD样 功能缺陷在目标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模型小鼠的非典型SUB-CA 1反向投射。人类文献和我们的初步数据 显示出我们所提出的阿尔茨海默病研究的高度相关性。总之，拟议的研究将 推进我们对AD病因学的特定神经机制的理解，并帮助识别新的 人体内的治疗靶点。

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.