Neural circuit mechanisms underlying AD-related memory impairments

项目摘要/摘要 在美国，痴呆症和与年龄相关的认知能力下降是一个日益严重的健康问题。 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 预计个人会患上阿尔茨海默病(AD)。我们建议研究与AD相关的详细信息 神经回路机制将是开发新的AD治疗策略的关键，通过使用两种 互补的AD小鼠模型，具有许多人类AD的特征。我们的指导性假设是 AD相关神经退行性变导致记忆回路连接和神经集合的不适应性改变 海马体的活动。我们最近在小鼠身上发现，非典型的小关节背部- 对海马CA1的投射是物体位置学习的基础，这是阿尔茨海默病的一个显著损害。这条线路有 最近在人脑中被发现。我们将测试我们的假设，在双向的显著损害 阿尔茨海默病大鼠海马CA1区与下丘脑亚核之间的信息加工 进步。在目标1中，我们将确定AD样神经退行性变对局部和全局回路的影响 与海马CA1区和亚兴奋性神经元的联系。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CA1和亚神经元的联系和输出投射 逆行单突触狂犬病追踪和顺行单突触单纯疱疹病毒追踪。 此外，我们将在年龄匹配的对照组和AD的死后人类海马区进行实验 患者绘制人脑中的亚CA1通路并了解这一大脑回路的详细变化 AD患者。在目标2中，我们将测试这一假说，即类AD小鼠的神经退行性变会降解对象- 海马CA1区和亚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，我们将使用活体微型显微成像来检查和比较空间 CA1兴奋性神经元和亚兴奋性神经元在野外探险、跟踪和运动中的表现 基于路线运行和目标位置记忆任务。因此，我们可以纵向跟踪类似AD的渐进式 功能缺陷。在目标3中，我们将确定是否可以通过模式化刺激来挽救空间记忆 阿尔茨海默病模型小鼠的非典型亚CA1反投影。人类文献和我们的初步数据 表明我们提议的阿尔茨海默病研究具有很高的相关性。总之，拟议的研究将 促进我们对AD病因的特定神经机制的理解，并有助于识别新的 人类的治疗靶点。

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.