Population Network Responses in AD Model Animals

AD 模型动物中的群体网络反应

基本信息

批准号：
10263296
负责人：
SRDJAN D ANTIC
金额：
$ 20.5万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
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：
2020-09-30 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10263296
关键词：
APP-PS1 Affect Age Alzheimer disease detection Alzheimer like pathology Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease diagnosis Alzheimer&apos s disease model Alzheimer&apos s disease pathology Amyloid beta-Protein Amyloid deposition Animal Disease Models Animal Diseases Animal Testing Animals Area Behavioral Biological Biological Assay Blindness Brain Breeding Cells Cerebral cortex Clinical Cognitive deficits Communication Control Animal Cortical Column Development Disease Early Intervention Electrodes Electrophysiology (science)Excitatory Synapse Experimental Designs Female Frequencies Functional disorder GABA-A Receptor Generations Genes Histologic Image Impaired cognition Impairment Inherited Inhibitory Synapse Injections Investigation Learning Light Long-Term Potentiation Measurement Measures Mediating Membrane Potentials Memory Memory impairment Mental Depression Methods Modeling Molecular Monitor Mus Nature Neurofibrillary Tangles Neuronal Dysfunction Neurons Neuropil Parents Pathologic Pathologic Processes Pathology Pathway interactions Photons Physiological Physiology Population Process Production Publishing Reproducibility Research Research Personnel Resolution Sampling Senile Plaques Signal Transduction Spottings Structure Symptoms Synapses Synaptic Membranes Synaptic Potentials Techniques Testing Time Training Transgenic Animals Viral abeta accumulation abeta deposition amyloid peptide base brain circuitry cell type cognitive function experimental group experimental study hippocampal pyramidal neuron imaging modality improved interest nervous system disorder neural circuit neuron loss new technology novel therapeutics optical imaging preempt rate of change response sex synaptic function tau Proteins tau aggregation tool trait voltage

项目摘要

Project Summary In Alzheimer’s disease (AD), the first signs of cognitive impairment are observed many years before a clinical AD diagnosis is established, and the loss of synaptic function in AD is evident long before any substantial loss of neurons. The excessive production or accumulation of β-amyloid peptide (Aβ) has been documented to have deleterious effects on synaptic activity by various mechanisms. Understanding the cellular and molecular mechanisms of the early AD-associated synaptic dysfunction (before the behavioral manifestations of severe learning and memory deficits) may be critical for the development of new therapies for slowing down the progression of AD. However, detection of the AD-associated changes in synaptic function among cortical circuits is technically challenging, especially so if it is needed in the earliest stages of the AD process, before the formation of plaques and tangles, when changes are small and difficult to spot. Where exactly, at which cortical layer, or which synapse, one should investigate? The current assays for detecting neural circuit deficiencies in AD model animals are based on traditional electrode electrophysiology and have several practical limitations including: poor spatial resolution, blindness for cell-types, and a labor intensive nature of experiments. New technologies bring an improved temporal and spatial resolution for monitoring activity in many neurons simultaneously, thus facilitating studies on brain circuitry disruptions in neurological disorders. We propose to use GEVI imaging (multi-cell optical imaging of the membrane potential changes using genetically-encoded voltage indicators). Our hypothesis is that “synaptic and neuronal dysfunctions emerge before significant Aβ deposition and pathological tau aggregation, and can be routinely detected by affordable imaging methods”. A simple and sensitive physiological assay for detecting changes in network physiology, prior to the substantial accumulation of the amyloid plaques or reproducible behavioral deficits in learning and memory, would accelerate the investigations of the earliest cellular and molecular changes mediated by the AD pathological process. Understanding the cellular and molecular mechanisms of the early AD-associated synaptic dysfunction (before the behavioral manifestations of the learning and memory deficits) may help the development of the new therapies for slowing down the progression of the AD.

项目摘要在阿尔茨海默氏病（AD）中，认知障碍的第一个迹象是在很多年之前观察到的建立了临床AD诊断，并且AD中突触功能的丧失是很久以前的证据任何严重的神经元丧失。 β-淀粉样肽的过量产生或积累（Aβ）已被证明通过各种机制删除了对合成活性的影响。了解早期AD相关突触的细胞和分子机制功能障碍（在严重学习和记忆定义的行为表现之前）可能是对于开发新疗法的至关重要，以减慢AD的发展。然而，从技术上看具有挑战性，特别是如果在广告过程的最早阶段需要的话，当变化较小且难以发现时，斑块和缠结的形成。到底在哪里，在哪个皮质层或哪个突触应该研究？目前检测的测定 AD模型动物中的神经回路缺陷基于传统电极电生理学并有几个实际局限性，包括：空间分辨率差，细胞类型的失明和实验的实验室密集型性质。新技术带来了改进的临时和空间简单地监测许多神经元的活动的分辨率，从而促进对大脑的研究神经系统疾病的电路中断。我们建议使用GEVI成像（多细胞光学）使用一般编码的电压指示剂对膜电位变化进行成像）。我们的假设是“突触和神经元功能障碍在明显的Aβ沉积和病理tau聚集，可以通过负担得起的成像方法常规检测到”。在检测网络生理变化之前，简单而敏感的物理测定淀粉样蛋白斑块的大量积累或繁殖行为定义了学习和记忆，会加速最早的细胞和分子变化的研究由广告遗传学过程介导。了解早期与广告相关的突触功能障碍（在学习的行为表现之前记忆定义）可能有助于开发新疗法以减缓广告的进展。