Neural network dysfunction in early HIV neuropathogenesis

HIV早期神经发病机制中的神经网络功能障碍

基本信息

批准号：
9751991
负责人：
RICK B MEEKER
金额：
$ 38.88万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9751991
关键词：
Acceleration Aging Alzheimer&apos s Disease Antibodies Appearance Axon Behavior Behavioral Calcium Calcium Signaling Cells Cognition Cognition Disorders Cognitive Cognitive deficits Communication Deposition Development Disease Disease Progression Early Diagnosis Early treatment Electrodes Electrophysiology (science)Fostering Frequencies Generations Goals HIV HIV Envelope Protein gp120 HIV Infections HIV tat Protein Hippocampus (Brain)Image Impaired cognition In Vitro Inflammation Inflammatory Intervention Lead Link Magnetic Resonance Imaging Microelectrodes Microglia Mitochondria Mus NGFR Protein Nerve Degeneration Nervous system structure Neuronal Dysfunction Neurons Neuropathogenesis Neurophysiology - biologic function Pathogenesis Pathogenicity Pathology Patients Pattern Peptides Phenotype Positron-Emission Tomography Process Property Proteins Series Swelling Synapses Synaptic Vesicles Therapeutic Intervention Transgenes Transgenic Mice Transgenic Organisms Translating Translations Wild Type Mouse aging hippocampus chronic infection cognitive function density design effective therapy experimental study immunocytochemistry immunoreactivity improved in vivo indexing insight macrophage morphometry mouse model multi-electrode arrays nervous system infection network dysfunction neural network neurodevelopment neuron development normal aging novel overexpression preservation prevent relating to nervous system release factor support network tau Proteins tau aggregation tau expression tau phosphorylation tau-1 transcriptional coactivator p75 treatment strategy uptake

项目摘要

HIV infection of the nervous system results in chronic infection, inflammation and cognitive decline in many patients with no effective treatments. Inflammation appears early in the disease process and causes progressive neural damage due, in part, to factors released by activated microglia and macrophages. In cultured neurons these factors induce intracellular calcium accumulation, cytoskeletal damage and focal swelling, much like the early Alzheimer disease (AD)pathology, suggesting a common substrate for disease progression. In gp120 transgenic mice and AD mouse models we recently identified a unique form of Tau that accumulated in the neuritic swellings. The same Tau accumulated naturally in the hippocampus of aging and gp120 Tg mice in parallel with p75NTR expression and Iba-1 immunoreactive microglia suggesting an important link between inflammation, aging and neurodegeneration. In preliminary multielectrode array (MEA) studies, these early indices of neural damage and Tau accumulation correlated with the appearance of burst-like activity patterns, increased spike frequencies and a decreased density of neuron interconnections, all signs of network dysfunction. At the cellular level, hyperresponsiveness contrasted with the restricted network activity highlighting the need to better understand how changes in neuronal function translate to network function. Treatment strategies targeted to these early, reversible manifestations of the disease process have the potential to stabilize cognitive function and perhaps suppress pathogenesis. We propose a series of experiments that will provide complementary in vitro and in vivo analyses of the temporal development of network dysfunction in mouse models of HIV-associated inflammation. In vitro studies of mixed neural cultures from gp120 Tg, Tau overexpressing, p75 neurotrophin receptor deficient and wild type mice will utilize high content recording of neural activity on 4096 electrode culture grids, calcium imaging of primary neurons, morphometry and immunocytochemistry to examine the contribution of HIV pathology to the development of neural and network dysfunction under both normal and disease prone conditions. Parallel studies will examine the relative contribution of microglia as well as HIV Tat protein. Subsequent microwire array recording in vivo to examine hippocampal mesoscale neural network activity, communication and function in gp120 Tg mice crossed to Tau overexpressing and p75 deficient mice will begin to reveal how network behavior is modified as pathology progresses. Mice with confirmed network dysfunction will be evaluated for cognitive function which will be correlated with MRI/PET studies of synaptic loss and microglial activation with the SV2A synaptic vesicle protein probe 11C-UCB-J and the mitochondrial TSPO probe 18F-PBR111, respectively. We believe this integrated approach will identify and characterize HIV-associated network dysfunction and open new avenues for disease modifying therapeutic intervention.

神经系统的艾滋病毒感染会导致许多人的慢性感染、炎症和认知能力下降没有有效治疗方法的患者。炎症出现在疾病过程的早期并导致进行性神经损伤部分归因于激活的小胶质细胞和巨噬细胞释放的因子。在在培养的神经元中，这些因素会诱导细胞内钙积累、细胞骨架损伤和局灶性损伤。肿胀，很像早期阿尔茨海默病 (AD) 病理学，表明疾病有一个共同的基础进展。我们最近在 gp120 转基因小鼠和 AD 小鼠模型中发现了一种独特形式的 Tau 积聚在神经炎肿胀中。同样的 Tau 蛋白在海马体中自然积累衰老和 gp120 Tg 小鼠与 p75NTR 表达和 Iba-1 免疫反应性小胶质细胞平行，表明炎症、衰老和神经退行性变之间的重要联系。在初步的多电极阵列中 (MEA) 研究表明，这些神经损伤和 Tau 积累的早期指标与外观相关爆发式活动模式、尖峰频率增加和神经元密度降低互连，网络功能障碍的所有迹象。在细胞水平上，高反应性与受限的网络活动强调需要更好地了解神经元的变化功能转化为网络功能。针对这些早期、可逆的治疗策略疾病过程的表现有可能稳定认知功能，也许抑制发病机制。我们提出了一系列实验，将在体外和体内提供补充 HIV相关小鼠模型网络功能障碍时间发展的体内分析炎。 gp120 Tg、Tau 过表达、p75 混合神经培养物的体外研究神经营养素受体缺陷型和野生型小鼠将利用高内容的神经活动记录 4096 个电极培养网格、原代神经元钙成像、形态测量和免疫细胞化学研究艾滋病毒病理学对神经和网络功能障碍发展的贡献正常情况和易患病情况。平行研究将检验以下方面的相对贡献：小胶质细胞以及 HIV Tat 蛋白。随后进行体内微丝阵列记录以检查海马 gp120 Tg 小鼠与 Tau 杂交的中尺度神经网络活动、通讯和功能过度表达和 p75 缺陷的小鼠将开始揭示网络行为如何被病理改变取得进展。将评估已确认网络功能障碍的小鼠的认知功能与 SV2A 突触小泡突触丢失和小胶质细胞激活的 MRI/PET 研究相关分别为蛋白质探针 11C-UCB-J 和线粒体 TSPO 探针 18F-PBR111。我们相信这一点综合方法将识别和描述与艾滋病毒相关的网络功能障碍，并开辟新的途径改变疾病治疗干预的途径。