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

• 批准号: 10204135
• 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
• 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/10204135
• 关键词: Acceleration; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; 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

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 没有有效治疗的患者。炎症在疾病过程的早期出现，原因 渐进性神经损害部分是由于活化的小胶质细胞和巨噬细胞释放的因素。在 培养的神经元这些因素诱导细胞内钙积累，细胞骨架损伤和局灶性 肿胀，就像早期的阿尔茨海默氏病（AD）病理学一样，表明疾病的常见底物 进展。在GP120转基因小鼠和AD小鼠模型中，我们最近确定了tau的独特形式 这积累在神经肿胀中。同一tau在海马自然积累 衰老和GP120 TG小鼠与P75NTR表达以及IBA-1免疫反应性小胶质细胞并联 炎症，衰老和神经变性之间的重要联系。在初步的多电极阵列中 （MEA）研究，这些神经损伤和TAU积累的早期指标与外观相关 爆发样活动模式，峰值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，超反应性形成鲜明对比 由于受到限制的网络活动强调了更好地了解神经元如何变化的需求 功能转换为网络功能。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 抑制发病机理。我们提出了一系列实验，这些实验将在体外和 在HIV相关的小鼠模型中，网络功能障碍的时间开发的体内分析 炎。 GP120 Tg的混合神经培养物的体外研究，Tau过表达P75 神经营养蛋白受体缺乏和野生型小鼠将利用高含量的神经活动记录 4096电极培养网格，原代神经元的钙成像，形态计量学和免疫细胞化学化学 检查HIV病理对神经和网络功能障碍发展的贡献 正常和疾病易发条件。平行研究将检查 小胶质细胞和HIV TAT蛋白。随后在体内记录以检查海马的阵列记录 中尺度神经网络活动，沟通和功能在GP120 TG小鼠中交叉到tau 过表达和p75不足的小鼠将开始揭示网络行为如何修饰为病理 进展。将评估具有确认网络功能障碍的小鼠的认知功能，这将是 与SV2A突触囊泡的突触损失和小胶质激活的MRI/PET研究相关 蛋白质探针11C-UCB-J和线粒体TSPO探针18F-PBR111。我们相信这一点 综合方法将识别并表征与HIV相关的网络功能障碍并打开新的 修改治疗干预的疾病途径。