Neural network dysfunction in early HIV neuropathogenesis

HIV感染神经系统会导致慢性感染、炎症和许多人的认知能力下降 没有有效治疗的患者。炎症在疾病过程和起因的早期就出现了 进行性神经损伤，部分原因是激活的小胶质细胞和巨噬细胞释放的因子。在……里面 培养的神经元这些因素导致细胞内钙积聚，细胞骨架损伤和局灶性 肿胀，很像早期阿尔茨海默病(AD)的病理，表明疾病的共同底物 进步。在gp120转基因小鼠和AD小鼠模型中，我们最近发现了一种独特的Tau 积聚在神经性肿胀中。同样的Tau在小鼠的海马区自然积累 衰老和gp120 TG小鼠与p75NTR表达和Iba-1免疫反应的小胶质细胞平行 炎症、衰老和神经退化之间的重要联系。在初步多电极阵列中 (MEA)研究，这些神经损伤和Tau积聚的早期指标与外观相关 爆发式活动模式，尖峰频率增加，神经元密度降低 互连，所有网络功能障碍的迹象。在细胞水平上，高反应性与 随着受限的网络活动突显出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 抑制病机。我们提出了一系列实验，将在体外和体内提供补充 HIV相关小鼠模型中网络功能障碍时间发展的活体分析 发炎。Gp120Tg、Tau高表达、p75混合神经培养的体外研究 神经营养素受体缺陷和野生型小鼠将利用高含量的神经活动记录 4096电极培养格子、原代神经元钙成像、形态计量学和免疫细胞化学 探讨人类免疫缺陷病毒(HIV)病理在神经和网络功能障碍发展中的作用 无论是正常情况还是易患疾病的情况。平行研究将检验以下因素的相对贡献 小胶质细胞和HIV Tat蛋白。随后的微丝阵列活体记录检查海马区 Gp120转基因小鼠与Tau杂交后的中尺度神经网络活性、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是如何被修改为病理的 进步了。确认有网络功能障碍的小鼠将接受认知功能评估，这将是 SV2A型突触小泡突触丢失和小胶质细胞活化的MRI/PET研究 蛋白质探针11C-UCB-J和线粒体TSPO探针18F-PBR111。我们相信这一点 综合方法将识别和表征艾滋病毒相关的网络功能障碍，并打开新的 疾病改变治疗干预的途径。

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.