Neural network dysfunction in early HIV neuropathogenesis

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 没有有效治疗的患者。炎症出现在疾病过程的早期， 进行性神经损伤，部分是由于活化的小胶质细胞和巨噬细胞释放的因子。在 这些因子诱导细胞内钙积聚、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）的病理，表明疾病的共同底物 进展在gp 120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形式， 聚集在神经炎的神经鞘中同样的Tau在海马体中自然积累， 与p75 NTR表达和Iba-1免疫反应性小胶质细胞平行的衰老和gp 120 Tg小鼠表明， 炎症、衰老和神经退化之间的重要联系。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， 放电频率增加，神经元密度降低 互联，所有网络功能障碍的迹象。在细胞水平上，高反应性与 有限的网络活动突出了更好地了解神经元变化的必要性， 功能转换为网络功能。治疗策略针对这些早期的，可逆的 疾病过程的表现有可能稳定认知功能， 抑制发病机制。我们提出了一系列的实验，将提供互补的体外和体内 在HIV相关的小鼠模型中网络功能障碍的时间发展的体内分析 炎症来自gp 120 Tg、Tau过表达、p75的混合神经培养物的体外研究 神经营养因子受体缺陷型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，原代神经元钙显像，形态计量学和免疫细胞化学 研究HIV病理学对神经和网络功能障碍发展的贡献， 正常和易患病的情况。平行研究将审查以下方面的相对贡献： 小胶质细胞以及HIV达特蛋白。随后在体微线阵列记录以检查海马 与Tau杂交的gp 120 Tg小鼠中的中尺度神经网络活动、通信和功能 过表达和p75缺陷小鼠将开始揭示网络行为是如何被修改为病理 进步。将评估具有确认的网络功能障碍的小鼠的认知功能， 与MRI/PET研究的突触丢失和SV 2A突触囊泡的小胶质细胞活化相关 蛋白探针11 C-UCB-J和线粒体TSPO探针18F-PBR 111。我们相信这 综合方法将识别和描述艾滋病毒相关的网络功能障碍， 改善疾病的治疗干预的途径。

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.