UNDERSTANDING ALTERED NEURONAL DENDRITE MORPHOLOGY IN A NHP MODEL OF HIV

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 人体免疫缺陷病毒（艾滋病毒）感染是一个全球性的健康负担，影响到全世界约4 000万人。 超过一半的感染者患有神经系统症状，从轻度认知缺陷到严重的痴呆和运动障碍;然而，感染艾滋病毒后神经系统改变的细胞机制仍不清楚。 该项目利用从接种猴免疫缺陷病毒（SIV）的恒河猴中收集的组织样本作为艾滋病毒的模型。 本研究的目的是建立一个时间过程中的神经元形态和连接的变化后，SIV感染不同的大脑区域，可能有助于观察到的神经功能缺损的HIV患者。 我们的初步研究集中在海马，与空间认知功能相关的大脑区域，其中有证据表明感染艾滋病毒的患者死后组织中的神经元形态发生了改变。 我们的初步数据表明，接种SIV后，一个复杂但强大的变化模式发生在海马CA 1子域，三突触通路的终端区锥体神经元的树突复杂性。 SIV感染后，我们观察到的乔木在基底树突内的总量增加，和相应的增加，在分支间段的长度，这表明树突段延伸超出其正常的终端领域在这些神经元。 相反，我们没有观察到在顶端树突的总乔木长度的增加，但相反，发现分支段的数量增加，并相应减少间分支长度，表明顶端树突乔木经历重新排列的方式与新的分支点的增加。 这些结果是重要的，因为树突复杂性和长度的变化是神经元放电模式变化和大脑内网络特性变化的关键指标。 我们的研究结果表明，网络发射改变海马神经元的方式，可能取决于不同的传入神经支配的顶端与基底树突。 这些结果与尸检大脑中海马神经元树突状细胞减少的发现相反，可能表明神经元结构的显著重排先于神经元的退行性变化。 我们现在已经扩展了对感染和对照动物海马神经元的分析，包括其他海马子区域，CA 3和齿状回，因为这三个区域支持可能受到SIV感染差异影响的认知功能的不同方面。 我们也开始检查背侧丘脑的神经元，这是一个对注意力功能和感觉门控至关重要的区域。 我们将继续收集样本进行RNA分析，并将使用这些样本和在TNPRC收集的存档标本，以确定树突状形态的改变是否与关键信号分子（如谷氨酸受体及其相关信号分子）的变化平行发生。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Human immunodeficiency virus (HIV) infection is a global health burden, affecting an estimated 40 million people worldwide. Over half those infected suffer from neurological symptoms, ranging from mild cognitive deficits to severe dementia and motor disorders; however the cellular mechanisms underlying neurological alterations following infection with HIV remain unclear. This project makes use of tissue samples collected from rhesus macaque monkeys inoculated with the simian immuno-deficiency virus (SIV), as a model for HIV. The aim of this study is to establish a time-course for changes in neuronal morphology and connectivity following SIV infection in distinct brain regions that are likely to contribute to neurological deficits observed in patients with HIV. Our preliminary studies have focused on the hippocampus, a region of brain associated with spatial cognitive functions, and in which there is evidence for altered neuronal morphology in post-mortem tissue from patients infected with HIV. Our preliminary data indicate that following inoculation with SIV, a complex but robust pattern of changes occurs in the dendrite complexity of pyramidal neurons within the hippocampal CA1 subfield, the terminal zone of the tri-synaptic pathway. Following SIV infection, we observed an increase in the total amount of arbor within basal dendrites, and a corresponding increase in the inter-branch segment length, suggesting that dendritic segments are extending beyond their normal terminal fields within these neurons. In contrast, we did not observe an increase in total arbor length in apical dendrites, but instead found an increase in the number of branch segments, and a corresponding reduction in inter-branch length, suggesting that apical dendrite arbor undergoes re-arrangement in a manner consistent with the addition of new branch-points. These results are significant, because alterations in dendrite complexity and length are key indicators of changes in firing patterns of neurons, and of network properties within the brain. Our findings suggest that network firing is altered in hippocampal neurons in a manner that may depend on distinct afferent innervation of apical vs. basal dendrites. These results are in contrast to findings in post-mortem brain that display reduced dendritic arbor in hippocampal neurons, and may suggest that significant rearrangement of neuronal architecture precedes degenerative changes in neurons. We have now extended our analyses of hippocampal neurons from infected and control animals to include other hippocampal subfields, the CA3 and dentate gyrus, since these three regions support distinct aspects of cognitive function that may be differentially affected by SIV infection. We have also begun examining neurons within the dorsal thalamus, a region critical for attentional functions and sensory gating. We are continuing to collect samples for RNA analyses, and will use these, and archival specimens collected at the TNPRC in order to determine whether alterations in dendritic morphology occur in parallel with changes in key signaling molecules, such as glutamate receptors and their associated signaling molecules.