UNDERSTANDING ALTERED NEURONAL DENDRITE MORPHOLOGY IN A NHP MODEL OF HIV

了解 HIV NHP 模型中神经元树突形态的改变

• 批准号: 8173050
• 负责人: FIONA M INGLIS
• 金额: $ 3.94万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8173050
• 关键词: Affect; Apical; Architecture; Brain; Brain region; Cognitive deficits; Complex; Computer Retrieval of Information on Scientific Projects Database; Control Animal; DNA Sequence Rearrangement; Data; Dementia; Dendrites; Dorsal; Funding; Glutamate Receptor; Grant; HIV; Hippocampus (Brain); Infection; Institution; Length; Macaca mulatta; Modeling; Monkeys; Morphology; Neurologic; Neurons; Pathway interactions; Patients; Pattern; Property; RNA; Research; Research Personnel; Resources; Sampling; Signaling Molecule; Source; Specimen; Symptoms; Thalamic structure; Time; Tissue Sample; Tissues; United States National Institutes of Health; Virus; Virus Diseases; cognitive function; dentate gyrus; global health; hippocampal pyramidal neuron; motor disorder; nerve supply; sensory gating

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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 人类免疫缺陷病毒（HIV）感染是全球健康负担，影响了全球估计有4000万人。 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HIV后神经系统改变的细胞机制尚不清楚。 该项目利用从接种了与猿猴免疫缺陷病毒（SIV）接种的恒河猴的组织样品，作为HIV的模型。 这项研究的目的是在不同的大脑区域中建立一个时间课，以实现SIV感染后神经元形态和连通性的变化，这可能会导致HIV患者观察到的神经缺陷。 我们的初步研究集中于海马，这是与空间认知功能相关的大脑区域，其中有证据表明感染HIV患者的验尸组织中神经元形态的改变。 我们的初步数据表明，接种SIV后，在海马CA1子场（三突触途径的末端区域）内的锥体神经元的树突复杂性发生了一种复杂但可靠的变化模式。 SIV感染后，我们观察到基底树突内的乔木总数增加，并且分支间节段的长度相应增加，这表明树突段延伸到这些神经元内正常末端场的延伸。 相比之下，我们没有观察到根尖树突中的总乔木长度的增加，而是发现分支段数量的增加，分支间长度的相应减小，这​​表明顶端树突植物Arbor会以与新的分支相一致的方式进行重新排列。 这些结果是显着的，因为树突复杂性和长度的改变是神经元发射模式变化以及大脑内网络特性的关键指标。 我们的发现表明，在海马神经元中，网络发射的方式可能取决于顶端和基础树突的明显传入神经。 这些结果与验尸大脑中的发现相反，后者在海马神经元中表现出降低的树突状乔木，并且可能表明神经元结构的显着重排在神经元的退行性变化之前。 现在，我们已经扩展了对感染动物和控制动物的海马神经元的分析，以包括其他海马子场，CA3和齿状回，因为这三个区域支持可能受SIV感染差异影响的认知功能的不同方面。 我们还开始检查背丘脑内的神经元，这是注意力功能和感觉门控至关重要的区域。 我们将继续收集样品进行RNA分析，并将使用这些样品，并在TNPRC收集的档案标本，以确定树突形态的改变是否与关键信号分子的变化（例如谷氨酸受体及其相关信号分子）同时发生。