Neuroimaging and Neuropathic Substrates of Cognitive Deficits in Mouse Models of HIV, METH and Aging

甲基苯丙胺（冰毒）滥用和艾滋病毒引起的神经退行性变可能导致与年龄相关的大脑变化加速，从而加剧老年艾滋病毒+人群的认知缺陷。hlv诱导的神经退行性变部分涉及包膜糖蛋白gpl20和非结构蛋白Tat。在之前的资助期内，我们发现gpl - 20的表达在成年小鼠中诱导了逆转学习和执行功能的特异性缺陷，并且当与甲基苯甲胺暴露结合时，会导致空间学习的进一步损害。我们还发现gp120的表达增加了伏隔核中多巴胺转运蛋白的水平，降低了海马中钙结合蛋白的水平，这可能是观察到的认知缺陷的基础。这项更新的应用将通过研究衰老和甲基安非他明对gpl 20和iTat转基因小鼠模型认知功能的影响来扩展当前的发现，分别模拟HIV对大脑的慢性和急性影响。老年小鼠将暴露于冰毒中，进行一系列认知测试（目的1），并使用TMARC Core资源进行神经病理和成像分析（目的2）。据预测，与年轻的成年小鼠相比，衰老和甲基甲氧胺暴露会增加gp120和TAT表达引起的认知缺陷，导致更明显的神经病理、炎症和氧化应激增加。在TMARC中使用相同的小鼠模型和甲基安非他明暴露将有助于解释和交叉比较本项目获得的结果与其他在小鼠中进行补充行为和神经病理学测试的项目的数据。本项目通过在动物中评估与人类研究直接类似的认知和神经成像测量，增强了TMARC的转化潜力，并交叉告知我们未来的研究方向。该项目将提高我们对慢性艾滋病毒感染的老年个体认知缺陷的神经生物学机制的理解，并可能有助于确定治疗艾滋病毒+冰毒使用者神经变性和认知缺陷的治疗目标。

Neurodegeneration induced by methamphetamine (METH) abuse and HIV may result in accelerated age-related brain changes leading to exacerbated cognitive deficits in the aged HIV+ population. HlV-induced neurodegeneration involves, in part, the envelope glycoprotein gpl20 and the nonstructural protein Tat. During the previous funding period we showed that gpl 20 expression induced specific deficits in reversal learning and executive function in adult mice and, when combined with METH exposure, resulted in further impairments of spatial learning. We also found that gp120 expression increased dopamine transporter levels in the nucleus accumbens and decreased calbindin levels in the hippocampus that may underlie the observed cognitive deficits. This renewal application will expand the current findings by investigating the impact of aging and METH on cognitive function in the gpl 20 and iTat transgenic mouse models that mimic the chronic and acute effects of HIV on the brain, respectively. Aged mice will be exposed to METH, tested in a battery of cognitive tests (Aim 1) and subjected to neuropathological and imaging analyses (Aim 2) using the TMARC Core resources. It is predicted that aging and METH exposure will augment cognitive deficits induced by gp120 and TAT expression and result in more pronounced neuropathology, increased inflammation and oxidative stress, compared to younger adult mice. The use of identical mouse models and METH exposure within the TMARC will facilitate the interpretation and cross comparisons of the results obtained in this project with data from other projects conducting complementary behavioral and neuropathological testing in mice. This project enhances the translational potential of TMARC by assessing in animals cognitive and neuroimaging measures that are directly analogous to those used in human studies, and cross-inform our future research directions. This project will improve our understanding of the neurobiological mechanisms underiying cognitive deficits in aging individuals with chronic HIV infection and may help identify targets for the development of therapies for neurodegeneration and cognitive deficits in HIV+ METH users.