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

甲基苯丙胺（METH）滥用和艾滋病毒引起的神经变性可能会导致加速与年龄相关的大脑变化，导致老年艾滋病毒+人群的认知缺陷加剧。HIV诱导的神经变性部分涉及包膜糖蛋白gp120和非结构蛋白达特。在先前的资助期间，我们表明，gpl 20表达诱导成年小鼠的逆转学习和执行功能的特定缺陷，并且当与METH暴露结合时，导致空间学习的进一步损伤。我们还发现，gp120的表达增加了多巴胺转运蛋白在脑桥核的水平，降低了钙结合蛋白在海马体的水平，这可能是观察到的认知缺陷的基础。该更新申请将通过研究衰老和METH对gpl 20和iTat转基因小鼠模型中认知功能的影响来扩展当前的发现，所述gpl 20和iTat转基因小鼠模型分别模拟HIV对大脑的慢性和急性影响。将老年小鼠暴露于METH，在一系列认知测试中进行测试（目标1），并使用TMARC核心资源进行神经病理学和成像分析（目标2）。据预测，老化和METH暴露将增加gp120和达特表达诱导的认知缺陷，并导致更明显的神经病理学，增加炎症和氧化应激，与年轻的成年小鼠相比。在TMARC中使用相同的小鼠模型和METH暴露将有助于解释和交叉比较本项目中获得的结果与其他项目中进行小鼠补充行为和神经病理学测试的数据。该项目通过评估动物的认知和神经成像措施来增强TMARC的翻译潜力，这些措施与人类研究中使用的措施直接类似，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HIV感染老年人认知缺陷神经生物学机制的理解，并可能有助于确定HIV+ METH使用者神经变性和认知缺陷治疗方法的发展目标。

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.