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

滥用甲基苯丙胺和艾滋病毒引起的神经变性可能会导致与年龄相关的大脑加速变化，从而加剧艾滋病毒+老年人群的认知障碍。HLV诱导的神经变性部分涉及包膜糖蛋白gp20和非结构蛋白Tat。在之前的资助期间，我们发现GPL20的表达导致成年小鼠的翻转学习和执行功能的特定缺陷，当与冰毒接触时，导致进一步的空间学习障碍。我们还发现，gp120的表达增加了伏隔核中的多巴胺转运体水平，降低了海马区的钙结合蛋白水平，这可能是观察到的认知缺陷的基础。这一更新应用程序将通过分别模拟HIV对大脑的慢性和急性影响的GPL 20和ITAT转基因小鼠模型来研究衰老和冰毒对认知功能的影响，从而扩展目前的发现。老年小鼠将暴露在冰毒中，在一系列认知测试中进行测试(目标1)，并使用TMARC核心资源接受神经病理和成像分析(目标2)。据预测，与年轻成年小鼠相比，衰老和冰毒暴露将增加gp120和TAT表达导致的认知缺陷，并导致更明显的神经病理，增加炎症和氧化应激。在TMARC中使用相同的小鼠模型和冰毒暴露，将有助于解释该项目获得的结果，并将其与在小鼠身上进行补充行为和神经病理学测试的其他项目的数据进行交叉比较。该项目通过在动物中评估直接类似于人类研究中使用的认知和神经成像措施，增强了TMARC的翻译潜力，并交叉告知我们未来的研究方向。该项目将提高我们对老年慢性HIV感染患者认知缺陷的神经生物学机制的理解，并可能有助于确定针对HIV+冰毒使用者神经退行性变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.