Methamphetamine, HIV, Neuroinflammation and Behavior

甲基苯丙胺、艾滋病毒、神经炎症和行为

• 批准号: 7388339
• 负责人: Rodney W Johnson
• 金额: $ 22.95万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7388339
• 关键词: AIDS Dementia Complex; Acquired Immunodeficiency Syndrome; Address; Affect; Animal Model; Area; Attention; Behavior; Behavioral; Brain; Cells; Cognition Disorders; Cognitive; Cognitive deficits; Corpus striatum structure; Daily; Development; Disease; Dopamine; Doxycycline; Drug abuse; Drug user; Exposure to; Fatigue; Frequencies; Glial Fibrillary Acidic Protein; Goals; HIV; HIV Envelope Protein gp120; HIV Infections; HIV-1; Hippocampus (Brain); Incidence; Individual; Infection; Inflammation; Inflammatory; Injection of therapeutic agent; Lead; Learning; Link; Localized; Measures; Mental Depression; Methamphetamine; Methodology; Microglia; Morbidity - disease rate; Motor; Motor Activity; Mus; Neurons; Numbers; Patients; Persons; Production; Proteins; Reporting; Research; Risk; Risk Behaviors; Serotonin; Sexually Transmitted Diseases; Site; Staining method; Stains; System; Techniques; Thinking; Tissues; Transgenic Organisms; United States; classical conditioning; cognitive change; cytokine; drug of abuse; experience; high risk sexual behavior; innovation; intraperitoneal; laser capture microdissection; motor deficit; motor learning; mouse model; neurobehavioral; neuroinflammation; neurotoxic; promoter; release factor; response; retinal rods; treatment effect

DESCRIPTION (provided by applicant): Methamphetamine (MA) is a common drug of abuse in the United States and is associated with increased frequency of high-risk sexual behavior leading to human immunodeficiency virus type 1 (HIV-1) exposure. Infection with HIV-1 can lead to HIV-associated dementia (HAD) and other co-morbidities like fatigue and depression. It has become apparent that HIV-1 infected individuals who abuse MA are more likely to experience neurobehavioral complications than are HIV-1 infected non-users. We propose that this is because MA sensitizes cells in the brain, particularly microglia, to HIV-1 proteins. HIV-1 infects microglial cells but because neurons are not productively infected by HIV-1, the development of neurobehavioral complications is thought to be due to soluble factors released by infected or activated microglia such as inflammatory cytokines. That MA abuse may activate or sensitize microglial cells and promote neuroinflammation in HIV-1 patients is highly relevant to HAD and other AIDS co-morbidities. Thus, if MA sensitizes the brain by increasing the number of activated microglia and/or potentiating the release of inflammatory cytokines and neurotoxic products in response to HIV-1 proteins, this might explain why infected drug users are more likely to develop neurobehavioral complications than infected non-users. Unfortunately, the relationship between MA abuse, neuroinflammation, and HAD and other AIDS co-morbidities has not been explored. Therefore, the goal of this proposal is to investigate if MA use and HIV-1 infection unite to exacerbate the cognitive and motor complications associated with HIV disease and produce a heightened neuroinflammatory state. In the first aim, mice sensitized to MA through daily i.p. injections will be injected i.c.v. with vehicle or HIV-1 gp120 and the cognitive effects of MA and gp120 will be explored by utilizing two different learning paradigms: a) an associative learning task that is considered striatal-dependent; and b) a spatial learning task that is considered hippocampal-dependent. This methodology allows for the delineation of cognitive changes that may occur due to alterations in these discrete brain areas. Furthermore, motor learning and coordination will be assessed on a Rota-rod. Similar studies will be conducted using a Tat transgenic mouse model in which targeted Tat expression is linked to a doxycycline-inducible GFAP promoter. The second aim will determine if MA sensitization exacerbates the production of inflammatory cytokines after exposure to HIV proteins. Inflammatory cytokines will be measured in hippocampal and striatal tissue obtained using laser capture microdissection techniques; and cytokine-positive microglia will be localized by immunohistochemical staining. Special attention is paid to the striatum because MA alters motor activity by inducing dopamine release at this site, and the hippocampus because it is densely populated with microglia and is involved in cognitive disorders that are evident in patients with HAD. In addition to inflammatory cytokines, treatment effects on the dopaminergic and serotoninergic systems will be measured. The proposed studies are critically needed to understand the insidious relationship between drug abuse, HIV-1 infection, and HAD. Methamphetamine abuse is associated with increased frequency of high-risk sexual behavior leading to HIV-1 exposure and it has become apparent that HIV-1 infected individuals who abuse MA are likely to experience more severe cognitive and motor complications than are non-users which may be due to an increase in neuroinflammation. Given the increasing number of HIV-1 infected persons that also abuse MA, a better understanding of how MA influences the neurobehavioral complications associated with HIV-1 infection is needed. Therefore, the goal of this proposal is to investigate if MA use and HIV-1 infection unite to exacerbate the cognitive and motor complications associated with HIV disease and produce a heightened neuroinflammatory state.

描述（由申请人提供）：甲基苯丙胺（MA）是美国常见的滥用药物，与导致人类免疫缺陷病毒1型（HIV-1）暴露的高危性行为频率增加相关。感染HIV-1可导致HIV相关性痴呆（HAD）和其他并发症，如疲劳和抑郁症。很明显，滥用MA的HIV-1感染者比HIV-1感染的非使用者更容易出现神经行为并发症。我们认为这是因为MA使大脑中的细胞，特别是小胶质细胞对HIV-1蛋白敏感。HIV-1感染小胶质细胞，但由于神经元不被HIV-1感染，神经行为并发症的发展被认为是由于感染或活化的小胶质细胞释放的可溶性因子，如炎性细胞因子。MA滥用可能激活或致敏小胶质细胞并促进HIV-1患者的神经炎症，这与HAD和其他AIDS合并症高度相关。因此，如果MA通过增加激活的小胶质细胞的数量和/或增强响应HIV-1蛋白的炎性细胞因子和神经毒性产物的释放来使大脑敏感，这可能解释了为什么受感染的吸毒者比受感染的非吸毒者更容易发展神经行为并发症。不幸的是，MA滥用，神经炎症，HAD和其他艾滋病合并症之间的关系尚未探讨。因此，本提案的目的是调查MA使用和HIV-1感染是否联合起来加剧与HIV疾病相关的认知和运动并发症，并产生高度的神经炎症状态。在第一个目标中，通过每日i. p.注射对MA致敏的小鼠将i. c. v.注射溶剂或HIV-1 gp 120，并将通过利用两种不同的学习范式探索MA和gp 120的认知效应：a）被认为是纹状体依赖性的联想学习任务;和B）被认为是纹状体依赖性的空间学习任务。这种方法允许描绘的认知变化，可能会发生由于这些离散的大脑区域的改变。此外，将在旋转杆上评估运动学习和协调。将使用达特转基因小鼠模型进行类似的研究，其中靶向的达特表达与多西环素诱导的GFAP启动子连接。第二个目标是确定MA致敏是否加剧了暴露于HIV蛋白后炎症细胞因子的产生。将在使用激光捕获显微切割技术获得的海马和纹状体组织中测量炎性细胞因子;并将通过免疫组织化学染色定位精氨酸阳性小胶质细胞。特别注意的是纹状体，因为MA通过诱导多巴胺释放在这个网站改变运动活动，和海马，因为它是密集的小胶质细胞，并参与认知障碍，这是明显的HAD患者。除炎性细胞因子外，还将测量对多巴胺能和多巴胺能系统的治疗效果。迫切需要拟议的研究来了解药物滥用，HIV-1感染和HAD之间的潜在关系。甲基苯丙胺滥用与导致HIV-1暴露的高风险性行为频率增加有关，并且已经明显的是，滥用MA的HIV-1感染者可能比非使用者经历更严重的认知和运动并发症，这可能是由于神经炎症的增加。鉴于越来越多的HIV-1感染者也滥用MA，需要更好地了解MA如何影响与HIV-1感染相关的神经行为并发症。因此，本提案的目的是调查MA使用和HIV-1感染是否联合起来加剧与HIV疾病相关的认知和运动并发症，并产生高度的神经炎症状态。