Examination of the Functional Consequences of HIV-1 Tat on Motivated Behavior

HIV-1 Tat 对动机行为的功能影响的检查

• 批准号: 8516355
• 负责人: Laurence L. Miller
• 金额: $ 2.17万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-16 至 2013-12-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8516355
• 关键词: AIDS Dementia Complex; Address; Affect; Agonist; Animal Model; Area; Behavior; Behavioral; Behavioral Model; Binding; Blood - brain barrier anatomy; Brain; Cognition Disorders; Cognitive; Competence; Corpus striatum structure; Data; Dendrites; Dendritic Spines; Deterioration; Disease; Dose; Electrodes; Functional disorder; Gene Expression; Goals; HIV; HIV Infections; HIV tat Protein; HIV-1; Human; Impaired cognition; Impairment; Implant; Implanted Electrodes; Infection; Inflammatory; Isomerism; Knowledge; Learning; Measures; Mediator of activation protein; Memory; Mental Depression; Mental disorders; Modeling; Monitor; Morphine; Morphology; Motivation; Mus; Naloxone; Nerve Degeneration; Neuraxis; Neurocognitive; Neurocognitive Deficit; Neuroglia; Neurons; Opiate Addiction; Opioid; Pathology; Patients; Performance; Pharmaceutical Preparations; Play; Procedures; Prosencephalon; Proteins; Research; Role; Self Stimulation; Severities; Structure; TLR4 gene; Testing; Therapeutic; Time; Toll-like receptors; Training; Transgenic Mice; Viral Proteins; Work; behavioral impairment; cytokine; density; design; dopamine system; dopaminergic neuron; high risk; macrophage; median forebrain bundle; mesolimbic system; motivated behavior; motor control; mouse model; nervous system disorder; neuroinflammation; neuropathology; neurotoxicity; novel; pre-clinical; receptor function; research study; response; toll-like receptor 4; tool

DESCRIPTION (provided by applicant): HIV-1 is associated with a range of neurocognitive deficits referred to as Human Immunodeficiency Virus-Associated Neurocognitive Disorders (HAND) which can have a dramatic impact on patients' lives. The mechanisms underlying these conditions are not entirely known, but there is evidence of HIV-associated neuropathology in brain areas that are consistent with the behavioral deficits associated with HAND. For instance, there is evidence of pathology in the striatum, which is a component of the mesolimbic dopamine system, and has an important role in functions including but not limited to, motor control, learning and memory, and motivation. One potential mediator of the effects outlined above is the HIV protein Tat. Infected glia release Tat and other viral proteins, as well as proinflammatory cytokines. Tat expression has been associated with synapto-dendritic changes in the striatum, neuroinflammation and alterations in the dopamine system in animal models and HIV patients. Research also suggests increased expression of Tat in patients presenting HIV-associated neuropathology. The underlying mechanisms of Tat-induced neuropathology are an active area of research and convergent data suggest a role for toll-like receptors (TLR) such as TLR4. TLR4 gene expression is correlated with neurodegeneration in HIV patients, and Tat and other HIV proteins increase the expression of TLRs. The deficits produced by HAND are ultimately expressed in the behavior of patients. Therefore, a primary goal of the proposed research is to determine the consequences of Tat expression on intracranial self-stimulation (ICSS) using an inducible Tat transgenic mouse model. ICSS is a preclinical behavioral model that is dependent on brain circuitry that is particularly vulnerable t Tat-induced neuropathology. This model is commonly used to explore the mechanisms underlying the abuse-related effects of drugs, and has also been used to examine mechanisms underlying other human disorders that are associated with dysfunction of forebrain dopaminergic circuitry. This proposal aims to adapt ICSS to examine the behavioral effects of the expression of Tat and to correlate effects on this endpoint with the pathology that has been demonstrated in neuroanatomical models. This proposal will also test the hypothesis that Tat-induced neurotoxicity and behavioral impairment can be blocked by treatment with the TLR4 antagonist (+)naloxone. Together, the aims of this proposal are designed to clarify the functional consequences and mechanisms of Tat-induced neurodegeneration and behavioral impairment, and the TLR4 antagonist (+)naloxone will be evaluated as a candidate medication to treat these HIV-related pathologies.

描述（由申请人提供）：HIV-1 与一系列被称为人类免疫缺陷病毒相关神经认知障碍 (HAND) 的神经认知缺陷相关，这会对患者的生活产生巨大影响。这些病症背后的机制尚不完全清楚，但有证据表明大脑区域中与 HIV 相关的神经病理学与 HAND 相关的行为缺陷一致。例如，有证据表明纹状体存在病理学现象，纹状体是中脑边缘多巴胺系统的组成部分，在包括但不限于运动控制、学习和记忆以及动机等功能中发挥重要作用。 上述效应的一种潜在介质是 HIV 蛋白 Tat。受感染的神经胶质细胞释放 Tat 和其他病毒蛋白，以及促炎细胞因子。在动物模型和 HIV 患者中，Tat 表达与纹状体突触树突变化、神经炎症和多巴胺系统改变有关。研究还表明，出现 HIV 相关神经病理学的患者中 Tat 表达增加。 Tat 诱导的神经病理学的潜在机制是一个活跃的研究领域，汇聚数据表明 TLR4 等 Toll 样受体 (TLR) 的作用。 TLR4 基因表达与 HIV 患者的神经变性相关，Tat 和其他 HIV 蛋白会增加 TLR 的表达。 HAND 产生的缺陷最终表现在患者的行为上。因此，本研究的主要目标是使用可诱导的 Tat 转基因小鼠模型确定 Tat 表达对颅内自我刺激（ICSS）的影响。 ICSS 是一种临床前行为模型，依赖于特别容易受到 Tat 诱导的神经病理学影响的大脑回路。该模型通常用于探索药物滥用相关作用的潜在机制，也已用于检查与前脑多巴胺能回路功能障碍相关的其他人类疾病的潜在机制。该提案旨在采用 ICSS 来检查 Tat 表达的行为影响，并将对该终点的影响与神经解剖模型中已证实的病理学相关联。该提案还将检验以下假设：Tat 诱导的神经毒性和行为障碍可以通过 TLR4 拮抗剂 (+) 纳洛酮治疗来阻断。 总之，该提案的目的旨在阐明 Tat 诱导的神经变性和行为障碍的功能后果和机制，并且 TLR4 拮抗剂 (+) 纳洛酮将作为治疗这些 HIV 相关病理的候选药物进行评估。