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

基本信息

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
项目类别：
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

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

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项目摘要

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与一系列神经认知缺陷有关，称为人类免疫缺陷病毒相关的神经认知障碍（手），这可能会对患者的生活产生巨大影响。这些条件下的机制尚不完全清楚，但是有证据表明，在大脑区域与HIV相关的神经病理学与与手相关的行为缺陷一致。例如，纹状体中有病理学的证据，纹状体是中断多巴胺系统的组成部分，并且在功能中具有重要作用，包括但不限于运动控制，学习和记忆以及动机。上面概述的效果的一个潜在介体是HIV蛋白TAT。感染的神经胶质释放TAT和其他病毒蛋白以及促炎细胞因子。 TAT表达与动物模型和HIV患者的多巴胺系统的纹状体，神经炎症和多巴胺系统的改变有关。研究还表明，在与HIV相关神经病理学的患者中TAT的表达增加。 TAT诱导的神经病理学的潜在机制是研究的活跃领域和收敛数据，这表明Toll样受体（TLR）（例如TLR4）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。手工产生的缺陷最终以患者的行为表达。因此，提出的研究的主要目标是确定使用诱导的TAT TAT转基因小鼠模型来确定TAT表达对颅内自我刺激（ICS）的后果。 ICSS是一种临床前行为模型，取决于脑电路，它特别脆弱地诱导了TAT诱导的神经病理学。该模型通常用于探索药物与滥用相关作用的基础机制，并且还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基础机制。该建议旨在调整ICS来检查TAT表达的行为效应，并将对该终点的影响与在神经解剖学模型中所证明的病理相关联。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用TLR4拮抗剂（+）纳洛酮治疗来阻止。总之，该提案的目的旨在阐明TAT诱导的神经退行性和行为障碍的功能后果和机制，而TLR4拮抗剂（+）纳洛酮将作为治疗这些与HIV相关的病理学的候选药物进行评估。