Cross-Species Studies of Risk Taking in METH, HIV, and Aging

冰毒、艾滋病毒和衰老的风险承担的跨物种研究

• 批准号: 8601375
• 负责人: ARPI MINASSIAN
• 金额: $ 27.99万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8601375
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adherence; Age; Aging; Alcohol or Other Drugs use; Animal Experimentation; Animal Model; Animals; Behavior; Behavioral; Biological; Clinical; Cognitive; Collaborations; Corpus striatum structure; DNA Damage; Decision Making; Disease; Funding; Gambling; General Population; Goals; HIV; HIV Infections; HIV Seropositivity; Human; Impairment; Incentives; Individual; Iowa; Learning; Life; Maps; Measures; Mediating; Methamphetamine; Methamphetamine dependence; Mitochondrial DNA; Modeling; Monitor; Motivation; Mus; Neurosciences; Novelty-Seeking Behaviors; Outcome; Pattern; Persons; Population; Prevention; Process; Psychological reinforcement; Public Health; Punishment; Recording of previous events; Request for Applications; Research; Rewards; Risk; Risk Behaviors; Risk-Taking; Substance Addiction; System; Telomere Shortening; Testing; Translating; Work; age effect; cognitive function; cohort; design; human study; human subject; indexing; mouse model; neurobiological mechanism; neuroimaging; preference; prepulse inhibition; protein expression; relating to nervous system; reward processing; social cognition; therapy design; transmission process; trend; white matter injury; willingness

HIV transmission risk behaviors are common and recalcitrant among persons with methamphetamine (METH) dependence, but their underlying cognitive and neurobiological mechanisms are not well understood. During the previous funding period we learned that METH dependence may differentially impact the expression of inhibitory deficits related to risk taking in the setting of HIV infection in humans and mouse models. Building on this work, the current application requests support for parallel human and animal research to determine the individual and combined effects of METH dependence, HIV infection and aging on risk taking. We will leverage our expertise in implementing cross-species measures by evaluating several important components of risk taking that will be isolated paradigmatically in humans and two mouse models of HIV: 1) Preference for risk, reward and/or novelty versus punishment avoidance, 2) motivation defined as willingness to work for a reward, and 3) inhibition. In the human study, we will test our hypothesis HIV and METH have differentiable effects on the multiple components that underlie risk taking in all 320 well-characterized subjects from the TMARC cohort that will be stratified by METH dependence, HIV serostatus, and age. We will also examine the impact of aging on the expression of risk behaviors in HIV and METH, as well as the unique effects of risk taking and its components on real-world outcomes (e.g., adherence) in our clinical groups. Shared human subjects with TMARC Project 2 will allow us to examine the neural substrates of risky decision-making, including neuroimaging indices of functional connectivity and white matter injury. The animal studies will employ two mouse models of HIV (i.e., constitutive gp120tg and conditional iTat-tg) with and without METH treatment that will be evaluated with cognitive paradigms that map directly on to those used with our human subjects. Collaborations with the TMARC Neuroimaging and Neuroscience and Animal Models Cores will us to parse out biological mechanisms of these critical cognitive functions in mouse models. The ultimate goal of this research is to propel the design prevention efforts that target specific components of risk taking in order to reduce HIV transmission.

艾滋病毒传播的危险行为是常见的和不确定的人与甲基苯丙胺 （METH）依赖，但其潜在的认知和神经生物学机制尚不清楚 明白在上一个资助期间，我们了解到甲基苯丙胺依赖可能会对 在人类和小鼠中HIV感染背景下与风险承担相关的抑制缺陷的表达 模型在这项工作的基础上，当前的应用程序请求支持并行的人类和动物 研究确定甲基苯丙胺依赖、艾滋病毒感染和衰老的单独和综合影响 关于冒险我们将利用我们的专业知识，通过评估几个跨物种措施， 风险承担的重要组成部分，将在人类和两个小鼠模型中典型分离 1）对风险、奖励和/或新奇事物的偏好与避免惩罚的偏好，2）动机定义为： 愿意为奖励而工作; 3）抑制。在人类研究中，我们将测试我们的假设艾滋病毒和 METH对所有320项风险承担的多个组成部分具有不同的影响 来自TMARC队列的充分表征的受试者，将按METH依赖、HIV 血清状态和年龄。我们还将研究衰老对艾滋病毒中危险行为表达的影响 和METH，以及风险承担及其组成部分对现实世界结果的独特影响（例如， 在我们的临床团队中。与TMARC项目2共享的人类受试者将使我们能够检查 风险决策的神经基质，包括功能连接的神经影像学指标， 白色物质损伤。动物研究将采用两种HIV小鼠模型（即，组成型gp 120 tg和 条件性iTat-tg），有和没有METH治疗，将用认知范式进行评价， 直接映射到我们人类实验对象身上。与TMARC Neuroimaging合作， 神经科学和动物模型核心将我们解析出这些关键认知的生物机制 在小鼠模型中的功能。本研究的最终目标是推动设计预防工作， 针对具体的风险因素，以减少艾滋病毒的传播。