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

艾滋病毒传播危险行为在服用甲基苯丙胺者中很常见且顽固不化 (冰毒)依赖，但其潜在的认知和神经生物学机制不是很好 明白了。在之前的资助期间，我们了解到冰毒依赖可能会对 人类和小鼠HIV感染环境中与冒险行为相关的抑制缺陷的表达 模特们。在这项工作的基础上，当前的应用程序要求支持并行的人类和动物 确定冰毒依赖、艾滋病毒感染和衰老的单独和综合影响的研究 关于冒险。我们将利用我们在实施跨物种措施方面的专业知识，通过评估几个 冒险的重要组成部分将在人类和两个小鼠模型中范例地分离出来 艾滋病毒：1)偏好风险、回报和/或新鲜感，而不是避免惩罚；2)动机定义为 愿意为报酬而工作，以及3)抑制。在人体研究中，我们将测试我们的假设艾滋病毒和 冰毒对所有320种冒险行为背后的多种成分有不同的影响 来自TMARC队列的特征良好的受试者，将按冰毒依赖、艾滋病毒 血清状态和年龄。我们还将研究衰老对艾滋病毒危险行为表达的影响 和冰毒，以及冒险及其组成部分对现实世界结果的独特影响(例如， 坚持)在我们的临床小组中。与TMARC项目2共享的人类受试者将允许我们检查 风险决策的神经基础，包括功能连通性和 脑白质损伤。动物研究将使用两种HIV小鼠模型(即结构性gp120tg和 有条件的ITAT-TG)，无论是否接受冰毒治疗，都将通过以下认知范式进行评估 直接映射到我们的人类受试者使用的那些。与TMARC神经成像和 以神经科学和动物模型为核心，我们将解析出这些关键认知的生物学机制 在鼠标模型中的功能。这项研究的最终目标是推动设计预防工作 以风险承担的具体组成部分为目标，以减少艾滋病毒传播。

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.