Neurobiological Mechanisms of Apathy in HAND

项目总结： 冷漠是HIV-1+个体中一种常见的动机变化，影响到30%-60%的人口， 尽管接受了抗逆转录病毒治疗。在HIV-1+个体中，冷漠的高流行率是最大的 艾滋病毒临床医生和研究人员面临的挑战；迫切需要开发治疗方法 换手牌。使用HIV-1转基因(TG)大鼠模型进行前瞻性纵向设计，我们将测试 假设动机过程的失调的发展和进展与 HIV-1是突触树突病理、神经炎症和多巴胺氧化应激的结果 (DA)系统的前额叶皮质-基底节轴，以及动机失调的轨迹将 通过针对中皮质边缘DA系统的治疗方法进行改变。具体目标是：1) 建立HIV-1转基因大鼠AS动力失调的发生和发展 用药物、食物和天然增强剂测量，与感官和生理上的潜在变化不同 活动令人困惑。神经认知功能障碍的进展将通过定期测试进行评估， 青春期前到高龄，考虑到65岁以上艾滋病毒+患者的指数增长。两者都有 男性和女性将接受检查。2)建立中枢神经系统突触树突的病理进展 HIV-1伏核的前额叶皮质(PFC)和中棘神经元(MSN) TG大鼠，专注于量化树突分支和脊柱参数的变化。具体来说， 突触树突复杂性、神经炎症和氧化应激将在不同的队列中进行评估，如 激励过程失调的基础。3)确立失调症的治疗方法。 慢性低水平炎症和HIV-1蛋白暴露所致的激励过程 当前使用的激动剂或拮抗剂或新药，靶向于已识别的DA系统 功能障碍。使用当前使用的激动剂或拮抗剂或新药，靶向已识别的DA 我们将从机械上测试神经生物学变化在DA中的功能作用 受体和多巴胺转运体(DAT)作为一种神经化学机制参与，如果不是中介的话 由于HIV-1转基因的慢性表达而导致的动机失调。最初，我们将建立 最佳治疗窗口。这些研究将确定突触变化的功能作用- 树突状细胞的复杂性、神经炎症和氧化应激作为神经生物学机制参与了IF HIV-1慢性表达导致的动机系统失调，而不是中介 转基因。我们纵向研究的项目目标是建立我们预测动机的能力 作为HIV-1转基因慢性表达的功能失调，提供了更大的机制 了解HIV-1诱导的冷漠和DA系统功能障碍的相互关系，并改进 与艾滋病毒-1+患者相关的治疗选择，并改善他们的生活质量。

Project Summary: Apathy is a common motivational alteration in HIV-1+ individuals, affecting between 30-60% of the population, despite antiretroviral therapy. The high prevalence of apathy in HIV-1+ individuals is one of the biggest challenges facing HIV clinicians and researchers alike; there is a critical need to develop treatment approaches for HAND. Using the HIV-1 transgenic (Tg) rat model in a prospective longitudinal design, we will test the hypothesis that the development and progression of dysregulation of motivational processes associated with HIV-1 are consequent to synaptodendritic pathology, neuroinflammation and oxidative stress of the dopamine (DA) system in the prefrontal cortex-basal ganglia axis, and that the trajectory of motivational dysregulation will be altered with a therapeutic approach targeted to the mesocorticolimbic DA system. The specific aims are: 1) To establish the development and progression of motivational dysregulation in the HIV-1 Tg rat as measured with drug, food, and natural reinforcers, as distinct from potential changes in sensory and activity confounds. The progression of neurocognitive dysfunction will be assessed with periodic tests from pre-adolescence through advanced age, given the exponential growth of 65+ year old HIV+ patients. Both males and females will be examined. 2) To establish the progression of CNS synaptodendritic pathology in the prefrontal cortex (PFC) and medium spiny neurons (MSN) of the nucleus accumbens of the HIV-1 Tg rat with a focus on quantifying dendritic branching and spine parameter alterations. Specifically, synaptodendritic complexity, neuroinflammation, and oxidative stress will be assessed in different cohorts as the basis of the dysregulation of motivational processes. 3) To establish the treatment of the dysregulation of motivational processes consequent to chronic, low-level inflammation and HIV-1 protein exposure with currently used agonists or antagonists, or novel agents, targeted to the identified DA system dysfunction. With currently used agonists or antagonists, or novel agents, targeted to the identified DA system dysfunction we will mechanistically test the functional role of the neurobiological changes in the DA receptors and dopamine transporter (DAT) as a neurochemical mechanism contributing to, if not mediating, the motivational dysregulation consequent to chronic expression of the HIV-1 transgene. Initially we will establish the optimal therapeutic window. These studies will establish the functional role of alterations in synapto- dendritic complexity, neuroinflammation and oxidative stress as neurobiological mechanisms contributing to, if not mediating, the dysregulation of motivational systems consequent to chronic expression of the HIV-1 transgene. The program goal of our longitudinal studies is to establish our ability to predict motivational dysregulation as a function of chronic expression of the HIV-1 transgene, to provide a greater mechanistic understanding of the interrelationships of HIV-1-induced apathy and DA system dysfunction, and to improve the therapeutic options relevant to HIV-1+ individuals and improve their quality of life.