Neurobiological Mechanisms of Apathy in HAND

手部冷漠的神经生物学机制

• 批准号: 10202743
• 负责人: Rosemarie M Booze
• 金额: $ 36.63万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10202743
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adherence; Affect; Agonist; Atrophic; Attention; Autopsy; Basal Ganglia; Behavior; Behavioral; Biological Factors; Brain; Carrier Proteins; Cells; Chronic; Data; Development; Disease; Dopamine; Dopamine Receptor; Dopaminergic Cell; Elderly; Employment; Exhibits; Female; Food; Functional disorder; Goals; Growth; HIV; HIV-1; High Prevalence; Histologic; Impaired cognition; Impairment; Individual; Inflammation; Injury; Knowledge; Link; Literature; Longitudinal Studies; Measures; Mediating; Modeling; Motivation; Motor; Neuraxis; Neurobiology; Neurocognitive; Neurons; Nucleus Accumbens; Oxidative Stress; Paris, France; Pathology; Pathway interactions; Patients; Performance; Periodicity; Persons; Pharmaceutical Preparations; Population; Positioning Attribute; Prefrontal Cortex; Process; Proteins; Quality of life; Rattus; Reporting; Research; Research Personnel; Rewards; Role; Sensory; Silver; Synapses; System; Testing; Therapeutic; Time; Training; Transgenes; Transgenic Organisms; Treatment Efficacy; Vertebral column; Viral; Viremia; antiretroviral therapy; biological sex; brain tissue; cohort; design; dopamine system; dopamine transporter; drug efficacy; human old age (65+); improved; in vivo; instrumental activity of daily living; latent infection; longitudinal design; male; model development; motivational processes; neurobiological mechanism; neurochemistry; neuroinflammation; neuropsychiatry; novel; preadolescence; prevent; programs; prospective; protein expression; putamen; reinforcer; relating to nervous system; response; translational model; viral RNA

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.

项目概要： 冷漠是HIV-1+个体中常见的动机改变，影响30-60%的人口， 尽管有抗逆转录病毒治疗在HIV-1阳性个体中冷漠的高流行率是最大的问题之一 艾滋病毒临床医生和研究人员面临的挑战;迫切需要制定治疗方法 对于手。在前瞻性纵向设计中使用HIV-1转基因（Tg）大鼠模型，我们将测试 假设的发展和进展的失调的动机过程相关的 HIV-1是突触树突病理学、神经炎症和多巴胺氧化应激的结果 (DA)系统在前额叶皮层-基底神经节轴，和动机失调的轨迹将 可以用靶向中皮质边缘DA系统的治疗方法来改变。具体目标是：1） 建立HIV-1 Tg大鼠中动机失调的发展和进展， 用药物、食物和天然甜味剂测量，与感官和 活动混乱。神经认知功能障碍的进展将通过定期检查进行评估， 鉴于65岁以上艾滋病毒阳性患者呈指数增长，两 将检查雄性和雌性。2)确定CNS突触树突病理学的进展 在HIV-1的前额叶皮层（PFC）和中脑核的中型棘神经元（MSN）中， 转基因大鼠，重点是量化树突分支和棘参数的变化。具体地说， 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， 动机过程失调的基础。3)为了建立治疗失调的方法， 慢性低水平炎症和HIV-1蛋白暴露后的动机过程 目前使用的激动剂或拮抗剂，或新的药物，靶向已确定的DA系统， 功能障碍目前使用的激动剂或拮抗剂，或新的药物，靶向确定的DA 系统功能障碍，我们将机械地测试DA中神经生物学变化的功能作用。 受体和多巴胺转运蛋白（DAT）作为一种神经化学机制，如果不是介导， HIV-1转基因的慢性表达导致的动机失调。首先，我们将建立 最佳治疗窗口这些研究将确定突触改变的功能作用， 树突的复杂性，神经炎症和氧化应激作为神经生物学机制，如果 不起中介作用，由于HIV-1的慢性表达而导致的动机系统的失调 转基因。我们的纵向研究的计划目标是建立我们预测动机的能力。 作为HIV-1转基因的慢性表达的功能的失调，以提供更大的机制， 了解HIV-1引起的冷漠和DA系统功能障碍的相互关系，并改善 与HIV-1阳性个体相关的治疗选择，并改善他们的生活质量。