Hiv-1 Infection: Central Serotonergic Activity and its Health Implications

HIV-1 感染：中枢血清素活性及其健康影响

• 批准号: 7849019
• 负责人: ADARSH M KUMAR
• 金额: $ 19.13万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7849019
• 关键词: AIDS/HIV problem; Adherence; Adult; Affect; African American; Age; Amygdaloid structure; Area; Attenuated; Autopsy; Basal Ganglia; Beck depression inventory; Behavior; Behavioral; Biogenic Amines; Brain; Brain Stem; Brain region; Caucasians; Caucasoid Race; Cells; Cessation of life; Complex; Consent; Data; Development; Disease; Disease Progression; Ethnic group; Etiology; Focal Infection; Functional disorder; Future; Globus Pallidus; HIV-1; Health; Highly Active Antiretroviral Therapy; Hippocampus (Brain); Hispanics; Human; Hydroxyindoleacetic Acid; Hypothalamic structure; Impairment; In Vitro; Individual; Infection; Intervention; Invaded; Investigation; Life; Life Expectancy; Mental Depression; Mental Health; Morbidity - disease rate; National NeuroAids Tissue Consortium; Nerve Degeneration; Neuraxis; Neurobiology; Neurocognitive; Neurons; Neuropathogenesis; Paroxetine; Penetration; Peripheral; Pharmaceutical Preparations; Physiological; Play; Quality of life; RNA; Regulation; Reporting; Risk Factors; Role; Sampling; Serotonin; Substantia nigra structure; System; Testing; Tissue Sample; Tissues; United States National Institutes of Health; Viral Load result; Virus; Woman; adverse outcome; assault; brain tissue; caudate nucleus; design; frontal lobe; improved; inhibitor/antagonist; men; mortality; nervous system disorder; neuronal cell body; neuropsychiatry; progressive neurodegeneration; public health relevance; putamen; raphe nuclei; reuptake; serotonin receptor; treatment strategy; viral RNA

DESCRIPTION (provided by applicant): This R21 exploratory application tests the hypothesis that the serotonergic activity will be adversely impacted in different brain regions of HIV-1+ cases. HIV-1 enters the central nervous system (CNS) immediately after initial infection and localizes itself with variable concentration in different brain regions, resulting in progressive neurodegeneration. It is proposed that HIV-1 induced degeneration of neurons of high monoaminergic activity, such as that of serotonin (5- hydroxytryptamine, 5-HT) may have a wide range of health implications, including depression and other neuropsychiatric disorders, neurological abnormalities, and neurocognitive impairment. Depression is one of the most common neuropsychiatric disorders in a large number of HIV-1 infected individuals, and affects their quality of life, interferes in adherence to treatment, and is a risk factor for disease progression, and mortality. The etiology of depression in HIV-1 infection is found to be complex and may involve a number of contributing factors including dysfunctions of neurobiological systems particularly, the central serotonin system. However, to date, investigations on the central serotonergic mechanisms and their relationship with depression in HIV-1 infection has remained under investigated and poorly understood. In order to investigate the central serotonergic mechanisms in HIV-1 infected individuals, the postmortem brain tissues, as well as the data related with assessment of depression during life of the corresponding individuals are required. In recent years, both of these requirements have been accomplished by the brain banks established by the NIH sponsored National NeuroAIDS Tissue Consortium (NNTC), which has made possible the availability of well characterized samples of different brain regions of HIV-1+ and HIV-1- cases, and has provided the opportunity for investigations such as those proposed in this project. It is proposed to investigate the central serotonergic activity in the postmortem tissue samples from different brain regions {raphe nuclei, hypothalamus, hippocampus, basal ganglia (caudate nucleus, putamen, globus pallidus), substantia nigra, amygdala and fronto-cortical regions (cingulate and subgenual cortical areas) as well as CSF} of a total of 40 adult men and women (HIV-1+ cases, N=25; HIV-1- cases N=15), age 25-55 years, belonging to the three ethnic groups (Caucasian, African Americans, Hispanics), who consented during life to participate in the NNTC project. It is hypothesized that the levels of 5-HT as well as its metabolite, 5-hydroxyindoleacetic acid (5-HIAA) will be decreased in the above mentioned brain regions of HIV-1+ cases, compared to that in the same brain regions of HIV-1- cases; and that the 5-HT and 5-HIAA levels will be negatively correlated with the viral load in the same brain regions of HIV-1+ cases, as well as with depression scores assessed during life of the corresponding HIV-1+ individuals. We propose to examine the 5-HT and 5-HIAA levels in these brain regions of HIV-1+ individuals who were assessed during life, at least six months before death, for depression using Beck Depression Inventory (BDI), and investigate the relationship between the central regional 5-HTactivity and viral load in the same brain regions of HIV-1+ individuals, who were treated or not treated with HAART during life. The findings from this exploratory R-21 project will delineate the specific regional vulnerability to assault by HIV-1 with respect to 5-HT activity. Furthermore, the data will provide us with an opportunity for an RO1 application to investigate the other parameters of serotonergic mechanisms including 5-HT-receptors and 5-HT transporter/s in different brain regions of HIV-1 infected cases, and for exploring the possibility for new relevant strategies for treatment. PUBLIC HEALTH RELEVANCE: This R-21 proposal explores the impact of HIV-1 infection on the central nervous system serotonergic activity in different regions of post mortem brains of HIV/AIDS cases. It is proposed that HIV-1 induces neurodegeneration of various areas of the brain that are involved in serotonergic activity. We will determine the levels of 5-HT and its metabolite, 5-HIAA in the brain stem raphe nuclei, where the cell bodies of serotonergic neurons are located and 5-HT is synthesized, as well as in various other regions which are highly innervated with serotonergic projections, and are involved in a number of physiological and behavioral functions. The findings from this study will significantly enhance our understanding of the impact of HIV-1 induced central serotonergic deficits, that may be helpful in designing the intervention strategies that will contribute to modify the central serotonergic activity, and improve the quality of life of HIV-1 infected individuals.

描述（由申请方提供）：该R21探索性应用测试了以下假设：在HIV-1+病例的不同脑区域中，多巴胺能活性将受到不利影响。HIV-1在初次感染后立即进入中枢神经系统（CNS），并以不同的浓度定位于不同的脑区域，导致进行性神经变性。有人提出，HIV-1诱导的高单胺能活性神经元的变性，如血清素（5-羟色胺，5-HT）的变性，可能具有广泛的健康影响，包括抑郁症和其他神经精神障碍、神经异常和神经认知障碍。抑郁症是大量HIV-1感染者中最常见的神经精神障碍之一，影响他们的生活质量，干扰治疗依从性，是疾病进展和死亡的危险因素。HIV-1感染后抑郁症的病因被发现是复杂的，可能涉及许多促成因素，包括神经生物学系统功能障碍，特别是中枢5-羟色胺系统。然而，迄今为止，对HIV-1感染的中枢多巴胺能机制及其与抑郁症的关系的研究仍处于调查和了解甚少的状态。 为了研究HIV-1感染者的中枢神经系统机制，需要死后脑组织，以及与相应个体生活期间抑郁症评估相关的数据。近年来，这两项要求都已由NIH赞助的国家神经艾滋病组织联盟（NNTC）建立的脑库完成，这使得获得HIV-1+和HIV-1-病例不同脑区的良好表征样本成为可能，并为本项目中提出的研究提供了机会。建议研究死后不同脑区（中缝核、下丘脑、海马、基底神经节）组织样品中的中枢多巴胺能活动（尾状核、壳核、苍白球）、黑质、杏仁核和额皮质区（扣带和膝下皮质区）以及CSF），共40名成年男性和女性（HIV-1+病例，N=25; HIV-1-病例N=15），年龄25-55岁，属于3个种族群体（高加索人、非裔美国人、西班牙裔），在生命期间同意参加NNTC项目。 假设与HIV-1-病例的相同脑区相比，HIV-1+病例的上述脑区中5-HT及其代谢产物5-羟基吲哚乙酸（5-HIAA）的水平将降低;并且5-HT和5-HIAA水平将与HIV-1+病例的相同脑区域中的病毒载量负相关，以及与相应HIV-1+个体的生活期间评估的抑郁评分。我们建议检查5-HT和5-HIAA水平在这些大脑区域的HIV-1+个人在生活中，至少6个月前死亡，抑郁症使用贝克抑郁量表（BDI）进行评估，并调查中央区域5-HT活性和病毒载量之间的关系，在相同的大脑区域的HIV-1+个人，谁是治疗或不治疗HAART在生活中。从这个探索性的R-21项目的结果将描绘特定的区域脆弱性攻击的HIV-1方面的5-HT活性。此外，这些数据将为我们提供一个机会，RO 1的应用程序，以调查其他参数的肾上腺素能机制，包括5-HT受体和5-HT转运蛋白/s在不同的大脑区域的HIV-1感染的情况下，并探索新的相关治疗策略的可能性。公共卫生关系：这项R-21提案探讨了HIV-1感染对HIV/AIDS病例死后大脑不同区域中枢神经系统多巴胺能活性的影响。有人提出，HIV-1诱导参与多巴胺能活动的大脑各个区域的神经变性。我们将确定脑干中缝核中5-HT及其代谢物5-HIAA的水平，脑干中缝核是多巴胺能神经元的细胞体所在地，5-HT是合成的，以及在其他各种区域中，这些区域高度受多巴胺能投射的支配，并参与许多生理和行为功能。本研究的结果将显著增强我们对HIV-1诱导的中枢多巴胺能功能缺陷的理解，这可能有助于设计干预策略，这将有助于改变中枢多巴胺能活性，改善HIV-1感染者的生活质量。