The Accumbens NMDA Receptor in HIV-induced Motivational Disorders

HIV 引起的动机障碍中的伏隔 NMDA 受体

• 批准号: 8011814
• 负责人: Yan Dong
• 金额: $ 7.48万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8011814
• 关键词: AIDS neuropathy; Acquired Immunodeficiency Syndrome; Address; Animal Model; Animals; Apoptosis; Attenuated; Behavior; Behavioral; Behavioral Assay; CREB-binding protein; CREB1 gene; Cessation of life; Clinical; Clinical Trials; Comorbidity; Coupled; Cyclic AMP; Data; Depressed mood; Desire for food; Development; Disease; Disease model; Elements; Emotional; Feedback; Goals; HIV; Human; In Vitro; Knowledge; Lead; Life; Link; Location; Measures; Mediating; Mental Depression; Mission; Modeling; Molecular; Motivation; Mus; N-Methyl-D-Aspartate Receptors; Nerve Degeneration; Neurons; Nitric Oxide; Nucleus Accumbens; Outcome; Output; Pathway interactions; Patients; Play; Prosencephalon; Proteins; Public Health; Receptor Signaling; Research; Role; Signal Transduction; Site; Structure; Symptoms; Synapses; Testing; Transgenic Mice; United States National Institutes of Health; Viral Proteins; Virus Diseases; Work; base; behavior measurement; disability; driving behavior; effective therapy; high risk behavior; human CREBBP protein; in vivo; innovation; neuron apoptosis; neuronal survival; neurotoxic; non-compliance; novel; prevent; receptor; receptor coupling; receptor-mediated signaling; response; suicidal; synaptic function; tool; ward

DESCRIPTION (provided by applicant): The HIV-associated emotional and motivational disorders (HEMDs) include severe depression, serious apathy, persistent sadness, and decreased appetite. These HEMDs cause non-compliance with treatment, an increase in high-risk behaviors, and suicidal death, and thus substantially impact the already-afflicted life of AIDS-patients. A gap in our knowledge that prevents us from developing effective treatments for HEMDs is that we do not know the neuronal mechanisms that mediate HEMDs. To address this knowledge gap, we will target the nucleus accumbens (NAc) because this site is one of the central targets for HIV-infection, and malfunction of the NAc results in a variety of emotional and motivational disorders similar to HEMDs. Our longterm goal is to identify the key molecular substrates in the NAc, the manipulation of which can prevent or ameliorate HEMDs. Our promising preliminary results suggest that the NR2A-containing N-methyl-Daspartate receptor (NMDAR) and its coupled signaling may be such key molecular substrates that can protect NAc neurons from the HIV insult. As an initial step toward our long-term goal, the objective of this R21 application is to 1) establish the relationship between HIV-induced NAc neurodegeneration and motivational deficits; and 2) determine the potential neuroprotective effect of manipulating the NMDAR-pathway in HIVinduced NAc neurodegeneration in a Tat-expressing mouse line. Tat is a neurotoxic protein released by HIV. Our central hypothesis is that Tat-induced NAc neurodegeneration is positively correlated with compromised motivational behaviors, and that activation of NR2A-containing NMDARs protects Tat-induced neurodegeneration of NAc neurons. Given that several NMDAR-based compounds have already been used in clinical trials, our proposed research may have immediate clinical impact on the treatment of HEMDs. Thus, our studies are highly relevant to the mission of the NIH to develop fundamental knowledge that will potentially help to reduce the burden of human disability. Guided by our promising preliminary data, our objective will be achieved by pursuing two specific aims: 1) Define the role of Tat-induced NAc neurodegeneration in HEMDs; and 2) Define the neuroprotective role of the NR2A-pathway in Tat-induced NAc neurodegeneration. Under both aims, we will use a line of transgenic mice in which expression of Tat can be temporally and quantitatively controlled. The proposed work is innovative because it will establish the first HEMD model linking the HIV-induced cellular and molecular changes to a detectable behavioral output. The proposed work also broadly and positively impacts the NeuroAIDS field as a whole in that the advanced behavioral and electrophysiological paradigms to be established are broadly applicable to studies of other HIV-induced neurodegenerative mechanisms. Furthermore, the NMDAR-based mechanism to be examined may have a general neuroprotective effect in other HIV-induced pathological conditions. PUBLIC HEALTH RELEVANCE: A set of devastating psychiatric symptoms, such as severe depression, profound apathy, persistent sadness, and decreased appetite, is often concurrent with Acquired Immunodeficiency Syndrome (AIDS) in Human Immunodeficiency Virus (HIV)-infected patients. This application will define the role of a subtype of NMDA receptors in the rescue of HIV-associated emotional and motivational disorders. The proposed research is highly relevant to public health, because the outcomes of our work may introduce a novel clinical approach to treat HIV-induced emotional and motivational disorders.

描述（由申请人提供）：与HIV相关的情绪和动机疾病（HEMD）包括严重的抑郁症，严重的冷漠，持续的悲伤和食欲下降。这些HEMD会导致不遵守治疗，高风险行为的增加和自杀死亡，从而实质上影响了已经影响的艾滋病患者生活。我们的知识差距阻止我们为HEMD开发有效的治疗方法，即我们不知道介导HEMD的神经元机制。为了解决这一知识差距，我们将针对伏隔核（NAC），因为该部位是HIV感染的核心目标之一，而NAC的故障导致了类似于HEMD的各种情绪和动机疾病。我们的长期目标是确定NAC中的关键分子底物，其操作可以预防或改善HEMD。我们有希望的初步结果表明，含NR2A的N-甲基 - 大赛受体（NMDAR）及其耦合信号传导可能是这样的关键分子底物，可以保护NAC神经元免受HIV损伤。作为朝着我们的长期目标迈出的第一步，R21应用的目的是1）建立艾滋病毒诱导的NAC神经变性与动机缺陷之间的关系； 2）确定在表达TAT的小鼠系中HIVAR诱导的NAC神经变性中操纵NMDAR-Pathway的潜在神经保护作用。 TAT是HIV释放的一种神经毒性蛋白。我们的中心假设是，TAT诱导的NAC神经退行性变性与受损的动机行为呈正相关，并且含NR2A的NMDAR的激活保护NAC神经元的TAT诱导的神经变性。鉴于已经在临床试验中使用了几种基于NMDAR的化合物，因此我们提出的研究可能会立即对HEMD的治疗产生临床影响。因此，我们的研究与NIH的使命高度相关，以发展基本知识，这有助于减轻人类残疾的负担。在我们有希望的初步数据的指导下，我们的目标将通过追求两个具体的目的来实现：1）定义TAT诱导的NAC神经变性在HEMD中的作用；和2）定义NR2A-Pathway在TAT诱导的NAC神经变性中的神经保护作用。在这两个目标下，我们都将使用一系列转基因小鼠，其中可以在时间上表达TAT的表达和定量控制。提出的工作具有创新性，因为它将建立第一个将HIV诱导的细胞和分子变化与可检测到的行为输出联系起来的HEMD模型。所提出的工作还广泛地对整个神经辅助领域产生了积极影响，因为要确定的先进的行为和电生理范式广泛地适用于其他HIV诱导的神经退行性机制的研究。此外，在其他HIV诱导的病理状况中，要检查的基于NMDAR的机制可能具有一般的神经保护作用。 公共卫生相关性：一系列毁灭性的精神病症状，例如严重的抑郁症，严重的冷漠，持续的悲伤和食欲下降，通常与可获得的免疫缺陷综合征（AIDS）在人类免疫缺陷病毒（HIV）感染的患者中同时发生。该应用将定义NMDA受体亚型在拯救与HIV相关的情绪和动机疾病中的作用。拟议的研究与公共卫生高度相关，因为我们工作的结果可能会引入一种新型的临床方法来治疗艾滋病毒引起的情绪和动机疾病。