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: 8225250
• 负责人: Yan Dong
• 金额: $ 2.42万
• 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 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8225250
• 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; Immunologic Deficiency Syndromes; 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; Virus Diseases; Work; base; behavior measurement; disability; driving behavior; effective therapy; high risk behavior; human CREBBP protein; in vivo; innovation; man; neuron apoptosis; neuronal survival; neurotoxic; non-compliance; novel; prevent; public health relevance; 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 相关的情绪和动机障碍 (HEMD) 包括严重抑郁、严重冷漠、持续悲伤和食欲下降。这些 HEMD 会导致治疗不依从、高危行为增加和自杀死亡，从而严重影响艾滋病患者本已饱受折磨的生活。阻碍我们开发有效治疗 HEMD 的知识差距是我们不知道介导 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 感染的中心目标之一，NAc 的功能障碍会导致与 HEMD 类似的各种情绪和动机障碍。我们的长期目标是确定 NAc 中的关键分子底物，对其进行操作可以预防或改善 HEMD。我们有希望的初步结果表明，含有 NR2A 的 N-甲基-Daspartate 受体 (NMDAR) 及其偶联信号可能是保护 NAc 神经元免受 HIV 损伤的关键分子底物。作为实现我们长期目标的第一步，R21 应用的目标是 1) 建立 HIV 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，在 HIV 诱导的 NAc 神经变性中操纵 NMDAR 通路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 神经变性与受损的动机行为呈正相关，并且含有 NR2A 的 NMDAR 的激活可以保护 Tat 诱导的 NAc 神经元神经变性。鉴于几种基于 NMDAR 的化合物已用于临床试验，我们提出的研究可能对 HEMD 的治疗产生直接的临床影响。因此，我们的研究与美国国立卫生研究院的使命高度相关，即开发可能有助于减轻人类残疾负担的基础知识。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目标来实现：1）定义 Tat 诱导的 NAc 神经变性在 HEMD 中的作用； 2) 定义 NR2A 通路在 Tat 诱导的 NAc 神经变性中的神经保护作用。在这两个目标下，我们将使用一系列转基因小鼠，其中 Tat 的表达可以在时间和数量上受到控制。拟议的工作具有创新性，因为它将建立第一个 HEMD 模型，将 HIV 诱导的细胞和分子变化与可检测的行为输出联系起来。拟议的工作还对整个 NeuroAIDS 领域产生了广泛而积极的影响，因为要建立的先进行为和电生理学范式广泛适用于其他 HIV 诱导的神经退行性机制的研究。此外，待检查的基于 NMDAR 的机制可能对其他 HIV 引起的病理状况具有一般的神经保护作用。 公共卫生相关性：人类免疫缺陷病毒 (HIV) 感染患者通常会出现一系列毁灭性的精神症状，例如严重抑郁、极度冷漠、持续悲伤和食欲下降。该应用将定义 NMDA 受体亚型在拯救 HIV 相关情绪和动机障碍中的作用。拟议的研究与公共卫生高度相关，因为我们的工作结果可能会引入一种新的临床方法来治疗艾滋病毒引起的情绪和动机障碍。