The Accumbens NMDA Receptor in HIV-induced Motivational Disorders

描述(申请人提供)：HIV相关的情绪和动机障碍(HEMD)包括严重的抑郁，严重的冷漠，持续的悲伤，和食欲下降。这些HEMD导致不遵守治疗，高危行为增加，以及自杀死亡，从而极大地影响了艾滋病患者本已饱受折磨的生活。我们知识中的一个空白阻碍了我们开发有效的治疗HEMDs的方法，那就是我们不知道调节HEMDs的神经机制。为了解决这一知识缺口，我们将目标是伏隔核(NAC)，因为这个部位是HIV感染的中心靶点之一，而NAC的故障会导致各种类似于HEMD的情绪和动机障碍。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-D-天冬氨酸受体(NMDAR)及其偶联信号可能是保护NAC神经元免受HIV攻击的关键分子底物。作为迈向我们长期目标的第一步，这项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)在表达TAT的小鼠系中，确定在HIV诱导的NAC神经变性中操纵NMDAR途径的潜在神经保护作用。Tat是一种由HIV释放的神经毒性蛋白质。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，而含有NR2A的NMDARs的激活保护了TAT诱导的NAC神经元的神经变性。鉴于几种基于NMDAR的化合物已经用于临床试验，我们拟议的研究可能会对HEMDs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发展基础知识的使命高度相关，这可能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目标来实现：1)确定TAT诱导的NAC神经变性在HEMD中的作用；2)确定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，我们将使用一种转基因小鼠，在其中TAT的表达可以在时间和数量上进行控制。这项拟议的工作具有创新性，因为它将建立第一个HEMD模型，将艾滋病毒诱导的细胞和分子变化与可检测的行为输出联系起来。这项拟议的工作也对整个神经艾滋病领域产生了广泛和积极的影响，因为即将建立的先进的行为和电生理范式广泛适用于其他艾滋病毒诱导的神经退化机制的研究。此外，将被检测的基于NMDAR的机制可能在其他HIV诱导的病理条件下具有普遍的神经保护作用。 与公共卫生相关：在感染人类免疫缺陷病毒(HIV)的患者中，一系列破坏性的精神症状，如严重抑郁、极度冷漠、持续悲伤和食欲下降，往往与获得性免疫缺陷综合征(AIDS)并发。这项应用将确定NMDA受体的一个亚型在拯救艾滋病毒相关的情绪和动机障碍中的作用。这项拟议的研究与公共卫生高度相关，因为我们的工作成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。

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.