The Accumbens NMDA Receptor in HIV-induced Motivational Disorders

描述（由申请人提供）：hiv相关的情绪和动机障碍（HEMDs）包括严重抑郁，严重冷漠，持续悲伤和食欲下降。这些hemd导致不遵守治疗，高风险行为增加和自杀死亡，从而严重影响了艾滋病患者已经痛苦的生活。阻碍我们开发有效治疗hemd的知识缺口是，我们不知道介导hemd的神经元机制。为了解决这一知识缺口，我们将针对伏隔核（NAc），因为该部位是hiv感染的中心靶点之一，而NAc的功能障碍会导致各种类似于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。我们的初步结果表明，含有nr2a的n -甲基-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侵袭的关键分子底物。作为我们实现长期目标的第一步，这项R21应用的目标是：1)建立hiv诱导的NAc神经变性和动机缺陷之间的关系；2)确定调控nmdar通路对hiv诱导的tat表达小鼠NAc神经退行性变的潜在神经保护作用。这是一种由HIV释放的神经毒性蛋白。我们的中心假设是，tat诱导的NAc神经变性与动机行为受损正相关，并且含有nr2a的NMDARs的激活可以保护tat诱导的NAc神经元的神经变性。鉴于几种基于nmda的化合物已经用于临床试验，我们提出的研究可能会对hemd的治疗产生直接的临床影响。因此，我们的研究与NIH发展基础知识的使命高度相关，这些知识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)明确tat诱导的NAc神经变性在HEMDs中的作用；2)明确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，在这种小鼠中Tat的表达可以暂时和定量地控制。这项工作具有创新性，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的行为输出联系起来的HEMD模型。所提出的工作也将广泛而积极地影响整个神经艾滋病领域，因为所建立的先进行为和电生理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，待研究的基于nmdar的机制可能在其他hiv诱导的病理条件下具有一般的神经保护作用。

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.