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（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，从而对艾滋病患者本已痛苦的生活产生重大影响。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。为了解决这一知识缺口，我们将靶向丘脑核（NAc），因为该部位是HIV感染的中心靶点之一，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，对其进行操纵可以预防或改善HEMD。我们有希望的初步结果表明，含NR 2A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损伤的关键分子底物。作为实现我们长期目标的第一步，R21申请的目的是1）建立HIV诱导的NAc神经变性和动机缺陷之间的关系; 2）确定在表达Tat的小鼠系中操纵NMDAR通路在HIV诱导的NAc神经变性中的潜在神经保护作用。达特是一种由HIV释放的神经毒性蛋白。我们的中心假设是，Tat诱导的NAc神经变性与受损的动机行为呈正相关，并且含有NR 2A的NMDAR的激活保护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NIH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特定的目标来实现：1）定义Tat诱导的NAc神经变性在HEMD中的作用; 2）定义NR 2A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品系，其中达特的表达可以在时间上和定量上得到控制。这项工作是创新的，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。拟议的工作也广泛和积极的影响NeuroAIDS领域作为一个整体，在先进的行为和电生理学的范例建立广泛适用于其他艾滋病毒引起的神经退行性机制的研究。此外，待检查的基于NMDAR的机制可能在其他HIV诱导的病理条件下具有一般神经保护作用。

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.