Tat mediation of HIV-associated mood disorders via functional deficits in brain

Tat 通过大脑功能缺陷介导 HIV 相关情绪障碍

• 批准号: 8287532
• 负责人: Jay P. McLaughlin
• 金额: $ 42.72万
• 依托单位: TORREY PINES INST FOR MOLECULAR STUDIES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8287532
• 关键词: AIDS neuropathy; Accounting; Acoustics; Adherence; Affect; Amygdaloid structure; Animals; Anterior; Anxiety; Apoptosis; Astrocytes; Behavior; Behavior Disorders; Behavioral; Behavioral Model; Biological; Biological Assay; Boxing; Brain; Brain region; Cell Death; Cells; Characteristics; Comorbidity; Control Groups; Corticosterone; Dementia; Development; Disease; Dose; Doxycycline; Environment; Exhibits; Exposure to; Functional Magnetic Resonance Imaging; Functional disorder; Future; HIV; HIV Infections; HIV Seropositivity; HIV-1; Hippocampus (Brain); Image; In Situ Nick-End Labeling; Infection; Light; Link; Magnetic Resonance; Magnetic Resonance Imaging; Marble; Measures; Mediating; Mediation; Mental Depression; Messenger RNA; Microglia; Mood Disorders; Moods; Morbidity - disease rate; Mus; Nerve Degeneration; Neurologic; Neuronal Dysfunction; Neurons; Patients; Personal Satisfaction; Pharmaceutical Preparations; Prevalence; Proteins; Protocols documentation; Quality of life; Reporting; Resolution; Rodent; Social Interaction; Staining method; Stains; Stress Tests; Structure; Swimming; Synapses; Syndrome; System; Testing; Time; Transgenic Mice; Virus; Work; behavior measurement; blood oxygen level dependent; density; experience; gene induction; gray matter; in vivo; insight; mRNA Expression; macrophage; magnetic field; mind control; mood regulation; mortality; mouse model; neuroimaging; neuronal circuitry; neuropathology; neurotoxic; neurotoxicity; phrases; protein expression; release factor; research study; response; selective expression; social stress; tat Protein; theories; white matter; white matter change

DESCRIPTION (provided by applicant): Depression and anxiety are prevalent mood disorders symptomatic of the syndrome described as "NeuroAIDS," and pose significant problems for the treatment and well-being of HIV-positive patients. Unfortunately, the biological mechanisms linking HIV-related neuropathology to the dysfunction of neuronal circuitry and the progression of behavioral mood disorders are not well understood. Recent evidence suggests that HIV-accessory proteins such as Tat may spread throughout the brain from HIV-infected cells, producing neurotoxicity and changes in neuronal activity that could account for the behavioral changes. We hypothesize that Tat protein expression is sufficient to produce neurodegeneration and dysfunction of neuronal circuitry mediating mood, resulting in an increase of depression- and anxiety-like behaviors. This proposal utilizes the GT-tg transgenic mouse and its doxycycline-gene induction strategy for a controlled, selective expression of Tat protein in the brain. Induced GT-tg bigenic mice will be used to test the hypothesis with behavioral and imaging studies that Tat-mediated increases in depression- and anxiety-like behaviors are correlated with Tat-induced alterations in brain structure and function in regions associated with depression and anxiety, including the amygdala, anterior cingulate, orbitofrontal cortex and hippocampus. Behavioral studies with these mice will assess how Tat expression affects depression-like behaviors with the forced swim stress and social aversion tests. Behavioral experiments also will examine effects of Tat expression on anxiety-like behaviors using the open field, elevated plus maze, light-dark box, acoustic startle and marble burying tests. Assays of Tat mRNA and protein levels will correlate expression of Tat to the observed changes in behavior. In preliminary studies, Tat-induced mice spent less time than uninduced littermates in social interactions and more time immobile in forced swim stress tests, suggestive of a Tat-mediated increase in depression-like behavior. Tat-induced mice also demonstrated increased anxiety-related behaviors, with less time spent in open-field environments and a 3-fold increase in marble burying. Concurrently, we will examine the effects of Tat protein on brain structure and cell death using ex vivo magnetic resonance imaging (MRI) at ultra high magnetic field strength and TUNEL staining for apoptosis in Tat-induced animals. Preliminary ex vivo structural imaging studies documented significant reductions in the grey matter density of amygdala and hippocampus in Tat-expressing mice. Additionally, we will use BOLD functional MRI with corticosterone challenge to identify functional changes in brain regions associated with mood disorders resulting from varying levels of induction and duration of exposure to Tat protein and the response to a challenge dose of corticosterone. Overall, this project seeks to prove that functional and structural deficits can be detected in the brain circuitry of Tat-induced animals, thereby defining mechanisms by which Tat may mediate the mood disorders characteristic of NeuroAIDS.

描述（由申请人提供）：抑郁和焦虑是被描述为“神经艾滋病”综合征的常见情绪障碍，并且给艾滋病毒阳性患者的治疗和健康带来重大问题。不幸的是，将艾滋病毒相关的神经病理学与神经元回路功能障碍和行为情绪障碍的进展联系起来的生物学机制尚不清楚。最近的证据表明，Tat 等 HIV 辅助蛋白可能从 HIV 感染细胞扩散到整个大脑，产生神经毒性和神经元活动变化，从而导致行为变化。我们假设 Tat 蛋白表达足以产生神经变性和介导情绪的神经元回路功能障碍，从而导致抑郁和焦虑样行为的增加。该提案利用 GT-tg 转基因小鼠及其多西环素基因诱导策略来控制、选择性地在大脑中表达 Tat 蛋白。诱导的 GT-tg 双基因小鼠将用于通过行为和成像研究来检验这一假设，即 Tat 介导的抑郁和焦虑样行为的增加与 Tat 诱导的抑郁和焦虑相关区域的大脑结构和功能的改变相关，包括杏仁核、前扣带回、眶额皮质和海马体。对这些小鼠的行为研究将通过强迫游泳压力和社交厌恶测试来评估 Tat 表达如何影响抑郁样行为。行为实验还将使用开放场地、高架十字迷宫、明暗盒、声音惊吓和大理石埋藏测试来检验 Tat 表达对焦虑样行为的影响。 Tat mRNA 和蛋白质水平的测定将 Tat 的表达与观察到的行为变化相关联。在初步研究中，与未诱导的同窝小鼠相比，Tat 诱导的小鼠在社交互动中花费的时间更少，而在强迫游泳压力测试中不动的时间更多，这表明 Tat 介导的抑郁样行为增加。 Tat 诱导的小鼠还表现出与焦虑相关的行为增加，在露天环境中花费的时间减少，并且埋弹子的时间增加了 3 倍。同时，我们将使用超高磁场强度下的离体磁共振成像（MRI）和 TUNEL 染色来检查 Tat 蛋白对脑结构和细胞死亡的影响，以观察 Tat 诱导的动物的细胞凋亡。初步的离体结构成像研究表明，表达 Tat 的小鼠杏仁核和海马体的灰质密度显着降低。此外，我们将使用 BOLD 功能 MRI 和皮质酮挑战来识别与情绪障碍相关的大脑区域的功能变化，这些变化是由于不同的诱导水平和暴露于 Tat 蛋白的持续时间以及对皮质酮挑战剂量的反应而引起的。总体而言，该项目旨在证明在 Tat 诱导的动物的大脑回路中可以检测到功能和结构缺陷，从而确定 Tat 可能介导 NeuroAIDS 特征的情绪障碍的机制。