Microglial modulation of neurocircuits in HIV/cocaine comorbidity

HIV/可卡因共病中神经回路的小胶质细胞调节

• 批准号: 10762502
• 负责人: Rosemarie M Booze
• 金额: $ 66.97万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10762502
• 关键词: Acceleration; Acute; Address; Affect; Animals; Architecture; Assessment tool; Behavior; Brain; Cell Culture Techniques; Choice Behavior; Chronic; Clinical; Cocaine; Cocaine Abuse; Consequences of HIV; Cytoskeleton; Dendritic Spines; Dopamine; Drug Addiction; Drug Exposure; Drug abuse; Drug usage; Dysmorphology; Excision; Executive Dysfunction; Exhibits; Exposure to; F-Actin; Female; Functional disorder; Future; Genes; Goals; Growth; HIV; HIV Infections; HIV-1; HIV-associated neurocognitive disorder; In Vitro; Individual; Infection; Knowledge; Measures; Medial; Mediating; Microglia; Microtubule-Associated Proteins; Modeling; Motivation; Natural regeneration; Neurocognitive; Neurocognitive Deficit; Neurologic; Neurons; Nucleus Accumbens; Outcome; Pathologic; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Prefrontal Cortex; Recording of previous events; Reporting; Resistance; Role; Scanning; Self Administration; Signal Pathway; Specific qualifier value; Stimulant; Substance Use Disorder; Substance of Abuse; Synapses; Synaptic plasticity; System; Techniques; Testing; Traction; Up-Regulation; Ventral Tegmental Area; Vertebral column; Virus; antiretroviral therapy; biological sex; brain cell; clinically significant; cocaine exposure; cocaine self-administration; comorbidity; density; design; dopamine system; dopamine transporter; executive function; frontal lobe; hippocampal pyramidal neuron; improved; in vivo; in vivo evaluation; male; neuroAIDS; neuromechanism; neuropathology; novel therapeutic intervention; programs; psychostimulant; sex; stimulant abuse; substance use; success; synaptic function; targeted treatment; therapeutic target

Project Summary: Despite the success of combination antiretroviral therapy (cART), a significant proportion of infected individuals exhibiting neurocognitive decline, and a prior history of substance use disorder (SUD) may result in an exacerbated rate of decline. Thus, prior drug history may be clinically significant in the treatment of neurological HIV-1 infection. The specific aims of the project are: 1) To define the dendritic “spine- targeted” - microglial interactions which produce HIV-1/psychostimulant-induced synaptodendritic loss and spine dysmorphology. Dendritic spine loss is a key pathology of HAND; however, the underlying mechanisms remain largely uncharacterized. We will investigate whether HIV-infected microglia play a key role in spine loss/dysmorphology using an in vitro HIV infection model and psychostimulant drug exposures in sex- specified brain cell cultures. 2) To establish whether a history of psychostimulant abuse drives an accelerated progression of microglial dysfunction and dendritic spine alterations following HIV infection. Dopamine will be assessed both prior to and after EcoHIV-infection in animals with or without a history of cocaine self-administration. The mechanisms by which HIV-infected microglia produce dopaminergic circuit dysfunction will be critically tested using proviral gene excision techniques; cART, and SABV are integral factors of the design. 3) To establish executive function “choice” deficits in EcoHIV-infected animals, and the role of microglial HIV infection, following psychostimulant self-administration. We will establish prior drug history and HIV-1 infection as variables that influence the effect of fronto-striatal circuit dysregulation on choice behavior, thereby identifying factors that may exacerbate resistance to treatment. We will examine synaptodendritic integrity in pyramidal neurons of the medial prefrontal cortex (mPFC) and medium spiny neurons (MSN) of the nucleus accumbens given their sensitivity to drug history and/or HIV-1 infection. Targeted proviral gene excision of HIV from microglial cells will be used to determine the role of infected microglial cells in executive function deficits. Thus, this proposal addresses two key questions regarding neuroHIV – 1) does a history of drug dependence alter the progression and clinical outcomes of HIV-1- associated neurocognitive disorders? and 2) how do substances of abuse and HIV interact to produce dendritic spine alterations, one of the key neuropathologies of neuroHIV in the current cART era? The program goal is to identify how microglial HIV infections produce synaptodendritic loss; knowledge that will lead to novel therapeutic strategies for restoring fronto-striatal circuitry.

项目概要： 尽管联合抗逆转录病毒疗法（cART）取得了成功，但仍有相当一部分感染者 表现出神经认知能力下降，以及先前的物质使用障碍（SUD）史可能导致 下降速度加快。因此，既往用药史可能在治疗 神经系统HIV-1感染该项目的具体目标是：1）定义树突“棘- 产生HIV-1/精神兴奋剂诱导的突触树突的“靶向”-小胶质细胞相互作用 损失和脊柱畸形。树突棘缺失是HAND的一个关键病理学;然而， 这些机制在很大程度上仍然没有特征。我们将调查是否艾滋病毒感染的小胶质细胞发挥关键作用 使用体外HIV感染模型和性行为中的精神兴奋剂药物暴露， 特定的脑细胞培养2)为了确定精神兴奋剂滥用史是否会导致 HIV后小胶质细胞功能障碍和树突棘改变的加速进展 感染多巴胺将在EcoHIV感染之前和之后在有或没有 可卡因自我管理的历史。HIV感染的小胶质细胞产生多巴胺能神经递质的机制 回路功能障碍将使用前病毒基因切除技术进行严格测试; cART和SABV是不可或缺的 设计的因素。3)为了在EcoHIV感染的动物中建立执行功能“选择”缺陷， 以及自我服用精神兴奋剂后小胶质细胞HIV感染的作用。我们将建立 既往吸毒史和HIV-1感染作为影响额-纹状体回路失调效应的变量 选择行为，从而确定可能加剧治疗抵抗的因素。我们将研究 内侧前额叶皮质（mPFC）和中型棘状核锥体神经元中的突触树突完整性 神经元（MSN）的神经元的药物史和/或HIV-1感染的敏感性。 从小胶质细胞中靶向切除HIV前病毒基因将用于确定感染者的作用。 小胶质细胞在执行功能缺陷。因此，这项建议涉及两个关键问题， neuroHIV - 1）药物依赖史是否会改变HIV-1的进展和临床结局？ 相关的神经认知障碍以及2）滥用物质和HIV如何相互作用以产生树突状细胞 脊柱改变，在当前cART时代neuroHIV的关键神经病理学之一？该计划的目标是 确定小胶质细胞HIV感染如何产生突触树突损失;知识将导致新的 恢复额-纹状体回路的治疗策略。