Microglial modulation of neurocircuits in HIV/cocaine comorbidity

项目总结： 尽管联合抗逆转录病毒疗法(CART)取得了成功，但相当大比例的感染者 表现出神经认知能力下降，并有物质使用障碍(SUD)的既往病史可能导致 加速下降的速度。因此，既往用药史可能在临床治疗上具有重要意义。 神经性HIV-1感染。该项目的具体目标是：1)定义树突棘- 产生HIV-1/精神刺激剂诱导的突触树突状细胞的靶向“-小胶质细胞相互作用 丢失和脊柱畸形。树突棘缺失是手部的一个关键病理；然而，潜在的 机制在很大程度上仍未确定。我们将调查感染艾滋病毒的小胶质细胞是否发挥了关键作用 在使用体外HIV感染模型和性行为中精神刺激性药物暴露的脊柱丢失/畸形方面- 特定的脑细胞培养。2)确定精神刺激性虐待的病史是否会导致 HIV感染后小胶质细胞功能障碍和树突棘改变的加速进展 感染。多巴胺将在感染EcoHIV之前和之后进行评估，无论有没有 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的机制 电路功能障碍将使用前病毒基因切除技术进行关键测试；CART和SABV是不可或缺的 设计的因素。3)在感染EcoHIV的动物中建立执行功能“选择”缺陷， 以及精神刺激剂自我给药后小胶质细胞艾滋病毒感染的作用。我们将建立 既往用药史和HIV-1感染是影响额纹状体回路失调疗效的变量 关于选择行为，从而确定可能加剧对治疗的抵抗力的因素。我们将研究 内侧前额叶皮质锥体神经元和中棘的突触树突完整性 伏隔核神经元(MSN)对药物史和/或HIV-1感染敏感。 从小胶质细胞中有针对性地切除HIV前病毒基因将被用来确定感染的作用 执行功能缺陷中的小胶质细胞。因此，这项提案涉及以下两个关键问题 药物依赖史是否会改变HIV-1的进展和临床结果- 相关的神经认知障碍？2)滥用物质和HIV如何相互作用产生树突状 脊柱改变，在当前的Cart时代，神经艾滋病毒的关键神经病理之一？该计划的目标是 确定小胶质细胞HIV感染如何导致突触树突起丢失；这一知识将导致新的 恢复额叶-纹状体回路的治疗策略。

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.