Cortical pathophysiology in cocaine sef-administering HIV-1 transgenic rats

可卡因自我给药 HIV-1 转基因大鼠的皮质病理生理学

• 批准号: 8410441
• 负责人: XIU-TI HU
• 金额: $ 19.13万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-15 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8410441
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Acute; Adult; Age; Age-Months; Behavior; Biochemical; Brain; Brain Injuries; Brain region; Cells; Cessation of life; Chronic; Cocaine; Cocaine Abuse; Cognition; Comorbidity; Diltiazem; Disease; Elderly; Emotions; Exhibits; Frequencies; Functional disorder; Future; Genetic Transcription; Gliosis; Goals; HIV; HIV Infections; HIV-1; Harvest; Homeostasis; Human; Immunohistochemistry; In Vitro; Individual; Infection; Injury; Intervention; Investigation; Knowledge; Lead; Literature; Medial; Mediating; Membrane; Methods; Microglia; Modeling; Molecular; Molecular Target; N-Methyl-D-Aspartate Receptors; Nature; Neurocognitive; Neurons; Neuropathogenesis; Outcome; Outcomes Research; Pathogenesis; Pathology; Prefrontal Cortex; Prosencephalon; Proteins; Protocols documentation; Pyramidal Cells; Rattus; Reporting; Research; Rewards; Role; Saline; Self Administration; Self-Administered; Severities; Site; Slice; Societies; Staging; Stimulus; Techniques; Testing; Therapeutic; Time; Toxic effect; Toxin; Training; Trans-Activators; Transgenic Organisms; Up-Regulation; Viral Proteins; Western Blotting; addiction; antiretroviral therapy; channel blockers; drug abstinence; dual diagnosis; experience; hippocampal pyramidal neuron; innovation; macrophage; molecular site; neuronal excitability; neuropathology; neuropsychiatry; novel; novel therapeutics; patch clamp; preclinical study; programs; research study; response; therapeutic target; young adult

DESCRIPTION (provided by applicant): Cocaine-abusing, HIV+ individuals experience more severe and rapidly evolving neuropsychiatric disorders and HIV-associated neurocognitive disorders (HAND) than non-abusing HIV+ individuals. These disorders reflect in part, a dysregulation of the medial prefrontal cortex (mPFC), but the underlying mechanisms are unclear. To significantly advance understanding of this phenomenon, we submit this R21 application to implement a new rat model of the comorbid human condition wherein critical features of both HIV+ and cocaine abuse are emulated to investigate the functional state of mPFC neurons. The research objectives are: (1) To reveal dysfunction of the mPFC in non-infectious, young (10-12 week old) adult HIV-1 transgenic (Tg) rats that chronically express multiple HIV-1 protein toxins in the brain, but do not exhibit the overt pathologies seen in old Tg rats (i.e., 10-12 months of age). (2 To determine if an exaggerated pathophysiology exists in the mPFC of HIV-1 Tg rats trained to self-administer cocaine. Our central hypothesis is that mPFC pyramidal neurons are more prone to over-activation in cocaine self-administering Tg rats than in saline-treated Tg rats or cocaine self-administering non-Tg rats. We will test this hypothesis with two Specific Aims. Aim 1 will validate [the level of microgliosis] in the mPFC, and determine their association with abnormally- enhanced neuronal excitability mediated via over-activated L-type Ca2+ channels in the young adult Tg rats. Non-Tg rats will serve as controls. Functional activity of mPFC pyramidal neurons will be assessed in ex vivo brain slices using patch-clamp recording techniques. We expect that the Tg rats will show [mPFC microgliosis] and hyper-excitability of pyramidal neurons mediated by over-activated L-channels, reflected by abnormally-increased responses to excitatory stimuli. Aim 2 will determine that cocaine self- administration enhances the pyramidal cell pathophysiology seen in the Tg rats. We expect that cocaine will exacerbate the hyper-excitability of mPFC pyramidal neurons observed in the Tg rats. This research is significant and innovative because it will provide the first means to ascertain the functional consequences of the chronic brain exposure of HIV-1 proteins under conditions of cocaine self-administration; in so doing, it will provide a completely novel method to investigate the molecular and cellular mechanisms responsible for this comorbid condition. The outcomes expected by the end of two years will determine that the HIV-1 proteins-induced pathology and cocaine abuse converge to dysregulate mPFC neuronal function via over- activated L-channels. These outcomes will guide our future investigations on mechanisms underlying the dysregulated Ca2+ homeostasis in the mPFC. Thus, this bold research will vertically elevate our understanding of the mechanisms that may contribute to the neuropathogenesis of HAND and neuropsychiatric disorders associated with HIV+ and cocaine abuse. This new knowledge will also lead to a R01 application in which novel therapeutic strategies will be developed to reduce such pathology. PUBLIC HEALTH RELEVANCE: The combination of cocaine abuse and AIDS accelerates the brain damage that can accompany either condition alone. Unfortunately, the frequency of this combination, or comorbidity, it is increasing in our society. This project will determine how toxic viral proteins produced by HIV in the rat brain, with or without cocaine self- administration, alter the function of neurons in a bran region (the medial prefrontal cortex) which, in humans, is vulnerable to both HIV infection and cocaine abuse. We propose that the detrimental effects of HIV toxins will be potentiated by cocaine on specific proteins that are critical for normal neuronal firing. By identifying common molecular targets of cocaine and HIV toxins, outcomes from this project should prove to be critically important in developing therapeutic means to slow the devastation of HIV/AIDS comorbidity with cocaine abuse, as well as to promote drug abstinence in these individuals.

描述(由申请人提供)： 与未滥用艾滋病毒的人相比，滥用可卡因的艾滋病毒感染者经历了更严重和快速演变的神经精神障碍和艾滋病毒相关的神经认知障碍(HAND)。这些障碍在一定程度上反映了内侧前额叶皮质(MPFC)的失调，但潜在的机制尚不清楚。为了显著促进对这一现象的理解，我们提交了这项R21申请，以实现一种新的人类共存条件的大鼠模型，在该模型中，模拟艾滋病毒+和可卡因滥用的关键特征，以研究mPFC神经元的功能状态。研究的目的是：(1)揭示非感染性、年轻(10-12周)成年HIV-1转基因(TG)大鼠的mPFC功能障碍，这些大鼠在脑中慢性表达多种HIV-1蛋白毒素，但不表现出老年TG大鼠(即10-12个月龄)的明显病理变化。(2)确定自我注射可卡因训练的HIV-1TG大鼠的mPFC是否存在夸大的病理生理学。我们的中心假设是可卡因自身给药的TG大鼠比生理盐水处理的TG大鼠或可卡因自身给药的非TG大鼠更容易出现mPFC锥体神经元的过度激活。我们将通过两个具体目标来检验这一假设。目的1验证小胶质细胞在幼年TG大鼠中的[小胶质细胞增生水平]，并确定其与通过过度激活的L钙通道介导的神经元兴奋性异常增强的关系。非甘油三酯大鼠作为对照。MPFC锥体神经元的功能活性将在体外脑片中使用膜片钳记录技术进行评估。我们预计TG大鼠将表现出[mPFC小胶质细胞增多症]和由过度激活的L通道介导的锥体神经元的高兴奋性，反映在对兴奋刺激的异常增强的反应中。目的2将确定可卡因自身给药增强了TG大鼠锥体细胞的病理生理学。我们预计可卡因将加剧在TG大鼠观察到的mPFC锥体神经元的过度兴奋性。这项研究具有重要意义和创新性，因为它将提供第一种手段来确定在可卡因自身给药条件下慢性脑暴露HIV-1蛋白的功能后果；通过这样做，它将提供一种全新的方法来研究导致这种共病的分子和细胞机制。预计两年内的结果将确定艾滋病毒-1蛋白诱导的病理和可卡因滥用通过过度激活的L通道汇聚到mPFC神经元功能失调。这些结果将指导我们未来研究mPFC中钙离子稳态失调的机制。因此，这项大胆的研究将垂直提升我们对可能导致与艾滋病毒+和可卡因滥用相关的手部和神经精神障碍的神经发病机制的理解。这一新知识还将导致R01的应用，其中将开发新的治疗策略来减少这种病理。 公共卫生相关性： 可卡因滥用和艾滋病的结合会加速大脑损伤，而这两种情况都可能单独伴随着这两种疾病。不幸的是，这种组合或共病的频率在我们的社会中正在增加。该项目将确定在有或没有可卡因自我注射的情况下，艾滋病毒在大鼠大脑中产生的有毒病毒蛋白如何改变人类大脑中易受艾滋病毒感染和可卡因滥用的大脑皮质区域(内侧前额叶皮质)的神经元功能。我们认为，可卡因将增强艾滋病毒毒素对正常神经元放电至关重要的特定蛋白质的有害影响。通过确定可卡因和艾滋病毒毒素的共同分子靶标，该项目的成果应被证明对开发治疗手段至关重要，以减缓艾滋病毒/艾滋病与可卡因滥用共病的破坏，并促进这些个人戒毒。